Tricyclic fused heterocyclic PDE3 / 4 dual inhibitor and preparation method for intermediate thereof

Abstract

The present invention provides a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor (formula (I)) and a preparation method for a key intermediate thereof. The method involves a novel reaction route, mild reaction conditions, simple operation, high reaction yield, high product purity, and convenient post-treatment, and is suitable for industrial production.

Description

Preparation method of a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor and intermediates thereof TECHNICAL FIELD

[0001] The present application relates to a preparation method of a pharmaceutical compound, in particular to a preparation method of a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor and intermediates thereof, and belongs to the technical field of pharmaceutical chemistry. BACKGROUND

[0002] Chronic obstructive pulmonary disease (COPD) and asthma are common respiratory diseases characterized by airway obstruction. In 2015, an estimated 3.17 million people died of COPD worldwide, accounting for 5% of all deaths worldwide that year. In 2016, there were 251 million cases of COPD worldwide; by 2030, COPD will become the third leading cause of death worldwide. In 2015, 383,000 people died of asthma, and by now, about 235 million people have suffered from asthma. Both are chronic inflammatory diseases of the respiratory system and are difficult to distinguish. Because they all have different degrees of airflow limitation, bronchial narrowing, dyspnea, increased airway secretions, and other clinical manifestations, and have different degrees of airway remodeling, their treatments are similar, and often require combination therapy with multiple drugs.

[0003] One of the most obvious characteristics of chronic respiratory diseases such as COPD and asthma is chronic inflammation, which usually involves complex inflammatory processes, including various inflammatory cells such as epithelial cells, macrophages, and neutrophils, as well as various inflammatory mediators and chemokines released by inflammatory cells. Based on the clinical efficacy of non-selective phosphodiesterase (PDE) inhibitors, xanthine compounds have been developed for the treatment of inflammation in respiratory diseases. PDE3 is an enzyme that can hydrolyze both cAMP and cGMP. The activity of PDE3 is mainly concentrated in alveolar macrophages, endothelial cells, and platelets in the respiratory system. Studies have found that PDE3 inhibitors can relax airway smooth muscle and can be developed as bronchodilators. PDE4 is a specific cAMP-hydrolyzing enzyme that is mainly distributed in airway smooth muscle cells and inflammatory and immune cells such as lymphocytes, mast cells, macrophages, neutrophils, eosinophils, basophils, monocytes, epithelial cells, etc., and regulates the level of cAMP in these cells. Inhibition of PDE4 can increase the level of cAMP in inflammatory and immune regulatory cells, thereby inhibiting the function of inflammatory cells and relaxing airway smooth muscle.

[0004] As a combination of PDE3 / PDE4 inhibitors, it has anti-inflammatory and bronchodilatory activity, and can be used for the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD) and asthma. Therefore, the development of dual PDE3 / PDE4 inhibitors for the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD) and asthma has important clinical significance.

[0005] WO2023109802A1 discloses a PDE3 / PDE4 dual inhibitor, which involves a compound of formula (C1):

[0006] The patent discloses its preparation route as follows:

[0007] The above preparation method introduces cyano group in the process, and the corresponding amino group is prepared by using hydrogenation reduction method. The hydrogenation process has a high safety risk. The process is a linear synthesis route, the route is long, and column chromatography purification is required after multi-step reaction treatment. The product yield is low, the cost is high, and it is not suitable for industrial production. SUMMARY

[0008] The present application provides a preparation method of a compound of formula (II-PG), which comprises the following reaction:

[0009] wherein R1, R2 are each independently alkyl, deuterated alkyl, preferably selected from methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl, further preferably selected from methyl, deuterated methyl, more preferably R1, R2 are both CH3 or CD3, or R1 is CH3 and R2 is CD3; PG is a protecting group selected from Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, PMB, preferably selected from Boc, Fmoc, Cbz;

[0010] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of tributylphosphine, triphenylphosphine, preferably tributylphosphine;

[0011] Optionally, in some embodiments, the reaction is carried out in the presence of an activating agent selected from at least one of N,N,N',N'-tetramethylazodicarbonamide, diisopropyl azodicarboxylate, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid dipiperidyl, cyano methylene tri-n-butyl phosphine, preferably N,N,N',N'-tetramethylazodicarbonamide;

[0012] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, 1,4-dioxane, toluene, dimethylsulfoxide, preferably from tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, 1,4-dioxane;

[0013] Optionally, in some embodiments, the reaction temperature of the reaction is -5-45°C, preferably 20±10°C.

[0014] Optionally, in some embodiments, the reaction temperature of the reaction is 60±5°C.

[0015] The present application also provides a preparation method of formula (III-H), which comprises the following reaction:

[0016] wherein R1, R2 are as defined above, and Y is a pharmaceutically acceptable acid, preferably selected from hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, acetic acid, fumaric acid, maleic acid;

[0017] The reaction is carried out in the presence of a base, preferably ammonia.

[0018] The present application also provides a preparation method of formula (II-nX), which comprises the following reaction:

[0019] wherein R1, R2, PG are as defined above; X is selected from hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid; n is selected from 0.5-4, preferably 1 or 2; the reaction is carried out in the presence of the corresponding acid represented by X, for example in the presence of concentrated hydrochloric acid;

[0020] Optionally, in some embodiments, the reaction solvent is selected from at least one of ethanol, methanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, methanol, preferably from ethanol, tetrahydrofuran, ethyl acetate;

[0021] Optionally, in some embodiments, the reaction temperature of the reaction is 30°C-90°C, preferably 55±5°C.

[0022] The present application also provides a preparation method of formula (I), which comprises the following reaction:

[0023] wherein R1, R2, n and X are as defined above; the reaction reagent is selected from phenyl carbamate, ammonia, ammonia, KOCN, NaOCN;

[0024] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, sodium carbonate, preferably from N,N-diisopropylethylamine, triethylamine;

[0025] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, preferably from dichloromethane, tetrahydrofuran;

[0026] Optionally, in some embodiments, the reaction temperature of the reaction is -5-50°C, preferably 25±5°C;

[0027] Further, the compound of formula (C1) is prepared by the following reaction:

[0028] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, triethylamine, potassium carbonate, sodium carbonate, preferably from N,N-diisopropylethylamine, triethylamine;

[0029] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, preferably from dichloromethane, tetrahydrofuran;

[0030] Optionally, in some embodiments, the reaction temperature of the reaction is -5-50°C, preferably 25±5°C;

[0031] Alternatively, the compound of formula (C1) is prepared by the following reaction:

[0032] Optionally, in some embodiments, the reaction is carried out in the presence of an alcohol solvent selected from at least one of methanol, ethanol, isopropanol, tert-butanol, preferably from methanol;

[0033] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of N,N-diisopropylethylamine, ethylenediamine, triethylamine, n-propylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, preferably diisopropylethylamine, triethylamine; at least one of N,N-diisopropylethylamine, triethylamine, preferably from N,N-diisopropylethylamine, triethylamine;

[0034] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, acetonitrile, tetrahydrofuran, N'N-dimethylformamide, N'N-dimethylacetamide, N-methylpyrrolidone, preferably dichloromethane;

[0035] Optionally, in some embodiments, the reaction temperature of the reaction is 10-80°C, preferably 25±5°C or 60±5°C.

[0036] The present application also provides a preparation method of the compound of formula (II-nX), comprising the following steps:

[0037] wherein, R1, R2are each independently deuterated or non-deuterated alkyl, selected from deuterated or non-deuterated methyl, ethyl, propyl or isopropyl, preferably from deuterated or non-deuterated methyl, more preferably R1, R2are both CH3or CD3, or R1is CH3and R2is CD3; Y is a pharmaceutically acceptable acid, preferably selected from hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid, sulfuric acid, acetic acid, fumaric acid, maleic acid; PG is a protecting group, selected from Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, PMB, preferably selected from Boc, Fmoc, Cbz; X is selected from hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid; n is selected from 0.5-4, preferably selected from 1 or 2.

[0038] Meanwhile, the present application also provides:

[0039] A preparation method of the compound of formula (I), comprising the steps of (III)→(II-PG)→(II-nX)→(I);

[0040] A preparation method of the compound of formula (I), comprising the steps of (IV)→(III)→(II-PG)→(II-nX)→(I).

[0041] The present application also provides a preparation method of the compound (C1), comprising the following reaction:

[0042] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of diisopropylethylamine, triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N-methylmorpholine, preferably diisopropylethylamine, triethylamine;

[0043] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane / methanol, preferably dichloromethane;

[0044] Optionally, in some embodiments, the reaction temperature of the reaction is -10°C to 30°C, preferably 20±10°C.

[0045] The present application also provides a preparation method of compound (C1), comprising the following reaction:

[0046] wherein X is selected from K or Na, preferably Na;

[0047] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, isopropanol, tert-butanol or water, preferably water.

[0048] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, preferably hydrochloric acid;

[0049] Optionally, in some embodiments, the reaction temperature of the reaction is 40°C to 80°C, preferably 70±5°C.

[0050] The present application also provides a preparation method of compound (C1-5), comprising the following reaction:

[0051] Optionally, in some embodiments, the reaction is carried out in the presence of a reducing agent selected from at least one of hydrazine hydrate, lithium aluminum hydride, hydrogen, sodium borohydride, potassium borohydride, preferably hydrazine hydrate, hydrogen;

[0052] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of ammonia, methylamine, preferably ammonia;

[0053] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of Raney nickel, palladium on carbon (10%), preferably Raney nickel;

[0054] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, preferably ethanol, methanol;

[0055] Optionally, in some embodiments, the reaction temperature of the reaction is -10°C to 85°C, preferably 45±10°C.

[0056] The present application also provides a preparation method of compound (E1-4), comprising the following reaction:

[0057] Optionally, in some embodiments, the reaction is performed in the presence of a catalyst selected from at least one of lithium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, DBU, preferably lithium carbonate;

[0058] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of acetonitrile, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetonitrile;

[0059] Optionally, in some embodiments, the reaction temperature of the reaction is -10℃ to 95℃, preferably 75±10℃.

[0060] The present application also provides a method for preparing a compound (E1-2), comprising the following reaction:

[0061] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of isopropanol acetonitrile, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, preferably isopropanol;

[0062] Optionally, in some embodiments, the reaction temperature of the reaction is 30 to 90℃, preferably 80±10℃.

[0063] The present application also provides a method for preparing a compound (A1), comprising the following steps:

[0064] The reaction for preparing a compound (A1-6) from a compound (A1-6a):

[0065] Optionally, in some embodiments, the reaction is performed in the presence of (Boc)2O;

[0066] Optionally, in some embodiments, the reaction is performed in the presence of a base selected from at least one of N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, DBU, preferably triethylamine;

[0067] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, preferably dichloromethane;

[0068] Optionally, in some embodiments, the reaction temperature of the reaction is -5℃ to 25℃, preferably 5-10℃.

[0069] The reaction of preparing compound (A1-7) from compound (A1-6):

[0070] Optionally, in some embodiments, the reaction is carried out in the presence of CD3I;

[0071] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, lithium carbonate, preferably potassium carbonate;

[0072] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, dimethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, preferably N,N-dimethylformamide;

[0073] Optionally, in some embodiments, the reaction temperature of the reaction is 5-35°C, preferably 20-25°C.

[0074] The reaction of preparing compound (A1-8) from compound (A1-7):

[0075] Optionally, in some embodiments, the reaction is carried out in the presence of hydrochloric acid;

[0076] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, preferably ethyl acetate.

[0077] The reaction of preparing compound (A1-9) from compound (A1-8):

[0078] Optionally, in some embodiments, the reaction is carried out in the presence of a cyanate selected from at least one of potassium cyanate, sodium cyanate, preferably potassium cyanate;

[0079] Optionally, in some embodiments, the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, preferably hydrochloric acid;

[0080] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of water, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, preferably water;

[0081] Optionally, in some embodiments, the reaction temperature of the reaction is 40-110°C, preferably 100°C.

[0082] The reaction of preparing compound (A1-10) from compound (A1-9):

[0083] Optionally, in some embodiments, the reaction is carried out in the presence of diethyl malonate;

[0084] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, preferably sodium methoxide;

[0085] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, preferably ethanol;

[0086] Optionally, in some embodiments, the reaction temperature of the reaction is 80-100°C, preferably 90°C.

[0087] The reaction of preparing compound (A1) from compound (A1-10):

[0088] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of phosphorus oxychloride, dichlorosulfoxide, preferably phosphorus oxychloride;

[0089] Optionally, in some embodiments, the reaction temperature of the reaction is ≤100°C, preferably the reaction temperature is 80-100°C, further preferably 90°C.

[0090] The present application also provides a preparation method of a certain compound prepared by sequentially combining each reaction described above, for example:

[0091] The preparation method of compound (A1) comprises the steps of (A1-9)→(A1-10)→(A1);

[0092] The preparation method of compound (A1) comprises the steps of (A1-8)→(A1-9)→(A1-10)→(A1);

[0093] The preparation method of compound (A1) comprises the steps of (A1-7)→(A1-8)→(A1-9)→(A1-10)→(A1);

[0094] The preparation method of compound (A1) comprises the steps of (A1-6)→(A1-7)→(A1-8)→(A1-9)→(A1-10)→(A1);

[0095] A method for producing the compound (Al) comprising the steps of (Al-6a)→(Al-6)→(Al-7)→(Al-8)→(Al-9)→(Al-10)→(Al).

[0096] A method for producing the compound (Al-10) comprising the steps of (Al-8)→(Al-9)→(Al-10).

[0097] A method for producing the compound (Al-10) comprising the steps of (Al-7)→(Al-8)→(Al-9)→(Al-10).

[0098] A method for producing the compound (Al-10) comprising the steps of (Al-6)→(Al-7)→(Al-8)→(Al-9)→(Al-10).

[0099] A method for producing the compound (Al-10) comprising the steps of (Al-6a)→(Al-6)→(Al-7)→(Al-8)→(Al-9)→(Al-10).

[0100] A method for producing the compound (Al-9) comprising the steps of (Al-7)→(Al-8)→(Al-9).

[0101] A method for producing the compound (Al-9) comprising the steps of (Al-6)→(Al-7)→(Al-8)→(Al-9).

[0102] A method for producing the compound (Al-9) comprising the steps of (Al-6a)→(Al-6)→(Al-7)→(Al-8)→(Al-9).

[0103] A method for producing the compound (Al-8) comprising the steps of (Al-6)→(Al-7)→(Al-8).

[0104] A method for producing the compound (Al-8) comprising the steps of (Al-6a)→(Al-6)→(Al-7)→(Al-8).

[0105] A method for producing the compound (Al-7) comprising the steps of (Al-6a)→(Al-6)→(Al-7).

[0106] The present application also provides a method for producing the compound (Al-6) comprising the steps of:

[0107] wherein the reaction of the compound (Al-1) to produce the compound (Al-2):

[0108] Optionally, in some embodiments, the reaction is carried out in the presence of benzyl bromide;

[0109] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, preferably potassium carbonate;

[0110] Optionally, in some embodiments, the reaction employs a reaction solvent selected from at least one of methanol, ethanol, acetonitrile, dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, preferably methanol;

[0111] Optionally, in some embodiments, the reaction is carried out at a temperature in the range of 5 to 35 °C, preferably 25-30 °C;

[0112] wherein the reaction of compound (A1-2) to prepare compound (A1-3) is carried out in the presence of a base selected from at least one of potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, preferably potassium carbonate;

[0113] Optionally, in some embodiments, the reaction is carried out in the presence of nitromethane;

[0114] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of ammonium acetate, sodium acetate, potassium acetate, preferably ammonium acetate;

[0115] Optionally, in some embodiments, the reaction employs a reaction solvent selected from at least one of acetic acid, methanol, ethanol, acetonitrile, dichloromethane, toluene, acetonitrile, tetrahydrofuran, dioxane, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, preferably acetic acid;

[0116] Optionally, in some embodiments, the reaction is carried out at a temperature in the range of 85 to 115 °C, preferably 105-110 °C;

[0117] wherein the reaction of compound (A1-3) to prepare compound (A1-4) is carried out in the presence of a reducing agent selected from at least one of lithium aluminum hydride, borane, borane dimethyl sulfide, sodium borohydride / nickel chloride, 10% palladium on carbon, preferably lithium aluminum hydride;

[0118] Optionally, in some embodiments, the reaction is carried out in the presence of a reducing agent selected from at least one of lithium aluminum hydride, borane, borane dimethyl sulfide, sodium borohydride / nickel chloride, 10% palladium on carbon, preferably lithium aluminum hydride;

[0119] Optionally, in some embodiments, the reaction employs a reaction solvent selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, preferably tetrahydrofuran;

[0120] Optionally, in some embodiments, the reaction temperature of the reaction is 5-35°C, preferably 0-10°C.

[0121] wherein the reaction of preparing compound (A1-5) from compound (A1-4):

[0122] Optionally, in some embodiments, the reaction is carried out in the presence of di-tert-butyl dicarbonate.

[0123] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, DBU, preferably sodium bicarbonate.

[0124] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of water, water / tetrahydrofuran, water / 2-methyltetrahydrofuran, water / dioxane, water / ethanol, water / methanol, preferably water / tetrahydrofuran.

[0125] Optionally, in some embodiments, the reaction temperature of the reaction is 0-40°C, preferably 20-30°C.

[0126] wherein the reaction of preparing compound (A1-6) from compound (A1-5):

[0127] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of palladium on carbon, Raney nickel, isopropyl chloroformate, preferably palladium on carbon.

[0128] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethyl acetate, preferably methanol.

[0129] Optionally, in some embodiments, the reaction temperature of the reaction is 5-35°C, preferably 25-30°C.

[0130] The present application also provides a preparation method of a certain compound by sequentially combining the above reactions, for example:

[0131] The preparation method of compound (A1-6) comprises the steps of (A1-4)→(A1-5)→(A1-6).

[0132] The preparation method of compound (A1-6) comprises the steps of (A1-3)→(A1-4)→(A1-5)→(A1-6).

[0133] A method for producing the compound (A1-6) includes the steps of (A1-2)→(A1-3)→(A1-4)→(A1-5)→(A1-6).

[0134] A method for producing the compound (A1-5) includes the steps of (A1-3)→(A1-4)→(A1-5).

[0135] A method for producing the compound (A1-5) includes the steps of (A1-2)→(A1-3)→(A1-4)→(A1-5).

[0136] A method for producing the compound (A1-5) includes the steps of (A1-1)→(A1-2)→(A1-3)→(A1-4)→(A1-5).

[0137] A method for producing the compound (A1-4) includes the steps of (A1-2)→(A1-3)→(A1-4).

[0138] A method for producing the compound (A1-4) includes the steps of (A1-1)→(A1-2)→(A1-3)→(A1-4).

[0139] A method for producing the compound (A1-3) includes the steps of (A1-1)→(A1-2)→(A1-3).

[0140] The present application also provides a method for producing a compound (C1) including the steps of:

[0141] The present application provides a method for producing a compound (C1) including the steps of (E1-4)→(C1-5)→(C1) described above.

[0142] The present application provides a method for producing a compound (C1) including the steps of (E1-2)→(E1-4)→(C1-5)→(C1) described above.

[0143] The present application provides a method for producing a compound (C1-5) including the steps of (E1-2)→(E1-4)→(C1-5) described above.

[0144] The present application provides a method for producing a compound (C1-5) including the steps of (A1)→(E1-2)→(E1-4)→(C1-5) described above.

[0145] The present application provides a method for producing a compound (E1-4) including the steps of (A1)→(E1-2)→(E1-4) described above.

[0146] The present application also provides compounds (A1), (E1-2), (A1-9), (A1-10), (C1-3), (C1-4) or salts thereof having the following structure:

[0147] Definitions of abbreviations and key terms of the present application:

[0148] Technical effects of the present application:

[0149] 1. The starting materials are cheap and easy to obtain, the process route is short, the operation is simple, the yield is high, the process is environmentally friendly, and the production can be easily scaled up;

[0150] 2. The intermediate products in the entire synthesis process can be crystallized and purified, the process is highly robust, and the product quality is more controllable. DETAILED DESCRIPTION

[0151] The present application is further described below in conjunction with examples, but is not limited thereto, and any equivalent replacement in the art according to the disclosure of the present application is within the scope of the present application.

[0152] NMR was measured by a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300);

[0153] The measurement solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0154] MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0155] HPLC was measured by Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100x4.6mm, 3.5μM);

[0156] Thin layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications of the silica gel plates used in thin layer chromatography (TLC) were 0.15mm-0.20mm, and the specifications of the thin layer chromatography separation and purification products were 0.4mm-0.5mm.

[0157] Example 1: Preparation of a compound of formula (I-D):

[0158] First step: 2-(mesityl imine)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H- pyrimido[6,1-a]isoquinolin-4-one (III-D-HCl)

[0159] 2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (III-D-HCl)

[0160] Method 1: Into a reaction kettle, add 62.8 kg of isopropyl alcohol, 13.72 kg of compound of formula (IV-D) and 10.00 kg of compound of formula (IV-1); after addition, start stirring and heat to 80±10°C for reaction. After about 6 hours of reaction, cool the reaction to 10±5°C, and then add 118.4 kg of methyl tert-butyl ether while maintaining the temperature at 10±5°C, and stir for 2 hours at 10±5°C. Centrifuge and wash the filter cake with 15.0 kg of methyl tert-butyl ether. Dry the filter cake at 55±5°C to obtain the compound of formula (III-D) hydrochloride salt (12.0 kg, about 87% yield).

[0161] Method 2: Into a reaction kettle, add 15.5 kg of acetonitrile, 2.5 kg of compound of formula (IV-D) and 3.15 kg of compound of formula (IV-1); after addition, start stirring and heat to 80±10°C for reaction. After about 6 hours of reaction, add 2.3 kg of N,N-diisopropylethylamine dropwise, and after the addition is complete, stir for about 0.5 h, then add 34 kg of purified water to the reaction liquid, and after the addition is complete, cool to 15±5°C for crystallization for 4 h, filter, and then rinse the filter cake with 3.2 kg of isopropyl alcohol. Dry the filter cake at 55±5°C to obtain the compound of formula (III-D) free base (5.56 kg, about 84% yield).

[0162] LCMS m / z = 395.2 [M+1].

[0163] Second step: 3-(2-aminoethyl)-2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one dihydrochloride salt (II-D-2HCl)

[0164] 3-(2-aminoethyl)-2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one.2hydrochloride (II-D-2HCl)

[0165] Method 1: Add 80.0 kg of dichloromethane to the reaction kettle, add 3.0 kg of the hydrochloride salt of the compound of formula (III-D), and stir until uniform. Add 1.25 kg of aqueous ammonia to 25.0 kg of purified water, stir until uniform, and then add to the reaction kettle. Stir for 1-2 hours. Control the temperature at 20 ± 10 °C, and allow to stand while separating into layers. Retain the organic phase, and extract the aqueous phase with 33.0 kg of dichloromethane once. Wash the combined organic phase with 15.0 kg of a 10% sodium chloride solution once. Add 1.5 kg of anhydrous sodium sulfate to the organic phase, and stir for 30 minutes while drying. Filter, and wash the filter cake with 2.5 kg of dichloromethane. Control the temperature at 30 ± 5 °C, and concentrate under reduced pressure to a residual volume of about 12 L ± 5 L. Add 40 kg of tetrahydrofuran, control the temperature at 40 ± 10 °C, and continue to concentrate to a residual volume of about 12 L ± 5 L. Add 12 kg of tetrahydrofuran, and continue to concentrate to a residual volume of about 12 L ± 5 L, and cool to 25 ± 5 °C.

[0166] Add 2.25 kg of the compound of formula (III-1) and 2.81 kg of tributylphosphine (TBUP) to the reaction kettle, and cool to 10 ± 10 °C. Add 2.39 kg of N,N,N',N'-tetramethylazodicimide (TMAD) in portions, and after the addition is complete, stir at 20 ± 10 °C for 5 h.

[0167] Continue to add 24.75 L of ethanol and 5.58 kg of concentrated hydrochloric acid to the reaction kettle, and stir until the reaction is complete and the solid dissolves. Continue to heat to 55 ± 5 °C, and react for about 3 h. Cool to 5 ± 5 °C, and stir for about 2 h while crystallizing. Filter, rinse the filter cake with 1.5 kg of isopropanol, and dry under vacuum at 50 ± 5 °C for about 7 h. Collect the product, and obtain 2.67 kg of the compound of formula (II-D-2HCl) (about 82% yield).

[0168] Method 2:

[0169] Add 23 kg of tetrahydrofuran to the reaction kettle, add 2.60 kg of the compound of formula (III-D), add 2.126 kg of the compound of formula (III-1), and start stirring. At 25 ± 5 °C, add 3.46 kg of triphenylphosphine, and then add 2.27 kg of N,N,N',N'-tetramethylazodicimide. After the addition is complete, heat to 60 ± 5 °C, and react for 6 h.

[0170] After the reaction is complete, add 20.8 kg of anhydrous ethanol and 5.2 kg of concentrated hydrochloric acid in sequence and slowly. Heat to 55 ± 5 °C, and stir for about 3 h. Cool to 15 ± 5 °C (cooling rate of about 20 °C / h), and stir for about 4 h while crystallizing. After the crystallization is complete, filter, and rinse the filtrate with 5.2 kg of isopropanol. Dry under vacuum at 50 ± 5 °C for about 7 h, collect the product, and obtain 2.90 kg of the compound of formula (II-D-2HCl) (about 86% yield).

[0171] LCMS m / z = 438.1 [M+1].

[0172] Step 3: 1-(2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (I-D)

[0173] 1-(2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (I-D)

[0174] Example 1:

[0175] Into a reactor, add 2 kg of compound of formula (II-D-2HCI), add 11.2 kg of methanol, 7.98 kg of dichloromethane, 4.45 kg of DIPEA and 2.58 kg of phenyl carbamate, stir at 25±5°C for about 10 hours, concentrate the reaction system at 50±5°C under vacuum to remove the solvent, then add 16.0 kg of methanol, stir at 25±5°C for about 2 hours, filter, and dry the filter cake at 50±5°C under vacuum for 6 hours to obtain the compound of formula (I-D) (1.61 kg, yield about 85%).

[0176] Example 2:

[0177] Into a reactor, add 2 kg of compound of formula (II-D-2HCI), 1.02 kg of DIPEA, 10 water and 26.6 kg of dichloromethane, stir at 25±5°C for about 0.5 hours, then separate the liquid, concentrate the organic phase at 45±5°C under reduced pressure, and evaporate twice with tetrahydrofuran (5.35 kg / time).

[0178] Continue to add 14.24 kg of tetrahydrofuran and 0.97 kg of N,N'-carbonyldiimidazole (CDI) into the reactor, stir at 25±5°C for about 2 hours, then add 0.98 kg of concentrated ammonia water, stir at 25±5°C for about 5 hours, concentrate the reaction system at 50°C under vacuum to remove the solvent, add 13.5 kg of methanol, stir at 25±5°C for about 2 hours, filter, and dry the filter cake at 50±5°C under vacuum for 6 hours to obtain the compound of formula (I-D) (1.53 kg, yield about 81%).

[0179] Example 3:

[0180] Into a reactor, was added 50 g of the compound of formula (II-D-2HCl), 120 mL of 1 N hydrochloric acid, and a solution of sodium cyanate (20 g of sodium cyanate dissolved in 400 mL of water) was added dropwise. The mixture was stirred at 70 ± 5 °C for about 5 h, cooled to 25 ± 5 °C, and the pH was adjusted to 8-9 with 2 N aqueous sodium hydroxide solution. The mixture was stirred at 25 ± 5 °C for about 1 h, filtered, the filter cake was rinsed with 120 mL of water, and dried under vacuum at 50 ± 5 °C for 6 h to give the compound of formula (I-D) (39.06 kg, about 83% yield).

[0181] LCMS m / z = 481.3 [M+1].

[0182] 1H NMR (400 MHz, Methanol-d4) 6.80 (s, 2H), 6.77 (s, 1H), 6.65 (s, 1H), 5.40 (s, 1H), 4.25-4.22 (m, 2H), 3.91-3 88 (m, 2H), 3.76 (s, 3H), 3.45-3 42 (m, 2H), 2.83-2.81 (m, 1H), 2 17 (s, 3H), 1.96 (s, 6H).

[0183] Example 4:

[0184] Into a reactor, was added 50 g of the compound of formula (II-D-2HCl), 120 mL of 1 N hydrochloric acid, and a solution of sodium cyanate (20 g of sodium cyanate dissolved in 400 mL of water) was added dropwise. The mixture was stirred at 70 ± 5 °C for about 5 h, cooled to 25 ± 5 °C, and the pH was adjusted to 8-9 with 2 N aqueous sodium hydroxide solution. The mixture was stirred at 25 ± 5 °C for about 1 h, filtered, the filter cake was rinsed with 120 mL of water, and dried under vacuum at 50 ± 5 °C for 6 h to give the compound of formula (I-D) (39.06 kg, about 83% yield).

[0185] Example 2: Preparation of Compound A1

[0186] First Step: tert-Butyl (4-hydroxy-3-methoxyphenethyl)carbamate (A1-6)

[0187] tert-Butyl (4-hydroxy-3-methoxyphenethyl)carbamate

[0188] Into a reaction flask was added compound A1-6 135.12 g and dichloromethane (1250 mL), stirred and cooled to an internal temperature of 5 °C, added 167.77 g triethylamine, controlled the temperature to be below 10 °C, dropwise added 159.17 g (Boc)20 (dissolved in 100 mL dichloromethane), after the addition, the reaction was carried out at room temperature for 2 hours, TLC showed that the reaction was complete. The reaction solution was washed twice with 10% sodium chloride solution 300 mL*2, dried with anhydrous sodium sulfate for 30 min, concentrated at 35 °C under reduced pressure, concentrated until no obvious liquid flowed out, added 150 mL methyl tert-butyl ether and 150 mL n-hexane to make a slurry for 30 min, filtered, and the filter cake was washed with 50 mL n-hexane. After drying, the white solid compound A1-6 (144.20 g, yield: 81.5%) was obtained.

[0189] LCMS m / z = 267.1 [M+1].

[0190] Second step: tert-butyl (3-methoxy-4-(methoxy-d3)phenethyl)carbamate (A1-7)

[0191] tert-butyl (3-methoxy-4-(methoxy-d3)phenethyl)carbamate

[0192] Into a reaction flask was added compound A1-6 140.32 g and DMF (700 mL), then added 144.72 g potassium carbonate powder, stirred and cooled to an internal temperature of 10 °C, dropwise added 91.23 g CD3I, after the addition, the reaction was carried out at room temperature for 4 hours, TLC showed that the reaction was complete. The reaction solution was added to 2.5 L ice water, and a solid was precipitated, stirred for 30 min, filtered, and the filter cake was washed with 50 mL water. After drying at 55 °C with air blowing, the white solid compound A1-7 (135.20 g, yield: 91.3%) was obtained.

[0193] LCMS m / z = 284.3 [M+1].

[0194] Third step: 2-(3-methoxy-4-(methoxy-d3)phenyl)ethan-1-amine (A1-8)

[0195] 2-(3-methoxy-4-(methoxy-d3)phenyl)ethan-1-amine

[0196] To the reaction flask was added compound A1-7 130.12 g and EA.HC1 650 mL, after addition, the reaction was carried out at room temperature, a large amount of solid precipitated during the reaction, the reaction was complete after 4 hours by TLC. The reaction solution was filtered, the filter cake was washed with 100 mL methyl tert-butyl ether. After drying at 50 °C under vacuum, the material was collected as a white solid A1-8 (91.66 g, yield: 90.8%)

[0197] LCMS m / z = 184.1 [M+1].

[0198] Fourth step: 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)urea (A1-9)

[0199] 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)urea

[0200] To the reaction flask was added compound A1-8 90.08 g and purified water (270 mL), after stirring uniformly, concentrated hydrochloric acid 41.34 g was added, potassium cyanate 49.63 g was added in batches, a large amount of bubbles was generated, after addition, the temperature was increased to 100 °C, stirring reaction for 4 hours. TLC reaction was complete, the reaction solution was cooled to 0±5 °C, stirring crystallization, filtration, the filter cake was washed with 50 mL purified water. The filter cake was added to 100 mL anhydrous ethanol, stirring and slurry for 0.5 h. Filtration, the filter cake was washed with 20 mL anhydrous ethanol. After drying, the material was collected as a white solid A1-9 (43.23 g, yield: 46.23%).

[0201] LCMS m / z = 228.1 [M+1].

[0202] Fifth step: 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)pyrimidine-2,4,6(1H,3H,5H)-trione (A1-10)

[0203] 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)pyrimidine-2,4,6(1H,3H,5H)-trione

[0204] Into a reaction flask, compound A1-9 (44.97 g, 0.20 mol) and anhydrous ethanol (400 mL) were added, and stirring was started. Diethyl malonate (47.69 g, 0.40 mol) was added, and then sodium methoxide (32.22 g, 0.59 mol) was added. The flask wall was rinsed with 50 mL of anhydrous ethanol, and the reaction was stirred at 90°C for 17 hours. The reaction solution was concentrated under reduced pressure to about 150 mL, and purified water (180 mL) was added. After stirring was completed, 5N HCl was added dropwise to adjust the pH to 2-3, and stirring was continued to precipitate crystals. Filtration was performed, and the filter cake was rinsed with 50 mL of purified water. After drying, white solid A1-10 (48.38 g, yield: 81.48%) was obtained.

[0205] LCMS m / z = 295.1 [M+1].

[0206] Sixth step: 2-chloro-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (A1)

[0207] 2-chloro-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one

[0208] Into a reaction flask, compound A1-10 (25.47 g, 84.66 mmol) and phosphorus oxychloride (250 mL) were added, and stirring was started. The reaction was stirred at 90°C for 6 hours. The reaction solution was concentrated under reduced pressure until no obvious fraction was left, and dichloromethane (600 mL) was added. After stirring until the solution was substantially clear, the solution was added to 400 mL of ice water to quench and continue stirring. Saturated sodium bicarbonate solution was added to adjust the pH of the system to 7-8. Filtration was performed, and the organic phase was collected. The aqueous phase was extracted twice with 300 mL of dichloromethane each time, and the organic phases were combined. To the organic phase, 200 g of anhydrous sodium sulfate was added, and stirring was continued to dry. Filtration was performed, and the filter cake was rinsed with 100 mL of dichloromethane. The filtrate was collected, and the filtrate was concentrated under reduced pressure to about 350 mL. A solid was precipitated. While stirring, 375 mL of n-hexane was added dropwise to the concentrate to precipitate crystals for 1 hour. Filtration was performed, and the filter cake was rinsed with 50 mL of n-hexane. After drying, brownish yellow solid compound A1 (21.88 g, yield 87.50%) was obtained.

[0209] LCMS m / z = 296.1 [M+1].

[0210] 1 H NMR (400 MHz, DMSO) δ 7.50, 7.27, 7.04, 4.07, 4.06, 3.86, 2.99, 2.98, 2.96.

[0211] Example 3: Preparation of compound A1

[0212] First step: 4-(benzyloxy)-3-methoxybenzaldehyde (A1-2)

[0213] 4-(benzyloxy)-3-methoxybenzaldehyde

[0214] Into a reaction kettle, add compound A1-1 70 kg and methanol 350 L, add potassium carbonate powder (1.2 eq) in batches. Add benzyl bromide (1.2 eq) dropwise into the system, control the temperature ≤ 30 ℃. After adding, warm up to reflux for 3-4 h. After the reaction is completed, concentrate the methanol under reduced pressure. Add 490 L of dichloromethane, 210 L of water, stir, stand, and separate. Wash the organic phase with 210 L of water once and 210 L of brine once, recover the dichloromethane, concentrate to a paste, and obtain a yellow solid crude product. Add 70 L of petroleum ether to the paste, stir at 15-20 ℃ for 2 h, filter out the solid, rinse with 70 L of petroleum ether, and dry at 30-35 ℃ under vacuum to obtain 103 kg of compound A1-2, with a yield of 91.06%.

[0215] LCMS m / z = 243.1 [M+1].

[0216] Second step: (E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene (A1-3)

[0217] (E)-1-(benzyloxy)-2-methoxy-4-(2-nitrovinyl)benzene

[0218] Into a reaction kettle, add 71 kg of compound A1-1 and acetic acid 284 L in sequence, and replace with nitrogen three times. Add ammonium acetate (1.0 eq) and nitromethane (3.0 eq), and replace with nitrogen three times. After adding, warm up to 105-110 ℃ and reflux for 3-5 h, and make sure to absorb the tail gas. After the reaction is completed, cool down to 80-85 ℃, and discharge into 710 L of ice water under stirring for 1-2 h, centrifuge, rinse with water 142 L, add 71-106 L of methanol to the wet product, and stir at 15-20 ℃ for 2 h, centrifuge, and dry at 30-35 ℃ under vacuum to obtain 70 kg of compound A1-3, with a yield of 83.72%.

[0219] LCMS m / z = 286.2 [M+1].

[0220] Third step: 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine (A1-4)

[0221] 2-(4-(benzyloxy)-3-methoxyphenyl)ethan-1-amine

[0222] Into the reactor, 30V of tetrahydrofuran was added, and the temperature was lowered to 0-10°C under nitrogen protection. After stirring to dissolve compound A1-3, 5.0 eq of lithium aluminum hydride was added portionwise. After stirring at 0-10°C for 2 h, the temperature was lowered to below 0°C, and an amount of water equivalent to the lithium aluminum hydride was slowly added to quench the reaction. The temperature was controlled at 0-10°C, and then an amount of 15% NaOH aqueous solution equivalent to the weight of the lithium aluminum hydride was added dropwise, followed by the addition of an amount of water equivalent to 150L of the lithium aluminum hydride, and the addition of 100L of 1N hydrochloric acid solution. An amount of 10V of petroleum ether was added to extract the impurities once, and the mixture was separated. The aqueous phase was adjusted to pH 7-8 with saturated sodium bicarbonate to obtain a compound A1-4 solution, and the yield was 100%.

[0223] LCMS m / z = 257.1 [M+1].

[0224] Fourth step: tert-butyl (4-(benzyloxy)-3-methoxyphenethyl)carbamate (A1-5)

[0225] tert-butyl (4-(benzyloxy)-3-methoxyphenethyl)carbamate

[0226] The pH value of the reaction kettle containing the aqueous phase of compound A1-4 was confirmed to be in the range of 7-8. After stirring, sodium bicarbonate (1.5 eq) was added to the system, and di-tert-butyl dicarbonate (0.9 eq) was added to the system. After incubation at 20-30°C for 2-4 h, 250L of ethyl acetate was added for extraction, and the mixture was separated. The organic phase was combined, washed once with 30L of water, and washed once with 30L of brine, dried, concentrated, and then 350L of petroleum ether was added. The temperature was raised to 45-50°C, and the mixture was slurried for 2 h. The temperature was then lowered to 10°C, and the mixture was filtered. The filter cake was rinsed with 70L of petroleum ether (10-15°C), and the material was discharged. After drying under vacuum at 30-35°C, 70kg of compound A1-5 was obtained, with a yield of 79.63%.

[0227] LCMS m / z = 358.2 [M+1].

[0228] Fifth step: tert-butyl (4-hydroxy-3-methoxyphenethyl)carbamate (A1-6)

[0229] tert-butyl (4-hydroxy-3-methoxyphenethyl)carbamate

[0230] Into a reactor, 50 kg of compound A1-5 and 400 L of methanol were added, 10% wet palladium on carbon was added into the reactor, replaced with nitrogen for three times, replaced with hydrogen for three times, the reactor was pressurized to 0.2 MPa, and the reaction was carried out at 25-30 °C. Filtration was performed, and the filtrate was transferred to a 50 L rotary evaporator flask, rotary evaporation was performed, and the solid was reslurried in 100 L of methanol at 15-20 °C for 2 h. Filtration was performed, and the solid was rinsed with 50 L of methanol at 15-20 °C. The combined solid was dried under vacuum at 30-35 °C to obtain 32.8 kg of compound A1-6, with a yield of 87.71%

[0231] LCMS m / z = 267.1 [M+1].

[0232] Sixth step: tert-butyl (3-methoxy-4-(methoxy-d3)phenethyl)carbamate (A1-7)

[0233] tert-butyl (3-methoxy-4-(methoxy-d3)phenethyl)carbamate

[0234] Into a reactor, 100 L of N,N-dimethylformamide was added, and the reactor was replaced with nitrogen for three times; 20 kg of compound A1-6 (1.0 eq) and deuterated methyl iodide (1.1 eq) and powdered potassium carbonate (2.0 eq) were added. The reaction was carried out at 25-30 °C for 14 h. Filtration was performed, and the filter cake was rinsed with 200 L of ethyl acetate. The filtrate was concentrated and dissolved in 80 L of ethyl acetate, washed with 40 L of water once and 20 L of brine once, and dried over anhydrous sodium sulfate. The organic phase was concentrated to 40%, and then directly used in the next step.

[0235] LCMS m / z = 285.1 [M+1].

[0236] Seventh step: 2-(3-methoxy-4-(methoxy-d3)phenyl)ethan-1-amine (A1-8)

[0237] 2-(3-methoxy-4-(methoxy-d3)phenyl)ethan-1-amine

[0238] Into a reactor, 195 L of 4 M hydrochloric acid ethyl acetate and 39.3 kg of compound A1-7 (ethyl acetate solution) were added, and the reaction was carried out at 10-20 °C for 5 h. Filtration was performed, and the solid was rinsed with 40 L of methyl tert-butyl ether. The solid was dried under vacuum at 30-35 °C to obtain 27.8 kg of compound A1-8, with a yield of 91.3%.

[0239] LCMS m / z = 185.1 [M+1].

[0240] Step 8: 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)urea (A1-9)

[0241] 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)urea

[0242] Into a reaction kettle, add water 62 L, 27.8 kg of compound A1-8 and urea (6.0 eq) and hydrochloric acid (1.0 eq). After addition, react at 95-100 °C; cool to 0-5 °C, solid precipitates, stir for 1 h, filter the solid, wash with water 55.6 L, and dry the solid in a 55-60 °C blast oven to obtain 25.3 kg of compound A1-9 with a yield of 88.19%.

[0243] LCMS m / z = 228.1 [M+1].

[0244] Step 9: 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)pyrimidine-2,4,6(1H,3H,5H)-trione (A1-10)

[0245] 1-(3-methoxy-4-(methoxy-d3)phenethyl-d3)pyrimidine-2,4,6(1H,3H,5H)-trione

[0246] Into a reaction kettle, add 25.3 kg of compound A1-9, dioxane 202 L, sodium methoxide (4.0 eq) and diethyl malonate (2.0 eq) in sequence, and after addition, react at reflux for 10-15 h. Cool to 0-5 °C, dissolve the solid in water 76 L, adjust the pH to 2-3 with 6N hydrochloric acid solution, continue to stir for 1 h after solid precipitates at 0-5 °C, filter, wash the filter cake with water 50 L, and dry the solid in a 55-60 °C blast oven to obtain 29.4 kg of compound A1-10 with a yield of 90.51%. P H = 2-3, stir for 30 min, cool to 0-5 °C to precipitate the solid, and continue to stir for 1 h, filter, wash the filter cake with water 50 L, and dry the solid in a 55-60 °C blast oven to obtain 29.4 kg of compound A1-10 with a yield of 90.51%.

[0247] LCMS m / z = 296.1 [M+1].

[0248] Step 10: 12-chloro-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (A1)

[0249] 2-chloro-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one

[0250] Into a reactor, 25.3 kg of compound A1-10 and 151.8 L of acetonitrile were sequentially added, and stirring was started. Phosphorus oxychloride (4.0 eq) was added dropwise, and the temperature was controlled to be less than 30 °C. After the dropwise addition was completed, the temperature was increased to reflux for 15 hours. When the temperature was lowered to below 35 °C, 1518 L of dichloromethane was added to dilute the reaction solution, which was slowly transferred to 30 V of 12.5% aqueous potassium phosphate dibasic solution, and the temperature was controlled to be -5-5 °C; after the pH was adjusted to 9-10 with 50% potassium carbonate solution, the temperature was adjusted to 15-20 °C, and the liquid was separated, and the organic phase was washed once with brine, dried over anhydrous sodium sulfate, concentrated to 177-253 V of the system, and the temperature was lowered to 10-15 °C. 304 L of n-hexane was added dropwise, the temperature was controlled to be 10-15 °C, and the slurry was stirred for 2 h, and the filter cake was rinsed with 50.6 L of n-hexane, and the filter cake was dried under vacuum at 30-35 °C to obtain 31 kg of compound A1-10, with a yield of 69.56%

[0251] LCMS m / z = 296.2 [M+1].

[0252] Example 4: Preparation of compound C1

[0253] First step: 2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (E1-2)

[0254] 2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one

[0255] Into a reactor, 25.3 kg of compound A1-10 and 151.8 L of acetonitrile were sequentially added, and stirring was started. Phosphorus oxychloride (4.0 eq) was added dropwise, and the temperature was controlled to be less than 30 °C. After the dropwise addition was completed, the temperature was increased to reflux for 15 hours. When the temperature was lowered to below 35 °C, 1518 L of dichloromethane was added to dilute the reaction solution, which was slowly transferred to 30 V of 12.5% aqueous potassium phosphate dibasic solution, and the temperature was controlled to be -5-5 °C; after the pH was adjusted to 9-10 with 50% potassium carbonate solution, the temperature was adjusted to 15-20 °C, and the liquid was separated, and the organic phase was washed once with brine, dried over anhydrous sodium sulfate, concentrated to 177-253 V of the system, and the temperature was lowered to 10-15 °C. 304 L of n-hexane was added dropwise, the temperature was controlled to be 10-15 °C, and the slurry was stirred for 2 h, and the filter cake was rinsed with 50.6 L of n-hexane, and the filter cake was dried under vacuum at 30-35 °C to obtain 31 kg of compound A1-10, with a yield of 69.56%

[0256] LCMS m / z = 395.2 [M+1].

[0257] Second Step: 2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H- pyrimido[6,1-a]isoquinolin-3(4H)-yl)acetonitrile (E1-4)

[0258] 2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)acetonitrile

[0259] Into a reactor, 320.0 kg of dichloromethane was added, followed by 12.00 kg of compound E1-2, which was stirred until uniform. 5.00 kg of ammonia water was added to 100.0 kg of drinking water, which was stirred until uniform and then added to the reactor, which was stirred for 1-2 hours. The temperature was controlled at 20±10°C, and the system was allowed to stand and separate. The organic phase was retained, and the aqueous phase was extracted with 132.0 kg of dichloromethane once. The organic phase was washed with 10% sodium chloride solution once, and anhydrous sodium sulfate was added to the organic phase for drying. Filtration was performed, and the filter cake was washed with dichloromethane. Concentration was performed under reduced pressure to about 50 L. Acetonitrile was added, and concentration was continued to about 50 L. Acetonitrile was added, and concentration was continued to about 50 L, which was used for subsequent reactions. Into the reactor, 181.6 kg of acetonitrile and 6.79 kg of lithium carbonate were added, and the temperature was increased to 75±10°C. 7.35 kg of compound E1-3 was added, and the reactor wall was washed with 5.0 kg of acetonitrile. After the reaction was allowed to proceed at 75±10°C for 4 hours, 3.68 kg of compound E1-3 was added for further reaction. After the reaction was allowed to proceed for about 18 hours, the reaction system was decreased to 25±5°C. The reaction liquid was filtered, and the filter cake was washed with acetonitrile. The filtrate was collected. Concentration was performed under reduced pressure to about 50 L. 39.0 kg of anhydrous ethanol was added, and concentration was continued to about 50 L. 39.0 kg of anhydrous ethanol was added, and concentration was continued to about 50 L. 17.2 kg of anhydrous ethanol was added. The system was increased to 70±10°C, and the reaction liquid was allowed to stand until the solids were dissolved. 313.2 kg of isopropyl acetate was added to the reaction liquid. After the addition was completed, the temperature was increased to 70±10°C, and the system was stirred for 1 hour. The temperature was decreased to 50±5°C, and the system was stirred for 2 hours. The temperature was decreased to 10±5°C, and the system was stirred for 4 hours. The reaction liquid was centrifuged, and the filter cake was rinsed with isopropyl acetate. Drying was performed, and the product was collected. The yield of 11.0 kg of compound E1-4 was about 83%.

[0260] LCMS m / z = 434.2 [M+1].

[0261] Third Step: 3-(2-Aminoethyl)-2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (C1-5)

[0262] 3-(2-aminoethyl)-2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one

[0263] Into a reactor, add 66.0 kg of anhydrous ethanol and 11.0 kg of compound E1-4. Under nitrogen protection, add 22.0 kg of Raney nickel (containing water) and use 88.0 kg of anhydrous ethanol to wash the Raney nickel adhered to the reactor wall. Finally, add 1.01 kg of ammonia water and the remaining 20.7 kg of anhydrous ethanol; under a slightly open nitrogen atmosphere, control the temperature at 30-55°C and drop 34.2 kg of hydrazine hydrate. After addition, keep the temperature at 45±10°C and react. After 5 hours of reaction, reduce the temperature to 30±10°C. After the temperature reduction is completed, pad 5.5 kg of diatomite, wash out the materials in the reactor with 165 kg of anhydrous ethanol, wash the filter cake, and collect the filtrate. At an external temperature of 60±10°C, concentrate under reduced pressure to about 60 L, add 43.4 kg of anhydrous ethanol, and continue to concentrate to about 60 L. Increase the temperature of the system to 75±10°C, add 7.5 kg of concentrated hydrochloric acid to the reaction solution. Keep the temperature at 75±10°C until the solids in the reaction system are dissolved. Add 191.4 kg of isopropyl acetate to the reaction solution, after addition, keep the temperature at 75±10°C and stir for 0.5 hours, reduce the temperature to 10±5°C and keep the temperature for 4 hours to crystallize. Centrifuge the material solution, and rinse the filter cake with 12.1 kg of isopropyl acetate. Collect the material to obtain 9.50 kg of compound C1-5 with a yield of about 68%.

[0264] LCMS m / z = 437.1 [M+1].

[0265] Fourth step: 1-(2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (C1)

[0266] 1-(2-(2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea

[0267] Reaction kettle was charged with 208.0 kg of dichloromethane, 10.4 kg of compound C1-5, and stirring was started. 13.2 kg of N,N-diisopropylethylamine was added. The temperature was controlled at 10±10 °C for about 1 hour. 3.35 kg of compound E1-5 and 4.6 kg of dichloromethane were added dropwise under nitrogen protection while the temperature was controlled at 20±10 °C. After 15 hours of reaction, 1.04 kg of ammonia water was added to 66.6 L of water, and the organic phase was washed. The organic phase was washed with 10% sodium chloride solution. 1.04 kg of activated carbon and 5.2 kg of anhydrous sodium sulfate were added to the organic phase, and stirring was continued for 1 hour. The mixture was filtered, and the filter cake was washed with dichloromethane. The volume was reduced to about 60 L under reduced pressure. 81.4 kg of anhydrous ethanol was added, and the volume was reduced to 60 L±5 L under reduced pressure. 81.4 kg of anhydrous ethanol was added, and the volume was reduced to 60 L±5 L under reduced pressure. The temperature was raised to 75±5 °C, and the mixture was stirred for 1 hour. The temperature was then lowered to 5±5 °C, and the mixture was stirred for 2 hours. The mixture was centrifuged, and the filter cake was washed with anhydrous ethanol. The filter cake was dried under reduced pressure for 6 hours, and the mass of the collected material was 8.80 kg (labeled as M5). The crude product M5 kg from the previous step and 7.7 M5 kg of dimethyl sulfoxide were added to the reaction kettle. The temperature was raised to 90±5 °C, and the mixture was stirred until the solid was dissolved. The temperature was then lowered to 55±10 °C, and 22.12 M5 kg of acetone was added. 1% M5 kg of C1 compound seed crystals were added when the internal temperature was 45±10 °C. The mixture was stirred for 1 hour, and then the temperature was lowered to 5±5 °C. The mixture was stirred for 15 hours to allow crystallization. The mixture was centrifuged, and the filter cake was washed with acetone. The filter cake was dried under reduced pressure for 10 hours, and 7.50 kg of crude C1 compound was obtained.

[0268] Purification: 108.0 kg of dimethyl sulfoxide and 7.00 kg of C1 crude product were added to a dissolving kettle. After the addition was completed, the internal temperature was raised to 70±5 °C, and the mixture was stirred until it was essentially clear. 77.3 kg of anhydrous ethanol was added, and the mixture was stirred at 70±5 °C until it was essentially clear. 98.0 kg of hot water at 70±10 °C was added, and the mixture was stirred for about 0.5 hour. The internal temperature was lowered to 50±5 °C, and the mixture was stirred for about 1 hour. The temperature was lowered to 20±5 °C at a rate of 10 °C / hour. The mixture was stirred at 20±5 °C for about 4 hours to allow crystallization. The mixture was centrifuged, and the filter cake was washed with anhydrous ethanol. The temperature of the material was controlled at 65±5 °C, and the mixture was dried under hot nitrogen for 15-20 hours. 5.350 kg of compound C1 was obtained with a yield of 76.8% (total yield of the fourth step).

[0269] LCMS m / z = 481.3 [M+1].

[0270] 'H NMR (400 MHz, Methanol-d4) 6.80 (s, 2H), 6.77 (s, 1H), 6.65 (s, 1H), 5.40 (s, 1H), 4.25-4.22 (m, 2H, 3.91-3 88 (m, 2H), 3.76 (s, 3H), 3.45-3 42 (m, 2H), 2.83-2.81 (m, 1H), 2 17 (s, 3H), 1.96 (s, 6H).

[0271] Preparation of compound C1 seed crystal:

[0272] Warming and dissolving: 770 g of dimethyl sulfoxide and 50 g of crude compound C1 were added to the dissolving kettle at an external temperature of 20±10 °C. After the addition was completed, the temperature was raised to 75±5 °C, and the solution was stirred at 75±5 °C until it was clear. At a temperature of 75±5 °C, 552 g of anhydrous ethanol was added.

[0273] Filtering: The reaction solution in the dissolving kettle was filtered into the crystallization kettle at a temperature of 75±5 °C.

[0274] Crystallization: The system was kept at a temperature of 75±5 °C, and 700 ml of purified water at 75 °C was added. The system was kept at a temperature of 75±5 °C for 0.5 hours, then the temperature was lowered to 50 °C and kept at this temperature for 1 hour. The temperature was then lowered to 20 °C at a rate of 10 °C / hour. The system was kept at an internal temperature of 20±5 °C and stirred for 4 hours for crystallization.

[0275] Centrifugation: After the crystallization was completed, the solution was centrifuged, and the filter cake was rinsed with 19 kg of anhydrous ethanol.

[0276] Drying: The filter cake was dried under a vacuum of ≤-0.07 MPa at an external temperature of 65±5 °C for 12 hours, with a weight loss of <0.5%. (The weight loss was measured using a rapid moisture meter at a temperature of 105 °C after the filter cake was dried for 8 hours. If the weight loss was ≥0.5%, the drying was continued. The filter cake was sampled every 2 hours to measure the weight loss until the weight loss was <0.5%. The compound C1 seed crystal was obtained.

Claims

1. A method for preparing a compound of formula (II-PG), comprising the following reaction: wherein R1, R2are each independently alkyl, deuterated alkyl, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, further preferably selected from the group consisting of methyl, deuterated methyl, more preferably R1, R2are both CH3or CD3, or R1is CH3and R2is CD3; PG is a protecting group selected from the group consisting of Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, PMB, preferably selected from the group consisting of Boc, Fmoc, Cbz.

2. A method for preparing a compound of formula (I), comprising the following reaction: wherein, the reaction reagent is selected from the group consisting of phenyl carbamate, KOCN, NaOCN; R1, R2are each independently alkyl, deuterated alkyl, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, further preferably selected from the group consisting of methyl, deuterated methyl, more preferably R1, R2are both CH3or CD3, or R1is CH3and R2is CD3; X is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid; n is selected from the group consisting of 0.5-4, preferably 1 or 2.

3. The method of claim 2 comprising the reaction: ###0001### 2 3 4. The method of claim 2 comprising the reaction: ###0002### 5. The preparation method according to claim 4, wherein the reaction is in the presence of an alcoholic solvent selected from at least one of methanol, ethanol, isopropanol, tert-butanol, preferably methanol.

6. A method for preparing a compound (E1-2), comprising the following reaction:

7. A process for the preparation of a compound of formula (II-nX) comprising the steps of: wherein R1, R2are each independently alkyl, deuterated alkyl, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, further preferably selected from the group consisting of methyl, deuterated methyl, more preferably R1, R2are both CH3or CD3, or R1is CH3and R2is CD3; Y is a pharmaceutically acceptable acid, preferably selected from the group consisting of hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, acetic acid, fumaric acid, maleic acid; PG is a protecting group selected from the group consisting of Boc, Fmoc, Cbz, Ac, Alloc, TFA, PMB, Bn, Pht, Tos, Ns, Trt, SEM, PMB, preferably selected from the group consisting of Boc, Fmoc, Cbz; X is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid; n is selected from the group consisting of 0.5-4, preferably 1 or 2.

8. Compound (Al), (El-2), (Al-9), (Al-10) or a salt thereof:

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