Synthesis method of 5-bromine-2-methyl benzoic acid

Abstract

The invention provides a synthesis method of 5-bromine-2-methyl benzoic acid, o-toluic acid and a bromination reagent are subjected to bromination reaction in an oxidizing solvent, the bromination reagent is HBr, and the oxidizing solvent is a sodium hypochlorite solution. The synthesis method provided by the invention is simple and convenient in process, strong in operability, easy to control and capable of remarkably improving the production efficiency and reducing the production cost, thereby having a good large-scale industrial application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediates, and in particular to a method for synthesizing 5-bromo-2-methylbenzoic acid. Background Art

[0002] Approximately 100 million people worldwide suffer from type 2 diabetes mellitus (NIDDM), which is characterized by hyperglycemia caused by excessive hepatic glucose secretion and peripheral insulin resistance, and the underlying cause is still unclear. Hyperglycemia is considered a major risk factor for the development of diabetic complications and may directly lead to impairment of insulin secretion in late-stage NIDDM.

[0003] Sustained control of plasma glucose levels in patients with diabetes could counteract the development of diabetic complications and beta-cell failure in advanced disease. Plasma glucose is normally reabsorbed in the glomeruli of the kidney and actively reabsorbed in the anterior tubules, and the sodium-dependent glucose transporter (SGLT2) in the kidney appears to be the major transporter responsible for glucose reuptake at this site. O-glucoside-SGLT-specific inhibitors, phlorizin or closely related analogs, inhibit this reuptake process in diabetic rodents and dogs, normalizing plasma glucose levels by promoting glucose excretion without hypoglycemic side effects. Chronic (6 months) treatment of Zucker diabetic rats with O-glucoside-SGLT2 inhibitors has been reported to improve insulin responses to blood glucose, increase insulin sensitivity, and delay the onset of nephropathy and neuropathy in these animals, without detectable pathology in the kidneys and without electrolyte imbalances in the plasma. Therefore, selective inhibition of SGLT2 in patients with diabetes is expected to improve insulin sensitivity and delay the development of diabetic complications by normalizing blood glucose through enhanced excretion of glucose in the urine.

[0004] C-aryl glucoside is a SGLT2 inhibitor found in the intestine and kidney, which can treat diabetes (especially type II diabetes) and related diseases such as hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, etc. C-aryl glucoside can be used alone or in combination with one, two or more other types of antidiabetic drugs and / or one, two or more other types of therapeutic drugs (such as lipid-lowering drugs).

[0005] Canagliflozin is an important C-arylglucoside SGLT2 inhibitor with the following structural formula:

[0006]

[0007] 5-Bromo-2-methylbenzoic acid is the starting material for the synthesis of canagliflozin, with a CAS number of 79669-49-1, a molecular weight of 215.05, a molecular formula of C8H7BrO2, and a structural formula as follows:

[0008]

[0009] At present, the preparation method of 5-bromo-2-methylbenzoic acid mainly comprises the following steps (as reported in patents WO 2002083066, WO2005100351, and US20070203116): using o-methylbenzoic acid as a raw material, reacting in the presence of iron powder-bromine to prepare 5-bromo-2-methylbenzoic acid. The selectivity of such reaction is poor, and the obtained bromination product contains a large amount of ortho-isomer (i.e., 3-bromo-2-methylbenzoic acid), the proportion of which can be as high as 40%. Due to the high content of by-products, the purification pressure is huge, and the yield loss is very obvious. Summary of the invention

[0010] In order to make up for the deficiencies in the prior art, the purpose of the present invention is to provide a method for synthesizing 5-bromo-2-methylbenzoic acid, which can effectively reduce the proportion of ortho-isomer by-products and improve the yield of the target product, thereby providing a process method with great application potential for the production of 5-bromo-2-methylbenzoic acid.

[0011] The synthesis method of 5-bromo-2-methylbenzoic acid provided by the present invention comprises: o-methylbenzoic acid and a brominating agent are subjected to bromination reaction in an oxidizing solvent to obtain the 5-bromo-2-methylbenzoic acid, wherein the brominating agent is HBr and the oxidizing solvent is a sodium hypochlorite solution.

[0012] The synthesis method provided by the present invention may also include: under alkaline conditions (i.e., in the presence of alkaline substances), o-toluic acid and a brominating agent are subjected to a brominating reaction in an oxidizing solvent to obtain the product, wherein the brominating agent is HBr and the oxidizing solvent is a sodium hypochlorite solution.

[0013] In the synthesis method provided by the present invention, the alkaline substance can be one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

[0014] In the synthesis method provided by the present invention, the molar ratio of the o-toluic acid to the brominating agent can be 1:1 to 3, for example, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.5, about 1:3 or any molar ratio interval. In some preferred embodiments, the molar ratio of the o-toluic acid to the brominating agent can be 1:1 to 1.5, for example, about 1:1.2.

[0015] In the synthesis method provided by the present invention, in molar ratio, the amount ratio of the o-toluic acid to the alkaline substance can be 1:0.5-2, for example, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2 or any molar ratio interval. In some preferred embodiments, in molar ratio, the amount ratio of the o-toluic acid to the alkaline substance can be 1:0.8-1.5, for example, about 1:1.15.

[0016] In the synthesis method provided by the present invention, the molar ratio of the o-toluic acid to the sodium hypochlorite can be 1:1 to 3, for example, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2, about 1:2.5, about 1:3 or any molar ratio interval. In some preferred embodiments, the molar ratio of the o-toluic acid to the sodium hypochlorite can be 1:1 to 1.5, for example, about 1:1.25.

[0017] In the synthesis method provided by the present invention, the reaction temperature of the bromination reaction can be 10 to 50° C., for example, about 10° C., about 20° C., about 30° C., about 40° C., about 50° C., or any temperature range. In some preferred embodiments, the reaction temperature of the bromination reaction can be 20 to 30° C.

[0018] The synthesis method provided by the present invention may further include the following process: mixing o-toluic acid with a solution of a brominating agent, then adding a solution of an alkaline substance, and then adding an oxidizing solvent to carry out a brominating reaction. Adding the brominating agent first and then adding the alkaline substance can avoid the formation of a salt between o-toluic acid and the alkaline substance, which makes it difficult to carry out a subsequent brominating reaction after the salt is formed.

[0019] In the synthesis method provided by the present invention, the solution of the bromination reagent can be an HBr solution with a mass percentage concentration of 40-50%, for example, it can be an HBr solution with a mass percentage concentration of 48%.

[0020] In the synthesis method provided by the present invention, the solution of the alkaline substance can be a sodium hydroxide solution with a mass percentage concentration of 1 to 20%, for example, a sodium hydroxide solution with a mass percentage concentration of 5 to 15%.

[0021] In the synthesis method provided by the present invention, the oxidizing solvent may be a sodium hypochlorite solution having a mass percent concentration of at least 5%, for example, a sodium hypochlorite solution having a mass percent concentration of 5 to 10%.

[0022] The synthesis method provided by the present invention also includes the following process: after the bromination reaction is completed, the reaction is quenched, the reaction solution is extracted with an organic solvent, the obtained extract is concentrated to obtain a crude product, and the crude product is recrystallized at least once to obtain purified 5-bromo-2-methylbenzoic acid.

[0023] In the synthesis method provided by the present invention, the organic solvent may be methyl tert-butyl ether.

[0024] In the synthesis method provided by the present invention, the recrystallization can use toluene as the crystallization solvent.

[0025] In the synthesis method provided by the present invention, the number of recrystallizations can be 1 to 3 times.

[0026] The synthesis method provided by the present invention preferably comprises the following steps: mixing o-methylbenzoic acid and a hydrobromic acid solution with a mass percentage concentration of 40-50%, dripping a sodium hydroxide solution with a mass percentage concentration of 5-15% at 20-30° C., stirring for 5-30 minutes after the dripping, dripping a sodium hypochlorite solution with a mass percentage concentration of 5-10% at 20-30° C., keeping the temperature for reaction after the dripping, dripping a sodium bisulfite solution with a mass percentage concentration of 5-15% at 20-30° C. after the reaction, quenching, adding hydrochloric acid at 0-5° C. to adjust the pH value, adding methyl tert-butyl ether for extraction, desolventizing the obtained extract, and recrystallizing the crude product with toluene to obtain 5-bromo-2-methylbenzoic acid.

[0027] In the synthesis method provided by the present invention, the desired material can be obtained through a separation step, for example, a precipitate can be separated, and the separation equipment or method can be a common equipment or method in the art, including but not limited to natural sedimentation, (normal pressure or vacuum) filtration, centrifugation and the like and their common equipment.

[0028] The technical solution provided by the present invention has the following advantages:

[0029] Compared with the existing "iron powder-bromine" synthesis system, the synthesis method provided by the present invention adopts the "HBr-sodium hypochlorite" reaction system, which can effectively reduce the proportion of ortho-isomer by-products when preparing 5-bromo-2-methylbenzoic acid, and can also inhibit the generation of dibromo impurities, thereby greatly improving the yield of the target product and reducing the subsequent purification pressure. In addition, the synthesis system of the present invention does not need to use reagents such as bromine and iron powder, and the operation safety is higher and the environment is more friendly. In summary, the synthesis method provided by the present invention has simple process, strong operability, easy control, can significantly improve production efficiency and reduce production costs, and therefore has good prospects for large-scale industrial applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The HPLC spectrum of the target product prepared in Example 1. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0032] Unless otherwise specified, the raw materials or reagents used in the examples and comparative examples of the present invention are commercially available products.

[0033] The percentages used in the embodiments and comparative examples of the present invention are all mass percentages unless otherwise specified.

[0034] Example 1 Synthesis of 5-bromo-2-methylbenzoic acid

[0035]

[0036] Add 100 g of o-toluic acid and 149 g of 48% hydrobromic acid solution to a 3L reaction bottle, control the internal temperature at 20-25°C, add 500 g of 10% potassium hydroxide solution dropwise, stir for 10 min after the addition, add 1350 g of 5% sodium hypochlorite solution dropwise at 20-25°C, stir for 1 h after the addition, and the reaction is completed. Take the reaction solution for central control detection (HPLC detection). At 20-25°C, 390g of 10% sodium bisulfite solution was added dropwise to quench, stirred for 30min, 102g of 30% hydrochloric acid was added at 0-5°C, stirred for 10min, 600g of methyl tert-butyl ether was added for extraction, stirred for 30min, the aqueous layer was separated and extracted again with 200g of methyl tert-butyl ether, the organic layers were combined, the solvent was removed under reduced pressure, 872g of toluene was added to the obtained crude product, the temperature was raised to 60°C to dissolve, the temperature was slowly lowered to 20-25°C, stirred for 1h, filtered, 453g of toluene was added to the filter cake, the temperature was raised to 60°C, the temperature was kept for 1h, the temperature was lowered to 20-25°C, stirred for 1h, filtered, the wet product was vacuum dried at 40-50°C for 24h, and 86.9g of product was obtained, with a yield of 55%. After testing, the molar ratio of 5-bromo-2-methylbenzoic acid to 3-bromo-2-methylbenzoic acid in the reaction solution was 70:15.

[0037] like Figure 1 As shown, the obtained 5-bromo-2-methylbenzoic acid product has good purity.

[0038] Example 2 Synthesis of 5-bromo-2-methylbenzoic acid

[0039]

[0040] To a 500mL reaction bottle, add 10g of o-toluic acid and 12.4g of 48% hydrobromic acid solution, control the internal temperature at 10°C, add 21g of 20% potassium tert-butoxide solution dropwise, stir for 10min after the addition, add 108g of 5% sodium hypochlorite solution dropwise at 10°C, stir for 1h after the addition, and the reaction is completed. Take the reaction solution for in-process control detection (HPLC detection). At 20-25°C, 39g of 10% sodium bisulfite solution was added dropwise to quench, stirred for 30min, 10.2g of 30% hydrochloric acid was added at 0-5°C, stirred for 10min, 60g of methyl tert-butyl ether was added for extraction, stirred for 30min, the aqueous layer was separated and extracted again with 20g of methyl tert-butyl ether, the organic layers were combined, the solvent was removed under reduced pressure, 87.2g of toluene was added to the obtained crude product, the temperature was raised to 60°C to dissolve, the temperature was slowly lowered to 20-25°C, stirred for 1h, filtered, 45.3g of toluene was added to the filter cake, the temperature was raised to 60°C, the temperature was kept for 1h, the temperature was lowered to 20-25°C, stirred for 1h, filtered, the wet product was vacuum dried at 40-50°C for 24h, and 7.11g of product was obtained, with a yield of 45%. After testing, the molar ratio of 5-bromo-2-methylbenzoic acid to 3-bromo-2-methylbenzoic acid in the reaction solution was 60:16.

[0041] Example 3 Synthesis of 5-bromo-2-methylbenzoic acid

[0042]

[0043] To a 500mL reaction bottle, add 10g of o-toluic acid and 37.2g of 48% hydrobromic acid solution, control the internal temperature at 50°C, add 155g of 10% sodium carbonate solution dropwise, stir for 10min after the addition, add 324g of 5% sodium hypochlorite solution dropwise at 50°C, stir for 1h after the addition, and the reaction is completed. Take the reaction solution for in-process control detection (HPLC detection). At 20-25°C, 78g of 10% sodium bisulfite solution was added dropwise to quench, stirred for 30min, 20.4g of 30% hydrochloric acid was added at 0-5°C, stirred for 10min, 60g of methyl tert-butyl ether was added for extraction, stirred for 30min, the aqueous layer was separated and extracted again with 20g of methyl tert-butyl ether, the organic layers were combined, the solvent was removed under reduced pressure, 87.2g of toluene was added to the obtained crude product, the temperature was raised to 60°C to dissolve, the temperature was slowly lowered to 20-25°C, stirred for 1h, filtered, 45.3g of toluene was added to the filter cake, the temperature was raised to 60°C, the temperature was kept for 1h, the temperature was lowered to 20-25°C, stirred for 1h, filtered, the wet product was vacuum dried at 40-50°C for 24h, and 6.32g of product was obtained, with a yield of 40%. After testing, the molar ratio of 5-bromo-2-methylbenzoic acid to 3-bromo-2-methylbenzoic acid in the reaction solution was 55:15.

[0044] Comparative Example 1 Synthesis of 5-bromo-2-methylbenzoic acid

[0045]

[0046] Add 40mL of bromine and 3.2g of iron powder to a 250mL reaction bottle, stir, add 10g of o-methylbenzoic acid under an ice bath, return to room temperature, and stir the reaction for 2h. After the reaction is completed, pour the reaction solution into water, filter, and dry the filter cake at 50°C. Add 100mL of ethanol to the solid, stir to dissolve, add 160mL of 0.1N dilute hydrochloric acid, stir, and filter. The crude product is recrystallized from ethanol to obtain 3g of finished product with a yield of 19%. After testing, the molar ratio of 5-bromo-2-methylbenzoic acid to 3-bromo-2-methylbenzoic acid in the reaction solution is 60:40.

[0047] Comparative Example 2 Synthesis of 5-bromo-2-methylbenzoic acid

[0048]

[0049] Add 10 g of o-toluic acid and 13.5 g of 48% hydrobromic acid solution into a 250 mL reaction bottle, stir, add 9.2 g of hydrogen peroxide dropwise in an ice bath, return to room temperature after addition, stir and react for 2 h. After testing, only a product with a purity of 10% was produced under this condition.

[0050] It can be seen from Comparative Example 1 that, relative to the existing "iron powder-bromine" synthesis system, the synthesis method provided by the present invention can significantly reduce the proportion of ortho isomers, and the yield of the target product is greatly improved. It can be seen from Comparative Example 2 that the selection of the oxidizing solvent is crucial for the bromination reaction. In other common oxidant solutions (such as hydrogen peroxide), the bromination reaction is difficult to proceed.

[0051] Unless otherwise defined, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0052] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above embodiments, but is only limited by the claims.

Claims

1. A method for synthesizing 5-bromo-2-methylbenzoic acid, characterized in that: The o-methylbenzoic acid and a brominating agent are subjected to a brominating reaction in an oxidizing solvent to obtain the product, wherein the brominating agent is HBr and the oxidizing solvent is a sodium hypochlorite solution.

2. The synthesis method according to claim 1, characterized in that The synthesis method comprises the following steps: under alkaline conditions, o-toluic acid and a bromination reagent are subjected to a bromination reaction in an oxidizing solvent.

3. The synthesis method according to claim 2, characterized in that The alkaline substance is selected from one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

4. The synthesis method according to any one of claims 1 to 3, characterized in that In terms of molar ratio, the usage ratio of o-toluic acid to the bromination reagent is 1:1 to 3, preferably 1:1 to 1.

5.

5. The synthesis method according to any one of claims 2 to 4, characterized in that In terms of molar ratio, the usage ratio of the o-toluic acid to the alkaline substance is 1:0.5-2, preferably 1:0.8-1.

5.

6. The synthesis method according to any one of claims 1 to 5, characterized in that In terms of molar ratio, the usage ratio of o-toluic acid to sodium hypochlorite is 1:1-3, preferably 1:1-1.

5.

7. The synthesis method according to any one of claims 1 to 6, characterized in that The reaction temperature of the bromination reaction is 10-50°C, preferably 20-30°C.

8. The synthesis method according to any one of claims 1 to 7, characterized in that The synthesis method also includes the following process: after the bromination reaction is completed, the reaction is quenched, the reaction solution is extracted with an organic solvent, the obtained extract is concentrated to obtain a crude product, and the crude product is recrystallized at least once to obtain purified 5-bromo-2-methylbenzoic acid.

9. The synthesis method according to claim 8, characterized in that The organic solvent is methyl tert-butyl ether.

10. The synthesis method according to claim 8, characterized in that: The recrystallization uses toluene as a crystallization solvent; Preferably, the recrystallization is performed 1 to 3 times.

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