Preparation method for 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester

Abstract

A scale-up preparation method for 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester, relating to the technical field of pharmaceutical intermediates. The method comprises: using 4-piperidinecarboxaldehyde as a raw material to react with a sulfite and protecting an aldehyde group to obtain intermediate A; then performing a coupling reaction with potassium 4-boronic acid pinacol ester phenyltrifluoroborate to generate intermediate B; then performing deprotection on the intermediate B in the presence of an inorganic base to obtain intermediate C; and finally reacting the intermediate C in the presence of trimethyl orthoformate to obtain 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester. The method significantly reduces reaction steps, reduces raw material costs, has a simple and reliable process, is suitable for industrial production, and provides a new reaction route for product synthesis.

Description

A method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester Technical Field

[0001] This invention relates to the field of pharmaceuticals, specifically to a method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester. Background Technology

[0002] According to the latest 2020 Global Cancer Burden Report released by the International Agency for Research on Cancer (IARC) of the World Health Organization, breast cancer has surpassed lung cancer in the number of women diagnosed with the disease for the first time, becoming the most common cancer globally. Approximately 70% of breast cancer patients are estrogen receptor (ER) positive. Endocrine therapy plays a crucial role in the treatment of these breast cancer patients. The only marketed drug that exerts its effect through the degradation of estrogen receptors is fulvestrant; however, due to its poor water solubility and low bioavailability, it is difficult to further increase the dosage when administered via intramuscular injection. Therefore, it is essential to develop drugs with better estrogen receptor degradation effects than fulvestrant.

[0003] CRBN ligands are widely used in the preparation of protein degrading agents, and a series of PROTAC molecules based on CRBN ligands have been developed; for example, novel tetrahydronaphthalene compounds, which have demonstrated their application as estrogen receptor degrading agents in the treatment of estrogen receptor-mediated or dependent diseases.

[0004] Patent applications for PROTACs molecules based on CRBN ligands include US20180215 731, WO2019199816, WO2022166879, and CN117466870. Existing processes disclosed in these patents generally involve the removal of bromine impurities and require the use of precious metal catalysts. Precious metal catalysts are expensive and require anhydrous and oxygen-free conditions for the reaction, making the process complex. Summary of the Invention

[0005] To overcome the aforementioned technical deficiencies, this invention provides a scaled-up preparation method for pinacol ester of 4-(dimethoxymethyl-4-piperidine)phenylboronic acid. Using 4-piperidinecarboxaldehyde as a starting material and sulfite, the aldehyde group is protected to obtain intermediate A; then, it undergoes a coupling reaction with potassium phenyltrifluoroborate of pinacol ester of 4-boronic acid to generate intermediate B; subsequently, deprotection is performed in the presence of an inorganic base to obtain intermediate C; finally, the reaction is carried out in the presence of trimethyl orthoformate to obtain pinacol ester of 4-(dimethoxymethyl-4-piperidine)phenylboronic acid. This method significantly shortens the reaction steps, reduces raw material costs, and is simple, reliable, and easy to industrialize, providing a new reaction route for the synthesis of this product.

[0006] The scale-up preparation method of 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester described in this invention uses 4-piperidinecarboxaldehyde, potassium phenyltrifluoroborate of 4-boronic acid pinacol ester, and trimethyl orthoformate as raw materials, and is represented by the following reaction equation:

[0007]

[0008] The preparation method of the technical solution described in this invention consists of four steps, specifically including the following steps:

[0009] Step 1: Using sulfite and 4-piperidinecarboxaldehyde as raw materials, react in solution to obtain intermediate A;

[0010] Furthermore, in the above technical solution, the sulfite is selected from potassium bisulfite or sodium bisulfite.

[0011] Furthermore, in the above technical solution, the molar ratio of 4-piperidinecarboxaldehyde to sulfite is 1:1-2.

[0012] Step 2: Intermediate A and potassium phenyl trifluoroborate 4-boronate pinacol ester are reacted in the presence of a copper catalyst, L-proline and an organic base to generate intermediate B.

[0013] Furthermore, in the above technical solution, the organic base is selected from triethylamine, ethylenediamine, tetramethylethylenediamine, DMAP, or pyridine.

[0014] Furthermore, in the above technical solution, the copper catalyst is selected from copper acetate, copper acetate monohydrate, cuprous oxide, cuprous sulfide, copper trifluoroacetate, or cuprous iodide.

[0015] Furthermore, in the above technical solution, the organic solvent is selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, dioxane, and N,N-dimethylformamide.

[0016] Furthermore, in the above technical solution, the molar ratio of intermediate A to potassium phenyl trifluoroborate of 4-boronic acid pinacol ester, copper catalyst, L-proline and organic base is 1:1-1.5:1-2:1-2:1-2.

[0017] Optimization experiments revealed that when 4-boronic acid pinacol ester phenyl trifluoroborate potassium was replaced with 1,4-phenyldiboronic acid pinacol ester in the same reaction, the reaction was relatively slow. When the temperature was increased or the reaction time was extended, the disubstituted byproducts increased rapidly, purification became more difficult, and the reaction yield decreased significantly.

[0018] Step 3: React intermediate B and an inorganic base in an organic solvent to obtain intermediate C.

[0019] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane, ethyl acetate, acetonitrile, 2-methyltetrahydrofuran, and toluene.

[0020] Furthermore, in the above technical solution, the inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

[0021] Furthermore, in the above technical solution, the molar ratio of intermediate B to inorganic base is 1:1.5-2.5.

[0022] Step 4: Intermediate C, trimethyl orthoformate, and p-toluenesulfonic acid are reacted in an alcohol solvent to obtain 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester.

[0023] Furthermore, in the above technical solution, the alcohol solvent is selected from methanol, ethanol or isopropanol, preferably in methanol.

[0024] Furthermore, in the above technical solution, the molar ratio of intermediate C, trimethyl orthoformate, and p-toluenesulfonic acid is 1:1.5-2.5:0.01-0.05.

[0025] The method of this invention is simple, reliable, and easy to industrialize; it reduces the amount of isomers generated, increases the reaction yield, and significantly reduces the overall production cost compared to existing literature or patents, making the product more competitive in the market. Attached Figure Description

[0026] Figure 1 shows the HNMR spectrum of the product 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester obtained in Example 1; Detailed Implementation

[0027] The present invention will be further illustrated below with reference to specific embodiments. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0028] Preparation of potassium phenyltrifluoroborate of pinacol 4-boronate:

[0029] A solution of potassium fluoride (6.16 g, 106.05 mmol) in water (30 mL) was added to a solution of 1,4-benzenediboric acid pinacol ester (10 g, 30.30 mmol) in acetonitrile (50 mL). Then, a solution of L-tartaric acid (11.37 g, 75.75 mmol) in methanol (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, slurried with cold methanol (60 mL), filtered again, and dried to obtain potassium phenyl trifluoroborate 4-boronate pinacol ester (7.61 g, yield 81%). ¹H NMR (Acetone-d6, 400 MHz): 7.77 (d, 2H), 7.75 (d, 2H), 1.22 (s, 12H).

[0030] Example 1

[0031] A solution of sodium bisulfite (2.37 g, 22.80 mmol) in water (20 mL) was added to a solution of 4-piperidinecarboxaldehyde (2.58 g, 22.80 mmol) in water (20 mL) and ethanol (40 mL) at room temperature. The mixture was stirred at room temperature for 24 hours, and TLC showed that the starting material had completely reacted. After cooling, the mixture was filtered to give a white solid intermediate A (4.16 g, yield 84%).

[0032] Intermediate A (4.0 g, 18.41 mmol), potassium phenyl trifluoroborate 4-boronate (6.85 g, 22.09 mmol), copper acetate (0.17 g, 0.92 mmol), L-proline (2.12 g, 18.41 mmol), triethylamine (1.86 g, 18.41 mmol), and 4A molecular sieve (4.0 g) were added to dioxane (40 mL). The reaction system was refluxed and stirred under nitrogen protection for 5 hours. After the reaction was completed, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and all oily substances were separated by silica gel column chromatography (petroleum ether / ethyl acetate 50:1, v / v) to give intermediate B (7.1 g, 92% yield).

[0033] Sodium carbonate (3.54 g, 33.38 mmol) was added to a solution of intermediate B (7.0 g, 16.69 mmol) in tetrahydrofuran (40 mL) and water (20 mL). The reaction mixture was stirred at 75 °C for 2 hours and then cooled to room temperature. The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give intermediate C (1.41 g, 85% yield).

[0034] Intermediate C (50 g, 158.62 mmol) and trimethyl orthoformate (33.66 g, 317.24 mmol) were dissolved in methanol (250 mL), and p-toluenesulfonic acid monohydrate (40.97 g, 237.93 mmol) was added with stirring. The mixture was stirred at 25 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 7-8. Then, 500 mL of dichloromethane and 500 mL of water were added, and the mixture was stirred for 10 min. The mixture was allowed to stand for separation of layers. The aqueous phase was extracted with dichloromethane (300 mL * 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester (48.71 g, yield 85%), HPLC 99.18%. 1 H- NMR (400MHz, CDCl3): 7.68-7.70(2H), 6.89-6.90(2H), 4.05-4.07(1H), 3.80- 3.83(2H), 3.36(6H), 2.73(2H), 1.78-1.84(2H), 1.61(2H), 1.32-1.43(12H).

[0035] Example 2

[0036] A solution of sodium bisulfite (5.21 g, 50 mmol) in water (50 mL) was added to a solution of 4-piperidinecarboxaldehyde (3.77 g, 33.33 mmol) in water (40 mL) and ethanol (90 mL) at room temperature. The mixture was stirred at room temperature for 24 hours, and TLC showed that the starting material had completely reacted. After cooling, the mixture was filtered to give a white solid intermediate A (6.15 g, yield 85%).

[0037] Intermediate A (6 g, 27.62 mmol), potassium phenyl trifluoroborate 4-boronate (10.70 g, 34.52 mmol), cuprous iodide (1.58 g, 8.29 mmol), L-proline (4.77 g, 41.43 mmol), 4A molecular sieve (6.0 g), and triethylamine (4.19 g, 41.43 mmol) were added to 30 mL of 2-methyltetrahydrofuran. The reaction mixture was refluxed and stirred under nitrogen protection for 12 hours. After the reaction was complete, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and all oily substances were separated by silica gel column chromatography (petroleum ether / ethyl acetate 50:1, v / v) to give intermediate B (10.60 g, 91.5% yield).

[0038] Sodium carbonate (2.53 g, 47.7 mmol) was added to a solution of intermediate B (10 g, 23.85 mmol) in tetrahydrofuran (50 mL) and water (16 mL). The reaction mixture was stirred at 75 °C for 2 hours and then cooled to room temperature. The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give intermediate C (6.47 g, 86% yield).

[0039] Intermediate C (6 g, 19.03 mmol) and trimethyl orthoformate (4.04 g, 38.06 mmol) were dissolved in methanol (50 mL), and p-toluenesulfonic acid monohydrate (6.55 g, 38.06 mmol) was added with stirring. The mixture was stirred at 25 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 7-8, and then 50 mL of dichloromethane and 50 mL of water were added and stirred for 10 min. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with dichloromethane (50 mL * 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)piperidine (5.98 g, yield: 87%).

[0040] Example 3

[0041] A solution of potassium bisulfite (2.12 kg, 17.68 mol) in water (10 L) was added to a solution of 4-piperidinecarboxaldehyde (1 kg, 8.84 mol) in water (5 L) and ethanol (15 mL) at room temperature. The mixture was stirred at room temperature for 24 hours, and TLC showed that the starting material had completely reacted. After cooling, the mixture was filtered to give a white solid intermediate A (1.67 kg, yield 87%).

[0042] Intermediate A (1.6 kg, 7.37 mol), potassium phenyl trifluoroborate 4-boronate (3.42 kg, 11.05 mol), copper trifluoroacetate hydrate (0.72 kg, 3.68 mol), L-proline (1.70 kg, 14.74 mol), 4A molecular sieve (1.6 kg), and pyridine (1.16 kg, 14.74 mol) were added to 2-methyltetrahydrofuran (20 L). The reaction system was refluxed and stirred under nitrogen protection for 12 hours. After the reaction was completed, water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and all oily substances were separated by silica gel column chromatography (petroleum ether / ethyl acetate 50:1, v / v) to obtain intermediate B (2.85 kg, yield 92.3%).

[0043] Sodium hydroxide (0.60 kg, 14.9 mol) was added to a solution of intermediate B (2.5 kg, 5.96 mol) in tetrahydrofuran (12.5 L) and water (12.5 L). The reaction mixture was stirred at 75 °C for 2 hours and then cooled to room temperature. The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give intermediate C (1.63 kg, yield 87%).

[0044] Intermediate C (1.5 kg, 4.76 mol) and trimethyl orthoformate (0.76 kg, 7.14 mol) were dissolved in methanol (8 L), and p-toluenesulfonic acid monohydrate (1.23 kg, 7.14 mol) was added with stirring. The mixture was stirred at 25 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, saturated sodium carbonate solution was added to the reaction solution to bring the pH to 7-8. Then, 8 L of dichloromethane and 5 L of water were added, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers. The aqueous phase was extracted with dichloromethane (8 L * 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester (1.44 kg, yield 84%).

[0045] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing pinacol ester of 4-(dimethoxymethyl-4-piperidine)phenylboronic acid, characterized in that, Includes the following steps: ； Step 1: Using sulfite and 4-piperidinecarboxaldehyde as raw materials, react in solution to obtain intermediate A; Step 2: Intermediate A and potassium 4-boronate pinacol ester phenyl trifluoroborate are reacted in the presence of a copper catalyst, L-proline and an organic base to generate intermediate B; Step 3: React intermediate B with an inorganic base in an organic solvent to obtain intermediate C; Step 4: Intermediate C, trimethyl orthoformate, and p-toluenesulfonic acid are reacted in an alcohol solvent to obtain 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester.

2. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the first step, the sulfite is selected from potassium bisulfite or sodium bisulfite.

3. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the first step, the molar ratio of 4-piperidinecarboxaldehyde to sulfite is 1:1-2.

4. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the second step, the organic base is selected from triethylamine, ethylenediamine, tetramethylethylenediamine, DMAP or pyridine; acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, dioxane and N,N-dimethylformamide.

5. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the second step, the copper catalyst is selected from copper acetate, copper acetate monohydrate, cuprous oxide, cuprous sulfide, copper trifluoroacetate, or cuprous iodide.

6. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the second step, the molar ratio of intermediate A to potassium phenyl trifluoroborate 4-boronic acid pinacol ester, copper catalyst, L-proline and organic base is 1:1-1.5:1-2:1-2:1-2.

7. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the third step, the organic solvent is selected from dichloromethane, ethyl acetate, acetonitrile, 2-methyltetrahydrofuran, or toluene; the inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, and potassium hydroxide.

8. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the third step, the molar ratio of intermediate B to inorganic base is 1:1.5-2.

5.

9. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the fourth step, the alcohol solvent is methanol, ethanol, or isopropanol, preferably methanol.

10. The method for preparing 4-(dimethoxymethyl-4-piperidine)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the fourth step, the molar ratio of intermediate C, trimethyl orthoformate, and p-toluenesulfonic acid is 1:1.5-2.5:0.01-0.05.

Images