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

Abstract

The invention discloses an amplified preparation method of 4-(dimethoxymethyl-4-piperidine) phenylboronic acid pinacol ester, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: reacting 4-piperidinecarboxaldehyde serving as a raw material with sulfite, and protecting an aldehyde group to obtain an intermediate A; then carrying out a coupling reaction with 4-boric acid pinacol ester phenyl potassium trifluoroborate to generate an intermediate B; performing deprotection in the presence of inorganic alkali to obtain an intermediate C; and finally, reacting in the presence of trimethyl orthoformate to obtain the 4-(dimethoxymethyl-4-piperidine) phenylboronic acid pinacol ester. According to the method, the reaction steps are greatly shortened, the raw material cost is reduced, the process is simple and reliable, industrial production is easy, and a new reaction path is provided for synthesis of the product.

Description

Technical Field

[0001] The invention relates to the field of medicine, and in particular to a method for preparing 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester. Background Art

[0002] According to the latest global cancer burden report for 2020 released by the World Health Organization's International Agency for Research on Cancer (IARC), the number of female breast cancer cases exceeded lung cancer for the first time, becoming the most common cancer in the world. About 70% of breast cancer patients have estrogen receptor (ER)-positive breast cancer. In the treatment of these breast cancer patients, endocrine therapy plays an important role. The only marketed drug that exerts its efficacy through the mechanism of degrading estrogen receptors is Fulvestrant, but due to the poor water solubility and low bioavailability of Fulvestrant, it is difficult to further increase the dosage by intramuscular injection. Therefore, it is very necessary to develop drugs that have better estrogen receptor degradation effects than Fulvestrant.

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

[0004] Patent applications for PROTACs molecules based on CRBN ligands include US20180215731, WO2019199816, WO2022166879, CN117466870, etc. The existing processes published in existing patents generally have bromine impurities and require the use of precious metal catalysts, which are expensive and require reactions under anhydrous and oxygen-free conditions, making the process operations complicated. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention provides an enlarged preparation method of 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester. 4-piperidinyl carboxaldehyde is used as a raw material and sulfite, and the aldehyde group is protected to obtain intermediate A; then a coupling reaction is carried out with 4-boronic acid pinacol ester phenyl trifluoroborate potassium to generate intermediate B; then deprotection is carried out 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 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester. The method greatly shortens the reaction steps, reduces the cost of raw materials, has a simple and reliable process, is easy to industrialize, and provides a new reaction path for the synthesis of the product.

[0006] The enlarged preparation method of 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester of the present invention uses 4-piperidinyl carboxaldehyde, 4-boric acid pinacol ester phenyl trifluoroborate potassium and trimethyl orthoformate as raw materials, and is expressed by the following reaction equation:

[0007]

[0008] The preparation method of the technical solution of the present invention is divided into four steps, which specifically include the following steps:

[0009] The first step: using sulfite and 4-piperidinecarboxaldehyde as raw materials, reacting in a 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: react intermediate A with potassium 4-boronic acid pinacol ester phenyl trifluoroborate 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 cupric acetate, cupric 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 scheme, the molar ratio of intermediate A to 4-boric acid pinacol ester phenyl potassium trifluoroborate, copper catalyst, L-proline and organic base is 1:1-1.5:1-2:1-2:1-2.

[0017] The optimization experiment found that when 4-boric acid pinacol ester phenyl trifluoroborate potassium was replaced with 1,4-phenyldiboric acid pinacol ester for the same reaction, the reaction was relatively slow. When the temperature was increased or the reaction time was extended, the disubstituted by-products increased rapidly, purification was more difficult, and the reaction yield decreased significantly.

[0018] Step 3: react intermediate B with 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: reacting the intermediate C, trimethyl orthoformate and p-toluenesulfonic acid in an alcohol solvent to obtain 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester.

[0023] Furthermore, in the above technical solution, the alcohol solvent is selected from methanol, ethanol or isopropanol, preferably carried out 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 the invention has simple and reliable process and is easy for industrial production; the amount of isomers generated is reduced, the reaction yield is improved, the comprehensive production cost is greatly reduced compared with the production process in the existing literature or patents, and the product is more competitive in the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The HNMR spectrum of the product 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester obtained in Example 1; DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes 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 4-boric acid pinacol ester phenyl trifluoroborate potassium:

[0029] A solution of potassium fluoride (6.16 g, 106.05 mmol) in water (30 mL) was added to a solution of 1,4-phenylenediboronic acid bispinacol ester (10 g, 30.30 mmol) in acetonitrile (50 mL), and then a solution of L-tartaric acid (11.37 g, 75.75 mmol) in methanol (50 mL) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the solution was filtered, slurried with cold methanol (60 mL), filtered, and dried to obtain potassium 4-boric acid bispinacol ester phenyl trifluoroborate (7.61 g, yield 81%). HNMR (Acetone-d6, 400 HMz): 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. TLC showed that the reaction of the raw materials was complete. After cooling, the mixture was filtered to obtain a white solid intermediate A (4.16 g, yield 84%).

[0032] Intermediate A (4.0 g, 18.41 mmol), potassium 4-boronic acid pinacol ester phenyl trifluoroborate (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), and the reaction system was stirred under reflux for 5 hours under nitrogen protection. After the reaction was completed, water and ethyl acetate were added, the organic layer was separated, and the water layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and all the oily substances were separated by silica gel column chromatography (developing solvent was petroleum ether / ethyl acetate 50:1, volume ratio) to obtain intermediate B (7.1 g, yield 92%).

[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 20 mL of water. The reaction solution 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 spin-dried to obtain intermediate C (1.41 g, yield 85%).

[0034] Dissolve intermediate C (50g, 158.62mmol) and trimethyl orthoformate (33.66g, 317.24mmol) in methanol (250mL), add p-toluenesulfonic acid monohydrate (40.97g, 237.93mmol) under stirring. Stir for 3 hours at 25°C under nitrogen atmosphere. After the reaction is completed, add saturated sodium carbonate solution to the reaction solution until pH=7-8, add 500mL of dichloromethane and 500mL of water, stir for 10min, stand for separation, extract the aqueous phase with dichloromethane (300mL*2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester (48.71g, yield 85%), HPLC99.18%. 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. TLC showed that the reaction of the raw materials was complete. After cooling, the mixture was filtered to obtain a white solid intermediate A (6.15 g, yield 85%).

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

[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 16 mL of water. The reaction solution 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 spin-dried to obtain intermediate C (6.47 g, yield 86%).

[0039] Dissolve intermediate C (6 g, 19.03 mmol) and trimethyl orthoformate (4.04 g, 38.06 mmol) in methanol (50 mL), add p-toluenesulfonic acid monohydrate (6.55 g, 38.06 mmol) under stirring. Stir for 3 hours at 25 ° C under nitrogen atmosphere. After the reaction is completed, add saturated sodium carbonate solution to the reaction solution until pH = 7-8, then add 50 mL of dichloromethane and 50 mL of water and stir for 10 min, stand for separation, extract the aqueous phase with dichloromethane (50 mL * 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-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. TLC showed that the reaction of the raw materials was complete. After cooling, the mixture was filtered to obtain a white solid intermediate A (1.67 kg, yield 87%).

[0042] Intermediate A (1.6kg, 7.37mol), potassium 4-boric acid pinacol ester phenyl trifluoroborate (3.42kg, 11.05mol), copper trifluoroacetate hydrate (0.72kg, 3.68mol), L-proline (1.70kg, 14.74mol), 4A molecular sieve (1.6kg) and pyridine (1.16kg, 14.74mol) were added to 2-methyltetrahydrofuran (20L), and the reaction system was refluxed and stirred for 12 hours under nitrogen protection. After the reaction was completed, water and ethyl acetate were added, the organic layer was separated, and the water layer was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and all the oily substances were separated by silica gel column chromatography (developing solvent was petroleum ether / ethyl acetate 50:1, volume ratio) to obtain intermediate B (2.85kg, 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 solution 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 spin-dried to obtain intermediate C (1.63 kg, yield 87%).

[0044] Dissolve intermediate C (1.5kg, 4.76mol) and trimethyl orthoformate (0.76kg, 7.14mol) in methanol (8L), add p-toluenesulfonic acid monohydrate (1.23kg, 7.14mol) under stirring. Stir for 3 hours at 25°C under nitrogen atmosphere. After the reaction is completed, add saturated sodium carbonate solution to the reaction solution until pH=7-8, add 8L of dichloromethane and 5L of water, stir for 10min, stand for separation, extract the aqueous phase with dichloromethane (8L*2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester (1.44kg, 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 by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester, characterized in that: The steps include: The first step: using sulfite and 4-piperidinecarboxaldehyde as raw materials, reacting in a solution to obtain intermediate A; Step 2: reacting intermediate A with potassium 4-boronic acid pinacol ester phenyl trifluoroborate in the presence of a copper catalyst, L-proline and an organic base to generate intermediate B; Step 3: reacting intermediate B with an inorganic base in an organic solvent to obtain intermediate C; Step 4: reacting the intermediate C, trimethyl orthoformate and p-toluenesulfonic acid in an alcohol solvent to obtain 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester.

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

6. The method for preparing 4-(dimethoxymethyl-4-piperidinyl)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the second step, the molar ratio of the intermediate A to potassium 4-boric acid pinacol ester phenyl trifluoroborate, 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-piperidinyl)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; and 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-piperidinyl)phenylboronic acid pinacol ester according to claim 1, characterized in that: In the third step, the molar ratio of the intermediate B to the inorganic base is 1:1.5-2.

5.

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

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