A method for preparing pyridine boronic esters

Abstract

The application provides a preparation method of 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborinane-2-yl)pyridine. The method can reduce the use amount of borate, reduce the cost, reduce the three wastes, and make the effective content of the product higher.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing pyridine borate ester, an intermediate for GLP-1 receptor agonists. Background Technology

[0002] (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxane-hexeno[2,3-g]isoquinoline-8-formylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid dihydrochloride is a non-peptide small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with the molecular formula C 50 H 49 Cl4N3O6 has a molecular weight of 929.76. (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxane-hexeno[2,3-g]isoquinoline-8-formylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid dihydrochloride contains four chiral centers. Among them, (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester dichloride is the last chiral center introduced in the synthesis and is a key intermediate in its preparation process.

[0003] CN102378574A discloses a method for synthesizing the free base of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxane-[2,3-g]isoquinoline-8-formylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid. Specifically, it discloses that (S)-2-amino-3-[4-(2,3-dimethylpyridin-4-yl)phenyl]propionic acid methyl ester dihydrochloride (IV) is prepared from (S)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester VI as the starting material through a three-step reaction including Suzuki coupling and deprotection. The method requires column chromatography for separation and purification, with an overall yield of only 49%. Furthermore, compound IX is expensive, and only gram-scale raw materials are available on the market, making it difficult to apply industrially.

[0004]

[0005] To achieve industrial application, researchers have developed two synthetic routes suitable for industrial use, as shown below. Both new processes use the intermediate 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridine (i.e., compound III). The preparation of compound III in the literature (WO2015153720A1) also uses compound IX as a starting material and couples it with di(pinacolyl)diboron. Due to the limited yield of compound IX, this method is not suitable for industrial application.

[0006]

[0007] Of the two newly developed routes, 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine (compound III) is prepared by coupling pyridine nitride XIII, which is relatively inexpensive and readily available, with di(pinacol)diboron. In this reaction, di(pinacol)diboron acts as both a deoxygenating agent and a coupling agent, resulting in a large consumption amount (more than 2 equivalents). It accounts for approximately 33% of the cost, making it a high-consumption material with a high selling price, directly impacting the overall process cost. Furthermore, the large-scale use of di(pinacol)diboron generates significant boric acid waste, placing considerable pressure on post-processing. Therefore, further optimization is urgently needed to find a more efficient method to prepare compound III, reducing the amount of borate esters used, lowering costs, and reducing waste. Summary of the Invention

[0008] This invention provides a novel method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine (compound III), which reduces the amount of borate ester used, lowers costs, and reduces waste.

[0009] The method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine (compound III) provided by the present invention includes the following steps:

[0010] 1) Compound XIII undergoes deoxygenation under the action of a reducing agent to generate intermediate A;

[0011] 2) Intermediate A undergoes a coupling reaction with di(pinacol)diboron in the presence of an organic acid salt and a catalyst to generate compound III.

[0012]

[0013] In one specific implementation, the reducing agent used in step 1) is selected from Fe, Fe / NH4Cl, Fe / AcOH, Fe / HCl, Zn / HCl, Zn / AcOH or PCl3.

[0014] As a specific implementation method, the reducing agent used in step 1) is preferably Fe / NH4Cl.

[0015] As one specific implementation, the reaction solvent used in step 1) is selected from any one of methanol, ethanol, n-propanol, tetrahydrofuran and water mixed solution.

[0016] As a specific implementation method, the reaction solvent used in step 1) is preferably ethanol / water.

[0017] In one specific implementation, the molar ratio of compound XIII to reducing agent in step 1) is 1:1.5 to 1:5.

[0018] In one specific implementation, the molar ratio of compound XIII to reducing agent in step 1) is preferably 1:2 to 1:3.

[0019] As one specific implementation method, post-processing can be performed after the reaction in step 1) is completed.

[0020] As a specific implementation method, the post-processing method of step 1) is as follows: after the reaction is completed, filter, concentrate to remove the organic solvent, extract to remove the aqueous phase, dry the organic phase, filter, and concentrate; wherein, the extraction reagent is selected from dichloromethane or ethyl acetate; and the drying reagent is sodium sulfate.

[0021] In one specific implementation, the reaction solvent in step 2) is selected from xylene or toluene.

[0022] As a specific implementation method, the reaction solvent in step 2) is preferably xylene.

[0023] In one specific implementation, the catalyst in step 2) is selected from palladium catalyst or a mixture of palladium catalyst and organophosphorus ligand; the palladium catalyst is selected from Pd2(dba)3, PdCl2(PPh3)2, Pd(OAc)2, and the organophosphorus ligand is selected from one or more of PCy3, PPh3, n-Bu3P, and P(OMe)3.

[0024] As a specific implementation, the catalyst in step 2) is preferably a mixed system of Pd2(dba)3 and PCy3.

[0025] As one specific implementation, the organic acid salt used in step 2) is selected from potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L-potassium tartrate, L-sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate.

[0026] As a specific implementation, the organic acid salt used in step 2) is preferably potassium acetate.

[0027] In one specific implementation, the molar ratio of compound A to di(pinacol)diboron in step 2) is 1:1 to 1:1.2.

[0028] As one specific implementation, the reaction temperature in step 2) is selected from 90 to 130°C.

[0029] As a specific implementation method, post-processing should be performed after the reaction in step 2) is completed.

[0030] As a specific implementation method, the post-processing method of step 2) is as follows: after the reaction is completed, an organic solvent is added and stirred, the insoluble matter is filtered out, then an acid solution is added to the filtrate to remove the organic layer, the acid water layer is washed, the pH of the acid water layer is adjusted to 8-9 with a dilute alkaline solution, filtered, and dried to obtain solid compound III; wherein, the organic solvent is selected from any one of heptane, n-hexane, and cyclohexane; the washing reagent is selected from dichloromethane or ethyl acetate.

[0031] The beneficial effects of this invention are as follows: By changing the deoxygenation method to use a reducing agent for deoxygenation followed by a coupling reaction, the amount of di(pinacol)diboron can be reduced by more than half, thereby significantly reducing raw material costs. Simultaneously, post-processing is simplified, and products with higher purity and thus higher effective content are obtained. Detailed Implementation

[0032] Experimental methods not specified in the embodiments of the present invention are generally under conventional conditions or according to the conditions recommended by the raw material or product manufacturer; reagents not specified in their source are generally commercially available conventional reagents or can be prepared from known reagents by conventional methods.

[0033] The present invention will be further described in detail below with reference to specific embodiments.

[0034] Example 1: Preparation of Compound III

[0035] Compound XIII (20 g, 126.9 mmol, 1 eq), iron powder (17.56 g, 317.26 mmol, 2.5 eq), ammonium chloride (20.4 g, 317.25 mmol, 2.5 eq), 6 mL of water, and 60 mL of methanol were added to a reaction flask. The mixture was reacted under nitrogen protection at 65 °C for 5 h. After the reaction was complete, the iron powder was filtered off, the ethanol was evaporated, and the mixture was extracted with 50 mL of water and dichloromethane (3 × 80 mL). The extract was washed with saturated brine (2 × 100 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 16.09 g of a yellow liquid. The yield was 89.5%, and the purity was 99.8%.

[0036] Intermediate A (11.74 g, 82.91 mmol, 1 eq) was added to toluene, followed by di(pinacol)diboron (23.16 g, 91.2 mmol, 1.1 eq), then potassium acetate (24.41 g, 248.73 mmol, 3 eq), Pd2(dba)3 (152 mg, 0.17 mmol, 0.002 eq), and PCy3 (186 mg, 0.66 mmol, 0.008 eq). The reaction was carried out under nitrogen protection at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, diluted with heptane, stirred for 1 h, filtered, and the solution was extracted with 2N dilute hydrochloric acid, washed twice with dichloromethane, and the pH of the aqueous phase was adjusted to 8–9 with saturated sodium carbonate. The mixture was filtered and dried to give 21.12 g of white solid. The yield was 94%, and the purity was 99%.

[0037] Example 2

[0038] Compound XIII (20 g, 126.9 mmol, 1 eq), iron powder (17.56 g, 317.26 mmol, 2.5 eq), acetic acid (19.05 g, 317.25 mmol, 2.5 eq), 6 mL of water, and 60 mL of methanol were added to a reaction flask. The mixture was reacted under nitrogen protection at 65 °C for 5 h. After the reaction was complete, the iron powder was filtered off, the ethanol was evaporated, and 50 mL of water was added. The mixture was then extracted with dichloromethane. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 13.48 g of a yellow liquid. The yield was 75.0%, and the purity was 98.8%.

[0039] Intermediate A (11.74 g, 82.91 mmol, 1 eq) was added to toluene, followed by di(pinacol)diboron (23.16 g, 91.2 mmol, 1.1 eq), then potassium acetate (24.41 g, 248.73 mmol, 3 eq), Pd2(dba)3 (152 mg, 0.17 mmol, 0.002 eq), and PCy3 (186 mg, 0.66 mmol, 0.008 eq). The reaction was carried out under nitrogen protection at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, diluted with heptane, stirred for 1 h, filtered, and the solution was extracted with 2N dilute hydrochloric acid, washed twice with dichloromethane, and the pH of the aqueous phase was adjusted to 8–9 with saturated sodium carbonate. The mixture was filtered and dried to give 21.12 g of white solid. The yield was 94%, and the purity was 99%.

[0040] Example 3

[0041] Compound XIII (20 g, 126.9 mmol, 1 eq), iron powder (17.56 g, 317.26 mmol, 2.5 eq), ammonium chloride (20.4 g, 317.25 mmol, 2.5 eq), 6 mL of water, and 60 mL of methanol were added to a reaction flask. The mixture was reacted under nitrogen protection at 65 °C for 5 h. After the reaction was complete, the iron powder was filtered off, the ethanol was evaporated, and 50 mL of water was added. The mixture was extracted with dichloromethane. The solution was washed with saturated brine (2 × 100 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 16.09 g of a yellow liquid. The yield was 89.5%, and the purity was 99.8%.

[0042] Intermediate A (11.74 g, 82.91 mmol, 1 eq) was added to toluene, followed by di(pinacol)diboron (23.16 g, 91.2 mmol, 1.1 eq), then potassium acetate (24.41 g, 248.73 mmol, 3 eq) and PdCl2(PPh3)2 (1.19 g, 1.7 mmol, 0.02 eq). The reaction was carried out under nitrogen protection at 100 °C. After the reaction was completed, the mixture was cooled to room temperature, diluted with heptane (80 mL), stirred for 1 h, filtered, and the solution was extracted with 2N dilute hydrochloric acid (3 × 100 mL). The solution was washed twice with dichloromethane (50 mL), and the pH of the aqueous phase was adjusted to 8–9 with saturated sodium carbonate. The mixture was filtered and dried to give 21.56 g of white solid. The yield was 96%, and the purity was 99.2%.

[0043] The above embodiments are only used to understand the method and core idea of ​​the present invention, and are not intended to limit the scope of the present invention. For those skilled in the art, any possible changes or substitutions made without departing from the concept of the present invention are within the protection scope of the present invention.

Claims

1. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine, comprising the following steps: 1) Compound XIII undergoes deoxygenation under the action of a reducing agent to generate intermediate A, wherein the reducing agent is selected from Fe / NH4Cl, Fe / AcOH, Fe / HCl, Zn / HCl, Zn / AcOH, and PCl3; 2) The intermediate A undergoes a coupling reaction with di(pinacol)diboron in the presence of an organic acid salt and a catalyst to generate 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyridine, wherein the catalyst is selected from palladium catalysts and mixed systems of palladium catalysts and organophosphorus ligands, wherein the palladium catalyst is selected from Pd2(dba)3, PdCl2(PPh3)2 and Pd(OAc)2, and the organophosphorus ligand is selected from one or more of PCy3, PPh3, n-Bu3P and P(OMe)3.

2. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, The reducing agent in step 1) is Fe / NH4Cl; And / or, the reaction solvent in step 1) is selected from any one of methanol, ethanol, n-propanol, tetrahydrofuran and water mixture.

3. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 2, wherein the reaction solvent in step 1) is ethanol / aqueous solution.

4. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, In step 1), the molar ratio of compound XIII to the reducing agent is 1:1.5 to 1:

5.

5. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 4, wherein, In step 1), the molar ratio of compound XIII to the reducing agent is 1:2 to 1:

3.

6. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, The reaction solvent in step 2) is xylene or toluene.

7. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 6, wherein, The reaction solvent in step 2) is xylene.

8. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, The catalyst added in step 2) is a mixture of Pd2(dba)3 and PCy3.

9. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, The organic acid salt added in step 2) is selected from potassium acetate, sodium acetate, potassium oxalate, sodium oxalate, sodium citrate, potassium citrate, L-potassium tartrate, L-sodium tartrate, potassium malate, sodium malate, potassium succinate, sodium succinate, potassium maleate, and sodium maleate.

10. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 9, wherein, The organic acid salt added in step 2) is potassium acetate.

11. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, In step 2), the molar ratio of intermediate A to di(pinacol)diboron is 1:1 to 1:1.

2. And / or, the reaction temperature of step 2) is 90~130℃.

12. A method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in claim 1, wherein, Post-processing is performed after step 1) and / or step 2) are completed.

13. The use of the method for preparing 2,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)pyridine as described in any one of claims 1 to 12 in the preparation of (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-((S)-1-phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxane-[2,3-g]isoquinoline-8-formylamino)-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionic acid.

Images