A process for the preparation of a toceranib intermediate

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a tucatinib intermediate. The compound N-hydroxy-N'-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]formamidine is used as a starting material, condensed with a compound 1-n-propyl phosphonic anhydride to prepare 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine. The 1-n-propyl phosphonic anhydride is a low-toxicity, stable and easy-to-operate reagent. The by-product after reaction is a water-soluble phosphoric acid substance, so that the purity of the related product is also high, the operation is safe and environmentally friendly, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, and specifically relates to a method for preparing a ticatinib intermediate. Background Technology

[0002] Tucatinib (also known as irbinitinib, ARRY-380, ONT-380, 1), chemically named N 4 -(4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylphenyl)-N 6 -(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)quinazolin-4,6-diamine. Tucatinib is an oral human epidermal growth factor receptor tyrosine kinase (HER2) inhibitor jointly developed by Array Biopharma and Cascadian Therapeutics. Its tablets (50mg and 150mg strengths) were approved by the US FDA on April 17, 2020, under the brand name... In clinical practice, tacardinib is used in combination with trastuzumab and capecitabine, primarily to treat patients with advanced HER2-positive breast cancer that cannot be surgically removed or has metastasized.

[0003] The chemical structure of tucatinib can be divided into three segments: A, B, and C. The key to its synthesis lies in the efficient construction of the crucial intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline (2), which forms the "A segment." The chemical structural formulas of the relevant compounds are as follows:

[0004]

[0005] There are currently many methods for synthesizing key intermediate 2. Among them, Joseph P. Resicatos et al. used 2-chloro-4-nitropyridine (3) as a raw material and reacted it with benzyl alcohol in the presence of sodium hydride to obtain 4-(benzyloxy)-2-chloropyridine (4); 4 was cross-coupled with hexamethyldisilamide lithium under the action of the catalyst tris(dibenzylideneacetone)dipalladium and the ligand 2-(dicyclohexylphosphine)-2',4',6'-triisopropyl-1,1'-biphenyl to obtain 4-(benzyloxy)pyridine-2-amine (5); Compound 5 reacted with ditert-butyl dicarbonate to obtain tert-butyl[4-(benzyloxy)pyridine-2-yl]carbamate (6); Compound 6 was subjected to palladium-carbon catalytic hydrogenolysis to remove benzyl group and generate tert-butyl(4-hydroxypyridine-2-yl)carbamate (7); Under alkaline conditions of potassium carbonate, compound 7 undergoes a nucleophilic substitution reaction with 2-methyl-4-nitrofluorobenzene (8) to prepare tert-butyl[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]carbamate (9); compound 9 is deprotected by tert-butyloxycarbonyl in the presence of trifluoroacetic acid to obtain 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (10), which is then further reacted with N,N-dimethylformamide dimethyl... The acetal (DMF-DMA) reaction yields N'-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]-N,N-dimethylformamidinium (11); 11 undergoes intramolecular cyclization with hydroxylamine-O-sulfonic acid (12) under the action of pyridine to obtain 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (13); finally, 13 is reduced by palladium-carbon catalytic hydrogenation to obtain 2. This process is the first reported method for preparing 2, involving a total of 9 steps and a long production cycle. In the coupling amination reaction in step 2 to prepare 5, expensive catalyst tris(dibenzylideneacetone)dipalladium and hexamethyldisilamide lithium, which are not suitable for industrial production, are required, making scale-up production difficult; in addition, the yields of intermediates 9 and 13 are only 30% and 49% respectively, which are low, so the total yield is only 5.7% (based on 3). The synthetic route is shown below:

[0006]

[0007] In 2021, Zhao Panfeng et al., in patent CN114031619A, also used 3 as the starting material, and replaced benzyl alcohol in the above process with 2-methyl-4-nitrophenol (14) to react and form ether to obtain 4-(2-methyl-4-nitrophenoxy)-2-chloropyridine (15); compound 15 was subjected to hydrazinolysis to obtain 2-hydrazino-4-(2-methyl-4-nitrophenoxy)pyridine (16); compound 16 was reacted with p-toluene The compound 17 undergoes intramolecular ring closure upon reaction with triethyl orthoformate under the action of sulfonic acid, generating 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[4,3-a]pyridine (17); compound 17 is then hydrogenated under palladium-carbon catalysis and reduced to 4-([1,2,4]triazolo[4,3-a]pyridine-7-hydroxy)-3-methylaniline (18); under the action of morpholine, compound 18 undergoes a Dimroth rearrangement reaction to obtain 2. This route consists of 5 steps with an overall yield of 65% (based on 3), which is significantly higher than the yield (5.7%) of the original patent CN101356171A. The raw materials for this process are readily available and the operation is simple, but the preparation of intermediate 16 requires a long reaction with highly toxic and explosive hydrazine hydrate under high temperature conditions, which reduces the overall production safety of the process. The synthetic route is shown below:

[0008]

[0009] In 2019, Yin Lingfeng et al. selected 2-amino-4-chloropyridine (19), which is slightly cheaper, to replace 3 as a raw material in patent CN109942576B and literature Synthesis, 2019, 51(13):2660-2664. Under high temperature conditions, 10 was obtained by nucleophilic substitution reaction with 14 to form an ether. After 10 reacted with DMF-DMA to generate formamidin intermediate 11, it was directly substituted with hydroxylamine hydrochloride without separation to obtain N-hydroxy-N'-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]formamidin (20). Compound 20 was intramolecularly cyclically closed under the action of trifluoroacetic anhydride to generate 13. Finally, 2 was obtained by catalytic hydrogenation. This route consists of 5 steps, increasing the overall yield from 5.7% in the original patent to 32%, and the raw materials are readily available, further reducing production costs. However, the preparation of 10 requires a high temperature (150℃) and a long reaction time (48h), placing high demands on the production equipment. The synthetic route is shown below:

[0010]

[0011] In 2019, Wang Yuxuan et al., in patent CN111825604A, used 2-pyridinecarboxylic acid (21) as the starting material, first reacting it with thionyl chloride and ammonia to obtain 4-chloro-2-pyridinecarboxamide (22), then reacting it with Hofmann degradation to generate 4-chloro-2-aminopyridine (23); under high temperature and pressure, 23 reacted with sodium hydroxide to obtain 4-hydroxy-2-aminopyridine hydrochloride (24); 24 hydrochloride was etherified with 8 or 2-methyl-4-nitrochlorobenzene (8′) under alkaline conditions of triethylamine / potassium hydroxide to generate 10; finally, the triazole ring was constructed using the original patent strategy to obtain 2. Although the starting material 21 used in this route is inexpensive and readily available, and avoids the use of expensive catalysts, the process route is long and the overall yield is low (≤11%); in addition, the preparation of 24 requires a long time (12h) at high temperature and pressure of 180℃, which poses a safety hazard for scale-up. The synthetic route is shown below:

[0012]

[0013] In addition, patent CN112898298A, literature Org.Prep.Proced.Int.,2021,53(6):554-561, and patents CN111587248A and CN114262327A respectively use 7-chloro-[1,2,4]triazolo[1,5-a]pyridine (25) and 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (26) as key intermediates to prepare 2. The relevant intermediate structural formulas are shown below:

[0014]

[0015] As can be seen from the above, the key to synthesizing intermediate 2 lies in the preparation of the "triazole" ring. The most commonly used method is to first prepare the key intermediate 4-(2-methyl-4-nitrophenoxy)pyridine-2-amine (10) by different methods, and then prepare the "triazole" ring intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (13) by the following two strategies (① 10 is first condensed with DMF-DMA and then intramolecularly cyclically fused under hydroxylamine-O-sulfonic acid conditions; ② 10 is first condensed with DMF-DMA and then reacted with hydroxylamine hydrochloride, and finally intramolecularly cyclically fused under trifluoroacetic anhydride conditions). Finally, the target intermediate 2 is synthesized by catalytic hydrogenation reduction of the nitro group. However, the yields of both strategies are generally low. For example, the cyclization step yield is 49% in the original patent CN101356171A, the two-step yield is 49% in patent CN111825604A, and the cyclization step yield is 68% in patent CN109942576B.

[0016] Therefore, 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (13,I) can serve as an intermediate in the preparation of ticatinib, thus directly affecting the production, market supply, and quality of this drug. Its specific structural formula is as follows:

[0017]

[0018] Based on the technical problems encountered in the cyclization of 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (I), the preparation of ticatinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (I), which is safe, simple, and yields high purity products, research is needed to find a safe and simple process route to produce ticatinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (I). Ensuring the production, market supply, and quality of ticatinib remains one of the issues that need to be addressed. Summary of the Invention

[0019] To address the numerous problems existing in the current technology for preparing the ticacutinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (I), this invention provides a novel method for preparing the ticacutinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (I). This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and high yield.

[0020] The specific technical solution of the present invention is as follows:

[0021]

[0022] A method for preparing the tocatinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine, comprising the following steps:

[0023] Under inert gas protection at room temperature, compound SM was added to reaction solvent A and stirred until dissolved. Then, 1-n-propylphosphoric anhydride (T3P) was added, and the temperature was controlled at T. A After the reaction is complete, the reaction solution is quenched with saturated NaHCO3 solution, extracted with organic solvent, and the organic phase is washed with water and saturated brine respectively. After being concentrated under reduced pressure to dryness, it is recrystallized with methanol to obtain the target product I.

[0024] In a preferred embodiment, the reaction solvent A is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, and toluene, with tetrahydrofuran being particularly preferred.

[0025] In a preferred embodiment, the molar ratio of SM to T3P is 1:1.2 to 2.0, with a particularly preferred ratio of 1:1.5.

[0026] In the preferred embodiment, the reaction temperature T A The temperature ranges from 40 to 90 degrees Celsius, with 55 to 60 degrees Celsius being particularly preferred.

[0027] In a preferred embodiment, the organic solvent used for extraction is one or a combination of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether, with ethyl acetate being particularly preferred.

[0028] In this invention, the inert gas is typically selected from nitrogen or argon, with nitrogen being particularly preferred.

[0029] In this invention, the T3P is typically selected from 50% organic solutions, such as ethyl acetate, N,N-dimethylformamide, and acetonitrile solutions, with ethyl acetate solution being particularly preferred.

[0030] The technical effects achieved by this invention are as follows:

[0031] Compared with existing technologies, this invention provides a novel method for synthesizing the tocatinib intermediate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine. This method is simple, efficient, and yields a high product. Furthermore, because T3P is a low-toxicity, stable, and easy-to-handle reagent, and its reaction byproducts are water-soluble phosphates, the purity of the related products is also high. The operation is safe and environmentally friendly, making it suitable for industrial production. Detailed Implementation

[0032] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0033] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0034] Example 1

[0035] Under nitrogen protection at room temperature, compound SM (28.83 g, 0.10 mol) was added to tetrahydrofuran (250 mL) and stirred until dissolved. Then, an ethyl acetate solution of 1-n-propylphosphonic anhydride (ω = 50%, 95.45 g, 0.15 mol) was added, and the reaction was carried out at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was quenched with saturated NaHCO3 solution (2500 mL), extracted with ethyl acetate (1000 mL × 3), and the organic phase was washed with water (1000 mL × 2) and saturated brine (1000 mL), respectively. After being concentrated to dryness under reduced pressure, the product was recrystallized from methanol to obtain the target product I, with a yield of 98.3% and an HPLC purity of 99.95%.

[0036] Example 2

[0037] Under nitrogen protection at room temperature, compound SM (28.83 g, 0.10 mol) was added to isopropyl acetate (250 mL) and stirred until dissolved. Then, a solution of 1-n-propylphosphonic anhydride in N,N-dimethylformamide (ω = 50%, 76.36 g, 0.12 mol) was added, and the reaction was carried out at 40–45 °C. After the reaction was detected to be complete, the reaction solution was quenched with saturated NaHCO3 solution (2500 mL), the organic phase was separated, and the aqueous phase was extracted with dichloromethane (1000 mL × 2). The organic phases were combined and washed with water (800 mL × 2) and saturated brine (800 mL), respectively. After being concentrated to dryness under reduced pressure, the product was recrystallized from methanol to obtain the target product I, with a yield of 94.6% and an HPLC purity of 99.72%.

[0038] Example 3

[0039] Under nitrogen protection at room temperature, compound SM (28.83 g, 0.10 mol) was added to ethyl acetate (250 mL) and stirred until dissolved. Then, a solution of 1-n-propylphosphonic anhydride in acetonitrile (ω = 50%, 127.27 g, 0.2 mol) was added dropwise. After the addition was complete, the reaction was controlled at 85–90 °C. After the reaction was detected to be complete, the reaction solution was quenched with saturated NaHCO3 solution (2500 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (1000 mL × 2). The organic phases were combined and washed with water (800 mL × 2) and saturated brine (800 mL), respectively. After being concentrated to dryness under reduced pressure, the product was recrystallized from methanol to obtain the target product I, with a yield of 95.3% and an HPLC purity of 99.62%.

[0040] Example 4

[0041] Under nitrogen protection at room temperature, compound SM (28.83 g, 0.10 mol) was added to toluene (250 mL) and stirred until dissolved. Then, an ethyl acetate solution of 1-n-propylphosphonic anhydride (ω = 50%, 73.18 g, 0.115 mol) was added, and the reaction was carried out at 35–40 °C. After the reaction was detected to be complete, the reaction solution was quenched with saturated NaHCO3 solution (2500 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 2). The organic phases were combined and washed with water (800 mL × 2) and saturated brine (800 mL), respectively. After being concentrated to dryness under reduced pressure, the product was recrystallized from methanol to obtain the target product I, with a yield of 85.3% and an HPLC purity of 98.88%.

[0042] Example 5

[0043] Under argon protection at room temperature, compound SM (28.83 g, 0.10 mol) was added to 2-methyltetrahydrofuran (250 mL) and stirred until dissolved. Then, an ethyl acetate solution of 1-n-propylphosphonic anhydride (ω = 50%, 140.00 g, 0.22 mol) was added, and the reaction was carried out at 90–95 °C. After the reaction was detected to be complete, the reaction solution was quenched with saturated NaHCO3 solution (2500 mL), the organic phase was separated, and the aqueous phase was extracted with chloroform (1000 mL × 2). The organic phases were combined and washed with water (800 mL × 2) and saturated brine (800 mL), respectively. After being concentrated to dryness under reduced pressure, the product was recrystallized from methanol to obtain the target product I, with a yield of 88.3% and an HPLC purity of 98.32%.

Claims

1. A method for preparing a tacardinib intermediate, characterized in that, The preparation method includes the following steps: Under inert gas protection at room temperature, compound SM was added to reaction solvent A and stirred until dissolved. Then, an organic solution of 1-n-propylphosphonic anhydride was added, and the temperature was controlled at T. A After the reaction was completed, the reaction solution was quenched with saturated NaHCO3 solution, extracted with organic solvent, and the organic phase was washed with water and saturated brine respectively. After being concentrated to dryness under reduced pressure and recrystallized with methanol, the target product I was obtained. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The reaction solvent A is selected from one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, and toluene.

3. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM to 1-n-propylphosphoric anhydride is 1:1.2 to 2.

0.

4. The preparation method according to claim 1, characterized in that, The reaction temperature T A The temperature ranges from 40 to 90 degrees Celsius.

5. The preparation method according to claim 1, characterized in that, The organic solvent used for extraction is selected from one of dichloromethane, chloroform, ethyl acetate, and methyl tert-butyl ether.

6. The preparation method according to claim 1, wherein the organic solution of 1-n-propylphosphonic anhydride is selected from one of ethyl acetate, N,N-dimethylformamide, and acetonitrile solutions with a mass fraction of 50%.

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