Method for preparing kinase inhibitor

Abstract

Provided is a method for preparing a kinase inhibitor. Specifically, disclosed is a method for preparing a compound, i.e. 6-(3-hydroxy-3-methylazetidin-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Further disclosed are an intermediate for preparing such inhibitor and a method for synthesizing a required intermediate. The preparation method involves a low reaction temperature and simple process steps, has a very high yield and product purity, and is suitable for industrial production.

Description

A method for preparing a kinase inhibitor

[0001] Cross-references

[0002] This application claims priority to Chinese Patent Application No. 202411008163.4, filed on July 25, 2024, entitled “A Method for Preparing a Kinase Inhibitor”, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention discloses a method for preparing a rearrangement (RET) kinase inhibitor compound during selective transfection. This invention also relates to intermediates required for the preparation of this inhibitor and methods for synthesizing these intermediates. Background Technology

[0004] The RET protein encoded by the RET gene is a receptor tyrosine kinase (RTK) located on the cell membrane and belongs to the cadherin superfamily. It plays an important role in the normal development of the peripheral sympathetic and parasympathetic nervous systems of the brain, in the production of calcitonin by thyroid C cells, and is also essential for the thyroid gland, lungs, hematopoietic progenitor cells, and other tissues (Nat. Rev. Cancer 2014; 14(3):173-86.). Because RET selective inhibitors are closely related to the occurrence and development of non-small cell lung cancer (NSCLC), medullary thyroid carcinoma (MTC), and thyroid cancer, RET inhibitors have become one of the research focuses of drugs for the treatment of NSCLC, MTC, and thyroid cancer. In the United States, several drugs targeting RET, such as Cabozantinib, Vandetanib, Lenvatinib, Sorafenib, and Alectinib, have shown promising clinical efficacy in RET-targeted therapy, and their significant inhibitory effects on other kinases (such as vascular endothelial growth factor receptor 2 (VEGFR2)) have led to toxic side effects (Nat Rev Clin Oncol. 2018; 15(3):151-167). Therefore, the development of highly selective and highly active RET inhibitors has attracted considerable research interest from pharmaceutical companies, and the development of specific RET inhibitors has become an emerging therapeutic approach to improve the treatment efficacy of RET-driven cancers.

[0005] Compound (I) is a small molecule RET selective protein activity inhibitor with high activity, strong drug resistance, and few clinical side effects. It can effectively overcome the problem of drug resistance in tumor treatment and has good economic value and application prospects.

[0006] Given the therapeutic effects of compounds of formula (I) on various tumors, their clinical application prospects are broad. Therefore, it is necessary to develop a method for preparing compounds of formula (I) suitable for industrial production.

[0007] For compounds of formula (I), there are no suitable preparation methods for industrial production in the existing literature. For example, in Example 114 of WO2020 / 228756A1, compound (I) is obtained by Buchwald-Hartwig coupling reaction using a brominated heteroaromatic ring as a starting material. However, this example involves a high reaction temperature (130°C), and because it requires microwave reaction and separation and purification by preparative chromatography, it is not suitable for industrial production. This example also does not provide the yield and product purity. Similarly, in Example 7 of CN 112209925A, compound (I) is also obtained by Buchwald-Hartwig coupling reaction using a brominated heteroaromatic ring as a starting material. This example also involves a high reaction temperature (110°C) and requires separation and purification by column chromatography, making it unsuitable for industrial production. Furthermore, the yield and product purity are not provided.

[0008] definition

[0009] Unless otherwise defined, all technical terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Some of the definitions are as follows: "1-Dodecanethiol" is dodecyl mercaptan; "NaOH" is sodium hydroxide; "NMP" is N-methylpyrrolidone; "Phenyl triflimide" is N-phenylbis(trifluoromethanesulfonyl)imide; "DIEA" is diisopropylethylamine; "DMF" is N,N-dimethylformamide; "STAB" is sodium triacetoxyborohydride; "DCM" is dichloromethane; "B2pin2" is pinacolyl diborate; "Pd(dppf)Cl2" is [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; "TFA" is trifluoroacetic acid; "KOAc" is anhydrous potassium acetate; "Dioxane" is 1,4-dioxane; "K3PO4" is anhydrous potassium phosphate; "Tol" is toluene; "n-PrOH" is n-propanol; “Pd2dba3” is tris(dibenzylacetone)dipalladium; “Pd(PPh3)4” is tetratetriphenylphosphine palladium; “BINAP” is 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); “X-Phos” is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl. Summary of the Invention

[0010] This invention provides a method for preparing compound (I).

[0011] The method includes the following steps:

[0012] (a) Compound (II) and compound (III) undergo a coupling reaction under a metal catalyst to give intermediate (1):

[0013] Where X is I, Cl, Br, or OTf,

[0014] The catalysts are Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, or Pd2dba3 / XPhos.

[0015] Compound (III) is a free base or its hydrochloride, sulfate, hydrobromide, acetate, trifluoroacetate, trichloroacetate, methanesulfonate, or p-toluenesulfonate;

[0016] (b) Intermediate (1) undergoes a demethylation reaction with a demethylating agent and a base to obtain intermediate (2):

[0017] in,

[0018] Intermediate (2) is in its free state or is its sodium or potassium salt;

[0019] (c) The intermediate (2) is esterified with an esterifying agent in the presence of a base to obtain the intermediate (3):

[0020] in,

[0021] The esterification reagent is N-phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride.

[0022] (d) The intermediate (3) and compound (IV) were coupled in the presence of a catalyst to obtain the target product compound (I):

[0023] in,

[0024] Catalysts include Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, Pd2dba3 / XPhos, etc.

[0025] In some embodiments of the present invention, X in step (a) is I, Cl, Br or OTf, preferably Br;

[0026] In some embodiments of the present invention, the compound (III) in step (a) is a free base or its hydrochloride, sulfate, hydrobromide, acetate, trifluoroacetate, trichloroacetate, methanesulfonate, or p-toluenesulfonate, preferably a free base or hydrochloride.

[0027] In some embodiments of the present invention, the catalyst in step (a) is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, or Pd2dba3 / XPhos, preferably Pd2dba3 / BINAP.

[0028] In some embodiments of the present invention, the alkali used in step (a) is sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, anhydrous potassium carbonate, anhydrous sodium carbonate, cesium triethylamine carbonate, or DIEA, preferably anhydrous potassium carbonate and cesium carbonate.

[0029] In some embodiments of the present invention, the reaction solvent in step (a) is N,N-dimethylformamide, N-methylpyrrolidone, or 1,4-dioxane, preferably N,N-dimethylformamide or 1,4-dioxane, more preferably 1,4-dioxane.

[0030] In some embodiments of the present invention, the reaction temperature in step (a) is 70–110°C, preferably 80–100°C, and more preferably 85–95°C.

[0031] In some embodiments of the present invention, the demethylating agent in step (b) is dodecyl thiophenol, thiophenol, or dodecyl mercaptan, preferably dodecyl mercaptan.

[0032] In some embodiments of the present invention, the base used in step (b) is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, triethylamine, or diisopropylethylamine (DIEA), etc., preferably sodium hydroxide and potassium hydroxide.

[0033] In some embodiments of the present invention, the solvent used in step (b) is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone or a mixture thereof, preferably dimethyl sulfoxide or N-methylpyrrolidone or a mixture thereof.

[0034] In some embodiments of the present invention, the reaction temperature in step (b) is 60–110°C, preferably 65–100°C, and more preferably 75–85°C.

[0035] In some embodiments of the present invention, the esterification agent described in step (c) is N-phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride, preferably N-phenylbis(trifluoromethanesulfonyl)imide or trifluoromethanesulfonic anhydride.

[0036] In some embodiments of the present invention, the base mentioned in step (c) is sodium hydroxide, sodium tert-butoxide, triethylamine, or DIEA, preferably triethylamine and DIEA.

[0037] In some embodiments of the present invention, the solvent used in step (c) is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or N-methylpyrrolidone or a mixture thereof, preferably N,N-dimethylformamide or N,N-dimethylacetamide.

[0038] In some embodiments of the present invention, the reaction temperature in step (c) is -20 to 50°C, preferably -10 to 30°C, and more preferably 0 to 30°C.

[0039] In some embodiments of the present invention, the catalyst in step (d) is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, or Pd2dba3 / XPhos, preferably Pd(dppf)Cl2 or Pd(PPh3)4.

[0040] In some embodiments of the present invention, the base used in step (d) is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium ethoxide, anhydrous potassium phosphate, anhydrous potassium acetate, triethylamine, or DIEA, preferably anhydrous potassium phosphate or DIEA.

[0041] In some embodiments of the present invention, the reaction solvent in step (d) is a mixture of toluene and water, a mixture of N,N-dimethylformamide and water, or a mixture of N-methylpyrrolidone and water, preferably a mixture of toluene and water.

[0042] In some embodiments of the present invention, the reaction temperature in step (d) is 60–110°C, preferably 70–90°C. Detailed Implementation

[0043] The invention is further explained below.

[0044] Compound I is prepared by the method of the present invention, as shown in process 1.

[0045] Process 1

[0046] In step (a), X is Br. Compound (III) is a free base or its hydrochloride, sulfate, hydrobromide, acetate, trifluoroacetate, trichloroacetate, methanesulfonate, or p-toluenesulfonate, preferably a free base or hydrochloride. The reaction base is sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, anhydrous potassium carbonate, anhydrous sodium carbonate, cesium triethylamine carbonate, or DIEA, preferably anhydrous potassium carbonate or cesium carbonate. The catalyst is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, or Pd2dba3 / XPhos, preferably Pd2dba3 / BINAP. The reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, 1,4-dioxane, or its ethylene glycol dimethyl ether, preferably N,N-dimethylformamide, or 1,4-dioxane, or a mixture thereof, more preferably 1,4-dioxane. The reaction temperature is 50–150°C, preferably 70–110°C, more preferably 80–100°C, and most preferably 85–95°C.

[0047] In step (b), the demethylating agent is dodecyl thiophenol, thiophenol, methanethiol, ethanethiol, or dodecyl mercaptan, preferably thiophenol or dodecyl mercaptan, more preferably dodecyl mercaptan. The base is sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, triethylamine, or DIEA, preferably sodium hydroxide or potassium hydroxide. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, water, dimethyl sulfoxide, or N-methylpyrrolidone or a mixture thereof, preferably dimethyl sulfoxide, water, or N-methylpyrrolidone or a mixture thereof. The reaction temperature is 60–110°C, preferably 65–100°C, more preferably 75–85°C.

[0048] In step (c), the esterification reagent is N-phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, etc., preferably N-phenylbis(trifluoromethanesulfonyl)imide or trifluoromethanesulfonic anhydride. The base used is sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, triethylamine, or DIEA, preferably triethylamine or DIEA. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, water, dimethyl sulfoxide, dichloromethane, dichloroethane, tetrahydrofuran, or N-methylpyrrolidone or a mixture thereof, preferably N,N-dimethylformamide, N,N-dimethylacetamide, or dichloromethane, more preferably N,N-dimethylformamide or N,N-dimethylacetamide. The reaction temperature is -20 to 50°C, preferably -10 to 30°C, more preferably 0 to 30°C.

[0049] In step (d), the reaction catalyst is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, or Pd2dba3 / XPhos, preferably Pd(dppf)Cl2 or Pd(PPh3)4. The reaction base is sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, anhydrous potassium phosphate, anhydrous potassium acetate, anhydrous sodium acetate, triethylamine, or DIEA, preferably anhydrous potassium acetate, anhydrous sodium acetate, triethylamine, or DIEA, more preferably anhydrous potassium phosphate or DIEA. The reaction solvent is a mixture of toluene and water, a mixture of N,N-dimethylformamide and water, or a mixture of N-methylpyrrolidone and water, preferably a mixture of toluene and water. The reaction temperature is 60–110°C, preferably 70–90°C.

[0050] Example

[0051] The preparation method of the present invention will be described in more detail below with reference to embodiments. Those skilled in the art should understand that the following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. The scope of protection of the present invention should be defined by the claims.

[0052] Unless otherwise stated, all operations shall be performed at room temperature.

[0053] Example 1: Synthesis of 6-(3-hydroxy-3-methylazacyclobutane-1-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxynitrile (intermediate 1)

[0054] Compound II (3000 g), Compound III (1912 g), BINAP (741 g), and 1,4-dioxane (75 L) were added to a 100 L reactor and stirred. Cs₂CO₃ (19385 g) was then added and stirred until homogeneous. The mixture was purged with nitrogen twice. Pd₂(dba)₃ (545.0 g) was quickly added, and the mixture was purged with nitrogen five times. The temperature was raised to 90 °C, and the mixture was stirred for 12 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a dark red solid. Toluene (15 L) was added and the mixture was stirred for 3 hours. The solid was then filtered, and the filter cake was washed with toluene (8 L) and dried to obtain 2872 g of a light yellow powdery solid, with a yield of 93.43% (HPLC: 98.42%).

[0055] 1H NMR (400MHz, DMSO-d6) δ: 8.35 (s, 1H), 7.66 (d, J = 1.2Hz, 1H), 6.51-6.46 (m, 1H), 5. 59(s,1H),3.98(s,3H),3.80(d,J=7.8Hz,2H),3.66(d,J=7.6Hz,2H),1.46(s,3H).

[0056] MS m / z(ESI): 259.06 [M+H] + .

[0057] Example 2: Synthesis of 4-hydroxy-6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (intermediate 2)

[0058] NMP (8 L), sodium hydroxide (733 g), and water (1.4 L) were added sequentially to a dry 100 L reactor. 1-Dodecanethiol (3711 g) was then added, precipitating a white solid. Intermediate 1 (2365 g) was added, and the mixture was heated to 75–85 °C. The reaction was monitored by HPLC. After completion, the mixture was cooled to 10 °C, and tetrahydrofuran (60 L) was added to the reactor. Crystallization was carried out by stirring. The mixture was centrifuged, and the filter cake was added to ethyl acetate (30 L). The pH was adjusted to 4–5 using 2N citric acid aqueous solution (4.5 L), and the mixture was completely dissolved. The aqueous phase was extracted with ethyl acetate (3 × 10 L). The extract was concentrated under reduced pressure to remove the solvent. The residue was slurried with n-heptane (10 L), filtered, and the filter cake was washed with n-heptane (5 L) and dried to constant weight. 1770 g of a yellow to brownish-yellow solid powder was obtained, with a yield of 79% (HPLC: 98.49%).

[0059] 1 H NMR(400MHz, DMSO-d6)δ:11.14(s,1H),8.28(s,1H),7.56(d,J=1.6Hz,1H),6.22(d,J =1.6Hz, 1H), 5.53 (s, 1H), 3.72 (d, J = 7.6Hz, 2H), 3.57 (d, J = 7.6Hz, 2H), 1.42 (s, 3H).

[0060] MS m / z(ESI): 245.09 [M+H] + .

[0061] Example 3: Preparation of 3-cyano-6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (intermediate 3)

[0062] DMF (8.6 L), intermediate 2 (1720 g), and DIEA (1821 g) were added sequentially to a dry 100 L reactor and stirred until homogeneous. The mixture was cooled to -10 to 5 °C, and Phenyl triflimide (2591 g) was added in portions, maintaining the temperature between -5 and 5 °C. After the addition was complete, the reaction was carried out at -10 to 30 °C. The reaction progress was monitored by HPLC. After the reaction was completed, water (60 L) was added and stirred to induce crystallization. The mixture was centrifuged and filtered. MTBE (4.5 L) was added to the filter cake and the mixture was slurried and centrifuged again. The filter cake was dried to constant weight. 1950 g of brown solid powder was obtained, with a yield range of 73% (HPLC: 99.41%).

[0063] 1 H NMR (400MHz, CDCl3) δ: 8.57 (s, 1H), 8.24 (d, J = 1.6Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 5.60 (s, 1H), 3.82 (d, J = 8.0Hz, 2H), 3.68 (d, J = 8.0Hz, 2H), 1.42 (s, 3H).

[0064] MS m / z(ESI): 377.08 [M+H] + .

[0065] Example 4: Preparation of 6-(3-hydroxy-3-methylmonoheterobutan-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (compound of formula 1)

[0066] Toluene (13L), anhydrous potassium phosphate (2.885kg, 13.59mol), and purified water (3.2L) were added sequentially to a 100L reactor and stirred until homogeneous. The reactor was then evacuated under reduced pressure (≥0.09MPa, 5 minutes / time), and the air in the reactor was replaced with nitrogen. This process was repeated twice. Intermediate 3 (1.278kg, 3.40mol), intermediate 5 (1.578kg, 3.74mol), and Pd(dppf)Cl2 (0.124kg, 0.17mol) were added. The reactor was again evacuated under reduced pressure (≥0.09MPa, 5 minutes / time), and the air in the reactor was replaced with nitrogen. This process was repeated three times. The temperature was rapidly increased to (T = 75–85℃), and the reaction was continued for 12–18 hours. The reaction was monitored by HPLC; the reaction was considered complete when the content of intermediate 3 was ≤1.0%.

[0067] Post-treatment: Cool down to (T=15~25℃), add purified water (3.2L), stir for 30 minutes, filter, and rinse the filter cake with a mixture of toluene (7.62kg) and purified water (9.02kg).

[0068] Add the above solid to a 100L reactor, then add dichloromethane (29.2L) and methanol (5.8L), stir to dissolve, and wash with 10% sodium carbonate aqueous solution (12L). Separate the layers; extract the aqueous phase with dichloromethane (4.2L) and methanol (0.8L). Separate the layers, combine the organic phases, filter under a diatomaceous earth (10kg) liner, and rinse the filter cake with a mixed solvent of dichloromethane (4.2L) and methanol (0.8L). Wash the organic phase again with sodium carbonate aqueous solution (12L), separate the layers, extract the aqueous phase with dichloromethane (4.2L) and methanol (0.8L), and separate the layers. Combine the organic phases, wash with purified water (12L), and separate the layers. The solvent was removed by concentration under reduced pressure (30–45°C, vacuum degree: ≥0.09 MPa). 12.8 L of n-propanol was added to the residue, and the mixture was stirred for 1–3 hours. The mixture was then filtered, and the filter cake was washed with 1.9 L of n-propanol. The filter cake was then dried in a vacuum oven (30–40°C, vacuum degree: ≥0.09 MPa, 4–24 hours) to constant weight, yielding 1.6 kg of gray powder. The yield was 90.2%, and the HPLC result was 99.50%.

[0069] 1 H NMR (400MHz, CDCl3) δ: 8.35 (d, J = 2.0Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.0Hz, 1H), 7.76 (dd ,J=8.8Hz,2.4Hz,1H),7.69(d,J=1.6Hz,1H),7.60(dd,J=8.4Hz,2.4Hz,1H),6.72(d,J=2. 0Hz,1H),6.69(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,1H),3.88-3.91(m,5H),3.72-3.85(m,6 H), 3.48-3.64 (m, 4H), 2.64-2.69 (m, 1H), 2.31 (s, 1H), 1.65 (s, 3H), 1.63 (d, J = 8.8Hz, 1H).

[0070] MS m / z(ESI): 523.26 [M+H] + .

[0071] The theoretical molecular weight of Hi-Mass(ESI) m / z:[M+H] is 523.2570, and the measured result is 523.2571, which are consistent. The theoretical molecular formula is C1. 29 H 31 N8O2, the measured result is also C.29 H 31 N8O2, the two are identical.

[0072] Example 5: Synthesis of 4-hydroxy-6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (intermediate 2)

[0073] Add NMP (31 kg), sodium hydroxide (2.11 kg, 52.65 mol), and purified water (4.08 kg) sequentially to a dry 300 L reactor, and stir until homogeneous. Add 1-Dodecanethiol (10.66 kg, 52.65 mol), intermediate 1 (6.8 kg, 26.33 mol), and NMP (4 kg). Heat to 75–85 °C and react for 4–5 hours. Monitor the reaction progress with HPLC; the reaction is complete when the concentration of intermediate 1 is ≤0.8%.

[0074] Cool to 60-70°C, add tetrahydrofuran (151 kg) to the reactor, cool to 5-15°C, and stir to induce crystallization for 2-3 hours. Filter by centrifugation to obtain crude intermediate 1 (7.4 kg, >100%).

[0075] Add 7.4 kg of crude intermediate 1 and 75 kg of ethyl acetate to a 300 L reactor. Adjust the pH to 4–5 using 23% citric acid aqueous solution (20.4 kg) and control the internal temperature (T = 20–35 °C) until completely dissolved. Separate the solutions; extract the aqueous phase with ethyl acetate (3 × 25 kg). Combine the organic phases and filter under vacuum with diatomaceous earth (1.5 kg). Wash the filter cake with ethyl acetate (10 kg). Concentrate the filtrate under reduced pressure to remove the solvent (30–45 °C, vacuum: ≥0.09 MPa). Add 18.7 kg of n-heptane to the residue and stir for 2 hours. Filter under vacuum; wash the filter cake with n-heptane (8.5 kg). Dry the filter cake in a vacuum oven (40–50 °C, vacuum: ≥0.09 MPa, 18–24 hours) to constant weight. Obtain 5.06 kg of brown powder, yield 78.7%. HPLC: 99.41%.

[0076] 1 H NMR(400MHz, DMSO-d6)δ:11.14(s,1H),8.28(s,1H),7.56(d,J=1.6Hz,1H),6.22(d,J =1.6Hz, 1H), 5.53 (s, 1H), 3.72 (d, J = 7.6Hz, 2H), 3.57 (d, J = 7.6Hz, 2H), 1.42 (s, 3H).

[0077] MS m / z(ESI): 245.09 [M+H]+ .

[0078] Example 6: Preparation of 3-cyano-6-(3-hydroxy-3-methylazacyclobutane-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (intermediate 3)

[0079] DMF (8.6 L), intermediate 2 (1720 g), and DIEA (1821 g) were added sequentially to a dry 100 L reactor and stirred until homogeneous. The mixture was cooled to -10 to 5 °C, and Phenyl triflimide (2591 g) was added in portions, maintaining the temperature between -5 and 5 °C. After the addition was complete, the reaction was carried out at -10 to 30 °C. The reaction progress was monitored by HPLC. After the reaction was completed, water (60 L) was added and stirred to induce crystallization. The mixture was centrifuged and filtered. MTBE (4.5 L) was added to the filter cake and the mixture was slurried and centrifuged again. The filter cake was dried to constant weight. 1950 g of brown solid powder was obtained, with a yield range of 73% (HPLC: 99.41%).

[0080] Add DMF (23.1 kg), intermediate 2 (4.9 kg, 20.06 mol), and DIEA (5.19 kg, 40.12 mol) sequentially to a dry 100 L reactor, and stir until homogeneous. Cool to (T = -5 to 5 °C), and add Phenyl triflimide (7.40 kg, 20.72 mol) in six batches over 45 minutes. Maintain the temperature at (T = 0 to 10 °C) and continue the reaction for 1.0 to 2.5 hours. Monitor the reaction progress with HPLC; the reaction is complete when the concentration of intermediate 2 is ≤ 1.6%.

[0081] Post-processing: 1.52 kg of diatomaceous earth was used as a filter, and the filter cake was washed with DMF (2.60 kg). 173 kg of purified water was added to a 500 L reactor, and the temperature was controlled (T = 5–10 °C). The filtrate was added, and the mixture was stirred to induce crystallization for 1–2 hours. The mixture was then centrifuged and filtered, and the filter cake was washed successively with 38.27 kg of saturated sodium chloride aqueous solution, 51.0 kg of purified water, and 24.5 kg of n-heptane. The filter cake was vacuum dried (30–40 °C, vacuum degree: ≥0.09 MPa, 18–24 hours) to constant weight to obtain crude intermediate 3 (7.09 kg).

[0082] 7.09 kg of crude intermediate 3 and 9.8 kg of MTBE were added to a 100 L reactor. The mixture was stirred at room temperature for 1–2 hours, centrifuged, and the filter cake was vacuum dried (30–40 °C, vacuum degree: ≥0.09 MPa, 18–24 hours) to constant weight. 6.06 kg of a pale yellow powder was obtained, with a yield of 80.3%. HPLC: 99.59%.

[0083] 1 H NMR (400MHz, CDCl3) δ: 8.57 (s, 1H), 8.24 (d, J = 1.6Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 5.60 (s, 1H), 3.82 (d, J = 8.0Hz, 2H), 3.68 (d, J = 8.0Hz, 2H), 1.42 (s, 3H).

[0084] MS m / z(ESI): 377.08 [M+H] + .

[0085] Example 7: Preparation of 6-(3-hydroxy-3-methylmonoheterobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxynitrile (compound of formula 1)

[0086] Add toluene (50.69 kg), anhydrous potassium phosphate (13.24 kg, 62.36 mol), and purified water (14.59 kg) sequentially to a 100 L reactor and stir until homogeneous. Vacuum the reactor under reduced pressure (≥0.09 MPa, 30 minutes / time), purging the air with nitrogen, repeating twice. Add intermediate 3 (5.86 kg, 15.57 mol), intermediate 5 (7.21 kg, 17.07 mol), and Pd(dppf)Cl2 (0.57 kg, 0.78 mol). Vacuum the reactor again under reduced pressure (≥0.09 MPa, 5 minutes / time), purging the air with nitrogen, repeating three times. Rapidly heat to (T = 75–85 °C) and continue the reaction for 12–18 hours. Monitor the reaction progress with HPLC; the reaction is complete when the content of starting material intermediate 3 is ≤1.0%.

[0087] Cool to (T = 15-25℃), add purified water (14.59 kg), stir for 30 minutes, filter, and rinse the filter cake with a mixture of toluene (7.62 kg) and purified water (9.02 kg).

[0088] The above solid was added to a 200L reactor, followed by dichloromethane (196.13 kg) and methanol (23.79 kg). The mixture was stirred to dissolve and then washed with an aqueous sodium carbonate solution (64.69 kg). The mixture was separated, and the aqueous phase was extracted with dichloromethane (27.78 kg) and methanol (4.10 kg). The organic phases were combined and filtered through a vacuum filter with diatomaceous earth (10.02 kg). The filter cake was then rinsed with a mixed solvent of dichloromethane (27.78 kg) and methanol (4.10 kg). The organic phase was washed with an aqueous sodium carbonate solution (64.69 kg), separated, and the aqueous phase was extracted with dichloromethane (27.78 kg) and methanol (4.10 kg). The combined organic phases were washed with purified water (58.6 kg), and the solvent was removed by vacuum concentration (30–45 °C, vacuum degree: ≥0.09 MPa). The residue was added with n-propanol (47.11 kg), stirred for 1–3 hours, filtered, and the filter cake was washed with n-propanol (7.09 kg). The filter cake was dried in a vacuum oven (30–40 °C, vacuum degree: ≥0.09 MPa, 4–24 hours) to constant weight, yielding 6.99 kg of gray powder, with a yield of 85.9% and an HPLC yield of 98.78%.

[0089] 1 H NMR (400MHz, CDCl3) δ: 8.35 (d, J = 2.0Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = 2.0Hz, 1H), 7.76 (dd ,J=8.8Hz,2.4Hz,1H),7.69(d,J=1.6Hz,1H),7.60(dd,J=8.4Hz,2.4Hz,1H),6.72(d,J=2. 0Hz,1H),6.69(d,J=8.8Hz,1H),6.66(d,J=8.8Hz,1H),3.88-3.91(m,5H),3.72-3.85(m,6 H), 3.48-3.64 (m, 4H), 2.64-2.69 (m, 1H), 2.31 (s, 1H), 1.65 (s, 3H), 1.63 (d, J = 8.8Hz, 1H).

[0090] MS m / z(ESI): 523.26 [M+H] + .

[0091] The theoretical molecular weight of Hi-Mass(ESI) m / z:[M+H] is 523.2570, and the measured result is 523.2571, which are consistent. The theoretical molecular formula is C1. 29 H 31 N8O2, the measured result is also C. 29 H 31 N8O2, the two are identical.

[0092] Experimental results show that the preparation method of the present invention has a low reaction temperature (75-85℃), high yield and product purity. More importantly, it only requires simple post-processing such as extraction, pulping and centrifugation to obtain high-purity compound (I), which is suitable for industrial production.

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutical salt thereof, Its features are, The method includes the following steps: (a) Compound (II) undergoes a coupling reaction with compound (III) to give intermediate (1): Where X is I, Cl, Br, or OTf, Compound (III) is a free base or its hydrochloride, sulfate, acetate, trifluoroacetate, or methanesulfonate; (b) Intermediate (1) undergoes a demethylation reaction to obtain intermediate (2): Intermediate (2) is in its free state or is its sodium or potassium salt; (c) The intermediate (2) is subjected to esterification to obtain trifluoromethanesulfonate intermediate (3): (d) The intermediate (3) and compound (IV) were coupled to obtain the target product compound (I):

2. The method according to claim 1, characterized in that, The method includes the following steps: (a) Compound (II) and compound (III) undergo a coupling reaction under a metal catalyst to give intermediate (1): Where X is I, Cl, Br, or OTf, Compound (III) is a free base or its hydrochloride, sulfate, acetate, trifluoroacetate, or methanesulfonate; (b) Intermediate (1) undergoes a demethylation reaction in the presence of a demethylating agent and a base to obtain intermediate (2): Intermediate (2) is in its free state or is its sodium or potassium salt; (c) The intermediate (2) is esterified with an esterifying agent in the presence of a base to obtain trifluoromethanesulfonate intermediate (3): The esterification reagent is N-phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride; (d) The intermediate (3) and compound (IV) were coupled in the presence of a catalyst to obtain the target product compound (I): The catalyst is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, Pd2dba3 / S-Phos, or Pd2dba3 / XPhos.

3. The method according to claim 2, wherein in step (a), X is Br. Compound (III) is a free base or its hydrochloride salt. The base used in the reaction is potassium tert-butoxide, anhydrous potassium carbonate, cesium carbonate, triethylamine, or DIEA. The catalyst is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, or Pd2dba3 / XPhos. The reaction solvent is N,N-dimethylformamide, N-methylpyrrolidone, or 1,4-dioxane. The reaction temperature is 50–150℃.

4. The method according to claim 2 or 3, wherein in step (a), X is Br. Compound (III) is a hydrochloride salt. The base used in the reaction is cesium carbonate. The catalyst is Pd2dba3 / BINAP. The reaction solvent is 1,4-dioxane. The reaction temperature is 85–95℃.

5. The method according to claim 2, wherein in step (b), The demethylating agent is dodecyl thiophenol, thiophenol, or dodecyl mercaptan. The base is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, triethylamine, or diisopropylethylamine. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone, or a mixture of any two or more of the above. The reaction temperature is 60–110℃.

6. The method according to claim 2 or 5, wherein in step (b), The demethylating agent is dodecyl thiophenol. The alkali is sodium hydroxide. The reaction solvent is N,N-dimethylformamide. The reaction temperature is 75–85℃.

7. The method according to claim 2, wherein in step (c) The esterification reagent is N-phenylbis(trifluoromethanesulfonyl)imide, trifluoromethanesulfonic anhydride, or trifluoromethanesulfonyl chloride. The base is sodium hydroxide, sodium tert-butoxide, triethylamine, or DIEA. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, or a mixture of any two or more of the above. The reaction temperature is -20 to 50℃.

8. The method according to claim 2 or 7, wherein in step (c) The esterification reagent is N-phenylbis(trifluoromethanesulfonyl)imide. The base is DIEA. The reaction solvent is N,N-dimethylformamide. The reaction temperature is 0–30℃.

9. The method according to claim 2, wherein in step (d), The catalyst is Pd(dppf)Cl2, Pd(PPh3)4, Pd2dba3 / BINAP, or Pd2dba3 / XPhos. The base used in the reaction is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium ethoxide, anhydrous potassium phosphate, anhydrous potassium acetate, triethylamine, or DIEA. The reaction solvent can be a mixture of toluene and water, a mixture of N,N-dimethylformamide and water, or a mixture of N-methylpyrrolidone and water. The reaction temperature is 60–110℃.

10. The method according to claim 2 or 9, wherein in step (d), The catalyst is Pd(dppf)Cl2. The base used in the reaction is anhydrous potassium phosphate. The reaction solvent is a mixture of toluene and water. The reaction temperature is 70–90℃.

Images