CN115960100A

CN115960100A - Synthetic method of drug Pi Mite Xibu for treating gastrointestinal stromal tumor

Info

Publication number: CN115960100A
Application number: CN202211700110.XA
Authority: CN
Inventors: 程刚
Original assignee: Beijing Kang Lisheng Pharmaceutical Technology Development Co ltd
Current assignee: Beijing Kang Lisheng Pharmaceutical Technology Development Co ltd
Priority date: 2022-12-28
Filing date: 2022-12-28
Publication date: 2023-04-14
Anticipated expiration: 2042-12-28
Also published as: CN115960100B

Abstract

The invention relates to a synthesis method of pimentoxib and an intermediate thereof. The synthesis method has the advantages of easily available raw materials, safe and simple operation, high product purity, low cost and the like, and the intermediate can be used for preparing Pi Mite Xibu through one-step nitrile group hydrolysis reaction.

Description

Synthetic method of drug Pi Mite Xibu for treating gastrointestinal stromal tumor

Technical Field

The invention belongs to the field of chemical drugs, and particularly relates to a synthetic method of a drug Pi Mite Xibu (Pimitespib) for treating gastrointestinal stromal tumors.

Background

Gastrointestinal stromal tumors (gist) are the most common tumors of mesenchymal origin in the digestive tract, but account for only 1% -3% of gastrointestinal tumors. Previous researches find that GISTs are derived from interstitial cells of Cajal around the intramuscular plexus of the gastrointestinal tract, most of the GISTs express a tyrosine kinase receptor (CD 117) and a bone marrow stem cell antigen (CD 34), and can be used for differential diagnosis of tumors derived from other gastrointestinal tract interstitials. The major sites of gist are stomach and small intestine, with gastric stromal tumors accounting for 56% of all gist, small intestine stromal tumors accounting for 32%, and colorectal stromal tumors being relatively rare, accounting for only 6%. Colorectal stromal tumors have a poorer prognosis compared to gastric stromal tumors. GISTs are less effective than traditional chemotherapy and radiation therapy, and surgical resection remains the most prominent treatment modality. The advent of tyrosine kinase inhibitors has led to a significant improvement in the prognosis of GISTs, but the overall efficacy is inferior to that of gastromesenchyme due to the more complex biological behavior of colorectal mesenchyme.

The literature reports that: pi Mite Xibu shows growth inhibitory effect on GIST-T1 cell lines derived from human gastrointestinal stromal tumors (in vitro). Tumor growth inhibitory activity was shown in nude mice subcutaneously implanted with GIST-T1 cell line (in vivo). The literature reports that: pi Mite coxib is a selective HSP90 inhibitor that acts on the N-terminal ATP binding site of heat shock protein 90 (HSP 90). HSP90 functions as a chaperone, helping to stabilize a group of proteins called client proteins. To date, over 200 HSP90 client proteins have been identified, many of which are important factors in cancer cell growth and survival, such as receptor tyrosine kinases, signal transduction factors, cell cycle-related factors, and transcription factors.

5363 the mechanism of action of Pi Mite Xibu is to inhibit the formation of higher structure of protein by HSP90, and to inhibit tumor growth by reducing the expression level of protein involved in tumor growth and inducing apoptosis.

Based on data provided by the american clinical oncology society of America (ASCO) year 2021, pi Mite coxib significantly improved Progression Free Survival (PFS) while also extending Overall Survival (OS) when used to treat advanced GIST patients compared to placebo.

Pi Mite Xibu Chinese cultural name: 3-Ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b]Pyridin-1-yl } benzamide of formula: c ₂₅ H ₂₆ N ₈ O, molecular weight: 454.53, CAS registry number 1260533-36-5, having the chemical structure:

the prior art document CN201080031144 reports the synthesis route of Pi Mite xib as follows:

step 1: the starting material 2-fluoro-4-iodo-pyridine and the isobutyric anhydride are subjected to a Friedel-crafts acylation reaction to obtain 1- (2-fluoro-4-iodopyridin-3-yl) -2-methylpropane-1-one, and then the 1- (2-fluoro-4-iodopyridin-3-yl) -2-methylpropane-1-one and hydrazine hydrate are subjected to a cyclization reaction to obtain an intermediate 4-iodo-3-isopropyl-1H-pyrazolo [3,4-b ] pyridine.

Step 2: reacting the intermediate 4-iodine-3-isopropyl-1H-pyrazolo [3,4-b ] pyridine with 4-methoxybenzyl chloride to obtain an intermediate 4-iodine-3-isopropyl-1- (4-methoxybenzyl) -1H-pyrazole [3,4-b ] pyridine;

and 3, step 3: the intermediate 4-iodo-3-isopropyl-1- (4-methoxybenzyl) -1H-pyrazolo [3,4-b ] pyridine is subjected to a butt-joint reaction with 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole hydrochloride to obtain 3-isopropyl-1- (4-methoxybenzyl) -4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine, and deprotection is carried out by trifluoroacetic acid to obtain an intermediate 3-isopropyl-4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine;

and 4, step 4: the intermediate 3-isopropyl-4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine was subjected to a docking reaction with the starting material 3-ethyl-4-fluorobenzonitrile to give 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile.

And 5: intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile hydrolysis reaction to give Pi Mite oxib (3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzamide).

The route has the following specific synthetic route, wherein the yield of the step 1 is 42%, the total yield of the

step

2,3 is 63%, and the total yield of the step 4,5 is only 15%:

the prior art document CN20171017476 reports the synthesis of 3-ethyl-4-fluorobenzonitrile as the starting material in the above route, which uses 3-bromo-4-fluorobenzaldehyde as the starting material to synthesize 3-bromo-4-fluorobenzonitrile first, and then obtains 3-ethyl-4-fluorobenzonitrile through coupling reaction, specifically as follows:

the synthetic route of Pi Mite Xibu reported in the prior art document has the problems of long route and low yield.

The method has the advantages of easily obtained raw materials, safe and simple operation, high product purity, low cost and the like; the intermediate prepared by the patent can be prepared into the pimetidine by one-step nitrile group hydrolysis reaction.

The invention is beneficial to improving the synthesis method of the drug for treating gastrointestinal stromal tumor, namely the pimentoxib, and improving the accessibility of the drug.

Disclosure of Invention

The invention provides a synthesis method of a medicine Pi Mite Xibu for treating gastrointestinal stromal tumor.

The invention provides a drug Pi Mite xib intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile for treating gastrointestinal stromal tumors and a synthesis method thereof, wherein the intermediate can be used for preparing Pi Mite xib through one-step nitrile group hydrolysis reaction.

The invention provides a synthesis method of a pimentoxib intermediate, which comprises the following steps:

step 1, carrying out C-N cross-coupling reaction on a compound 1 and 4-iodo-3-ethylbenzonitrile in an aprotic solvent by using inorganic base as a catalyst to obtain a compound 2;

and 2, carrying out C-N cross-coupling reaction on the compound 2 and 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole in an aprotic solvent under the catalysis of an inorganic base, a copper catalyst, a ligand and a carrier to obtain the 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile.

The inventive route is different from the prior art document. In the prior art patent CN20171017476, 4-iodo-3-isopropyl-1H-pyrazolo [3,4-b ] pyridine is firstly protected by 4-methoxybenzyl chloride (PMB-Cl), then is subjected to butt-joint reaction with 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole hydrochloride, and then is subjected to PMB protecting group removal and then is subjected to 3-ethyl-4-fluorobenzonitrile to obtain a synthetic route of 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile.

According to the invention, without amino protection on the compound 1, the compound 2 is obtained by carrying out C-N cross coupling reaction on excessive 3-ethyl-4-iodobenzonitrile with stronger activity, and then the compound 2 and 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole are subjected to C-N cross coupling reaction to obtain the 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile.

The route of the invention is shorter, and although the compound 1 is not protected by amino, the by-products in the compound 2 can be controlled to a lower level through the selection of X groups in the compound 1 and the control and post-treatment of the reaction conditions in the step 1. Meanwhile, the activity of the X group in the compound 2 directly influences the reaction process of the step 2, and the control of the reaction conditions of the step 2 also has great influence on the reaction process and the generation of byproducts.

In the invention, X in the compound 1 and the compound 2 is chlorine, bromine and iodine, preferably bromine, and when the halogen group in the compound 1 is too strong in activity, the compound 1 possibly competes with 3-ethyl-4-iodobenzene to generate self C-N coupling reaction; however, if the activity is too weak, the reactivity in step 2 is lowered.

Fortunately, in the step 1, the excessive feeding of the 3-ethyl-4-iodobenzene and the activity of the halogen in the compound 1 is far lower than that of the 3-ethyl-4-iodobenzene, and no C-N coupling reaction by-product is generated by controlling the reaction at 75-85 ℃ without adding cuprous oxide or copper iodide catalyst.

More fortunately, when X is chlorine with weaker activity in the compound 2, the reaction in the step 2 can be basically completed by controlling the reaction conditions. The reaction is characterized in that the activity difference between halogen and 3-ethyl-4-iodobenzene in the compound 1 in the step 1 is fully utilized, and the C-N coupling reaction with 3-ethyl-4-iodobenzene is firstly carried out without amino, and then the C-N coupling reaction with 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole is carried out, so that the synthetic route of the Pi Mite coxib intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole-1-yl) -1H-pyrazolo [3,4-b ] pyridine-1-yl } benzonitrile is shortened, and the reaction yield is greatly improved.

In the present invention the reaction of step 1 must be carried out in an aprotic solvent selected from dioxane, DMF, DMSO, N-methylpyrrolidone, preferably DMF to minimize the formation of by-products.

In the reaction of step 1 of the present invention, the inorganic base catalyst is selected from potassium carbonate, cesium carbonate and potassium phosphate, wherein cesium carbonate is most basic, which is favorable for the reaction, and is preferred.

In the reaction of the step 1 of the invention, the excessive feeding of the 4-iodo-3-ethylbenzonitrile can avoid the C-N coupling reaction of the compound 1 to the maximum extent, and the excessive material can be removed by post-treatment extraction, but the excessive material can increase the material cost. Through research, the molar charge ratio of the compound 1 to the 4-iodo-3-ethylbenzonitrile is 1:1 to 1:2, preferably 1.2 to 1.8, and particularly preferably 1.

In the invention, the 4-iodo-3-ethylbenzonitrile in the reaction in the step 1 has stronger iodine activity, catalysts such as cuprous oxide or copper iodide and the like do not need to be added, byproducts can be generated at higher reaction temperature and longer reaction time, and the proposed reaction conditions comprise: the reaction temperature is 70-90 ℃, and the stirring reaction is preferably carried out for 16-20 hours at 75-85 ℃, so that the generation of byproducts can be reduced to the maximum extent.

In the present invention, the reaction of step 2 must be carried out in an aprotic solvent to minimize the production of by-products, and the reaction temperature is about 150 ℃, and the solvent is selected from the group consisting of high boiling point solvents DMF, DMSO, N-methylpyrrolidone, and propylnitrile, and preferably N-methylpyrrolidone, in view of the solubility of the materials.

In the reaction of step 2 in the present invention, the inorganic base catalyst is selected from potassium carbonate, cesium carbonate and potassium phosphate, wherein cesium carbonate is most basic, and since the reaction of this step is difficult to perform, the reaction is facilitated by using cesium carbonate with stronger basicity as the base catalyst, preferably.

The copper catalyst in the step 2 reaction of the present invention is selected from the group consisting of CuI, cu ₂ O、CuO、Cu(OAc) ₂ CuBr, cuCl, copper catalyst and ligand are complexed, halogenated aromatic hydrocarbon can be activated, wherein cuprous activity is stronger, reaction is more favorably carried out, and the preferable copper catalyst is Cu ₂ O and the CuI are added into the mixture,particularly preferably Cu ₂ O。

In the reaction of step 2 of the present invention, the copper catalyst is complexed with a ligand, which can activate the halogenated aromatic hydrocarbon, because high temperature reaction is required, and the ligand is selected from 1,10-phenanthroline, 4,7-dimethoxy-1, 10-phenanthroline, and 4,7-dimethoxy-1, 10-phenanthroline which is more suitable for high temperature reaction and is better complexed with the copper catalyst is preferred.

In the invention, a carrier with moderate polymerization degree is added in the reaction of the step 2 to promote the reaction process, and the carrier is selected from polyethylene glycol with the polymerization degree of 1500-6000, wherein the polymerization degree of the polyethylene glycol 3400 is moderate, and is preferred.

In the reaction of the step 2 in the invention, because the material price of the compound 2 is relatively high, in order to ensure the reaction to be complete, the 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole needs to be fed in an excessive amount, and the excessive material can be removed by washing with post-treatment water, but the excessive material increases the material cost. Through research and investigation, the molar charge ratio of the compound 2 and the 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole is 1:1-1:2, preferably 1.2-1, and particularly preferably 1.2.

In the reaction of step 2 in the present invention, the copper catalyst is complexed with the ligand, the halogenated aromatic hydrocarbon can be activated by the carrier, and the dosage of the copper catalyst is small, the molar charge ratio of the compound 2 to the copper catalyst is 1. The molar charge ratio of the compound 2 to the ligand catalyst is 1; the weight charge ratio of the compound 2 to the carrier is 1. The dosage proportion of the copper catalyst, the ligand and the carrier can play the best catalytic effect.

In the reaction of step 2, the halogen activity in the compound 2 is weaker, a copper catalyst, a ligand and a carrier catalyst are added, the reaction can be completed only by higher reaction temperature and longer reaction time, and the proposed reaction conditions comprise: the reaction is stirred for 48 to 50 hours at the temperature of between 145 and 155 ℃, so that the compound 2 can be completely reacted to the maximum extent.

The invention provides a new synthesis route design of a pimetide intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole-1-yl) -1H-pyrazolo [3,4-b ] pyridine-1-yl } benzonitrile, optimization of the synthesis method, and a synthesis method of Pi Mite coxib with shorter route, lower cost and more industrialization potential, and benefits from the synthesis method.

Drawings

FIG. 1: synthetic route of Pi Mite Xibu

The specific implementation method comprises the following steps:

the technical solutions in the embodiments of the present invention will be described in detail below with reference to the embodiments of the present invention, but the following embodiments are only for understanding the present invention and do not limit the present invention, and the present invention can be implemented in various ways as defined and covered by the claims.

The novel synthesis of Pi Mite coxib intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile and the advantages resulting from this process will be further illustrated below in conjunction with examples 1-5 and comparative examples.

This intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile reference patent CN201080031144 example 102 can be hydrolyzed to prepare pimelobixib.

Example 1:3-Ethyl-4- (4-bromo-3-isopropyl-1H-pyrazolo [3,4-b ] pyridin-1-yl) benzonitrile

4-bromo-3-isopropyl-1H-pyrazolo [3,4-b]Pyridine (24.0 g,0.1 mol), 4-iodo-3-ethylbenzonitrile (51.4 g,0.2 mol) and cesium carbonate (48.9 g,0.15 mol) were added to DMF (200 ml), the reaction was stirred at 75 to 85 ℃ for 16 to 20 hours, ethyl acetate 400ml and water 300ml were added for partition with stirring, the organic phase was washed with 200ml of water, 1mol/L hydrochloric acid solution (300 ml) was added to the organic phase, partition with stirring, the aqueous phase was extracted with 200ml of ethyl acetate, ethyl acetate 300ml was added to the aqueous phase, the pH was adjusted to 8 to 9 with a saturated carboxylic acid solution with stirring, partition, the organic phase was washed with water (200 ml) and saturated sodium chloride (200 ml), and the organic phase was washed with water (200 ml) successively, and the organic phase was extractedDistilling off about 3/4 of solvent under reduced pressure, adding n-hexane (200 ml) into the residue, stirring, and filtering to obtain the target product 3-ethyl-4- (4-bromo-3-isopropyl-1H-pyrazolo [3,4-b)]Pyridin-1-yl) benzonitrile (28.2 g, yield 82%, purity 98.3%). Ms M/z 369.1 (M + 1). ¹ H NMR(300MHz d ₆ -DMSO)：δ1.19(t，3H)，1.32(d，6H),2.72(q，2H)，3.45(m，1H)，7.51(d，1H)，7.72(m，2H)，7.80(d，1H)，8.51(d，1H)。

Example 2:3-Ethyl-4- (4-chloro-3-isopropyl-1H-pyrazolo [3,4-b ] pyridin-1-yl) benzonitrile

4-chloro-3-isopropyl-1H-pyrazolo [3,4-b]Pyridine (19.6 g,0.1 mol), 4-iodo-3-ethylbenzonitrile (51.4 g,0.2 mol) and cesium carbonate (48.9 g,0.15 mol) were added to DMF (200 ml), stirred and reacted at 75-85 ℃ for 16-20 hours, 400ml of ethyl acetate and 300ml of water were added, the organic phase was washed with 200ml of water, 1mol/L hydrochloric acid solution (300 ml) was added to the organic phase, the solution was stirred and separated, the aqueous phase was extracted with 200ml of ethyl acetate, 300ml of ethyl acetate was added to the aqueous phase, ph was adjusted to 8-9 with saturated hydrochloric acid solution under stirring, the organic phase was separated, washed with water (200 ml) and saturated sodium chloride (200 ml), about 3/4 solvent was removed by vacuum evaporation from the organic phase, n-hexane (200 ml) was added to the residue, stirred and filtered to obtain the target product, 3-ethyl-4- (4-chloro-3-isopropyl-1H-pyrazolo [3,4-b 63 b]Pyridin-1-yl) benzonitrile (28.2 g, 87% yield, 99.1% purity). Ms M/z 369.1 (M + 1). ¹ H NMR(300MHz d ₆ -DMSO)：δ1.18(t，3H)，1.31(d，6H),2.72(q，2H)，3.44(m，1H)，7.43(d，1H)，7.51(d，1H)，7.72(d，2H)，7.79(d，1H)，8.43(d，1H)。

Example 3:3-Ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile

3-ethyl-4- (4-bromo-3-isopropyl-1H-pyrazolo [3,4-b)]Pyridin-1-yl) benzonitrile (18.5g, 0.05mol), 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole (8.9g, 0.06mol), cuprous oxide (7.2g, 5mmol), 4,7-dimethoxy-1, 10-phenanthroline (1.8g, 7.5mmol), cesium carbonate (24.4g, 0.075mol), polyethylene glycol (Mn = 3400) (10 g) were added to N-methylpyrrolidone (300 ml), reacted at 145-155 ℃ for 48-50 hours, cooled, 400ml of dichloromethane and 300ml of water were added, the organic phase was stirred and separated, then washed with 300ml of water, 300ml of saturated sodium chloride solution, 300ml of dilute hydrochloric acid solution of 0.5mol/L was added to the organic phase, stirred and separated, 300ml of dichloromethane was added to the aqueous phase, the pH was adjusted to 8-9 with saturated solution, separated, washed with 200ml of water, anhydrous sodium sulfate, 15g, filtered under reduced pressure, filtered to obtain a filtrate, filtered, and the desired product was filtered by adding 2- { 4H-1H-3-pyrazole-1H-4-1H-1-yl) -1H-imidazole, and filtered to obtain a product]Pyridin-1-yl } benzonitrile (16.8 g, 77% yield, 98.0% purity), ms M/z 437.2 (M + 1). ¹ H NMR(300MHz d ₆ -DMSO)：δ1.18(t，3H)，1.31(d，6H),2.71(q，2H)，3.44(m，1H)，3.94(d，3H)，7.15(s，1H)，7.40(d，1H)，7.50(d，1H)，7.71(d，1H)，7.79(d，1H)，7.95(d，2H)，8.42(d，1H)，9.13(s，1H)。

Example 4:3-Ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile

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3-Ethyl-4- (4-chloro-3-isopropyl-1H-pyrazolo [3,4-b ] pyridin-1-yl) benzonitrile (16.2g, 0.05mol), 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole (8.9g, 0.06mol), cuprous oxide (7.2g, 5mmol), 4,7-dimethoxy-1, 10-phenanthroline (1.8g, 7.5mmol), cesium carbonate (24.4g, 0.075mol), polyethylene glycol (Mn = 3400) (10 g) were added to N-methylpyrrolidone (300 ml), reacting at 145-155 ℃ for 48-50 hours, cooling, adding 400ml dichloromethane and 300ml water, stirring and separating, washing an organic phase with 300ml water and 300ml saturated sodium chloride solution, adding 300ml diluted hydrochloric acid solution of 0.5mol/L into the organic phase, stirring and separating, adding 300ml dichloromethane into an aqueous phase, adjusting the pH to 8-9 with saturated sodium carbonate solution, separating, washing the organic phase with 200ml water, drying for 2 hours with 15g anhydrous sodium sulfate, filtering, decompressing and concentrating the filtrate to remove 3/4 of the solvent, adding 250ml n-hexane, and filtering to obtain the target product 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile (18.6 g, yield 65.5%, purity 97.2%).

Example 5 pimetib

3-Ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile (21.8g, 0.05mol), 4N-sodium hydroxide aqueous solution (25 mL), and 30% hydrogen peroxide (12.4 mL) were added to DMSO (110 mL) and absolute ethanol (110 mL), the reaction was stirred at room temperature for 30 minutes, 500mL of water was added to precipitate a large amount of solid, and the solid was filtered and water-filtered to near neutrality. The filter cake was recrystallized from absolute ethanol-water to give Pi Mite coxib (17.9 g, 82% yield, 99.2% purity), ms M/z 455.2 (M + 1).

Comparative example:

the synthesis process of pimelobixib related in Chinese patent CN201080031144 comprises the following steps:

the specific synthesis process of Pi Mite Xibu in the patent CN201080031144 is as follows:

example 100 (1)

4-iodo-3-isopropyl-1H-pyrazolo [3,4-b ] pyridine (100 a)

To a solution of N, N-diisopropylamine (16.5 mL) in tetrahydrofuran (hereinafter referred to as THF,300 mL) was added dropwise N-butyllithium (2.6M in hexane, 41.0 mL) at-78 ℃ from-5 ℃ to 0 ℃ under a nitrogen atmosphere, and a solution of 2-fluoro-4-iodo-pyridine (24 g) in THF (200 mL) was added dropwise and stirred for 15 minutes. Then, isobutyric anhydride (20.0 mL) was added dropwise at-78 ℃ and stirred at that temperature for 1 hour, followed by addition of hydrazine monohydrate (10.4 mL) and stirring at 60 ℃ for 1 hour. The reaction solution was partitioned with ethyl acetate and water, and the organic layer was washed with saturated brine. The washed organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (100 a) (12.9 g, 42%) as a white solid.

Example 100 (2)

3-isopropyl-4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine (100 b)

According to example 97 (1), by using compound (100 a) (15.5 g) in place of compound (40 d) and 4-methoxybenzyl chloride in place of {2- (chloromethoxy) ethyl } silane, 4-iodo-3-isopropyl-1- (4-methoxybenzyl) -1H-pyrazolo [3,4-b ] pyridine was obtained and used in the following reaction without purification.

According to example 97 (2), by using 4-iodo-3-isopropyl-1- (4-methoxybenzyl) -1H-pyrazolo [3,4-b ] pyridine instead of compound (97 a) and using 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole, 3-isopropyl-1- (4-methoxybenzyl) -4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine was obtained and used in the following reaction without purification.

3-isopropyl-1- (4-methoxybenzyl) -4- {4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl } -1H-pyrazolo [3,4-b ] pyridine was dissolved in trifluoroacetic acid (60 mL) and anisole (19 mL) and refluxed for 5 hours. The reaction solution was concentrated, diluted with acetonitrile, and saturated sodium bicarbonate was added. The precipitate was collected by filtration and dried under reduced pressure, whereby compound (100 b) (12.3 g, 3-stage yield 63%) was obtained as a white solid.

Example 97 (1)

4-chloro-3-methyl-1- { (2- (trimethylsilyl) ethoxy) methyl } -1H-pyrrolo [2,3-b ] pyridine (97 a)

Compound (40 d) (1.0 g) was dissolved in DMF (20 mL), and sodium hydride (0.288g, dispersion in Paraffin liquid (55%)) was added thereto at 0 ℃ and stirred for 10 minutes, followed by addition of 4-methoxybenzyl chloride (1.16 mL) and stirring at room temperature for 1 hour. Ice water was added to the reaction solution, followed by extraction with ethyl acetate, washing of the organic layer with saturated brine, and drying over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to give compound (97 a) (4.50g, 84%) as a colorless oily substance.

Example 97 (2)

3-methyl-4- (4-phenyl-1H-imidazol-1-yl) -1- { (2- (trimethylsilyl) ethoxy) methyl } -1H-pyrrolo [2,3-b ] pyridine (97 b)

Compound (97 a) (2.00 g), copper (I) oxide (0.048 g), 4,7-dimethoxy-1, 10-phenanthroline (0.243 g), cesium carbonate (3.07 g), polyethylene glycol (Mn = 3400) (1.35 g), 4-phenyl-1H-imidazole (1.17 g) were suspended in NMP and stirred at 150 ℃ for 48 hours. The reaction solution was suspended in ethyl acetate, and the insoluble matter was filtered through Celite (Celite), and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to give compound (97 b) (0.272g, 10%) as a colorless oily substance.

Example 102

3-Ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzamide (102)

According to example 80, compound (102) was obtained as a white solid by using compound (100 b) in place of compound (6 c) and 3-ethyl-4-fluorobenzonitrile in place of 4-fluoro-3-methylbenzonitrile (2-stage yield, 15%).

Example 80

4- { 3-isopropyl-4- (quinolin-3-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } -3-methylbenzamide (80)

To a solution of compound (6 c) (0.150 g) in DMF (1.73 mL) were added 4-fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g), and the mixture was stirred at 80 ℃ for 18 hours. The reaction solution was partitioned with ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by neutral silica gel column chromatography (N-hexane/ethyl acetate) to give 4- { 3-isopropyl-4- (quinolin-3-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } -3-methylbenzonitrile (0.154g, 73%), 4- { 3-isopropyl-4- (quinolin-3-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } -3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL), and a 4N-aqueous sodium hydroxide solution (0.195 mL) and 30% aqueous hydrogen peroxide (0.088 mL) were added to stir at room temperature for 30 minutes. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure, whereby compound (80) (0.135g, 83%) was obtained as a white solid.

Compared with the synthesis method of the pimetidine provided by the comparative example, the synthesis method of the pimetidine provided by the examples 1-5 has the advantages of short route, high yield, higher chemical purity of the obtained pimetidine, reduced health damage to production operators due to the short route and more environment-friendly effect.

The present invention has been described in terms of the preferred embodiment, and it is not intended to be limited to the embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A synthetic method of a drug Pi Mite Xibu for treating gastrointestinal stromal tumor is characterized in that: pi Mite intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile was synthesized as follows:

step 1, carrying out C-N cross coupling reaction on a compound 1 and 4-iodo-3-ethylbenzonitrile to obtain a compound 2;

step 2, performing C-N cross coupling reaction on the compound 2 and 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole to obtain 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile;

the X group in the structures of the compound 1 and the compound 2 is chlorine, bromine or iodine, and is preferably bromine.

2. The synthesis process according to claim 1, characterized in that the solvent of the reaction of step 1 is an aprotic solvent selected from dioxane, DMF, DMSO, N-methylpyrrolidone, preferably DMF.

3. The synthesis process according to claim 1, characterized in that the catalyst of the reaction of step 1 is an inorganic base selected from potassium carbonate, cesium carbonate, potassium phosphate, preferably cesium carbonate.

4. The synthesis method according to claim 1, wherein the molar charge ratio of the compound 1 and the 4-iodo-3-ethylbenzonitrile in the step 1 reaction is 1:1-1:2, preferably 1.2-1, 1.8, and particularly preferably 1.5.

5. The synthesis method according to claim 1, wherein the reaction conditions of the step 1 comprise: the reaction temperature is 70-90 ℃, and the stirring reaction is preferably carried out at 75-85 ℃ for 16-20 hours.

6. The synthesis process according to claim 1, characterized in that the solvent of the reaction of step 2 is an aprotic solvent selected from DMF, DMSO, N-methylpyrrolidone, propylnitrile, preferably N-methylpyrrolidone.

7. The synthesis method according to claim 1, wherein the step 2 reaction is catalyzed by an inorganic base, and the inorganic base catalyst is selected from potassium carbonate, cesium carbonate and potassium phosphate, and is preferably cesium carbonate.

8. The synthesis method according to claim 1, wherein the step 2 reaction is catalyzed by a copper catalyst selected from the group consisting of CuI and Cu ₂ O、CuO、Cu(OAc) ₂ CuBr and CuCl, preferablyCu ₂ O and CuI, particularly preferably Cu ₂ O。

9. The synthesis method of claims 1-8, wherein the reaction in step 2 is catalyzed by a ligand catalyst, and the ligand is selected from 1,10-phenanthroline, 4,7-dimethoxy-1, 10-phenanthroline, preferably 4,7-dimethoxy-1, 10-phenanthroline; and/or;

the reaction in the step 2 needs to be catalyzed by adding a carrier, wherein the carrier is polyethylene glycol with the polymerization degree of 1500-6000, preferably polyethylene glycol 3400; and/or;

in the step 2 reaction, the molar charge ratio of the compound 2 to the 4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazole is 1:1-1:2, preferably 1.2-1, and particularly preferably 1.2; and, or;

the molar charge ratio of the compound 2 to the copper catalyst in the step 2 reaction is 1; and/or;

the molar charge ratio of the compound 2 to the inorganic base catalyst in the reaction in the step 2 is 1:1-1:2, preferably 1; and/or;

the molar charge ratio of the compound 2 to the ligand catalyst in the step 2 reaction is 1; and, or;

in the step 2 reaction, the weight feeding ratio of the compound 2 to the carrier is 1; and/or;

the step 2 reaction comprises the following steps: the reaction is stirred for 48 to 50 hours at 145 to 155 ℃.

10. The synthesis method according to claims 1-9, characterized in that the intermediate 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzonitrile is subjected to hydrolysis reaction to prepare Pi Mite coxib.