Preparation method for PDE4b inhibitor

Abstract

The present invention provides a preparation method for a PDE4B inhibitor (formula (A1)). The method involves mild reaction conditions, and simple and convenient operations, has a high product yield, and is suitable for large-scale industrial production.

Description

A preparation method of PDE4B inhibitor Technical Field

[0001] The present invention relates to a method for preparing a pharmaceutical compound, in particular to a method for preparing a PDE4B inhibitor, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] PDE4 inhibitors produce antidepressant effects in humans and animals by enhancing cAMP signaling in the brain. PDE4 inhibitors also play an important role in the treatment of other central nervous system diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, stroke, and Huntington's disease. Significant progress has also been made in the research and development of PDE4 inhibitors for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. The rationale behind the development of these drugs stems from the role of PDE4 in inhibiting the functions of a range of inflammatory cells and resident cells, which is believed to be involved in the pathogenesis of these diseases. Numerous clinical studies have demonstrated that cyclic adenosine monophosphate (cAMP) can block the proliferation and chemotaxis of inflammatory cells and inhibit the release of inflammatory and cytotoxic mediators in the lungs. Furthermore, PDE4 is particularly abundant in immune cells, inflammatory cells, and smooth muscle cells.

[0003] PDE4 inhibitors primarily exert their anti-inflammatory effects by inhibiting PDE4 hydrolysis, increasing cAMP levels in the body, suppressing the release of inflammatory factors, and promoting the production of anti-inflammatory mediators. Roflumilast is clinically used to treat COPD and has significant anti-inflammatory effects, inhibiting the release of inflammatory mediators such as TNF-α, interleukins, and chemokines by monocytes, macrophages, and T cells. However, these inhibitors are commonly associated with serious side effects such as nausea and vomiting, which limits their clinical application. Numerous studies have shown that in humans, isoform B of phosphodiesterase 4 (PDE4B) is involved in inflammatory responses and participates in the release of various inflammatory mediators, while isoform D is closely associated with side effects such as nausea and vomiting. This provides new insights into the identification of PDE4 inhibitors with reduced side effects. Designing PDE4B inhibitors may reduce the impact of these side effects and promote further clinical application.

[0004] Phosphodiesterase 4 (PDE4A), a phosphodiesterase (PDE4B), is highly selective for cAMP and has four isoforms: PDE4A, 4B, 4C, and 4D, with at least 25 splice variants. The protein sequences of the catalytic domains of the four PDE4 isoforms are highly homologous, and inhibitors targeting the catalytic domain do not exhibit isoform selectivity. However, most reported classical PDE4 inhibitors target the catalytic domain. In recent years, novel modes of action of PDE4 inhibitors have been reported, in which inhibitors interact simultaneously with both the catalytic domain and regulatory sequences, enabling the regulatory sequences to stabilize the protein's closed conformation, preventing cAMP entry and exerting inhibitory effects. Studies have revealed amino acid differences between PDE4B and 4D in these regulatory sequences, which can be exploited to design inhibitors that exhibit isoform selectivity. Therefore, targeting the two amino acid differences (Leu674 in PDE4B and Gln594 in PDE4D) within the downstream regulatory sequence CR3 (Conserved Region 3) offers the potential to achieve selectivity for isoform B, while maintaining activity and minimizing inhibitor side effects.

[0005] PCT / CN2023 / 112061 describes a compound of formula (A1) that has a good inhibitory effect on PDE4B. The preparation method described in this patent is complex and has a low yield, making it unsuitable for industrial production. Summary of the Invention

[0006] The present invention provides a method for preparing a compound of formula (A1), comprising the following reaction:

[0007] In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from one or more of N,N-diisopropylethylamine, triethylamine, n-propylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and lithium carbonate;

[0008] In some embodiments, the reaction solvent used in the reaction is selected from one of anhydrous ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl isobutyl ketone, cyclopentyl methyl ether, ethyl acetate and ethyl acetate, or a mixture of these solvents and water;

[0009] In some embodiments, the reaction temperature of the reaction is 60±15°C, preferably 55±5°C.

[0010] The present invention also provides a method for preparing the compound of formula (A1-i), comprising the following reaction:

[0011] in,

[0012] The reaction reagent is selected from N,N'-carbonylbis(1,2,4-triazole) / ammonia or N,N'-carbonyldiimidazole / ammonia;

[0013] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane, tetrahydrofuran, N,N dimethylformamide, N,N dimethylacetamide, N methylpyrrolidone, tetrahydrofuran, 2 methyltetrahydrofuran, methyl isobutyl ketone, cyclopentyl methyl ether, ethyl acetate and ethyl acetate;

[0014] In some embodiments, the reaction temperature of the reaction is 0±15°C, preferably 0±5°C.

[0015] The present invention also provides a method for preparing a compound of formula (A1), comprising the following reaction:

[0016] In some embodiments, the reaction is carried out in the presence of an organic base catalyst and a reaction solvent, and water is added for crystallization after the reaction is completed; the organic base catalyst is selected from one or more of N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylimidazole, and N-methylmorpholine; the reaction solvent is selected from one or more of methanol and tetrahydrofuran;

[0017] In some embodiments, the reaction is carried out in the presence of an inorganic base catalyst and a reaction solvent, and crystallization is performed after the reaction is completed; the inorganic base catalyst is selected from one or more of potassium carbonate, sodium carbonate, potassium phosphate, ammonia water, potassium bicarbonate, and sodium bicarbonate, and the reaction solvent is selected from water;

[0018] In some embodiments, the reaction temperature is 0°C to 30°C, preferably 25±5°C.

[0019] In some embodiments, after the reaction is completed and crystallization is performed, centrifugation or filtration is performed, and the filter cake is washed with water and then stirred in a solution selected from one or more of methanol-water solution, ethanol-water solution, n-propanol-water solution, and isopropanol-water solution.

[0020] The present invention also provides a method for preparing a compound of formula (A1-g), comprising the following reaction:

[0021] In some embodiments, the molar ratio of the compound of formula (A1-g) to trichloroacetyl isocyanate in the reaction is 1:1.0-1.5, preferably 1:1.1;

[0022] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane and tetrahydrofuran;

[0023] In some embodiments, after the reaction is completed, anhydrous methanol is added to the reaction solution to quench the reaction;

[0024] In some embodiments, activated carbon is added to the reaction solution after quenching the reaction, and the temperature is controlled at 10±5° C. After the reaction is completed, diatomaceous earth is placed on the solution, and the solution is filtered. The filtrate is concentrated to obtain the compound of formula (A1-g).

[0025] The present invention also provides a method for preparing a compound of formula (A1-f), comprising the following reaction:

[0026] In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from one or more of N,N-diisopropylethylamine, triethylamine, and diazabicycle;

[0027] In some embodiments, the molar ratio of formula (A1-d) to formula (A1-e) in the reaction is 1:1.0-1.5, preferably 1:1.05;

[0028] In some embodiments, the reaction solvent used in the reaction is selected from one or more of tetrahydrofuran / water, ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate; the reaction temperature of the reaction is 30-90° C., preferably 55±5° C.;

[0029] In some embodiments, after the reaction is completed, 10% ethanol aqueous solution is added for crystallization.

[0030] In some embodiments, the crude product of formula (A1-f) is dissolved in N-methylpyrrolidone and then anhydrous ethanol is added for crystallization and purification.

[0031] The present invention also provides a method for preparing the compound of formula (A1-d), comprising the following reaction:

[0032] In some embodiments, the reaction is carried out in the presence of an oxidant, wherein the oxidant is selected from one or more of tert-butyl hydroperoxide, hydrogen peroxide, and m-chloroperbenzoic acid;

[0033] In some embodiments, the reaction is carried out in the presence of a catalyst selected from one or more of Ti(OiPr)4, ClTi(OiPr)3, ClTi(OtBu)3, and Ti(OtBu)4;

[0034] In some embodiments, the reaction is carried out in the presence of a ligand, and the ligand is selected from one or more of (S)-1,1-bin-2-naphthol and diethyl L-tartrate;

[0035] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane, chloroform, toluene, tetrahydrofuran, and dichloromethane / methanol;

[0036] In some embodiments, the reaction temperature of the reaction is 0-40°C, preferably 25±5°C.

[0037] The present invention also provides a method for preparing a compound of formula (A1-c), which comprises the following reaction:

[0038] The molar ratio of formula (A1-a) to formula (A1-b) is 1:1.0-8.0, preferably 1:6.0;

[0039] In some embodiments, the reaction solvent used in the reaction is selected from one or more of acetonitrile, ethanol, methanol, n-propanol, and isopropanol.

[0040] In some embodiments, water is added for crystallization after the reaction is completed.

[0041] In some embodiments, a method of purifying Al-c comprises recrystallization using acetonitrile and water.

[0042] The present invention also provides another method for preparing the compound of formula (A1), comprising the following reaction:

[0043] In some embodiments, the reaction is carried out in the presence of a basic catalyst, and the basic catalyst is selected from one or more of N,N-diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylimidazole, and N-methylmorpholine;

[0044] In some embodiments, the molar ratio of formula (A1-h) to formula (A1-e) in the reaction is 1:1.0-1.5, preferably 1:1.05;

[0045] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane / water, tetrahydrofuran / water, ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0046] In some embodiments, the reaction temperature is 15-65°C, preferably 45±5°C.

[0047] In some embodiments, the method for purifying the compound of formula (A1) comprises: dissolving the crude compound of formula (A1) with N-methylpyrrolidone, cooling and adding anhydrous ethanol for crystallization, centrifuging or filtering, and slurrying the filter cake with anhydrous ethanol to obtain a refined compound of formula (A1).

[0048] The present invention also provides a method for preparing a compound of formula (A1-h), comprising the following reaction:

[0049] In some embodiments, the molar ratio of the compound of formula (A1-d) to trichloroacetyl isocyanate in the reaction is 1:1.0-1.5, preferably 1:1.1;

[0050] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane and tetrahydrofuran;

[0051] In some embodiments, the reaction temperature is -15 to 10±5°C, preferably -10±5°C.

[0052] The present invention also provides a method for preparing a compound by combining the above-mentioned steps in sequence, for example:

[0053] A method for preparing a compound of formula (A1), comprising the steps of (A1-d) → (A1-i) → (A1);

[0054] A method for preparing a compound of formula (A1), comprising the steps of (A1-c) → (A1-d) → (A1-i) → (A1);

[0055] A method for preparing a compound of formula (A1), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-i) → (A1);

[0056] A method for preparing a compound of formula (A1), comprising the steps of (A1-f) → (A1-g) → (A1);

[0057] A method for preparing a compound of formula (A1), comprising the steps of (A1-d) → (A1-f) → (A1-g) → (A1);

[0058] A method for preparing a compound of formula (A1), comprising the steps of (A1-c) → (A1-d) → (A1-f) → (A1-g) → (A1);

[0059] A method for preparing a compound of formula (A1), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-f) → (A1-g) → (A1);

[0060] A method for preparing a compound of formula (A1), comprising the steps of (A1-d) → (A1-h) → (A1);

[0061] A method for preparing a compound of formula (A1), comprising the steps of (A1-c) → (A1-d) → (A1-h) → (A1);

[0062] A method for preparing a compound of formula (A1), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-h) → (A1);

[0063] A method for preparing the intermediate (A1-i), comprising the steps of (A1-c) → (A1-d) → (A1-i);

[0064] A method for preparing the intermediate (A1-i), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-i);

[0065] A method for preparing the intermediate (A1-g), comprising the steps of (A1-d) → (A1-f) → (A1-g);

[0066] A method for preparing the intermediate (A1-g), comprising the steps of (A1-c) → (A1-d) → (A1-f) → (A1-g);

[0067] A method for preparing the intermediate (A1-g), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-f) → (A1-g);

[0068] A method for preparing the intermediate (A1-f), comprising the steps of (A1-c) → (A1-d) → (A1-f);

[0069] A method for preparing the intermediate (A1-f), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-f);

[0070] A method for preparing the intermediate (A1-d), comprising the steps of (A1-a) → (A1-c) → (A1-d);

[0071] A method for preparing the intermediate (A1-h), comprising the steps of (A1-c) → (A1-d) → (A1-h);

[0072] A method for preparing the intermediate (A1-h), comprising the steps of (A1-a) → (A1-c) → (A1-d) → (A1-h);

[0073] The preparation method of the intermediate (A1-d) comprises the steps of (A1-a) → (A1-c) → (A1-d).

[0074] In particular, the present invention also provides a method for preparing a compound of formula (A1), comprising the following steps:

[0075] The present invention also provides a method for preparing a compound of formula (A1-e), comprising the following reaction:

[0076] In some embodiments, the reaction is carried out in the presence of an acid, and the acid is selected from one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and DL-camphorsulfonic acid;

[0077] In some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0078] In some embodiments, the reaction temperature is 0-50°C, preferably 25±5°C.

[0079] The present invention also provides a method for preparing a compound of formula (D5), comprising the following reaction:

[0080] In some embodiments, the reaction is carried out in the presence of a catalyst selected from one or more of 1,1-bis(diphenylphosphine)dibrominated iron palladium chloride, Pd(PPh3)4, (APhos)2PdCl2, [PdCl(C3H5)]2, and XPhos-Pd-G2;

[0081] In some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0082] In some embodiments, the reaction temperature is 50-105°C, preferably 75±5°C.

[0083] The present invention also provides a method for preparing a compound of formula (D3), comprising the following reaction:

[0084] In some embodiments, the reaction is carried out in the presence of a catalyst selected from one or more of Pd(OAc)2, Pd(PPh3)4, (APhos)2PdCl2, [PdCl(C3H5)]2, and XPhos-Pd-G2;

[0085] In some embodiments, the reaction is carried out in the presence of a ligand selected from one or more of tricyclohexylphosphine, XPhos, and APhos;

[0086] In some embodiments, the reaction is carried out in the presence of an activator selected from one or more of potassium carbonate, cesium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, and sodium carbonate;

[0087] In some embodiments, the molar ratio of formula (D1) to formula (D2) in the reaction is 1:1.0-1.5, preferably 1:1.1;

[0088] In some embodiments, the reaction solvent used in the reaction is selected from one or more of toluene, tetrahydrofuran / water, ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0089] In some embodiments, the reaction temperature is 50-100±5°C, preferably 85-95°C.

[0090] The preparation method of each of the above-mentioned compounds is not limited to obtaining a certain compound by the above-mentioned single reaction step, but also includes the preparation step of the intermediate of the compound, that is: the preparation method of the compound of formula (A1-e) of the present invention mentioned above also includes the steps (D3)→(D5)→(A1-e), and the reaction conditions of each step are consistent with the reaction conditions of the corresponding step in the above text.

[0091] In particular, a method for preparing the compound of formula (A1-e) of the present invention comprises the following steps:

[0092] In some embodiments, wherein formula (D1) reacts with formula (D2) to obtain formula (D3), the reaction is carried out in the presence of a catalyst, and the catalyst is selected from one or more of Pd(OAc)2, Pd(PPh3)4, (APhos)2PdCl2, [PdCl(C3H5)]2, and XPhos-Pd-G2;

[0093] In some embodiments, the reaction is carried out in the presence of a ligand selected from one or more of tricyclohexylphosphine, XPhos, and APhos;

[0094] In some embodiments, the reaction is carried out in the presence of an activator selected from one or more of potassium carbonate, cesium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, and sodium carbonate;

[0095] In some embodiments, the molar ratio of formula (D1) to formula (D2) in the reaction is 1:1.0-1.5, preferably 1:1.1;

[0096] In some embodiments, the reaction solvent used in the reaction is selected from one or more of toluene, tetrahydrofuran / water, ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0097] In some embodiments, the reaction temperature is 50-100±5°C, preferably 85-95°C.

[0098] In some embodiments, wherein formula (D3) reacts with formula (D4) to obtain formula (D5), the reaction is carried out in the presence of a catalyst, and the catalyst is selected from one or more of 1,1-bis(diphenylphosphine)dibrominated iron palladium chloride, Pd(PPh3)4, (APhos)2PdCl2, [PdCl(C3H5)]2, and XPhos-Pd-G2;

[0099] In some embodiments, the reaction is carried out in the presence of a base, and the base is selected from one or more of potassium carbonate, cesium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, and sodium carbonate;

[0100] In some embodiments, the molar ratio of formula (D3) to formula (D4) in the reaction is 1:1.0-1.5, preferably 1:1.2;

[0101] In some embodiments, the reaction solvent used in the reaction is selected from one or more of 1,4-dioxane, tetrahydrofuran / water, ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0102] In some embodiments, the reaction temperature is 50-105°C, preferably 75±5°C.

[0103] In some embodiments, the reaction of formula (D5) to obtain formula (A1-e) is carried out in the presence of an acid selected from one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and DL-camphorsulfonic acid;

[0104] In some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, isopropanol, n-propanol, ethanol / water, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0105] In some embodiments, the reaction temperature is 0-50°C, preferably 25±5°C.

[0106] The preparation method of the intermediate (D5) comprises the steps of (D1)→(D3)→(D5).

[0107] The present invention also provides another method for preparing the compound of formula (A1-e), comprising the following reaction:

[0108] In some embodiments, the reaction is carried out in the presence of a debenzylation protecting group reagent, wherein the debenzylation protecting group reagent is selected from one or more of 1-chloroethyl chloroformate, hydrochloric acid, palladium carbon / triethylsilane, palladium carbon / formic acid, palladium carbon / ammonium formate, and Raney nickel / hydrogen;

[0109] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane and tetrahydrofuran;

[0110] In some embodiments, the reaction temperature is 0-45°C, preferably 25±5°C.

[0111] Furthermore, the present invention also provides a method for preparing a compound of formula (C5), comprising the following reaction:

[0112] In some embodiments, the reaction is carried out in the presence of a reducing agent, and the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, and lithium borohydride;

[0113] In some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, acetonitrile, and tetrahydrofuran;

[0114] In some embodiments, the reaction temperature is 0-45°C, preferably 25±5°C.

[0115] Furthermore, the present invention also provides a method for preparing a compound of formula (C4), comprising the following reaction:

[0116] Wherein formula (C3) reacts with BnCl to obtain formula (C4);

[0117] In some embodiments, the molar ratio of formula (C3) to BnCl is 1:1.0-3.5, preferably 1:2.0;

[0118] In some embodiments, the reaction temperature is 0-95°C, preferably 80±5°C;

[0119] In some embodiments, the reaction solvent used in the reaction is selected from one or more of acetonitrile, methanol, isopropanol, n-propanol, ethanol, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate.

[0120] Furthermore, the present invention also provides a method for preparing a compound of formula (C3), comprising the following reaction:

[0121] In some embodiments, the reaction is carried out in the presence of a catalyst, and the catalyst is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium tert-amylate;

[0122] In some embodiments, the molar ratio of formula (C1) to formula (C2) in the reaction is 1:1.0-3.5, preferably 1:2.6;

[0123] In some embodiments, the reaction solvent used in the reaction is selected from one or more of methanol, isopropanol, n-propanol, ethanol, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0124] In some embodiments, the reaction temperature is 0-50°C, preferably 20±5°C.

[0125] A method for preparing a compound of formula (A1-e), comprising the steps of (C4) → (C5) → (A1-e);

[0126] The preparation method of the compound of formula (A1-e) comprises the steps of (C3)→(C4)→(C5)→(A1-e).

[0127] In particular, another method for preparing the compound of formula (A1-e) of the present invention comprises the following steps:

[0128] In some embodiments, wherein formula (C1) reacts with formula (C2) to obtain formula (C3), the reaction is carried out in the presence of a catalyst, and the catalyst is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium tert-amylate;

[0129] In some embodiments, the molar ratio of formula (C1) to formula (C2) in the reaction is 1:1.0-3.5, preferably 1:2.6;

[0130] In some embodiments, the reaction solvent used in the reaction is selected from one or more of methanol, isopropanol, n-propanol, ethanol, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0131] In some embodiments, the reaction temperature is 0-50°C, preferably 20±5°C.

[0132] In some embodiments, wherein formula (C3) reacts with BnCl to obtain formula (C4), the molar ratio of formula (C3) to BnCl is 1:1.0-3.5, preferably 1:2.0;

[0133] In some embodiments, the reaction solvent used in the reaction is selected from one or more of acetonitrile, methanol, isopropanol, n-propanol, ethanol, acetonitrile, 2-methyltetrahydrofuran, and isopropyl acetate;

[0134] In some embodiments, the reaction temperature is 0-95°C, preferably 80±5°C.

[0135] In some embodiments, formula (C4) is reacted to obtain formula (C5), wherein the reaction is carried out in the presence of a reducing agent, wherein the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, and lithium borohydride;

[0136] In some embodiments, the reaction solvent used in the reaction is selected from one or more of ethanol, methanol, acetonitrile, and tetrahydrofuran;

[0137] In some embodiments, the reaction temperature is 0-45°C, preferably 25±5°C.

[0138] In some embodiments, the reaction of formula (C5) to obtain formula (A1-e) is carried out in the presence of a debenzylation protecting group reagent, wherein the debenzylation protecting group reagent is selected from one or more of 1-chloroethyl chloroformate, hydrochloric acid, palladium carbon / triethylsilane, palladium carbon / formic acid, palladium carbon / ammonium formate, and Raney nickel / hydrogen;

[0139] In some embodiments, the reaction solvent used in the reaction is selected from one or more of dichloromethane and tetrahydrofuran;

[0140] In some embodiments, the reaction temperature is 0-45°C, preferably 25±5°C.

[0141] A method for preparing the intermediate (C5), comprising the steps of (C3) → (C4) → (C5);

[0142] A method for preparing the intermediate (C5), comprising the steps of (C1) → (C3) → (C4) → (C5);

[0143] The preparation method of the intermediate (C4) comprises the steps of (C1) → (C3) → (C4).

[0144] In addition, the present invention also provides a compound of formula (A1-h), formula (C3), formula (C4), formula (C5) or a salt thereof:

[0145] Definitions of abbreviations and key terms in this invention:

[0146] Technical effects of the present invention:

[0147] 1. The process route has mild reaction conditions, high chiral selectivity, simple operation, and high yield of intermediate synthesis in each step.

[0148] 2. Each intermediate product and final product can be purified by recrystallization or distillation without the need for column chromatography, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0149] The present invention is further described in detail below with reference to the embodiments, but the present invention is not limited thereto. Any equivalent replacements in the art made according to the disclosure of the present invention shall fall within the scope of protection of the present invention.

[0150] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of ppm is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0151] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0152] HPLC analysis was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SC-A18 100×4.6 mm, 3.5 μm).

[0153] Example 1: Preparation of compound of formula (A1)

[0154] Step 1: 2-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol (A1-c)

[0155] 2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol

[0156] Under nitrogen, 14.16 kg of acetonitrile, 3.00 kg of compound A1-a, and 7.74 kg of compound A1-b were added to the reactor in sequence. The internal temperature was raised to 75 ± 5°C and the reaction was allowed to proceed for 15 hours. The internal temperature of the reactor was lowered to 25 ± 5°C, and 36.00 kg of water was added dropwise to induce crystallization. After the addition, the internal temperature was maintained at 15 ± 5°C and stirred to allow crystallization for approximately 2 hours. After crystallization, the liquid was centrifuged and the contents of the reactor were washed with a mixture of 1.56 kg of acetonitrile and 3.99 kg of water. The filter cake was then washed. The wet product A1-c obtained by centrifugation in the previous step and 11.79 kg of acetonitrile were added to the reactor in sequence. The temperature was raised to 70 ± 5°C and stirred until the solution was essentially clear. The internal temperature of the reactor was lowered to 25 ± 5°C. 45.00 kg of water was added dropwise to induce crystallization. After the addition, the internal temperature was maintained at 20 ± 5°C and stirred to allow crystallization. After crystallization, the liquid was centrifuged and washed with a mixed solvent of 1.17 kg acetonitrile and 4.50 kg water to remove the contents of the kettle. The filter cake was then washed and dried at an external temperature of 55 ± 5°C to obtain 2.70 kg of compound A1-c, with a yield of 72%.

[0157] LCMS m / z=260.1[M+1].

[0158] Step 2: (R)-2-chloro-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (A1-d)

[0159] (R)-2-chloro-4-((1-hydroxy-2-methylpropan-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0160] Under nitrogen protection, maintaining the temperature at 10±5°C, 47.72 kg of dichloromethane, 264.56 g of (S)-1,1-bi-2-naphthol, 131.32 g of Ti(OiPr)4, and 166.48 g of water were added to the reactor in sequence. Stirring was continued for approximately 2 hours. Under nitrogen protection, maintaining the temperature at 10±5°C, 2 kg of Al-c was added to the reactor. Stirring was continued for approximately 2 hours. Maintaining the temperature below 30°C, 1.31 kg of tert-butyl hydroperoxide was added dropwise. After the reaction was complete, the reaction solution was added dropwise to 156.6 kg of isopropyl ether. Stirring was continued at 5±5°C for approximately 3 hours to allow crystallization. Filter the mixture, and wash the filter cake with isopropyl acetate. The filter cake was vacuum dried at an external temperature of 40±5°C to yield 2.16 kg of compound Al-d, with a yield of approximately 85%.

[0161] LCMS m / z=276.1[M+1].

[0162] Step 3: (R)-2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (A1-f)

[0163] (R)-2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0164] Under nitrogen protection, 1.56kg A1-e, 2.10kg A1-d, 1.03kg DIPEA, 14.91kg tetrahydrofuran and 4.20kg water were added to the reactor in sequence. After the addition was completed, stirring was started, the temperature in the reactor was raised to 55±5°C and kept warm for reaction. After the reaction was completed, 29.82kg 10% ethanol aqueous solution was added to the system at 25±5°C for crystallization. The temperature was controlled at 15±5°C and the mixture was stirred and kept warm for crystallization. After the crystallization was completed, the feed liquid was centrifuged and the filter cake was rinsed with water. The filter cake was slurried with anhydrous ethanol and slurried at 45±5°C. The temperature was controlled at 15±5°C and the mixture was stirred and kept warm for crystallization. After the crystallization was completed, the feed liquid was centrifuged and the filter cake was rinsed with ethanol. The filter cake was dried at an external temperature of 50±5°C to obtain 2.35kg compound A1-f with a yield of 70%.

[0165] LCMS m / z=441.1[M+1].

[0166] Step 4: (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl(2,2,2-trichloroacetyl)carbamate (A1-g)

[0167] (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl(2,2,2-trichloroacetyl)carbamate

[0168] Under nitrogen protection, 23.82 kg of dichloromethane and 1.80 kg of A1-f were added to the reactor in sequence; after the addition, stirring was started. The internal temperature was controlled at -10±5°C, and a mixture of 0.85 kg of trichloroacetyl isocyanate and 11.11 kg of dichloromethane was added dropwise. After the addition, the temperature was controlled at -10±5°C for reaction. After the reaction, 0.30 kg of anhydrous methanol was added to the reaction solution to quench the reaction. 0.18 kg of activated carbon was added to the reaction solution, and the temperature was controlled at 10±5°C for about 0.5 hours. 0.36 kg of diatomaceous earth was added, the reaction solution was filtered, and the filter cake was washed with dichloromethane. The external temperature of the reactor was controlled at 35±5°C, and the reaction was concentrated under reduced pressure until there was no obvious fraction, to obtain 2.35 kg of compound A1-g, with a yield of 100%.

[0169] LCMS m / z=629.1[M+1].

[0170] Step 5: (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropylcarbamate (A1)

[0171] (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl carbamate

[0172] Method 1: Add 2.35 kg of Compound A1-g, 0.105 kg of NN-diisopropylethylamine, and 14 kg of anhydrous methanol to a reaction flask. After addition, control the temperature at 25 ± 5°C and allow to react for 3 hours. Add 18 kg of water to induce crystallization. After crystallization, centrifuge the solution and wash the filter cake with water. Control the temperature at 15 ± 5°C and wash the filter cake with 15 kg of a 2:1 mixture of anhydrous methanol and water for approximately 1 hour. After washing, centrifuge the solution and wash the filter cake with water. Dry the filter cake at an external temperature of 50 ± 5°C until dry to yield 2.02 kg of Compound A1, with a yield of 86%.

[0173] Method 2: Add 2.35 kg of Compound A1-g to a reaction flask, followed by 4.78 kg of a mixture of potassium carbonate and water (preparation method: add 0.28 kg of potassium carbonate to 4.50 kg of water and stir until completely dissolved). After addition, control the temperature at 25±5°C to react for 3 hours. After crystallization, centrifuge the solution and wash the filter cake with water. Control the temperature at 15±5°C and wash the filter cake with 15 kg of a 2:1 mixture of anhydrous methanol and water for approximately 1 hour. After washing, centrifuge the solution and wash the filter cake with water. Dry the filter cake at an external temperature of 50±5°C until dry to obtain 2.0 kg of Compound A1, with a yield of 85%.

[0174] LCMS m / z=484.1[M+1].

[0175] 1H NMR(400MHz,DMSO-d6)δ8.55(s,2H),7.19(t,1H),6.54(s,2H),5.46(s,1H),4.48(s,2H),4.27(s,2H),4.01(t,2 H),3.49(t,2H),3.09(t,2H),2.68(d,2H),2.01-1.83(m,1H),1.47(s,6H),1.11-0.97(m,2H),0.92-0.76(m,2H).

[0176] Example 2: Preparation of compound of formula (A1)

[0177] Step 1: 2-((2-chloro-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol (A1-c)

[0178] 2-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropan-1-ol

[0179] Under nitrogen, 600 ml of acetonitrile, 100 g of compound A1-a, and 258 g of compound A1-b were added sequentially to a reactor. The internal temperature was raised to 75°C and the reaction was allowed to proceed for 15 hours. The internal temperature of the reactor was lowered to 25°C, and water was added. Crystallization occurred at 15°C with stirring. Upon completion of crystallization, the liquid was centrifuged, and the filter cake was washed. The filter cake was dried at an external temperature of 55°C to yield 90 g of compound A1-c, a 70% yield.

[0180] LCMS m / z=260.1[M+1].

[0181] Step 2: (R)-2-chloro-4-((1-hydroxy-2-methylpropyl-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (A1-d)

[0182] (R)-2-chloro-4-((1-hydroxy-2-methylpropan-2-yl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide

[0183] Under nitrogen protection, the temperature was controlled at 10±5°C. To the reactor, 477.2g of dichloromethane, 26.5g of (S)-1,1-bi-2-naphthol, 13.1.32g of Ti(OiPr)4, and 166.48g of water were added sequentially. After addition, stirring was continued for approximately 2 hours. Under nitrogen protection, the temperature was controlled at 10°C. 60.0g of Al-c was added to the reactor. After addition, stirring was continued for approximately 2 hours. While maintaining the temperature below 30°C, 131g of tert-butyl hydroperoxide was added dropwise. After completion of the reaction, the reaction solution was added dropwise to 2500ml of isopropyl ether. After addition, stirring was continued at 5°C to allow crystallization. After crystallization, the reaction mixture was filtered, and the filter cake was washed with isopropyl acetate. The filter cake was dried under vacuum at an external temperature of 40°C to yield 55.0g of compound Al-d, with a yield of approximately 85%.

[0184] LCMS m / z=276.1[M+1].

[0185] Step 3: (R)-2-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl(2,2,2-trichloroacetyl)carbamate (A1-h)

[0186] (R)-2-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl(2,2,2-trichloroacetyl)carbamate

[0187] Under nitrogen protection, 500ml of dichloromethane and 50g of compound A1-d were added to the reactor in sequence; after the addition, stirring was started. The internal temperature was controlled at -10±5℃, and a mixture of 37.6g of trichloroacetyl isocyanate and 500ml of dichloromethane was added dropwise. After the addition was completed, the temperature was controlled at -10℃ and the reaction was continued for about 0.5 hours, and 7ml of anhydrous methanol was added to the reaction solution to quench the reaction. 5g of activated carbon was added to the reaction solution, and the temperature was controlled at 10℃ and the reaction was continued for about 0.5 hours. 5g of diatomaceous earth was added, the reaction solution was filtered, and the filter cake was washed with dichloromethane. The external temperature of the reactor was controlled at 35℃, and the solution was concentrated under reduced pressure until there was no obvious fraction to obtain 84g of compound A1-h with a yield of 100%.

[0188] LCMS m / z=629.1[M+1].

[0189] Step 4: (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropylcarbamate (A1)

[0190] (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl carbamate

[0191] Under nitrogen, 1.56 g of Compound A1-e, 2.10 g of Compound A1-h, 1.03 g of DIPEA, 20 ml of tetrahydrofuran, and 5 ml of water were added to a reaction kettle in sequence. After the additions were complete, stirring was initiated, and the reactor temperature was raised to 55°C and maintained for approximately 3 hours. After the reaction terminated, the product was crystallized, filtered, and the filter cake dried at an external temperature of 50°C to yield 2.35 g of Compound A1 (yield: 60%).

[0192] LCMS m / z=484.1[M+1]

[0193] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,2H),7.19(t,1H),6.54(s,2H),5.46(s,1H),4.48(s,2H),4.27(s,2H),4.01(t,2 H),3.49(t,2H),3.09(t,2H),2.68(d,2H),2.01-1.83(m,1H),1.47(s,6H),1.11-0.97(m,2H),0.92-0.76(m,2H).

[0194] Example 3: Preparation of compound of formula (A1)

[0195] Step 1: (R)-2-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl 1H-1,2,4-triazole-1-carboxylate (A1-i)

[0196] (R)-2-((2-chloro-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl carbamate

[0197] Add 13 kg of dichloromethane and 1 kg of the compound of formula (A1-d) to the reactor and cool to 0±5°C. While maintaining the temperature at 0±5°C, add 0.7 kg of N,N'-carbonylbis(1,2,4-triazole). After addition, maintain the temperature at 0±5°C and allow to react for approximately 1 hour. Then, add 0.15 kg of N,N'-carbonylbis(1,2,4-triazole) and maintain the temperature at 0±5°C and allow to react for approximately 3 hours.

[0198] After the reaction is completed, 0.37 kg of ammonia water is added dropwise while controlling the temperature at 0±5°C, and the reaction is continued while controlling the temperature at 0±5°C for about 3 hours.

[0199] After the reaction is complete, add 3.00 kg of 10% sodium chloride solution; after the addition is complete, stir at 20±10°C for about 0.5 h, let it stand to separate the layers, and collect the lower organic phase.

[0200] The organic phase was concentrated under reduced pressure at 40±10°C, and 5 kg of ethyl acetate and 1.5 kg of isopropanol were added, followed by stirring at 60±5°C for approximately 0.5 h. The mixture was cooled and crystallized for approximately 2 h, then filtered. The filter cake was dried under vacuum at 25±10°C for 2 h to obtain the compound of formula (A1-i) (0.98 kg, 85% yield).

[0201] LCMS m / z=319.1[M+1].

[0202] Step 2: (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropylcarbamate (A1)

[0203] (R)-2-((2-(4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)-2-methylpropyl carbamate

[0204] Preparation Example 1:

[0205] Add 7.9 kg of anhydrous ethanol, 1 kg of the compound of formula (A1-i), and 0.64 kg of the compound of formula (A1-e) to a reactor, followed by 0.52 kg of N,N-diisopropylethylamine. Raise the temperature to 55±5°C and allow to react for approximately 5 hours. After the reaction is complete, add 1.5 kg of water, raise the temperature to 75±5°C, and stir for approximately 1.5 hours. Then, add 2.5 kg of acetonitrile, maintain the temperature at 75±5°C, and continue stirring for approximately 0.5 hours.

[0206] The mixture was cooled to 0±5°C and crystallized for about 4 hours. The filter cake was collected by filtration and dried under vacuum at 55±5°C for 2 hours to obtain the compound of formula (A1) (1.32 kg, yield 87%).

[0207] LCMS m / z=484.2[M+1].

[0208] Preparation Example 2:

[0209] To a reactor, add 7.9 kg of anhydrous ethanol, 1 kg of the compound of formula (A1-i), and 0.64 kg of the hydrochloride of the compound of formula (A1-e) (A1-e-HCl). Then, add 1.63 kg of N,N-diisopropylethylamine and heat to 55±5°C for approximately 5 hours. After the reaction is complete, add 1.5 kg of water, heat to 75±5°C, and stir for approximately 1.5 hours. Then, add 2.5 kg of acetonitrile and continue stirring at 75±5°C for approximately 0.5 hours.

[0210] The mixture was cooled to 0±5°C and crystallized for about 4 hours. The filter cake was collected by filtration and dried under vacuum at 55±5°C for 2 hours to obtain the compound of formula (A1) (1.23 kg, yield 81%).

[0211] LCMS m / z=484.2[M+1].

[0212] Example 4 Purification of the compound of formula (A1)

[0213] Under nitrogen protection, 10g of crude compound A1 and 60ml of N-methylpyrrolidone were added to the reactor, the system was heated to 70±5℃, and stirred until the solid was basically dissolved. Turn off the heating, cool to 40±10℃, add 360ml of anhydrous ethanol; cool to 5±5℃, and keep warm for crystallization for 4 hours. After crystallization, the liquid was centrifuged and the filter cake was washed with 20ml of anhydrous ethanol. Under nitrogen protection, the filter cake was slurried and stirred with 20ml of anhydrous ethanol at 40±5℃ for about 1 hour. The liquid was centrifuged and the filter cake was washed with 10ml of anhydrous ethanol. The filter cake was dried at an external temperature of 50±5℃ to obtain 8.2g of compound A1, with a yield of about 82%.

[0214] Example 5 Preparation of the compound of formula (A1-e)

[0215] Step 1: 2-chloro-5-cyclopropylpyrimidine (D3)

[0216] 2-chloro-5-cyclopropylpyrimidine

[0217] Toluene (13 L) was added to the reaction flask at 20-30°C; D1 (1.0 kg, 1.0 eq.) was added and stirred to dissolve; D2 (1.1 eq.), K3PO4 (2.0 eq.), and tricyclohexylphosphine (0.5 eq.) were added in sequence; N2 was replaced three times, Pd(OAc)2 (0.025 eq.) was added, and N2 was replaced three times; the temperature was raised to 85-95°C (internal temperature) with stirring, and the reaction was stirred. After the reaction, the temperature was lowered to 60°C; filtered, the filter cake was rinsed with 2L of toluene, and the filtrate was collected; L-sodium cysteine ​​aqueous solution (5L*2) was added to the organic phase to wash the liquid fraction, and the organic phase was collected; H2O (5L×2) was added to the organic phase to wash the liquid fraction, and the organic phase was collected; the organic phase was concentrated, MTBE (5V) was added after distillation, and MTBE (5L) was added, and stirred to dissolve; mercapto silica gel (10%) was added, and the mixture was stirred at 50°C for 3-5 hours and then filtered; the organic phase was concentrated, cyclohexane (5L) was added after distillation, cyclohexane (2L) was added for slurrying, stirred at 20-30°C for 1-2 hours, cooled to 0°C, and stirred for 3-5 hours; filtered, and the wet product was dried at 40-50°C for 12-16 hours to obtain the compound of formula (D3) with a yield of 80%.

[0218] LCMS m / z=155.1[M+1].

[0219] Step 2: tert-Butyl 4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (D5)

[0220] tert-butyl4-(5-cyclopropylpyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0221] 1,4-dioxane (15.61 kg, 15.1 L) was added to the kettle, and nitrogen was blown into the reaction mixture under stirring for 1 h. D3 (1375.57 g, 8.90 mol) and D4 (3301.47 g, 10.68 mol) were added. Potassium carbonate (3074.12 g, 22.24 mol) was dissolved in 5 L of ice water and added. After the addition was completed, the system was replaced with nitrogen three times. 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (181.65 g, 222 mmol) was added. The mixture was heated to 75±5°C under nitrogen protection for 4 h, then cooled to 30±5°C, 15 L of purified water was added, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with MTBE 10 L×2, the combined organic phases were washed with 10% L-cysteine ​​+ ammonia mixed aqueous solution 10 L×2, and then washed with water 10 L. The organic phase was concentrated and slurried with n-hexane to give D5 (1.88 kg, yield 70%).

[0222] LCMS m / z=302.1[M+1]

[0223] Step 3: 5-cyclopropyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (A1-e)

[0224] 5-cyclopropyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine

[0225] To a reaction flask, ethanol (201.45 g, 255 ml) and D5 (85.00 g, 282 mmol) were added sequentially. Hydrochloric acid (138.06 g, 118 ml) was dissolved in 510 ml of ice water and added to the flask. After addition, the mixture was reacted at 25±5°C for 16 h (overnight). After completion of the reaction, the reaction solution was extracted with 400 ml of dichloromethane three times. The aqueous phase was collected and adjusted to pH 11-12 with 188.75 g of 25% aqueous NaOH solution. The resulting solution was then extracted with 400 ml of dichloromethane three times. The combined organic phases were washed once with water, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated to yield A1-e (47.54 g, 70% yield).

[0226] LCMS m / z=202.1[M+1].

[0227] Example 6 Preparation of the compound of formula (A1-e)

[0228] Step 1: 5-cyclopropyl-2-(pyridin-4-yl)pyrimidine (C3)

[0229] 5-cyclopropyl-2-(pyridin-4-yl)pyrimidine

[0230] Compound C1 (30.00 g) and anhydrous methanol (200 mL) were added to a 500 mL three-necked flask. After cooling in an ice-water bath for ten minutes, a solution of sodium methoxide (25.71 g) in anhydrous methanol (100 mL) was slowly added. After addition, the ice-water bath was removed, the temperature was returned to 20±5°C, and the reaction was allowed to proceed for 1 hour. Compound C2 (81.28 g) was then added in batches. After addition, the temperature was maintained at 20±5°C with stirring and the reaction was continued overnight (16 hours). After completion of the reaction, the reaction solution was concentrated under reduced pressure at 45°C until essentially liquid-free. 300 mL of purified water was added, and the mixture was extracted with ethyl acetate (500 mL x 2). The organic phases were combined and concentrated under reduced pressure until no liquid was present. 200 mL of MTBE was added, and the mixture was stirred at 20±5°C for 2 hours. Filter the mixture, and rinse the filter cake with 60 mL of MTBE. The filter cake was transferred to a single-necked flask and dried under reduced pressure at 45°C to obtain compound C3 (28.96 g, yield: 76.2%).

[0231] LCMS m / z=202.1[M+1].

[0232] Step 2: 1-Benzyl-4-(5-cyclopropylpyrimidin-2-yl)pyridin-1-ium (C4)

[0233] 1-benzyl-4-(5-cyclopropylpyrimidin-2-yl)pyridin-1-ium

[0234] Compound C3 (26.00 g) and acetonitrile (260 mL) were added to a reaction flask, followed by BnCl (34.35 g). After addition, the mixture was heated to 80°C and refluxed for 24 h. After completion, the mixture was concentrated under reduced pressure at 40°C until no visible liquid was present. 60 mL of acetonitrile was then added and the mixture was beaten at 20°C for 0.5 h. Filtered, the filter cake was rinsed with 30 mL of acetonitrile and dried by vacuum drying. The filter cake was transferred to a single-necked flask and dried under reduced pressure at 50°C to afford compound C4 (39.62 g, 90% yield).

[0235] LCMS m / z=289.1[M+1].

[0236] Step 3: 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-cyclopropylpyrimidine (C5)

[0237] 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-cyclopropylpyrimidine

[0238] Compound C4 (35.00 g, 110 mmol) and anhydrous ethanol (350 mL) were added to the reaction flask, stirred to dissolve, and cooled in an ice-water bath. NaBH4 (10.40 g, 275 mmol) was added in batches at 10 ± 5 °C until the addition was complete; the reaction was allowed to proceed overnight at 25 ± 5 °C. The reaction solution was concentrated under reduced pressure at 48 °C until almost no fraction was distilled out. 400 mL of purified water and 300 mL of EA were added for extraction; if there was a large amount of insoluble solid, the filtrate was filtered, collected, and separated; the organic phase was washed once with 200 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with EA. The organic phase was concentrated under reduced pressure at 40 °C until no obvious distillate was found. 50 mL of MTBE was added and the mixture was beaten at 20 °C for 0.5 h, filtered, and the filter cake was washed with MTBE. The filter cake was heated to 70°C with 40 mL of ethanol to dissolve, then naturally cooled to 20°C for crystallization, filtered, and rinsed with a small amount of ethanol. The filter cake was transferred to a single-necked bottle and dried under reduced pressure at 55°C to obtain compound C5 (12.72 g, yield 40%).

[0239] LCMS m / z=292.1[M+1].

[0240] Step 4: 5-cyclopropyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (A1-e)

[0241] 5-cyclopropyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine

[0242] Compound C5 (10.00 g) was added to the reaction flask, followed by dichloromethane (90 mL) and stirred to dissolve. The mixture was cooled in an ice-water bath, and a solution of 1-chloroethyl chloroformate (5.50 g) in dichloromethane (30 mL) was added dropwise at 5±5°C. After the addition, the mixture was heated to 40°C and refluxed for 3 h. After the reaction, the reaction solution was concentrated under reduced pressure at 35°C until no significant distillation occurred. Anhydrous methanol (120 mL) was added to the concentrate, and the temperature was raised to 68°C and refluxed for 1 h, resulting in the precipitation of a large amount of white solid. After the reaction was completed, the temperature was naturally lowered to 35°C, filtered, and the filter cake was rinsed with 5 mL of methanol and dried. The filter cake was transferred to a single-necked flask and dried under reduced pressure at 50°C for 1 h to obtain A1-e (6.21 g, 61.8% yield).

[0243] LCMS m / z=202.1[M+1].

Claims

1. A method for preparing a compound of formula (A1), comprising the following reaction:

2. A method for preparing a compound of formula (A1-i), comprising the following reaction: in, The reaction reagent is selected from N,N'-carbonylbis(1,2,4-triazole) / ammonia water or N,N'-carbonyldiimidazole / ammonia water.

3. A method for preparing a compound of formula (A1), comprising the following reaction:

4. A method for preparing a compound of formula (A1-g), comprising the following reaction:

5. A method for preparing a compound of formula (A1-f), comprising the following reaction:

6. A method for preparing a compound of formula (A1-d), comprising the following reaction:

7. A method for preparing a compound of formula (A1), comprising the following reaction:

8. A method for preparing a compound of formula (A1-h), comprising the following reaction:

9. A method for preparing a compound of formula (A1-e), comprising the following steps:

10. A method for preparing a compound of formula (A1-e), comprising the following steps:

11. A method for preparing a compound of formula (C3), comprising the following reaction:

12. The preparation method according to claim 11, wherein the reaction is carried out in the presence of a catalyst, and the catalyst is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium tert-amylate.

13. A compound of formula (A1-h), formula (C3), formula (C4), or formula (C5), or a salt thereof:

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