A method for synthesizing a crizotinib intermediate

Abstract

The present invention is a method for synthesizing a crizotinib intermediate (compound 1). The method uses (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and compound 3-hydroxy-2-nitropyridine as starting materials, and obtains compound 1 through three steps of mitsnobu reaction, nitro reduction and NBS bromination. Compared with other existing methods, the method has the characteristics of simple route, avoiding the use of some dangerous reagents, convenient operation, short reaction time, cheap and easy-to-recycle solvents, high reaction yield, and is conducive to industrial production.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a crizotinib intermediate (Compound 1), belonging to the field of pharmaceutical chemistry. The structure of Compound 1 is as follows: . Background Art

[0002] Crizotinib is a targeted anticancer drug developed by Pfizer. It is a multi-target tyrosine kinase inhibitor and is mainly used to treat non-small cell lung cancer (NSCLC) with positive anaplastic lymphoma kinase (ALK) fusion gene. Crizotinib was first approved for marketing in the United States in 2011 by inhibiting ALK kinase activity and blocking the proliferation and survival signal transduction of tumor cells.

[0003] Crizotinib exerts its anti-tumor effect by selectively inhibiting the activity of ALK and c-Met tyrosine kinases. Its mechanism of action is to inhibit the growth and proliferation of tumor cells and induce apoptosis by blocking the conduction of key signaling pathways in tumor cells. Crizotinib has a significant targeted therapeutic effect on non-small cell lung cancer carrying ALK fusion gene mutations, and also shows efficacy on tumors related to c-Met and ROS1 rearrangements. Because crizotinib has a high degree of targeting and significant clinical efficacy, it can be used to treat patients with ALK-positive advanced or metastatic NSCLC. Its listing marks a major breakthrough in the field of precision tumor treatment and has important clinical application value.

[0004] The literature Organic Process Research & Development (2020), 24(10), 2252-2259 reported a synthetic route for crizotinib. This route uses (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (compound 2) and compound 3-hydroxy-2-nitropyridine (compound 3) as starting materials, and undergoes mitsnobu reaction, nitro reduction and bromination reaction to obtain key intermediate 1. Compound 1 and compound 6 then undergo Suzuki coupling reaction to obtain compound 7, and finally remove the Boc protecting group to obtain crizotinib.

[0005] .

[0006] Compound 1 is a key intermediate in this route, and its synthesis efficiency and quality have an important impact on the subsequent process and the overall yield of crizotinib. However, there are currently few reports on the synthesis of compound 1, especially in terms of the optimized route that meets the needs of industrial production, there is still a large research gap.

[0007] At present, the most representative synthetic route of compound 1 is the method proposed in Organic Process Research & Development (2020), 24(10), 2252-2259. This route uses (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (compound 2) and 3-hydroxy-2-nitropyridine (compound 3) as starting materials, generates intermediate 4 through Mitsunobu reaction, and then uses Raney nickel as a catalyst for hydrogenation reduction reaction to obtain the key intermediate 1. However, this method has obvious defects: the residual triphenylphosphine oxide in intermediate 4 can easily lead to poisoning and deactivation of the Raney nickel catalyst, thereby significantly reducing the reaction efficiency. In addition, the reaction process is time-consuming, the product color is poor, and purification is difficult, which affects the smooth progress of subsequent reactions.

[0008] .

[0009] Patents CN101967140 A, CN101857594 A, WO2013177092 A1 and CN103387535 A also report a method for synthesizing compound 1, i.e., reducing the nitro group by iron hydrochloride powder. However, this method also has many problems. For example, its yield is significantly lower than that of the hydrogenation reduction method, and a large amount of iron mud is generated during the reaction, which not only increases the complexity of post-processing, but also leads to more serious environmental pollution. In addition, the processing difficulty of iron mud is relatively large, the reaction operation is complicated, and it is difficult to meet the needs of industrial production. Summary of the invention

[0010] In view of the deficiencies in the prior art of crizotinib intermediates (compound 1), the present invention provides an improved synthesis scheme of crizotinib intermediates (compound 1), especially innovative optimization of the synthesis method of compound 5. In step 2, the synthesis of compound 5 uses Raney nickel or ferric chloride and activated carbon as catalysts, and hydrazine hydrate as a reducing agent to achieve nitro reduction reaction. This method avoids the high-pressure operation risk brought by traditional hydrogen as a reducing agent, and also overcomes the problem of a large amount of iron mud generated during the post-treatment process of the iron powder reduction method. The present invention has significant advantages: simple operation, high safety, and more environmentally friendly production process; at the same time, the reaction yield is greatly improved, the product purity is high, and it meets the needs of industrial production. The improvement of this method provides a more valuable technical solution for the preparation of crizotinib intermediates and has broad application prospects.

[0011] The preparation method of the crizotinib intermediate (Compound 1) of the present invention uses (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the compound 3-hydroxy-2-nitropyridine as starting materials, and obtains Compound 1 through three steps of Mitsnobu reaction, nitro reduction and NBS bromination. Specifically, the following steps are included: Step 1: Dissolve (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and 3-hydroxy-2-nitropyridine in toluene, add triphenylphosphine and stir evenly, add diisopropyl azodicarboxylate toluene solution dropwise at low temperature, and warm to room temperature to react for 5 hours after the addition is completed. Add water to quench the reaction for 3 hours, crystallize at low temperature for 2 hours, and filter to remove triphenylphosphine oxide. Remove toluene from the filtrate under reduced pressure, add isopropanol and heat to dissolve, add water dropwise at high temperature to precipitate the product, then crystallize at low temperature for 2 hours, and filter to obtain the product compound 4.

[0012] Step 2: Compound 4 is dissolved in an organic solvent, a catalyst is added, the temperature is raised to reflux for 10 minutes, hydrazine hydrate is added dropwise, and the reaction is carried out for 1-5 hours after the addition is completed. After the reaction is completed, the mixture is hot filtered, and the organic solvent is removed by decompression of the filtrate. Methanol is added to the residue and heated to reflux to dissolve, and then water is added dropwise at high temperature, and then crystallized at low temperature for 2 hours, and filtered to obtain compound 5.

[0013] Step 3: Dissolve compound 5 in dichloromethane, then dropwise add NBS acetonitrile solution, and react for 1 hour after the addition is complete. Then dropwise add a mixture of sodium metabisulfite, potassium hydroxide and water, and stir and react for 1 hour after the addition is complete. Stand to separate the organic layer, extract the water layer again with dichloromethane once, combine the organic layers, add triethylamine and stir for 15 minutes, add water to wash the organic layer, remove the solvent from the organic layer under reduced pressure, add methanol and heat under reflux to dissolve, then cool to -10°C for crystallization, and filter and collect the solid to obtain the target compound 1.

[0014] In the above method for preparing crizotinib intermediate compound 1, the solvent used in step 2 is selected from methanol and ethanol, preferably methanol; the ratio of the amount of solvent to the amount of compound 4 is 6L / kg~30L / kg, preferably 12L / kg~18L / kg, the catalyst is selected from Raney nickel and ferric chloride + activated carbon, preferably ferric chloride + activated carbon combination, the molar ratio of compound 4 to the catalyst is ferric chloride: activated carbon: compound 0.05:0.05:1~0.12:0.12:1, preferably 0.1:0.1:1. The reaction temperature is 50°C~80°C, preferably 62-66°C. The reaction time is 1h~6h, preferably 2h~3h, the recrystallization solvent is methanol, ethanol, isopropanol and a mixed solvent thereof with water, preferably a mixed solvent of methanol and water, further preferably methanol: water = 1:1, and the crystallization temperature is 0~-10°C.

[0015] The present invention is further described below by way of examples. Various substitutions or combinations made according to common technical knowledge and conventional means in the art should all be included in the scope of the present invention. DETAILED DESCRIPTION

[0016] Example 1 Stir (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (100.0 g), 3-hydroxy-2-nitropyridine (67.7 g) and toluene (808 ml) in a three-necked flask, add triphenylphosphine (150.6 g) and stir, cool to -5±3°C, and start to drop diisopropyl azodicarboxylate (114.9 g). ml) and toluene (144ml), control the temperature at -10℃ to 0℃, add all the solution, keep the temperature at -5±3℃ for 1h, then remove the coolant, slowly raise the temperature to 25℃-30℃ for about 30min, react for 5h, take a sample of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the reaction is completed. Add water (13.2ml) to quench, stir for 3h, add a small amount of seed crystals 15min after adding water, cool to -3±2℃ after 3h, stir for 3h, filter, wash the filter cake with toluene (100ml) for 10min, filter, wash the filter cake with a small amount of toluene, combine the filter cakes Liquid, filtrate rotary evaporate at 60 ℃, when rotary evaporate to oily mixture, add isopropanol to bring out solid (200.0ml), then add a small amount of isopropanol (40.0ml) × 2 to bring out, finally rotary evaporate to get oily solid mixture, add isopropanol 250ml, heat to 75 ℃ to dissolve, keep warm at 65-75 ℃, then add 250ml water dropwise, solid will precipitate in the process of adding water, slowly cool to room temperature (20-30 ℃) after dropping, precipitate for 2h, then precipitate at -10 ℃ for 2h, filter, wash solid with 100ml cold isopropanol: water = 1:1, dry solid at 45 ℃ at normal pressure to get 145.8g white solid.

[0017] Example 2 Add compound 4 (100.0 g), Raney nickel (9.0 g) and methanol (1800.0 ml) to a three-necked flask, heat and reflux for about 10 min, then drop hydrazine hydrate (80%, 91.6 ml), nitrogen gas is generated, and the drop rate should be controlled to avoid material rush. After the drop addition is completed, reflux for 1 hour. HPLC is used to measure the reaction, and the reaction is stopped when the content of compound 4 is less than 0.1%. Let it stand and cool to room temperature, take out the reaction solution from the top of the reaction solution and filter it, and wash the residue in the reaction bottle with methanol twice, 100.0 ml each time. The filtrate was rotary evaporated at 40°C. After the methanol was evaporated to dryness, methanol (200.0 ml) was added again. The temperature was raised to 65°C to dissolve. Water (200.0 ml) was added dropwise at 60-65°C. Solids were precipitated during the addition of water. The temperature was lowered and crystallized at 20-30°C for 30 minutes. Then, crystallized at -10±3°C for 2 hours. Filtered with suction, the filter cake was washed with a small amount of methanol, and the solid was dried at 45°C to obtain 87.4 g of off-white solid.

[0018] Example 3 Add compound 4 (100.0 g), Raney nickel (9.0 g) and ethanol (1800.0 ml) to a three-necked flask, heat and reflux for about 10 min, then drop hydrazine hydrate (80%, 91.6 ml), nitrogen gas is generated, and the drop rate should be controlled to avoid material rush. After the drop is completed, reflux for 1 hour. HPLC is used to measure the reaction, and the reaction is stopped when the content of compound 4 is less than 0.1%. Let it stand and cool to room temperature, take out the reaction solution from the top of the reaction solution and filter it, and wash the residue in the reaction bottle with methanol twice, 100.0 ml each time. The filtrate was rotary evaporated at 40°C. After the methanol was evaporated to dryness, methanol (200.0 ml) was added again. The temperature was raised to 65°C to dissolve. Water (200.0 ml) was added dropwise at 60-65°C. Solids were precipitated during the addition of water. The temperature was lowered and crystallized at 20-30°C for 30 minutes. Then, crystallized at -10±3°C for 2 hours. Filtered with suction, the filter cake was washed with a small amount of methanol, and the solid was dried at 45°C to obtain 86.2 g of black solid.

[0019] Example 4 Compound 4 (100.0 g), ferric chloride hexahydrate (9.0 g), activated carbon () and ethanol (1800.0 ml) were added to a three-necked flask, heated to reflux for about 10 min, and then hydrazine hydrate (80%, 91.6 ml) was added dropwise. Nitrogen gas was generated. The dropwise addition rate should be controlled to avoid material impact. After the dropwise addition was completed, the reaction was refluxed for 1 h. The reaction was measured by HPLC. The reaction was stopped when the content of compound 4 was less than 0.1%. The filtrate was allowed to cool to room temperature, the activated carbon was removed by filtration, and the solid was washed with a small amount of methanol. The filtrate was rotary evaporated at 40°C, and after the methanol was evaporated to dryness, methanol (200.0 ml) was added again, and the temperature was raised to 65°C to dissolve. Water (200.0 ml) was added dropwise at 60-65°C. Solids were precipitated during the addition of water. The temperature was lowered, and crystallization was carried out at 20-30°C for 30 min, and then crystallization was carried out at -10±3°C for 2 h. The filter cake was washed with a small amount of methanol, and the solid was dried at 45°C to obtain 84.9 g of white solid.

[0020] Example 5 Compound 4 (100.0 g), ferric chloride hexahydrate (9.0 g), activated carbon () and methanol (1800.0 ml) were added to a three-necked flask, heated to reflux for about 10 min, and then hydrazine hydrate (80%, 91.6 ml) was added dropwise. Nitrogen gas was generated. The dropwise addition rate should be controlled to avoid material impact. After the dropwise addition was completed, the reaction was refluxed for 1 h. The reaction was measured by HPLC. The reaction was stopped when the content of compound 4 was less than 0.1%. The filtrate was allowed to cool to room temperature, the activated carbon was removed by filtration, and the solid was washed with a small amount of methanol. The filtrate was rotary evaporated at 40°C, and after the methanol was evaporated to dryness, methanol (200.0 ml) was added again, and the temperature was raised to 65°C to dissolve. Water (200.0 ml) was added dropwise at 60-65°C. Solids were precipitated during the addition of water. The temperature was lowered, and crystallization was carried out at 20-30°C for 30 min, and then crystallization was carried out at -10±3°C for 2 h. The filter cake was washed with a small amount of methanol, and the solid was dried at 45°C to obtain 84.9 g of white solid.

[0021] Example 6 Compound 5 (100.0 g) and dichloromethane (1000.0 ml) were placed in a three-necked flask and stirred. A mixture of NBS (60.9 g) and acetonitrile (410.0 ml) was added dropwise at 0-10°C. After addition, the mixture was reacted at 10-20°C for 30 min. The liquid phase was detected until the concentration of compound 5 was less than 0.1%, and the reaction was completed. A mixture of sodium pyrosulfite (31.6 g) + KOH (0.6 g) + water (200.0 ml) (temperature between 10-20°C) was added dropwise at 10-20°C. After addition, the mixture was reacted at 20°C for 1 h. The layers were separated. The aqueous layer was extracted once with 100.0 ml of dichloromethane. The dichloromethane layers were combined, triethylamine (46.2 ml) was added at 10-20°C and stirred for 15 min. Water (139.0 ml) was added and stirred for 10 min. The dichloromethane layer was evaporated to dryness at 40°C. Distill with 600.0 ml of methanol x 2 times. Add methanol (360.0 ml) to dissolve the residue, heat to about 55°C to dissolve, cool to -10°C to crystallize for 3 hours, filter, drain, add 50.0 ml of ice methanol (-10°C) to wash, dry at 50°C to obtain 115.1 g of light yellow solid.

Claims

1. The synthesis method of crizotinib intermediate (Compound 1), the synthesis route is as follows: ； Features The following steps: 1) Step 1, (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (compound 2) and compound 3-hydroxy-2-nitropyridine (compound 3) undergo mitsnobu reaction in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine oxide to obtain compound 4 with chirality inversion; 2) Step 2, compound 4 is treated with hydrazine hydrate as a reducing agent to reduce the nitro group in the presence of a catalyst to obtain compound 5; 3) Step 3, compound 5 undergoes bromination reaction with NBS to obtain compound 1.

2. According to claim 1, the method for preparing compound 4 in step 1 is characterized in that: The molar ratio of compound 2 to DIAD is 1:1.1-1:1.3, preferably 1:1.2; the recrystallization solvent is methanol, ethanol, isopropanol or a mixed solvent thereof with water, preferably a mixed solvent of isopropanol and water, and the volume ratio is isopropanol:water=1:

1.

3. According to claim 1, the method for preparing compound 5 in step 2 is characterized in that: The catalyst used is selected from Raney nickel or ferric chloride and activated carbon, and the molar ratio of the catalyst to compound 4 is 0.05:1-0.2:1, and the preferred ratio is 0.09:1-0.12:1; the reducing agent is hydrazine hydrate, and the molar ratio of the hydrazine hydrate to compound 4 is 4:1-8:1, and the preferred ratio is 5:1; the solvent used is selected from methanol, ethanol and isopropanol, and methanol is preferred; the amount of the solvent is 6 times to 30 times, and more preferably 15 times to 20 times; the reaction temperature is 55-80°C, and more preferably 60-68°C; the reaction time is 0.5h-5h, and preferably 1h-2h; the crystallization solvent is selected from methanol, ethanol and isopropanol and a mixed solvent thereof with water, and preferably a mixed solvent of methanol and water, and the mixed solvent ratio is 1:

1.

4. According to claim 1, the method for preparing compound 1 in step 3 is characterized in that: The solvent is a mixed solvent of dichloromethane and acetonitrile, the reaction temperature is 10-20°C, the reaction time is 1h, and the recrystallization solvent is methanol.

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