Synthesis method of bromopyridine intermediate for preparing loratinib
A simplified two-step synthesis for Larotrectinib intermediates using commercially available starting materials addresses the inefficiencies of existing methods, achieving high yields and cost reduction in the production of Larotrectinib intermediates.
Patent Information
- Application Number
- CN202510282129.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-11
- Publication Date
- 2025-07-15
AI Technical Summary
The existing loratinib synthesis route is complicated, with low yields and high costs. There are few synthesis solutions for key intermediate compound 7, making it difficult to industrialize.
Compound 2 is reacted with methylsulfonyl chloride to produce compound 3, and then compound 9 is produced by substitution reaction with compound 8, followed by palladium-catalyzed intercarbonate reaction to produce compound 7, simplifying the synthesis route and increasing yield.
The yield of the two-step process reaches more than 80%, the yield of palladium catalytic carbonyl interpolation reaction reaches 90%, the total yield is high, the route is simple, the cost is greatly reduced, and it has industrialization potential.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for synthesizing a brominated pyridine intermediate for preparing lorlatinib. Background Art
[0002] Lorlatinib is a targeted therapy drug used to treat certain types of non-small cell lung cancer (NSCLC). Figure 2 As shown; it is a small molecule anaplastic lymphoma kinase (ALK) and ROS1 inhibitor; lorlatinib can penetrate the blood-brain barrier and is effective against tumor cells in the central nervous system. It has been approved in many countries and regions around the world, based on its significant efficacy and acceptable safety in patients with advanced ALK-positive NSCLC in multiple clinical trials. Due to its unique mechanism of action, efficient therapeutic effect, and effective response to drug resistance and brain metastasis, it occupies a key position in the treatment of ALK-positive non-small cell lung cancer. Multiple patent documents disclose multiple routes for the synthesis of lorlatinib, including the following two schemes: Scheme 1: The following route for synthesizing lorlatinib is disclosed in patent WO2014207606:
[0003]
[0004] Solution 2 is another route disclosed in patent WO2014207606:
[0005]
[0006] Both of the above routes use the key intermediate compound 7:
[0007]
[0008] However, the synthesis process of compound 7 given in patent WO2014207606 is very complicated, as follows:
[0009]
[0010] This synthetic route has a long number of steps, and the yield of the third step is as low as 37%, so the total yield of the five steps is 13.8%. Therefore, the cost of this route is very high. After searching the literature, there are relatively few synthetic schemes for compound 7, and a simple and low-cost synthetic scheme is urgently needed.
[0011] In addition, the synthesis of compound 9 is reported in patent WO2013132376 (same family CN104169286):
[0012]
[0013] This route uses compound 2 and compound 8 through the Mitsunobu reaction to obtain compound 9, with a yield of only 44%. The reaction effect is not good and the yield is too low, so it does not have the prospect of industrialization. Summary of the Invention
[0014] Aiming at the deficiencies existing in the prior art, the purpose of the present invention is to provide a synthesis method of a bromopyridine intermediate for the preparation of lorlatinib, which can solve the existing problems.
[0015] In order to achieve the above purpose, the technical solution of the present invention is as follows:
[0016] The present invention is realized through the following technical solutions:
[0017] A synthesis method of a bromopyridine intermediate for the preparation of lorlatinib includes the following steps:
[0018] S1: React compound 3 with compound 8 through a substitution reaction to obtain compound 9;
[0019] S2: Subject compound 9 to a palladium-catalyzed carbonylation reaction to obtain compound 7, which is the key intermediate of lorlatinib;
[0020] The synthesis route in the above steps is as follows:
[0021]
[0022] Further, compound 3 is obtained by reacting compound 2 with methanesulfonyl chloride. The specific synthesis route is as follows:
[0023]
[0024] Among them, the two key starting materials used are: compound 2, named (S)-1-(2-iodo-5-fluorophenyl)ethanol, with a CAS number of 1454847-96-1; compound 8, named 2-amino-3-hydroxy-5-bromopyridine, with a CAS number of 39903-01-0;
[0025] Further, the solvents for the synthesis reaction of compound 3 include dichloromethane, tetrahydrofuran, acetonitrile, and toluene.
[0026] Further, the specific operation steps of the synthesis reaction of compound 3 include: adding dichloromethane as the solvent to the reaction kettle, replacing with nitrogen, and then successively adding compound 2 and triethylamine. Lower the temperature in the reaction kettle below 10 °C, and add methanesulfonyl chloride dropwise through the high-level tank; after adding, slowly raise the temperature of the reaction solution to 15-25 °C and keep stirring for 3-4 h, and monitor the reaction to completion by TLC; add water to the reaction kettle, stir and then let it stand for liquid separation; obtain the organic phase, wash it with water, and then separate out the organic phase and concentrate to obtain compound 3.
[0027] Further, the reaction solvent for S1 includes one or a combination of two of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and acetonitrile; the base added in the S1 reaction includes sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate; the reaction temperature for S1 is 40-60°C.
[0028] Further, the reaction solvent for S1 includes N-methylpyrrolidone; the base added in the S1 reaction includes sodium carbonate.
[0029] Further, the specific operation steps for S1 are as follows: Add N-methylpyrrolidone, compound 8, and sodium carbonate to the reaction kettle of compound 3, control the temperature at 50°C, react and stir for 12 h; after monitoring the reaction to be complete by HPLC, lower the temperature of the reaction solution to 25°C, filter off the salt, add water to the filtrate; precipitate the product; centrifuge and wash with water, collect the filter cake, and dry it at 50°C to obtain product compound 9.
[0030] Further, the palladium catalyst in the S2 reaction includes dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium; the reaction solvent in the S2 reaction is methanol, or a mixed solvent of methanol and tetrahydrofuran, or a mixed solvent of methanol and acetonitrile; the base used in S2 includes triethylamine or N,N-diisopropylethylamine; the carbon monoxide pressure in the S2 reaction is 0.3 to 0.8 MPa.
[0031] Further, the palladium catalyst in the S2 reaction includes 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; the reaction solvent in the S2 reaction is methanol; the base used in the S2 reaction includes triethylamine.
[0032] Further, the specific operation steps for S2 are as follows: Add compound 9 to the autoclave, pump in methanol and triethylamine, add 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium, displace with nitrogen and then switch to carbon monoxide for one displacement, make up the carbon monoxide pressure to 0.5 MPa, raise the temperature to 50-60°C, react for 8-10 hours, and take a sample to monitor the reaction to be complete; concentrate by vacuum distillation to a small volume, then add isopropanol and water, stir and cool to crystallize, and centrifuge to obtain compound 7.
[0033] Compared with the prior art, the beneficial effects of the present invention include:
[0034] The present invention provides a method for synthesizing a bromopyridine intermediate for the preparation of lorlatinib. Specifically, the present invention uses compound 2 to react with MsCl to obtain compound 3, and then compound 3 and compound 8 undergo a substitution reaction to obtain compound 9, with the two-step yield reaching over 80%; compound 9 is subjected to a palladium-catalyzed carbonylation reaction to obtain compound 7, with a yield of 90%; compared with the traditional route, the compound 8 used in the route of the present invention is commercially available and easy to obtain; it already has a bromine in its structure, shortening the main route, and finally obtaining the target molecule compound 7 after carbonylation, with a high total yield, a concise route, and a significant reduction in cost. Therefore, this patent has great economic value and innovative technology. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.
[0036] Figure 1 1H NMR spectrum of compound 7 in the embodiment of the present invention;
[0037] Figure 2 1H NMR spectrum of lorlatinib in the embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0038] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.
[0039] The present invention provides a method for synthesizing a bromopyridine intermediate for the preparation of lorlatinib, including the following steps:
[0040] Step 1: React compound 2 with methanesulfonyl chloride to obtain compound 3;
[0041] Specifically, the reaction solvent in Step 1 includes dichloromethane, tetrahydrofuran, acetonitrile, and toluene. Exemplarily, the reaction solvent in Step 1 includes dichloromethane.
[0042] The specific operating steps of the first step include: adding dichloromethane as the solvent into the reaction kettle, successively adding Compound 2 and triethylamine after nitrogen replacement, cooling the temperature in the reaction kettle below 10 °C, and dropwise adding methanesulfonyl chloride (MsCl) through a high-level tank; after adding, slowly heating the reaction solution to 15 - 25 °C and keeping it warm and stirring for 3 - 4 h, monitoring the reaction by TLC until it is complete; adding water into the reaction kettle, stirring and then standing for liquid separation; obtaining the organic phase, washing it with water and then separating out the organic phase, and concentrating to obtain Compound 3.
[0043] Step 2: Obtaining Compound 9 by the substitution reaction of Compound 3 and Compound 8;
[0044] The reaction solvents for the second step include one or a combination of two of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and acetonitrile; the bases added in the second step reaction include sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate; the reaction temperature in the second step is 40 - 60 °C. Exemplarily, the reaction solvent for the second step includes N-methylpyrrolidone; the base added in the second step reaction includes sodium carbonate.
[0045] The specific operating steps of the second step are: adding N-methylpyrrolidone, Compound 8, and sodium carbonate into the reaction kettle of concentrated Compound 3, controlling the temperature at 50 °C and reacting with stirring for 12 h; after monitoring the reaction by HPLC until it is complete, cooling the temperature of the reaction solution to 25 °C, filtering off the salt, adding water to the filtrate; precipitating the product; centrifuging and washing with water, collecting the filter cake, and drying at 50 °C to obtain the product Compound 9.
[0046] Step 3: Obtaining Compound 7, i.e., the key intermediate of lorlatinib, through the palladium-catalyzed carbonylation reaction of Compound 9; the palladium catalyst in the third step reaction includes [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium; the reaction solvent in the third step reaction is methanol, or a mixed solvent of methanol and tetrahydrofuran, or a mixed solvent of methanol and acetonitrile; the bases used in the third step reaction include triethylamine or N,N-diisopropylethylamine; the carbon monoxide pressure in the third step reaction is 0.3 to 0.8 MPa.
[0047] Exemplarily, the palladium catalyst in the third step reaction includes 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; the reaction solvent in the third step reaction is methanol; the base used in the third step reaction includes triethylamine.
[0048] The specific operating steps of Step 3 are as follows: Add Compound 9 into the autoclave, draw in methanol and triethylamine, add 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium, replace with nitrogen and then switch to replace with carbon monoxide once, make up the carbon monoxide pressure to 0.5 MPa, heat up to 50 - 60 °C and react for 8 - 10 hours, take samples to monitor the completion of the reaction; concentrate by vacuum distillation to a small volume, then add isopropanol and water, stir and cool down to crystallize, and centrifuge to obtain Compound 7.
[0049] The above synthetic route is as follows:
[0050]
[0051] Implementation example:
[0052] Both Compound 2 and Compound 8 are commercially available and can be purchased for use in this example.
[0053] Synthesis of Compound 3: Add 650 L of dichloromethane into a 2000 L reaction kettle, replace with nitrogen, then successively add 86 kg of Compound 2 and 45 kg of triethylamine, lower the temperature in the kettle to below 10 °C, and dropwise add 65 kg of methanesulfonyl chloride through a high-level tank. After adding, slowly heat up the reaction solution to 15 - 25 °C and keep stirring for 3 - 4 h, monitor the completion of the reaction by TLC. Add 300 kg of water into the reaction kettle, stir and then let it stand for liquid separation. The obtained organic phase is washed with 200 kg of water and then the organic phase is separated out, concentrated to a small volume and directly used for the next feeding.
[0054] Synthesis of Compound 9: Add 880 L of N-methylpyrrolidone, 58 kg of Compound 8, and 100 kg of sodium carbonate into the reaction kettle of concentrated Compound 3, control the temperature at 50 °C and react with stirring for 12 h. After monitoring the completion of the reaction by HPLC and lowering the temperature of the reaction solution to 25 °C to filter out the salt, add 800 L of water to the filtrate to precipitate the product. Centrifuge and wash with water, collect the filter cake, and dry it at 50 °C to obtain 119 kg of the product Compound 9, with a liquid phase purity of 99.2% and a two-step yield of 85% (the theoretical yield should be 1.64 times the mass of the raw material).
[0055] Synthesis of Compound 7: 100 kg of Compound 9 was added into a 1000 L autoclave, 500 kg of methanol and 60 kg of triethylamine were pumped in, and 1.0 kg of Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene dichloropalladium) was added. After purging with nitrogen, it was switched to purging with carbon monoxide once, the carbon monoxide pressure was replenished to 0.5 MPa, the temperature was raised to 50 - 60 °C and the reaction was carried out for 8 - 10 hours. Sampling was carried out to monitor the completion of the reaction. After concentration by vacuum distillation to a small volume, 200 kg of isopropanol and 200 kg of water were added, and the mixture was stirred and cooled for crystallization, followed by centrifugation to obtain 76 kg of Compound 7 (the theoretical product amount was 0.844 times the feeding amount), with a yield of 90%, and the purity detected by liquid phase was 99.5%. The 1H NMR spectrum of Compound 7 is shown in the appendix Figure 1 .
[0056] Specifically, in the present invention, Compound 2 reacts with MsCl to obtain Compound 3, and then Compound 3 and Compound 8 undergo a substitution reaction to obtain Compound 9, with a two-step yield of over 80%; Compound 9 undergoes a palladium-catalyzed carbonylation reaction to obtain Compound 7, with a yield of 90%. Compared with the traditional route, the compound 8 (CAS No.: 39903-01-0) used in the route of the present invention is commercially available and already has a bromine atom in its structure, shortening the main route. Finally, after carbonylation, the target molecule Compound 7 is obtained, with a high total yield, a simple route, and a significant reduction in cost. Therefore, this patent has great economic value and innovative processes.
[0057] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variant thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "including a..." does not exclude the existence of additional identical elements in the process, method, article or device including the said element.
[0058] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.
Claims
1. A method for synthesizing a bromopyridine intermediate for the preparation of lorlatinib, characterized in that, It includes the following steps: S1: Obtain compound 9 by the substitution reaction of compound 3 and compound 8; S2: Obtain compound 7, i.e., the key intermediate of lorlatinib, through the palladium-catalyzed carbonylation reaction of compound 9; The above synthetic route of the steps is:
2. The synthetic method of the bromopyridine intermediate for preparing lorlatinib according to claim 1, characterized in that, The said compound 3 is obtained by the reaction of compound 2 and methylsulfonyl chloride, and the specific synthetic route is:
3. The synthetic method of the bromopyridine intermediate for preparing lorlatinib according to claim 2, characterized in that, The solvents for the synthesis reaction of the said compound 3 include dichloromethane, tetrahydrofuran, acetonitrile, and toluene.
4. The synthesis method of the bromopyridine intermediate for preparing lorlatinib according to claim 3, characterized in that, The specific operation steps for the synthesis reaction of the said compound 3 include: adding the solvent dichloromethane into the reaction kettle, replacing with nitrogen, then successively adding compound 2 and triethylamine, lowering the temperature in the reaction kettle below 10 °C, and dropwise adding methylsulfonyl chloride through the high-level tank; after adding, slowly raise the temperature of the reaction solution to 15 - 25 °C and keep stirring for 3 - 4 h, monitoring the reaction by TLC until it is complete; adding water to the reaction kettle, stirring, and then standing for liquid separation; washing the obtained organic phase with water and then separating out the organic phase, and concentrating to obtain compound 3.
5. The synthesis method of the bromopyridine intermediate for preparing lorlatinib according to claim 1, characterized in that, The reaction solvents for S1 include one or a combination of two of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and acetonitrile; the bases added in the S1 reaction include sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium phosphate; the reaction temperature for S1 is 40 - 60 °C.
6. The synthesis method of the bromopyridine intermediate for preparing lorlatinib according to claim 5, characterized in that, The reaction solvent for S1 includes N-methylpyrrolidone; the base added in the S1 reaction includes sodium carbonate.
7. The synthesis method of the bromopyridine intermediate for preparing lorlatinib according to claim 6, characterized in that, The specific operation steps for S1 are: adding N-methylpyrrolidone, compound 8, and sodium carbonate into the reaction kettle of compound 3, controlling the temperature at 50 °C and reacting with stirring for 12 h; after monitoring the reaction by HPLC until it is complete, lowering the temperature of the reaction solution to 25 °C, filtering off the salt, adding water to the filtrate; precipitating the product; centrifuging and washing with water, collecting the filter cake, and drying at 50 °C to obtain the product compound 9.
8. The synthetic method of the bromopyridine intermediate for preparing lorlatinib according to claim 1, characterized in that, The palladium catalysts in the S2 reaction include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium; the reaction solvent in the S2 reaction is methanol, or a mixed solvent of methanol and tetrahydrofuran, or a mixed solvent of methanol and acetonitrile; the bases used in S2 include triethylamine or N,N-diisopropylethylamine; the carbon monoxide pressure in the S2 reaction is 0.3 to 0.8 MPa.
9. The synthetic method of the bromopyridine intermediate for preparing lorlatinib according to claim 8, wherein The palladium catalyst in the S2 reaction includes 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium; the reaction solvent in the S2 reaction is methanol; the base used in the S2 reaction includes triethylamine.
10. The synthesis method of the bromopyridine intermediate for preparing lorlatinib according to claim 9, wherein, The specific operation steps for S2 are: adding compound 9 into the autoclave, pumping in methanol and triethylamine, adding 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium, replacing with nitrogen and then switching to replace with carbon monoxide once, replenishing the carbon monoxide pressure to 0.5 MPa, raising the temperature to 50 - 60 °C and reacting for 8 - 10 hours, sampling and monitoring the reaction until it is complete; concentrating by vacuum distillation to a small volume, then adding isopropanol and water, stirring and cooling to crystallize, and centrifuging to obtain compound 7.
Citation Information
Patent Citations
Macrocyclic derivatives for the treatment of proliferative diseases
WO2013132376A1
Solid forms of a macrocyclic kinase inhibitor
WO2014207606A1