Method for preparing key intermediate of tricyclic fused heterocyclic PDE3 / 4 dual inhibitor

Abstract

The present invention provides a method for preparing a key intermediate (formula (I)) of a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor. The method has 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 key intermediate of a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor TECHNICAL FIELD

[0001] The present application relates to a preparation method of a pharmaceutical intermediate compound, in particular to a preparation method of a key intermediate of a tricyclic fused heterocyclic PDE3 / 4 dual inhibitor, 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, they tend to be similar in treatment 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, various PDEs 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, and formula (A) is one of the key intermediates thereof:

[0006] The PDE3 / PDE4 dual inhibitor disclosed in the patent also relates to a key intermediate compound of formula (I):

[0007] The patent discloses its preparation route as follows:

[0008] The above preparation method introduces a 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. The product yield is low, the cost is high, and it is not suitable for industrial production. SUMMARY

[0009] The present application provides a preparation method of a compound of formula (B), which comprises the following reaction:

[0010] wherein R is H or D; R' is methyl, ethyl or tert-butyl; X is selected from H, trichloroacetyl, chloroacetyl, trifluoroacetyl, phenyl, trimethylsilyl, preferably trichloroacetyl;

[0011] In some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, imidazole, N-methylimidazole, triethylenediamine, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene;

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

[0013] In some embodiments, the reaction temperature of the reaction is 0-60°C, preferably 25±5°C.

[0014] The present application also provides a method for preparing a compound of formula (A), comprising the following reaction:

[0015] wherein R is H or D;

[0016] The reaction is carried out in the presence of a chlorinating agent, and in some embodiments, the chlorinating agent is selected from at least one of phosphorous oxychloride, phosphorous pentachloride, thionyl chloride, oxalyl chloride, preferably phosphorous oxychloride.

[0017] 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, N-methylmorpholine, 2,6-lutidine, imidazole, N-methylimidazole, preferably N’N-diisopropylethylamine;

[0018] In some embodiments, the reaction solvent used in the reaction is selected from at least one of acetonitrile, 2-methyltetrahydrofuran, isopropyl acetate, acetone, dichloromethane, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, methyl isobutyl ketone, preferably at least one of acetonitrile, dichloromethane, N,N-dimethylformamide;

[0019] In some embodiments, the reaction temperature of the reaction is 30-100°C, preferably 80±5°C.

[0020] The present application also provides a method for preparing a compound of formula (A), comprising the following reaction:

[0021] wherein R is H or D; R’ is methyl, ethyl or tert-butyl; X is selected from H, trichloroacetyl, chloroacetyl, trifluoroacetyl, phenyl, trimethylsilyl, preferably trichloroacetyl.

[0022] The present application also provides a method for preparing a compound of formula (A), comprising the following steps:

[0023] wherein R is H or D; R’ is methyl, ethyl or tert-butyl; X is selected from H, trichloroacetyl, chloroacetyl, trifluoroacetyl, phenyl, trimethylsilyl, preferably trichloroacetyl.

[0024] Meanwhile, the present application also provides:

[0025] A method for preparing a compound of formula (A), comprising the steps of (D)→(C)→(B)→(A);

[0026] A process for preparing a compound of formula (A) comprising the steps of (E)→(D)→(C)→(B)→(A);

[0027] A process for preparing a compound of formula (A) comprising the steps of (F)→(E)→(D)→(C)→(B)→(A);

[0028] A process for preparing a compound of formula (B) comprising the steps of (D)→(C)→(B);

[0029] A process for preparing a compound of formula (B) comprising the steps of (E)→(D)→(C)→(B);

[0030] A process for preparing a compound of formula (B) comprising the steps of (F)→(E)→(D)→(C)→(B);

[0031] A process for preparing a compound of formula (B) comprising the steps of (G)→(F)→(E)→(D)→(C)→(B).

[0032] The present application also provides a process for preparing a compound of formula (III) comprising the reaction:

[0033] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0034] Optionally, in some embodiments, the reaction is carried out without solvent, or with a solvent selected from one or more of xylene, toluene, n-octane, dodecane, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-dibutylformamide, dibenzofuran, sulfolane, preferably xylene or without solvent;

[0035] Optionally, in some embodiments, the reaction is carried out at a temperature of 125-155°C, preferably 135±5°C.

[0036] The present application also provides a process for preparing a compound of formula (I) comprising the reaction:

[0037] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0038] Optionally, in some embodiments, the compound of formula (V) is reacted with diethyl pyrocarbonate or dimethyl pyrocarbonate to prepare the compound of formula (C);

[0039] Optionally, in some embodiments, the compound of formula (V) is reacted with diethyl pyrocarbonate to prepare the compound of formula (C), wherein R is H or D, and R' is ethyl;

[0040] Optionally, in some embodiments, the compound of formula (V) is reacted with dimethylpyrocarbonate to prepare the compound of formula (C), wherein R is H or D, and R' is methyl;

[0041] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from one or more of toluene, acetonitrile, pyridine, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, preferably one or more of toluene, 1,4-dioxane, 2-methyltetrahydrofuran;

[0042] Optionally, in some embodiments, the reaction temperature of the reaction is 45-75 °C, preferably 50±5 °C.

[0043] The present application also provides a method for preparing a compound of formula (I), which comprises the following reaction:

[0044] wherein R is H or D;

[0045] Optionally, in some embodiments, the reaction is carried out in the presence of a catalyst selected from at least one of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, N-chlorosuccinimide, preferably thionyl chloride, oxalyl chloride;

[0046] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of the organic bases triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,8-diazabicyclo[5.4.0]undecane-7-ene, imidazole, N-methylimidazole, triethylenediamine, diethylamine, and the inorganic bases sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, preferably triethylamine, N,N-diisopropylethylamine;

[0047] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, 1,4-dioxane, pyridine, ethyl acetate, isopropyl methyl acetate, toluene, preferably tetrahydrofuran;

[0048] Optionally, in some embodiments, the reaction temperature of the reaction is 60-80 °C, preferably 70±5 °C.

[0049] The present application also provides a method for preparing a compound of formula (I), which comprises the following reaction:

[0050] wherein R is H or D;

[0051] Optionally, in some embodiments, the reaction is carried out in the presence of a deprotecting agent selected from at least one of hydrazine hydrate, sodium hydroxide, potassium hydroxide, sodium borohydride-acetic acid, concentrated hydrochloric acid, preferably hydrazine hydrate.

[0052] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, isopropanol, tert-butanol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, water, preferably one or more of ethanol, methanol, water;

[0053] Optionally, in some embodiments, the reaction temperature of the reaction is 30-60°C, preferably 45±5°C.

[0054] The present application also provides a preparation method of the compound of formula (I), comprising the following steps:

[0055] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0056] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0057] The present application also provides a preparation method of the compound of formula (I), comprising the following steps:

[0058] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0059] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0060] The present application also provides a preparation method of the compound of formula (I), comprising the following steps:

[0061] wherein R is H or D;

[0062] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0063] The present application also provides a preparation method of the compound of formula (II), comprising the following steps:

[0064] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0065] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0066] The present application also provides a method for preparing a compound of formula (II), comprising the following steps:

[0067] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0068] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0069] The present application also provides a method for preparing a compound of formula (III), comprising the following steps:

[0070] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0071] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0072] The present application also provides a method for preparing a compound of formula (V-D), comprising the following reaction:

[0073] The present application also provides a method for preparing a compound of formula (V-D), comprising the following steps:

[0074] The present application also provides a method for preparing a compound of formula (VI-D), comprising the following reaction:

[0075] The present application also provides a method for preparing a compound of formula (VII), comprising the following reaction:

[0076] The present application also provides a method for preparing a compound of formula (IV-D2), comprising the following steps:

[0077] wherein the reaction for preparing a compound of formula (VII) from a compound of formula (VIII):

[0078] Optionally, in some embodiments, the reaction is carried out in the presence of acetic anhydride;

[0079] 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, N-methylmorpholine, DBU, sodium hydroxide, potassium hydroxide, and the like, preferably triethylamine;

[0080] Optionally, in some embodiments, the reaction solvent employed in the reaction is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, preferably acetonitrile;

[0081] Optionally, in some embodiments, the reaction temperature of the reaction is -15 to 30°C, preferably -5±10°C;

[0082] wherein the reaction of preparing the compound of formula (VI-D) from the compound of formula (VII):

[0083] Optionally, in some embodiments, the reaction is carried out in the presence of CD3I;

[0084] Optionally, in some embodiments, the reaction is carried out in the presence of a base selected from at least one of potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, potassium phosphate, N,N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, DBU, preferably potassium carbonate;

[0085] Optionally, in some embodiments, the reaction solvent employed in the reaction is at least one selected from the group consisting of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, preferably acetonitrile;

[0086] Optionally, in some embodiments, the reaction temperature of the reaction is -5 to 25°C, preferably 20-25°C;

[0087] wherein the reaction of preparing the compound of formula (V-D) from the compound of formula (VI-D):

[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 solvent employed in the reaction is at least one selected from the group consisting of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, preferably toluene;

[0090] Optionally, in some embodiments, the reaction temperature of the reaction is 85 to 105°C, preferably 110°C;

[0091] wherein the reaction of preparing the compound of formula (IV-D2) from the compound of formula (V-D):

[0092] Optionally, in some embodiments, the reaction is carried out in the presence of diethyl carbonate;

[0093] Optionally, in some embodiments, the reaction solvent used in the reaction is selected from at least one of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, preferably toluene;

[0094] Optionally, in some embodiments, the reaction temperature of the reaction is 35-65 °C, preferably 50 °C;

[0095] The present application also provides a preparation method of a certain compound prepared by sequentially combining the above reactions, for example:

[0096] A preparation method of the compound of formula (C-D2), comprising the steps of (VI-D)→(V-D)→(C-D2);

[0097] A preparation method of the compound of formula (C-D2), comprising the steps of (VII)→(VI-D)→(V-D)→(C-D2);

[0098] A preparation method of the compound of formula (C-D2), comprising the steps of (VIII)→(VII)→(VI-D)→(V-D)→(C-D2);

[0099] A preparation method of the compound of formula (V-D), comprising the steps of (VII)→(VI-D)→(V-D);

[0100] A preparation method of the compound of formula (V-D), comprising the steps of (VIII)→(VII)→(VI-D)→(V-D);

[0101] A preparation method of the compound of formula (VI-D), comprising the steps of (VIII)→(VII)→(VI-D);

[0102] A preparation method of the compound of formula (B), comprising the steps of (V)→(C)→(B);

[0103] A preparation method of the compound of formula (B), comprising the steps of (VI)→(V)→(C)→(B);

[0104] A preparation method of the compound of formula (B), comprising the steps of (VII)→(VI)→(V)→(C)→(B);

[0105] A preparation method of the compound of formula (A), comprising the steps of (V)→(C)→(B)→(A);

[0106] A preparation method of the compound of formula (A), comprising the steps of (VI)→(V)→(C)→(B)→(A);

[0107] In particular, the present application also provides a preparation method of the compound of formula (A), comprising the steps of (VII)→(VI)→(V)→(C)→(B)→(A):

[0108] wherein R is H or D, and R' is methyl, ethyl or tert-butyl;

[0109] The reaction conditions of each step are consistent with the reaction conditions of the corresponding steps in the present application.

[0110] In addition, the present application also provides a compound of formula (II-D), formula (III-H), formula (III-D), formula (C-D), formula (V-D), formula (VI-D), formula (B-D) or a salt thereof as follows:

[0111] wherein R' in formula (C-D) is methyl, ethyl or tert-butyl.

[0112] Abbreviations and key terms of the present application are defined as follows:

[0113] Technical effects of the present application:

[0114] 1. The present application provides a new, simple and more green method for constructing a chlorinated pyrimidine ring, which has low production cost.

[0115] 2. The entire process is simple to operate, the new ethylenediamine introduction strategy avoids the hydrogenation reduction process of the original process, is more green and safe, is beneficial to production scale-up, and has high yield of each intermediate synthesis, and the starting material is low in price and easy to obtain.

[0116] 3. The intermediate products in the entire synthesis process can be crystallized and purified, the process has high robustness, and the product quality is more controllable. DETAILED DESCRIPTION

[0117] The present application is further described in detail below in combination with examples, but is not limited to the present application. Any equivalent replacement in the art according to the disclosure of the present application is within the scope of the present application.

[0118] The NMR measurement uses a nuclear magnetic instrument (Bruker Avance III 400 and Bruker Avance 300);

[0119] The measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0120] MS was determined by Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0121] HPLC was determined by Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 μM);

[0122] Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15 mm-0.20 mm, and the specification of the product purified by thin layer chromatography is 0.4 mm-0.5 mm.

[0123] Example 1: Preparation of compounds of formula (A-D):

[0124] First step: N-(4-hydroxy-3-methoxyphenethyl)acetamide (F)

[0125] N-(4-hydroxy-3-methoxyphenethyl)acetamide (F)

[0126] Into the reaction bottle, compound of formula (G) (19.95 g, 0.098 mol) and acetonitrile (200 mL) were added, then triethylamine (30.02 g, 0.29 mol) was added, stirring was started, the temperature was lowered to -5±10℃, and acetic anhydride (10.54 g, 0.10 mol) was added dropwise while controlling the temperature at -5±10℃. After the dropwise addition was completed, the reaction was stirred for 2 hours while controlling the temperature at -5±10℃. Purified water (150 mL) was added to quench the reaction, and stirring was continued for 15 minutes. Dichloromethane (300 mL x 2) was added to extract twice, and the organic phases were combined. After drying, the mixture was filtered under suction, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated to dryness under reduced pressure to obtain a purple red oil VI (16.86 g, yield 82.04%).

[0127] LCMS m / z = 210.2 [M+1].

[0128] Second step: N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide (E-D)

[0129] N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide (E-D)

[0130] Into a reaction flask was placed F (6.13 g, 29.30 mmol) and acetonitrile (50 mL), stirred to dissolve, then added potassium carbonate (8.12 g, 58.59 mmol), cooled to 0±10 °C, controlled temperature 0±10 °C, added dropwise CD3I (5.18 g, 35.15 mmol), after dropwise addition, naturally warmed to room temperature, stirred for 22 hours. Added purified water 100 mL to quench the reaction, stirred to dissolve, extracted twice with dichloromethane (100 mL x 2), combined the organic phase, added saturated sodium chloride solution 100 mL to wash once, retained the organic phase. Dried, suction filtered, the filter cake was washed with 20 mL of dichloromethane. The filtrate was concentrated under reduced pressure to no obvious fraction, added 30 mL of methyl tert-butyl ether, stirred to paddle, crystallized for 30 min, suction filtered, the filter cake was washed with 10 mL of methyl tert-butyl ether, the filter cake was dried to obtain E-D (3.93 g, yield: 59.27%).

[0131] LCMS m / z = 227.1 [M+1].

[0132] Third step: 6-methoxy-7-(methoxy-d3)-1-methyl-3,4-dihydroisoquinoline (D-D)

[0133] 6-methoxy-7-(methoxy-d3)-1-methyl-3,4-dihydroisoquinoline (D-D)

[0134] Into a reaction flask was placed E-D (34.79 g, 0.15 mol) and toluene (175 mL), began to stir and warmed to 40 °C, when the internal temperature reached 40 °C, added phosphorus oxychloride (55.37 g, 0.37 mol), after addition, warmed to 110 °C and refluxed for 2 h. After the reaction was completed, the system was naturally cooled to room temperature, a large amount of solid was precipitated, rapid stirring was performed to disperse it, after the internal temperature was less than 30 °C, the ice bath was continued to cool to 0-10 °C, stirred for 30 min, filtered, and the filter cake was washed with 50 mL of toluene. The filter cake was added to a 500 mL single-neck flask, 300 mL of dichloromethane was added, the internal temperature was controlled to be less than 20 °C under ice bath stirring, and sodium hydroxide solution (sodium hydroxide (31.67 g, 0.3 M) was dissolved in purified water (105 mL, 3V)) was added dropwise to quench, a large amount of salt was precipitated from the system, the solution was poured into a 2 L beaker, 300 mL of dichloromethane was added, purified water 1.0 L was added, stirred until the system was dissolved, separated, dichloromethane 300 mL was added to extract once, the organic phase was combined, purified water 300 mL was added to wash once, and the organic phase was retained. Dried, suction filtered, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated under reduced pressure to obtain yellow-brown solid D-D (29.83 g, yield 85%).

[0135] LCMS m / z = 209.1 [M+1].

[0136] Fourth Step: 6-methoxy-7-(methoxy-d3)-1-methylene-3,4-dihydroisoquinoline-2(1H)- carboxylate (C-D)

[0137] methyl 6-methoxy-7-(methoxy-d3)-1-methylene-3,4-dihydroisoquinoline-2(1H)-carboxylate (C-D)

[0138] In a reaction flask, 900 mL of ethyl acetate was added, 100.00 g of D-D was added under stirring, after stirring and dissolving, it was cooled to 10±5°C, 128.76 g of dimethyl carbonate was added, and it was stirred for 1 h at 10±5°C, and then it was warmed to 50±5°C and stirred for 2 h. The reaction liquid was concentrated to about 200 mL at 40±5°C, and it was stirred to crystallize, after the solid was precipitated, 600 mL of n-hexane was added dropwise, and it was further stirred to crystallize at 15±5°C for about 3 h. It was filtered, the filter cake was washed with 200 mL of n-hexane, and then it was dried to obtain the product C-D (108.71 g; yield: 85%).

[0139] LCMS m / z = 267.3 [M+1].

[0140] Fifth Step: 9-methoxy-10-(methoxy-d3)-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)- dione (B-D)

[0141] 9-methoxy-10-(methoxy-d3)-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-2,4(3H)-dione (B-D)

[0142] In a reaction flask, 2 L of acetonitrile was added, 100.00 g of C-D was added under stirring, and it was stirred and dissolved, and then it was cooled to -5±5°C. A solution of 106.11 g of trichloroacetyl isocyanate in 200 mL of acetonitrile was added dropwise at -5±5°C, and after the dropwise addition was completed, it was reacted for about 3 h, and then 171.50 g of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) was added, and it was stirred and reacted at 25±5°C for about 5 h. It was filtered, the filter cake was washed with 200 mL of acetonitrile, and then it was dried to obtain the product B-D (78.10 g, yield 75%).

[0143] LCMS m / z = 278.1 [M+1].

[0144] Step 6: 2-chloro-9-methoxy-10-(methoxy-d3)-6,7-dihydro-4H-pyrimidino[6,1-a]isoquinolin-4-one (A-D)

[0145] 2-chloro-9-methoxy-10-(methoxy-d3)-6,7-dihydro-4H-pyrimidino[6,1-a]isoquinolin-4-one (A-D)

[0146] In a reaction flask, add 1 L of acetonitrile and 100.00 g of B-D, add 110.59 g of phosphorus oxychloride under stirring, and drop 34.96 g of N’N-diisopropylethylamine under temperature control below 30°C, after adding, increase the temperature to 80±5°C, and react for about 6 hours, cool to 20±10°C, stir for about 1 h, filter, wash the filter cake with 200 mL of acetonitrile, and dry to obtain the product A-D (92.87 g, yield 87%).

[0147] LCMS m / z = 296.1 [M+1].

[0148] Example 2: Preparation of the compound of formula (I-D):

[0149] Step 1: methyl 6-methoxy-7-(methoxy-d3)-1-methylene-3,4-dihydroisoquinoline-2(1H)-carboxylate (formula (C-D1))

[0150] methyl 6-methoxy-7-(methoxy-d3)-1-methylene-3,4-dihydroisoquinoline-2(1H)-carboxylate (formula (C-D1))

[0151] Add 100 g of the compound of formula (V-D) to 2000 ml of toluene and stir until uniform, then add 200 ml of dimethyl pyrocarbonate, and increase the temperature to 50±5°C under nitrogen protection, and react for about 6 h.

[0152] After the reaction is complete, concentrate and remove the solvent at 65±5°C under reduced pressure, add 300 ml of toluene to the concentrate, increase the temperature to 60±5°C under nitrogen protection, and after the solution is clear, add 1300 ml of n-heptane, after adding, stir at 15±5°C for about 2 hours to crystallize.

[0153] After crystallization, filter and rinse with n-heptane, and dry the filter cake at 55±5°C under vacuum ≤-0.07 MPa for about 8 h to obtain 108.68 g of solid compound of formula (C-D1).

[0154] HPLC purity, 98.91%; yield 85%

[0155] Second Step: 2-(2-(9-methoxy-10-(methoxy-d3)-4-oxo-2-thioxo-6,7-dihydro-2H- pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)isoindoline-1,3-dione (Formula (III-D))

[0156] 2-(2-(9-methoxy-10-(methoxy-d3)-4-oxo-2-thioxo-6,7-dihydro-2H- pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)isoindoline-1,3-dione (Formula (III-D))

[0157] Under nitrogen protection, 20.80 g of the compound of Formula (C-1) and 22.42 g of the compound of Formula (C-D1) were added into 60 ml of dimethylbenzene, and the temperature was raised to 135±5°C for about 4 h.

[0158] After the reaction was completed, the system was cooled to 60±5°C, and 120 mL of methyl tert-butyl ether was added. After crystallization at room temperature for about 16 h, filtration was performed, the filter cake was washed with DCM, and the filter cake was dried at 55±5°C under vacuum at ≤-0.07 MPa for about 10 h.

[0159] After drying was completed, 29.14 g of the compound of Formula (III-D) was obtained.

[0160] HPLC purity: 97.00%, yield: 80%.

[0161] Third Step: 2-(2-(2-(trisilylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H- pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)isoindoline-1,3-dione (Formula (II-D))

[0162] 2-(2-(2-(trisilylimino)-9-methoxy-10-(methoxy-d3)-4-oxo-6,7-dihydro-2H- pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)isoindoline-1,3-dione (Formula (II-D))

[0163] Under nitrogen protection, 23.29 g of the compound of formula (III-D) was added into 116 ml of tetrahydrofuran, and 17.80 g of sulfoxide chloride was added, and then the temperature was raised to 70±5°C for about 16 h.

[0164] After the reaction, the system was concentrated under reduced pressure at 50±5°C to remove the solvent, 50 ml of ethyl acetate was continuously added, and stirred at room temperature for about 1 h, and then filtered, and the filter cake was washed with ethyl acetate, and then dried at 55±5°C under vacuum at ≤-0.07 MPa for about 8 h to obtain 23.5 g of solid.

[0165] The above 23.5 g of solid was added into a reaction bottle, and then 124 ml of tetrahydrofuran, 10.2 g of triethylamine and 10.5 g of 2,4,6-trimethyl aniline (compound of formula (III-1)) were added. After completion of the reaction, the temperature was lowered to room temperature and stirred for about 1 h, and then filtered, and the filter cake was washed with ethyl acetate, and then the filter cake was dried at 55±5°C under vacuum at ≤-0.07 MPa for about 12 h to obtain 21.5 g of solid compound of formula (II-D).

[0166] HPLC purity: 97.82%, yield: 76%.

[0167] Fourth step: 3-(2-aminoethyl)-2-(2,4,6-trimethylphenylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (formula (I-D))

[0168] 3-(2-aminoethyl)-2-(mesitylimino)-9-methoxy-10-(methoxy-d3)-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one (formula (I-D))

[0169] The above 23.5 g of solid was added into a reaction bottle, and then 124 ml of tetrahydrofuran, 10.2 g of triethylamine and 10.5 g of 2,4,6-trimethyl aniline (compound of formula (III-1)) were added. After completion of the reaction, the temperature was lowered to room temperature and stirred for about 1 h, and then filtered, and the filter cake was washed with ethyl acetate, and then the filter cake was dried at 55±5°C under vacuum at ≤-0.07 MPa for about 12 h to obtain 21.5 g of solid compound of formula (II-D).

[0170] After the reaction, the system was concentrated under reduced pressure at 50±5°C to remove the solvent, 50 ml of ethyl acetate was continuously added, and stirred at room temperature for about 1 h, and then filtered, and the filter cake was washed with ethyl acetate, and then dried at 55±5°C under vacuum at ≤-0.07 MPa for about 8 h to obtain 23.5 g of solid.

[0171] HPLC purity: 98.52%, yield: 87%.

[0172] The compounds of formula (I), formula (II), formula (III), formula (IV) can be prepared according to the same method as in Example 1 to obtain the corresponding compounds when R is H.

[0173] Example 3: Preparation of the compound of formula (V-D):

[0174] Step 1: N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide (formula (VI-D))

[0175] N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide (formula (VI-D))

[0176] Into the reaction bottle, 5L of acetonitrile and 600g of the compound of formula (VII) are added, and then 800g of potassium carbonate is added. 500g of deuterated methyl iodide (CD3I) is added dropwise at 0±5°C, and after the dropwise addition is completed, the reaction is stirred at 25±5°C for about 10 hours.

[0177] After the reaction is completed, purified water is added to quench the reaction, and dichloromethane is added for extraction. The organic phase is washed once with saturated sodium chloride solution, and the organic phase is retained.

[0178] The organic phase is filtered and concentrated under reduced pressure at 40±5°C. After the concentration is completed, 3L of methyl tert-butyl ether is added, and the mixture is stirred at 25±5°C for about 1 hour. The filter cake is dried at 45±5°C under vacuum at ≤-0.07MPa for about 8h to obtain 551.2g of the compound of formula (VI-D).

[0179] HPLC purity: 98.73%, yield: 85%.

[0180] Step 2: 6-methoxy-7-(methoxy-d3)-1-methyl-3,4-dihydroisoquinoline (formula (V-D))

[0181] 6-methoxy-7-(methoxy-d3)-1-methyl-3,4-dihydroisoquinoline (formula (V-D))

[0182] Into the reaction bottle, 1.75L of toluene and 340g of the compound of formula (VI-D) are added, and then 550g of phosphorus oxychloride is added after the temperature is raised to 45±5°C. After the addition is completed, the temperature is raised to reflux, and the reaction is carried out for about 2h.

[0183] After the reaction, the system was cooled to 5±5°C and kept stirring for about 1 h, filtered, and the filter cake was added to the reaction bottle. 4 L of dichloromethane was added, and sodium hydroxide solution (310 g of sodium hydroxide dissolved in 2.1 L of purified water) was added under the control of internal temperature below 20°C. After the addition was completed, the mixture was stirred at 25±5°C for about 30 minutes, and then separated. The filtrate was concentrated under reduced pressure, and then 1.2 L of ethyl acetate was added to the mixture, which was stirred at 25±5°C for about 1 h, filtered, and the filter cake was dried at 45±5°C under vacuum (≤-0.07 MPa) for about 8 h to obtain 253.36 g of the compound of formula (V-D).

[0184] HPLC purity: 99.03%, yield: 81%.

[0185] Example 4: Preparation of the compound of formula (C-D2)

[0186] First step: N-(4-hydroxy-3-methoxyphenethyl)acetamide (VII)

[0187] N-(4-hydroxy-3-methoxyphenethyl)acetamide

[0188] To the reaction bottle were added VIII (19.95 g, 0.098 mol) and acetonitrile (200 mL), and then triethylamine (30.02 g, 0.29 mol) was added. After the stirring was started, the temperature was lowered to -5±10°C, and acetic anhydride (10.54 g, 0.10 mol) was added dropwise under the control of temperature -5±10°C. After the dropwise addition was completed, the mixture was stirred at -5±10°C for 2 h. Purified water (150 mL) was added to quench the reaction, and the mixture was stirred for 15 min. Dichloromethane (300 mL x 2) was added to extract twice, and the combined organic phase was dried, filtered, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated to dryness under reduced pressure to obtain purple red oil VII (16.86 g, yield 82.04%).

[0189] LCMS m / z = 210.2 [M+1].

[0190] Second step: N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide (VI-D)

[0191] N-(3-methoxy-4-(methoxy-d3)phenethyl-d3)acetamide

[0192] Into a reaction flask was placed VII (6.13 g, 29.30 mmol) and acetonitrile (50 mL), stirred to dissolve, then potassium carbonate (8.12 g, 58.59 mmol) was added, the temperature was lowered to 0±10 °C, and CD3I (5.18 g, 35.15 mmol) was added dropwise while maintaining the temperature at 0±10 °C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 22 hours. The reaction was quenched by adding purified water (100 mL), stirred to dissolve, extracted twice with dichloromethane (100 mL x 2), the organic phases were combined, washed once with saturated sodium chloride solution (100 mL), and the organic phase was retained. The organic phase was dried, filtered, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure until no obvious fraction was obtained, 30 mL of methyl tert-butyl ether was added, stirred to form a slurry, and allowed to crystallize for 30 minutes. The slurry was filtered, the filter cake was washed with 10 mL of methyl tert-butyl ether, and the filter cake was dried to obtain VI-D.

[0193] LCMS m / z = 227.1 [M+1].

[0194] Third Step: 6-methoxy-7-(methoxy-d3)-l-methyl-3,4-dihydroisoquinoline (V-D)

[0195] 6-methoxy-7-(methoxy-d3)-l-methyl-3,4-dihydroisoquinoline

[0196] Into a reaction flask was placed VI-D (34.79 g, 0.15 mol) and toluene (175 mL), and the mixture was stirred and heated to 40 °C. When the internal temperature reached 40 °C, phosphorus oxychloride (55.37 g, 0.37 mol) was added, and the reaction was heated to 110 °C and refluxed for 2 hours. After the reaction was complete, the system was allowed to cool to room temperature, and a large amount of solid was precipitated. The solid was dispersed by rapid stirring, and the internal temperature was lowered to less than 30 °C. The system was then cooled to 0-10 °C in an ice bath, and stirred for 30 minutes. The mixture was filtered, and the filter cake was washed with 50 mL of toluene. The filter cake was placed in a 500 mL separatory funnel, 300 mL of dichloromethane was added, and the internal temperature was controlled to be less than 20 °C by ice bath. The reaction was quenched by dropwise addition of a sodium hydroxide solution (sodium hydroxide (31.67 g, 0.3 M) dissolved in purified water (105 mL, 3V)) while stirring. The solution was poured into a 2 L beaker, and 300 mL of dichloromethane and 1.0 L of purified water were added. The mixture was stirred until the system was clear, and the phases were separated. The organic phase was extracted once with 300 mL of dichloromethane, and the organic phase was retained after washing once with 300 mL of purified water. The organic phase was dried, filtered, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated under reduced pressure to obtain V-D (29.83 g, yield: 93.04%) as a yellow-brown solid.

[0197] LCMS m / z = 209.1 [M+1].

[0198] Fourth Step: Ethyl 6-methoxy-7-(methoxy-d3)-l-methylene-3,4- dihydroisoquinoline-2(lH)-carboxylate (IV-D2)

[0199] ethyl 6-methoxy-7-(methoxy-d3)-l-methylene-3,4- dihydroisoquinoline-2(lH)-carboxylate

[0200] To the reaction flask was added V-D (18.02 g, 0.086 mol) and toluene (450 mL), warmed to 50 °C, when the internal temperature reached 50 °C, added diethyl carbonate (29 mL), continued to react for 4 h. After the reaction was completed, the system was concentrated to no obvious fraction, ice bath was added n-hexane 360 mL, stirred to crystallize to solid, slurry for 1 h, filtered, 50 mL n-hexane washed the filter cake, the filter cake was dried to give IV-D2 crude product (17.77 g, yield: 73.33%). IV-D2 crude product (17.77 g) was added to a 2 L single neck flask, added ethanol (178 mL, 10V), stirred to warm to 50 °C, stirred until the solution was clear. Turn off the heat, dropwise added purified water (890 mL, 50V) to crystallize, after dropping, ice water bath was cooled to 10±5 °C, stirred to slurry for 1 h, filtered, 50 mL purified water washed the filter cake. The filter cake was placed in an oven at 55 °C to dry to give C-D2 (14.79 g, yield 83.21%).

[0201] LCMS m / z = 292.1 [M+l].

Claims

1. A method for preparing a compound of formula (B), comprising the following reaction: in, R is H or D; R' is methyl, ethyl or tert-butyl; X is selected from H, trichloroacetyl, chloroacetyl, trifluoroacetyl, phenyl, trimethylsilyl, preferably trichloroacetyl.

2. The preparation method according to claim 1, wherein the reaction is carried out in the presence of a catalyst selected from at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, 2,6-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, imidazole, N-methylimidazolium, and triethylenediamine, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.

3. A method for preparing a compound of formula (A), comprising the following reaction: in, R is either H or D.

4. The preparation method according to claim 3, wherein the reaction is carried out in the presence of a chlorinating agent selected from at least one of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, and oxalyl chloride, preferably phosphorus oxychloride.

5. The preparation method according to claim 3, wherein the reaction is carried out in the presence of a base, wherein the base is selected from at least one of N'N-diisopropylethylamine, triethylamine, pyridine, N-methylmorpholine, 2,6-dimethylpyridine, imidazole, and N-methylimidazole, preferably N'N-diisopropylethylamine.

6. A method for preparing a compound of formula (A), comprising the following reaction: in, R is H or D; R' is methyl, ethyl or tert-butyl; X is selected from H, trichloroacetyl, chloroacetyl, trifluoroacetyl, phenyl, trimethylsilyl, preferably trichloroacetyl.

7. A method for preparing a compound of formula (C), comprising the following reaction: in, R is H or D, and R' is methyl, ethyl or tert-butyl.

8. A method for preparing a compound of formula (VD), comprising the following reaction:

9. A method for preparing a compound of formula (VD), comprising the following steps:

10. A method for preparing a compound of formula (VI-D), comprising the following reaction:

11. A compound of formula (CD), formula (VD), formula (VI-D), formula (BD), or a salt thereof: in, In formula (IV-D), R' is methyl, ethyl, or tert-butyl.

Images