Preparation method of sinocarbamate intermediate

Abstract

The invention provides a method for preparing a sinocarbamate intermediate as shown in a formula IV, which comprises the following steps: S3, carrying out substitution reaction on a compound as shown in a formula III and tetrazole salt to obtain a compound as shown in a formula IV and a compound as shown in a formula V; wherein R is hydrogen or alkyl, preferably hydrogen or C1-4 alkyl, and more preferably hydrogen or methyl. Under the reaction conditions, the selectivity of the compound as shown in the formula IV in the ketone compound can be improved, the product yield can be improved, the cost can be reduced, and the high-purity sinocarbamate intermediate can be obtained after post-treatment.

Description

Technical Field

[0001] This invention relates to the preparation of a pharmaceutical intermediate, specifically to a method for preparing a sinoaluminate intermediate. Background Technology

[0002] Cenobamate, a novel tetrazolium carbamate derivative developed by SK Biopharmaceuticals of South Korea, was launched in the United States on November 21, 2019. It exhibits significant clinical advantages in the treatment of focal epilepsy in adults. Studies have shown that cenobamate inhibits sustained sodium ion currents and possesses broad-spectrum anticonvulsant activity, effectively suppressing epilepsy in focal epilepsy models. Simultaneously, it exerts its antiepileptic effect by modulating γ-aminobutyric acid (GABA) receptors to inhibit nerve impulses, reducing neuronal excitability.

[0003] The preparation route proposed by the original research company in compound patent CN200680013472.4 is as follows:

[0004]

[0005] Starting with (R)-2-chlorostyrene, a ring-opening reaction was carried out with 1H-tetrazole to obtain the intermediate (R)-alcohol compound (compound of formula IV), which was then acylated to give the product cinnoamino ester.

[0006] This method suffers from poor selectivity during ring-opening because 1H-tetrazole has two reaction sites, generating not only the desired 2-position nitrogen-substituted derivative but also an isomer with a 1-position nitrogen-substituted derivative. Furthermore, the physicochemical properties of these two isomers are very similar, making separation difficult. Therefore, the original research company subsequently improved the synthetic route of cinnoamino ester in its published process patents CN200980160004.3 and CN201080046299.4.

[0007]

[0008] This route uses 2-bromo-2'-chloroacetophenone as a starting material, which reacts with 1H-tetrazole to generate a mixture containing two ketone isomers (referred to as 2N ketone and 1N ketone in the patent). These two isomers have different solubilities in different solvents and can be separated by stepwise crystallization to obtain pure 2N ketone (compound of formula IV). Chiral reduction then yields an (R)-alcohol compound, which is finally acylated to give cinnoamino ester.

[0009] This method achieves the separation of two isomer mixtures relatively easily, but the reaction selectivity is not high. As seen in the examples provided in the patent, the amounts of 2N ketone (compound IV) and 1N ketone (compound V) produced are essentially the same. This results in low material utilization, and the presence of numerous isomer impurities further increases the difficulty of separation and reduces efficiency. The original research company has made further improvements in this area. In patent US16 / 662547, a method is proposed to first prepare 1H-tetrazole into a tetrazolium potassium salt before reacting it with 2-bromo-2'-chloroacetophenone, which can improve the selectivity from 5:5 to 6:4. Although this is an improvement, the overall selectivity is still relatively low. Therefore, improvements to the existing process have significant practical value. Summary of the Invention

[0010] The problem the invention aims to solve

[0011] To address the aforementioned problems in the existing technology, the technical issue to be resolved is to overcome the poor selectivity in the preparation of intermediates in the existing technology, and to provide a new method for preparing cinnoamino ester intermediates. When the leaving group is changed from bromine to sulfonate ester during the substitution reaction with tetrazolium, the selectivity of the substitution position can be improved, and a product with higher purity can be obtained.

[0012] Solution for solving the problem

[0013] Therefore, the present invention provides the following technical solution:

[0014] This invention provides a method for preparing the sinoamine intermediate as shown in Formula IV, comprising the following steps:

[0015] S3: Compound III undergoes a substitution reaction with a tetrazolium salt to give compounds IV and V.

[0016]

[0017] Wherein, R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

[0018] Preferably, in step S3, the tetrazolium salt is obtained by reacting tetrazolium with a base.

[0019] Preferably, the alkali is added to the reaction in batches.

[0020] Preferably, the alkali is an inorganic alkali.

[0021] Preferably, the inorganic base is a metal hydroxide or a metal carbonate; more preferably, it is one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; more preferably, it is potassium carbonate or cesium carbonate.

[0022] Preferably, step S3 further includes a post-processing step.

[0023] Preferably, the post-processing step involves obtaining compound IV via a stepwise crystallization method.

[0024] Preferably, the stepwise crystallization includes a first-step crystallization and a second-step crystallization.

[0025] Preferably, the solvent used in the first crystallization step is water or C. 1-4 One or more of the following: lower alcohols, diethyl ether, methyl tert-butyl ether, isopropyl ether, pentane, hexane, cyclohexane, and heptane; preferably methyl tert-butyl ether or isopropyl ether.

[0026] Preferably, the solvent used in the second crystallization step is acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C 1-4 One or more of the lower alcohols; preferably C10. 1-4 Lower alcohols; more preferably anhydrous ethanol or isopropanol.

[0027] Preferably, the above preparation method further includes the following steps:

[0028] S2: Compound II reacts with reagent A via a condensation reaction to yield compound III;

[0029]

[0030] The structural formula of reagent A is:

[0031]

[0032] R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

[0033] Preferably, the condensation reaction in step S2 is carried out in the presence of an acid-binding agent.

[0034] Preferably, the acid-binding agent is an organic base, preferably triethylamine or pyridine.

[0035] Preferably, the above preparation method further includes the following steps:

[0036] S1: Compound I is hydrolyzed in the presence of a base to give compound II;

[0037]

[0038] Preferably, the alkali is one or more of sodium oxalate, sodium acetate, sodium bicarbonate, and sodium formate, and more preferably sodium formate.

[0039] The effects of the invention

[0040] 1. The method provided by this invention can significantly improve the position selectivity in the preparation of ketone intermediates of cinnoamino esters, improve the selectivity of Formula IV compounds, increase the utilization rate of materials, increase yield and reduce costs.

[0041] 2. As the content of the desired product in the reaction solution increases, the separation difficulty is reduced. With simple operation, a good yield and high purity of the cinuo amino ester intermediate as shown in Formula IV can be obtained, which meets the quality requirements and reduces the quality risk of the final product. Attached Figure Description

[0042] Figure 1 The image shows the MS chromatogram of the product (compound of formula IV) from Example 1.

[0043] Figure 2 The image shows the 1H-NMR spectrum of the product (compound of formula IV) from Example 1.

[0044] Figure 3 The image shows the C-NMR spectrum of the product (compound of formula IV) from Example 1. Detailed Implementation

[0045] To make the technical solutions and beneficial effects of this disclosure more apparent and understandable, a detailed description is provided below by citing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0046] This disclosure provides a method for preparing a sinoamine intermediate as shown in Formula IV, comprising the following steps:

[0047] S3: Compound III undergoes a substitution reaction with a tetrazolium salt to give compounds IV and V.

[0048]

[0049] Wherein, R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

[0050] In some embodiments, the tetrazolium salt in step S3 is obtained by reacting tetrazolium with a base.

[0051] In some embodiments, the base is added to the reaction in batches.

[0052] In some embodiments, the base is an inorganic base.

[0053] In some embodiments, the inorganic base is a metal hydroxide or a metal carbonate; preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; more preferably potassium carbonate or cesium carbonate.

[0054] In some implementations, step S3 further includes a post-processing step.

[0055] In some embodiments, the post-processing step is to obtain compound of formula IV by a stepwise crystallization method.

[0056] In some embodiments, the stepwise crystallization includes a first-step crystallization and a second-step crystallization.

[0057] In some embodiments, the solvent used in the first crystallization step is water, C 1-4 One or more of the following: lower alcohols, diethyl ether, methyl tert-butyl ether, isopropyl ether, pentane, hexane, cyclohexane, and heptane.

[0058] In some embodiments, the solvent used in the first step of crystallization is methyl tert-butyl ether.

[0059] In some embodiments, the solvent used in the first crystallization step is isopropyl ether.

[0060] In some embodiments, the solvent used for the second crystallization step is acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C 1-4 One or more of the lower alcohols.

[0061] In some embodiments, the solvent used in the second crystallization step is C 1-4 Lower alcohols.

[0062] In some implementations, the solvent used for the second crystallization step is anhydrous ethanol.

[0063] In some embodiments, isopropanol is used as the solvent for the second crystallization step.

[0064] In some embodiments, the above preparation method further includes the following steps:

[0065] S2: Compound II reacts with reagent A via a condensation reaction to yield compound III;

[0066]

[0067] The structural formula of reagent A is:

[0068]

[0069] R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

[0070] In some embodiments, the condensation reaction in step S2 is carried out in the presence of an acid-binding agent.

[0071] In some embodiments, the acid-binding agent is an organic base.

[0072] In some embodiments, the acid-binding agent is triethylamine.

[0073] In some embodiments, the acid-binding agent is pyridine.

[0074] In some embodiments, the above preparation method further includes the following steps:

[0075] S1: Compound I is hydrolyzed in the presence of a base to give compound II;

[0076]

[0077] In some embodiments, the base is one or more selected from sodium oxalate, sodium acetate, sodium bicarbonate, and sodium formate.

[0078] In some embodiments, the base is sodium formate.

[0079] The method of the present invention will be described below through specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0080] The following examples 1 The 1H-NMR spectra were obtained using an OXFORD Quantum-I instrument (500 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H-NMR representation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, its unit is Hz.

[0081] Mass spectrometry results were obtained using an Agilent 1290-6470 triple quadrupole liquid chromatography-mass spectrometry system, with ESI as the ionization mode.

[0082] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0083] In the following examples, unless otherwise specified, all temperatures are in Celsius; unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods; commercially available materials and reagents are used directly without further purification; unless otherwise specified, commercially available manufacturers include, but are not limited to, Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., and Shanghai Mairui Chemical Technology Co., Ltd.

[0084] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0085] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0086] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0087] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0088] The material and equipment information involved in the embodiments and comparative examples are shown in Tables 1 and 2 below.

[0089] Table 1 Material Information

[0090]

[0091]

[0092] Table 2 Equipment Information

[0093] Instrument Name model Electronic balance Shanghai Balance Instruments YP202N Thermostatic heating stirrer DF-101S Rotary evaporator BUCHIR-300 Vacuum drying oven Shanghai Jinghong DZF-6050 High performance liquid chromatography ThermoUltimate3000 mass spectrometer Agilent 1290-6470 Triple Quadrupole Liquid Chromatography-Mass Spectrometer Nuclear magnetic resonance spectrometer OXFORD Quantum-I

[0094] Example 1

[0095] This embodiment provides a preparation route for the sinoaluminate intermediate as shown in Formula IV, and its reaction equation and preparation method are as follows:

[0096]

[0097] (1) 2-Bromo-2'-chloroacetophenone (116.8 g, 0.5 mol), sodium formate (170 g, 2.5 mol), and 85% ethanol (1500 mL) were heated under reflux for 10 hours. The ethanol was evaporated under reduced pressure, and the residue was separated by adding water (500 mL) and dichloromethane (200 mL). The aqueous phase was extracted again with dichloromethane (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was transferred to a reaction flask. Triethylamine (50.6 g, 0.5 mol) was added, and the mixture was cooled to 0–5 °C. P-toluenesulfonyl chloride (95.3 g, 0.5 mol) was added in portions with stirring, and the mixture was then allowed to rise to room temperature for 2 hours. The mixture was washed with water (200 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. After evaporation under reduced pressure, the organic layer was dissolved in ethyl acetate (500 mL).

[0098] (2) 1H-tetrazole (35.0 g, 0.5 mol) was added to water (100 ml) and remained suspended. Anhydrous potassium carbonate (75.6 g, 0.55 mol) was added in portions with stirring. After the solid was completely dissolved, the mixture was evaporated to dryness under reduced pressure. Then, 100 ml of anhydrous ethanol was added and distillation was continued to remove water. The ethyl acetate solution from the previous step was added, and the reaction was carried out at 40–45 °C for 15 hours. HPLC analysis showed that the normalized content ratio of compound IV to compound V in the reaction solution was 75:16.

[0099] Cool to room temperature and wash with 10% saline solution (200 ml). Concentrate the organic layer under reduced pressure, add methyl tert-butyl ether (300 ml), reflux to dissolve, cool to precipitate solid, filter, and the filter cake mainly consists of compound of formula V.

[0100] After the filtrate was evaporated to dryness under reduced pressure, the residue was recrystallized with anhydrous ethanol (200 ml) to give 62.6 g of product compound IV, with a yield of 56.2% and a purity of 98.4% (HPLC normalization method, the content of isomer compound V was 1.4%).

[0101] ESI(+)-MS: m / z = 223.1 [M+H] + .

[0102] 1 H-NMR (DMSO-d6, 500MHz): 9.08(s,1H), 8.04(m,1H), 7.65(m,1H), 7.64(m,1H), 7.55(m,1H), 6.55(s,2H).

[0103] 13 C-NMR (DMSO-d6, 500MHz): 192.3, 153.5, 134.0, 133.8, 131.0, 130.8, 130.2, 127.5, 60.3.

[0104] The HPLC normalization chromatographic conditions are as follows:

[0105]

[0106] Example 2

[0107] This embodiment provides a preparation route for the sinoaluminate intermediate as shown in Formula IV, and its reaction equation and preparation method are as follows:

[0108]

[0109] (1) 2-Bromo-2'-chloroacetophenone (70.1 g, 0.3 mol), sodium formate (110 g, 1.6 mol), and 85% ethanol (1000 mL) were heated under reflux for 12 hours. The mixture was concentrated under reduced pressure, and the residue was separated by adding water (300 mL) and dichloromethane (150 mL). The aqueous phase was extracted again with dichloromethane (50 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was transferred to a reaction flask. Pyridine (23.7 g, 0.3 mol) was added, and the mixture was cooled to 0–5 °C. Benzenesulfonyl chloride (52.3 g, 0.3 mol) was added dropwise with stirring. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 2 hours. The mixture was washed with water (100 mL × 3), and the organic layer was dried over anhydrous sodium sulfate. After evaporation under reduced pressure, the mixture was dissolved in ethyl acetate (300 mL).

[0110] (2) 1H-tetrazole (21.0 g, 0.3 mol) was added to water (80 ml) and remained suspended. Anhydrous cesium carbonate (107.4 g, 0.33 mol) was added in portions with stirring. After the solid was completely dissolved, it was evaporated to dryness under reduced pressure. Then, 50 ml of anhydrous ethanol was added and distillation was continued to remove water. The ethyl acetate solution from the previous step was added, and the reaction was carried out at 40–45 °C for 12 hours. HPLC analysis showed that the normalized content ratio of compound IV to compound V in the reaction solution was 75:17.

[0111] Cool to room temperature and wash with 10% saline solution (100 ml). Concentrate the organic layer under reduced pressure, add isopropyl ether (200 ml), reflux to dissolve, cool to precipitate solid, filter, and the filter cake mainly consists of compound of formula V.

[0112] After the filtrate was evaporated to dryness under reduced pressure, the residue was recrystallized from isopropanol (150 ml) to give 35.6 g of product compound IV, with a yield of 53.4% ​​and a purity of 98.1% (HPLC normalization method, the content of isomer compound V was 1.8%).

[0113] Comparative Example 1

[0114] Patents CN200980160004.3 and CN201080046299.4 disclose a method for preparing 2N ketone, the reaction equation and preparation method of which are as follows:

[0115]

[0116] A DMF solution of 1H-tetrazole (215.1 g, 1.080 mol) was added to a suspension of 2-bromo-2'-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 ml). The mixture was stirred at 45 °C for 2 hours, and approximately 1500 ml of solvent was evaporated under reduced pressure. Ethyl acetate (2000 ml) was added, followed by washing with 10% saline solution (2000 ml × 3). The organic phase was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (432 ml). Heptane (600 ml) was slowly added, and crystallization occurred at room temperature. The solution was filtered to obtain compound V (90.1 g, 0.405 mol). The filtrate was concentrated under reduced pressure, dissolved in isopropanol (100 ml), and heptane (400 ml) was added. The mixture was cooled, crystallized, and filtered to obtain compound IV (94.7 g, 0.425 mol).

[0117] Comparative Example 2

[0118] US16 / 662547 discloses a method for preparing 2N ketone, and the reaction equation and preparation method are as follows:

[0119]

[0120] Tetrazazole (0.165 g) was dissolved in methanol (9 ml), and potassium carbonate (0.538 g) was added. The mixture was stirred at room temperature for 15 minutes. The methanol was evaporated, and butyl acetate (9 ml) was added, followed by 2-bromo-2'-chloroacetophenone (0.50 g). The mixture was reacted at 50 °C for 12 hours. HPLC analysis showed selectivity of 40% for compound V and 60% for compound IV.

[0121] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A method for preparing a sinoamine ester intermediate as shown in Formula IV, characterized in that, It includes the following steps: S3: The compound of formula III undergoes a substitution reaction with a tetrazolium salt to obtain a compound of formula IV and a compound of formula V; Wherein, R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

2. The preparation method according to claim 1, characterized in that, In the step S3, the tetrazolium salt is obtained by reacting tetrazole with a base; Preferably, the base is added to the reaction in batches.

3. The preparation method according to claim 2, characterized in that, The base is an inorganic base; Preferably, the inorganic base is a metal hydroxide or a metal carbonate; preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; more preferably potassium carbonate or cesium carbonate.

4. The preparation method according to any one of claims 1-3, characterized in that, The step S3 further includes a post-treatment step; Preferably, the post-treatment step is to obtain the compound of formula IV by a fractional crystallization method.

5. The preparation method according to any one of claims 4, characterized in that, The fractional crystallization includes a first crystallization and a second crystallization.

6. The preparation method according to claim 5, characterized in that, The solvent used in the first crystallization step is water and C. 1-4 One or more of the following: lower alcohols, diethyl ether, methyl tert-butyl ether, isopropyl ether, pentane, hexane, cyclohexane, and heptane; preferably methyl tert-butyl ether or isopropyl ether; Preferably, the solvent used in the second crystallization step is acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, n-butyl acetate, dichloromethane, chloroform, 1,4-dioxane, C 1-4 One or more of the lower alcohols; preferably C10. 1-4 Lower alcohols; more preferably anhydrous ethanol or isopropanol.

7. The preparation method according to any one of claims 1-6, characterized in that, It also includes the following steps: S2: The compound of formula II undergoes a condensation reaction with reagent A to obtain a compound of formula III; Among them, the structural formula of reagent A is: R is hydrogen or alkyl, preferably hydrogen or C. 1-4 Alkyl, more preferably hydrogen or methyl.

8. The preparation method according to claim 7, characterized in that, The condensation reaction in the step S2 is carried out in the presence of an acid-binding agent; Preferably, the acid-binding agent is an organic base, preferably triethylamine or pyridine.

9. The preparation method according to any one of claims 7-8, characterized in that, It also includes the following steps: S1: The compound of formula I undergoes a hydrolysis reaction in the presence of a base to obtain a compound of formula II; 10. The preparation method according to claim 9, characterized in that, The base is one or more of sodium oxalate, sodium acetate, sodium bicarbonate, sodium formate, preferably sodium formate.

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