Synthesis method of bromo-pyrazole intermediate for preparing loratinib

Abstract

The invention provides a synthetic method of a bromo-pyrazole intermediate for preparing loratinib, which comprises the following steps: 1, adding a solvent and a compound 19 into a reaction kettle, and then adding a bromination reagent N-bromo-succinimide in batches to synthesize a compound 14; 2, adding dichloromethane, the compound 14 and triethylamine into a reaction kettle, and then dropwise adding trifluoroacetic anhydride to synthesize a compound 15, namely the key intermediate bromo-pyrazole of the loratinib; according to the synthetic method of the bromo-pyrazole intermediate for preparing the loratinib, the adopted starting materials are low in price, the route is simple, the yield is high, the purity is good, the cost is reduced by 40% or above compared with an existing synthetic route, the production cost can be greatly reduced, and the industrial competitiveness is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and specifically to a synthesis method of a bromopyrazole intermediate for the preparation of lorlatinib. Background Art

[0002] Lorlatinib is a targeted therapy drug for the treatment of certain types of non-small cell lung cancer (NSCLC), and its proton nuclear magnetic resonance spectrum is as Figure 1 shown; it is a small molecule anaplastic lymphoma kinase (ALK) and ROS1 inhibitor developed by Pfizer; lorlatinib can penetrate the blood-brain barrier and is effective against tumor cells in the central nervous system;

[0003] It has been approved in many countries and regions around the world, and is based on its significant efficacy and acceptable safety shown in multiple clinical trials for patients with advanced ALK-positive NSCLC. Due to its unique mechanism of action, high treatment efficacy, 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;

[0004] Multiple patent documents have disclosed multiple routes for the synthesis of lorlatinib. For example, in patent WO2014207606, the following route for the synthesis of lorlatinib is disclosed, and the synthesis route is as Figure 5 shown: The key intermediate compound 15 is used in the route; the synthesis process of compound 15 given in patent WO2014207606 is very cumbersome, and the synthesis route is as Figure 6 shown. The synthesis steps are long, the starting materials are expensive and difficult to obtain, and a solvent with relatively high toxicity such as dichloroethane is used, and dangerous reagents such as methylamine and sodium amide are also used. The route yield is low and the cost is very high. After searching the literature, there are relatively few reported synthesis schemes for compound 15, and a simple and low-cost synthesis scheme is urgently needed. Summary of the Invention

[0005] Aiming at the deficiencies existing in the prior art, the purpose of the present invention is to provide a synthesis method of a bromopyrazole intermediate for the preparation of lorlatinib, which can solve the existing problems.

[0006] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0007] The present invention is implemented through the following technical solutions:

[0008] A synthesis method of a bromopyrazole intermediate for the preparation of lorlatinib, comprising the following steps:

[0009] Step 1: Add a solvent and compound 19 to a reaction kettle, and then add the brominating reagent N-bromosuccinimide in batches to synthesize compound 14;

[0010] Step 2: Add dichloromethane, Compound 14 and triethylamine into the reaction kettle, and then dropwise add trifluoroacetic anhydride to synthesize Compound 15, namely the key intermediate of lorlatinib, bromopyrazole.

[0011] The synthetic route of the above steps is as follows:

[0012]

[0013] Further, the solvent includes any one or a combination of two or more of acetonitrile, dichloromethane or tetrahydrofuran.

[0014] Further, the solvent includes dichloromethane.

[0015] Further, the brominating agent uses dibromohydantoin or bromine to replace N-bromosuccinimide.

[0016] Further, the specific operation steps of Step 1 are as follows: Add dichloromethane into the reaction kettle, add Compound 19, stir and dissolve at room temperature, then cool down to 0-10°C, start to add N-bromosuccinimide in batches, after adding, stir for 4-5 hours and then take a sample to detect that the reaction is complete; add 3% aqueous sodium sulfite solution, stir and then separate the liquid, separate the organic phase, wash it with water, concentrate it, and then crystallize by adding n-heptane, and filter to obtain Compound 14.

[0017] Further, the specific operation steps of Step 2 are as follows: Add dichloromethane, Compound 14 and triethylamine into the reaction kettle, cool the reaction to 0-5°C under nitrogen protection, slowly dropwise add trifluoroacetic anhydride to the reaction, keep the temperature not higher than 10°C, after dropping, slowly warm up to room temperature, monitor and show that the reaction is over, slowly dropwise add water to quench, let it stand and separate the layers, collect the organic layer, extract the aqueous phase with dichloromethane, combine the organic phases, wash with water and then wash with saturated brine, separate the organic phase and evaporate to dryness, and add methyl tert-butyl ether for crystallization to obtain Compound 15.

[0018] Compared with the prior art, the beneficial effects of the present invention include:

[0019] The present invention provides a synthetic method of the bromopyrazole intermediate for the preparation of lorlatinib. The starting materials used in the present invention are low in price, the route is simple, the yield is high and the purity is good. The cost is more than 40% lower than the existing synthetic route, which can greatly reduce the production cost and improve the industry competitiveness. Description of the Drawings

[0020] 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 the description of the embodiments or the prior art. Obviously, the drawings in the following description 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.

[0021] Figure 1 1H NMR spectrum of lorlatinib in the embodiment of the present invention;

[0022] Figure 2 1H NMR spectrum of compound 14 in the embodiment of the present invention;

[0023] Figure 3 1H NMR spectrum of compound 15 in the embodiment of the present invention;

[0024] Figure 4 Liquid chromatography spectrum of compound 15 in the embodiment of the present invention;

[0025] Figure 5 Route diagram of Scheme 1 in the background technology;

[0026] Figure 6 Route diagram for synthesizing compound 15 in the background technology. Detailed implementation manners

[0027] 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. 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 belong to the scope of protection of the present invention.

[0028] The present invention provides a method for synthesizing a bromopyrazole intermediate for the preparation of lorlatinib, comprising the following steps:

[0029] Step 1: Add a solvent and compound 19 into a reaction kettle, and then add the brominating reagent N-bromosuccinimide in batches to synthesize compound 14; the specific operation steps are as follows: Add dichloromethane into the reaction kettle, add compound 19, stir and dissolve at room temperature, then cool down to 0-10 °C, start adding N-bromosuccinimide in batches, after adding, stir for 4-5 hours and then take a sample to detect that the reaction is complete; add 3% aqueous sodium sulfite solution, stir and then separate the liquid, separate the organic phase, wash it with water, concentrate, and then crystallize by adding n-heptane, and filter to obtain compound 14.

[0030] Step 2: Add dichloromethane, Compound 14 and triethylamine (TEA) into the reaction kettle, and then dropwise add trifluoroacetic anhydride (TFAA) to synthesize Compound 15, namely the key intermediate of lorlatinib, bromopyrazole. The specific operation steps are as follows: Add dichloromethane, Compound 14, and triethylamine into the reaction kettle. The reaction is cooled to 0 - 5 °C under nitrogen protection. Trifluoroacetic anhydride is slowly dropped into the reaction while maintaining the temperature not higher than 10 °C. After the addition is complete, the temperature is slowly raised to room temperature. When the monitoring shows that the reaction is over, slowly add water to quench the reaction. Let it stand for phase separation, collect the organic layer. The aqueous phase is extracted with dichloromethane. After combining the organic phases, wash with water and then with saturated brine. The separated organic phase is evaporated to dryness and methyl tert-butyl ether is added for crystallization to obtain Compound 15.

[0031] The synthetic routes of Step 1 and Step 2 are as follows:

[0032]

[0033] The solvents described in the present invention include any one or a combination of two or more of acetonitrile, dichloromethane or tetrahydrofuran; preferably, the solvent includes dichloromethane.

[0034] In the present invention, the brominating reagent replaces N-bromosuccinimide with 1,3-dibromo-5,5-dimethylhydantoin or bromine. Preferably, the brominating reagent is N-bromosuccinimide.

[0035] Next, the preparation method of the present invention will be specifically disclosed in combination with implementation cases:

[0036] Synthesize Compound 14, and the nuclear magnetic resonance hydrogen spectrum of Compound 14 is as Figure 2 shown; Next, how to obtain Compound 14 will be specifically introduced; the specific synthetic route is as follows:

[0037]

[0038] tert-butyl((5-carbamoyl-1-methyl-1H-pyrazol-3-yl)methyl)(methyl)carbamate (Compound 19, CAS: 1643141-19-8) is used as a raw material to synthesize Compound 14, and Compound 19 can be prepared according to the method in the examples of Patent WO2014207606.

[0039]

[0040] The specific reaction is: the bromination reaction of Compound 19, which can be carried out with brominating reagents such as N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin or bromine. Taking NBS as the brominating reagent as an example for illustration;

[0041] In solvents such as acetonitrile, dichloromethane, or tetrahydrofuran, or in any two of the above three solvents mixed, or in a mixture of all three solvents; Compound 14 is synthesized by adding a brominating reagent in batches. Taking dichloromethane as the solvent as an example for illustration;

[0042] The specific operation steps are as follows: Add 60 liters of dichloromethane (10 v / w) to a 100 L reaction kettle, add Compound 19 (6 kg, 22.36 mol, 1.0 eq), stir and dissolve at room temperature, then cool to 0 - 10 °C. Start adding N-bromosuccinimide (4.8 kg, 26.8 mol, 1.2 eq) in batches. After adding, stir for 4 - 5 hours and then take a sample to detect that the reaction is complete. Add an aqueous solution of 3% sodium sulfite, stir and then separate the layers. The organic phase is separated, washed with water, concentrated, and then crystallized by adding n-heptane. Filter to obtain 6.99 kg of Compound 14 (theoretical yield 7.77 kg, yield 90%), purity 99%. The NMR spectrum of Compound 14 is shown in the appendix Figure 1 .

[0043] (2) Synthesis of Compound 15: Then, Compound 15 is conveniently synthesized from the obtained 14, with a purity of over 99% and a high yield.

[0044] The specific operation steps for the second-step synthesis of Compound 15 are as follows: Add dichloromethane, Compound 14, and triethylamine to the reaction kettle. The reaction is cooled to 0 - 5 °C under nitrogen protection. Trifluoroacetic anhydride is slowly added dropwise to the reaction, keeping the temperature not higher than 10 °C. After the addition is complete, slowly warm up to room temperature. Monitoring shows that the reaction is over. Slowly add water to quench the reaction, let it stand and separate the layers. Collect the organic layer. The aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water and saturated brine, and the separated organic phase is evaporated to dryness and methyl tert-butyl ether is added for crystallization to obtain Compound 15, with a yield of 90% and a purity of 99.8%. The NMR spectrum of the synthesized Compound 15 is as shown in Figure 3 shown and the liquid chromatography spectrum of the synthesized Compound 15 is as shown in Figure 4 shown.

[0045] The present invention provides a synthesis method for a bromopyrazole intermediate for the preparation of lorlatinib, that is, a preparation method for bromopyrazole. The starting materials used in the preparation method of the present invention are low in price, the route is concise, the yield is high, the purity is good, and the cost is more than 40% lower than the existing synthesis route, which can greatly reduce the production cost and improve the industry competitiveness.

[0046] It should be noted that in this text, 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 term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising an..." does not exclude the presence of additional identical elements in the process, method, article or device comprising said element.

[0047] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended 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 described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A synthesis method of a bromopyrazole intermediate for the preparation of lorlatinib, characterized in that, It includes the following steps: Step 1: Add a solvent and Compound 19 into a reaction kettle, and then add the brominating reagent N-bromosuccinimide in batches to synthesize Compound 14; Step 2: Add dichloromethane, Compound 14 and triethylamine into a reaction kettle, and then dropwise add trifluoroacetic anhydride to synthesize Compound 15, that is, the key intermediate of lorlatinib, bromopyrazole; The synthetic route of the above steps is:

2. The synthetic method of the bromopyrazole intermediate for preparing lorlatinib according to claim 1, characterized in that, The solvent includes any one or a combination of two or more of acetonitrile, dichloromethane or tetrahydrofuran.

3. The synthesis method of the bromopyrazole intermediate for preparing lorlatinib according to claim 2, characterized in that, The solvent includes dichloromethane.

4. The synthesis method of the bromopyrazole intermediate for preparing lorlatinib according to claim 1, characterized in that, The brominating reagent is replaced with dibromo hydantoin or bromine instead of N-bromosuccinimide.

5. The synthetic method of the bromopyrazole intermediate for preparing lorlatinib according to claim 3, characterized in that, The specific operation steps of Step 1 are: Add dichloromethane into a reaction kettle, add Compound 19, stir and dissolve at room temperature, then cool down to 0-10°C, start to add N-bromosuccinimide in batches, after adding, stir for 4-5 hours and then take a sample to detect that the reaction is complete; add 3% aqueous sodium sulfite solution, stir and then separate the liquid, separate the organic phase, wash it with water, concentrate it, and then crystallize by adding n-heptane, and filter to obtain Compound 14.

6. The synthetic method of the bromopyrazole intermediate for preparing lorlatinib according to claim 5, wherein, The specific operation steps of Step 2 are: Add dichloromethane, Compound 14 and triethylamine into a reaction kettle, cool the reaction to 0-5°C under nitrogen protection, slowly dropwise add trifluoroacetic anhydride to the reaction, keep the temperature not higher than 10°C, after dropping, slowly warm up to room temperature, monitor and show that the reaction is over, slowly dropwise add water to quench, let it stand and separate layers, collect the organic layer, extract the aqueous phase with dichloromethane, combine the organic phases, wash with water, wash with saturated brine, separate the organic phase and evaporate to dryness, and add methyl tert-butyl ether for crystallization to obtain Compound 15.

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