CN111171062A

CN111171062A - Method for synthesizing 2-carboxyl sodium phenylboronate

Info

Publication number: CN111171062A
Application number: CN202010014943.5A
Authority: CN
Inventors: 刘启宾; 郑鹏
Original assignee: Dalian Shuangbo Pharmaceutical Chemical Co Ltd
Current assignee: Dalian Shuangbo Pharmaceutical Chemical Co Ltd
Priority date: 2020-01-07
Filing date: 2020-01-07
Publication date: 2020-05-19

Abstract

The invention discloses a method for synthesizing 2-carboxyl sodium phenylboronate, which comprises the following two steps: 1) taking methyl 2-bromobenzoate as a starting material, carrying out one-pot reaction on the starting material by using butyl lithium to remove bromine and triisopropyl borate or trimethyl borate to obtain a product 2-methoxycarbonylphenylboronic acid, hydrolyzing 2) 2-methoxycarbonylphenylboronic acid in a sodium hydroxide methanol solution, and pulping acetone to obtain a sodium 2-carboxyphenylboronic acid monohydrate. The method has the advantages of easily obtained raw materials, simple and convenient operation, safety, environmental protection, lower cost and higher yield.

Description

Method for synthesizing 2-carboxyl sodium phenylboronate

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing sodium 2-carboxylbenzborate.

Background

Sodium 2-carboxyphenylboronate has been widely used in drug synthesis as a coupling aid. The literature contains few sodium 2-carboxyphenylboronate synthesized by DIPHARMA FRANCIS s.r.l. US 2008/15357, 2008, A1Location in Page 3-4 and Dipharma Francis S.r.l. EP1878735,2008, A1Location in Page 6.

The first step is as follows: reacting 2-bromobenzoic acid with thionyl chloride to generate 2-bromobenzoyl chloride, then reacting with 1, 1-dimethyl amino alcohol to obtain amide, then reacting with thionyl chloride to change alcoholic hydroxyl into chlorine again, and finally adding sodium hydroxide to close a ring to generate 2-bromo-4, 4-dimethyl oxazolylbenzene.

The second step is that: 2-bromo-4, 4-dimethyloxazolylbenzene reacts with Grignard reagent or butyl lithium and trimethyl borate at ultralow temperature to obtain 4, 4-dimethyloxazolylbenzene-boronic acid dimethyl ester.

The third step: adding 4, 4-dimethyl oxazole phenylboronic acid dimethyl ester into tetrahydrofuran, refluxing, cooling to a certain temperature, adding concentrated hydrochloric acid until solid is dissolved, distilling, washing with toluene, concentrating, passing through MSC cation exchange resin, washing, adjusting pH to be =8-9 with sodium hydroxide, distilling and dehydrating, adding n-butyl alcohol for dehydration again, pulping with toluene and other complex treatments to obtain the product.

The method has long steps and is too complicated to operate, and is not suitable for being used as a preparation process of the sodium 2-carboxyl phenylboronate.

Disclosure of Invention

The invention aims to overcome the defects, and provides a method for preparing 2-sodium carboxyphenylboronate, which comprises the steps of using 2-methyl bromobenzoate as a starting material, boronizing by a butyl lithium one-pot method, carrying out aftertreatment to obtain a product 2-methoxycarbonylphenylboronic acid, hydrolyzing in a sodium hydroxide methanol solution, and pulping with acetone to obtain a 2-sodium carboxyphenylboronate monohydrate. The method has the advantages of easily obtained raw materials, simple and convenient operation, safety, environmental protection, lower cost and higher yield.

The technical scheme adopted by the invention for realizing the purpose is as follows: a method for synthesizing 2-carboxyl sodium phenylboronate comprises the following two steps:

1) taking methyl 2-bromobenzoate as a starting material, carrying out one-pot reaction on the starting material by using butyl lithium to remove bromine and triisopropyl borate or trimethyl borate to obtain a product 2-methoxycarbonylphenylboronic acid;

2) hydrolyzing the 2-methoxycarbonyl phenylboronic acid in a sodium hydroxide methanol solution, and pulping with acetone to obtain the 2-carboxyl sodium phenylboronate monohydrate.

Further, the step 1) is specifically as follows: under the protection of nitrogen, adding THF, 2-methyl bromobenzoate and trimethyl borate or triisopropyl borate, cooling to-85 to-75 ℃, dropwise adding n-butyllithium n-hexane solution, and stirring for 2 hours after dropwise adding; naturally heating up, stirring and heating up to-20-15 ℃, dropwise adding 10% hydrochloric acid aqueous solution to quench reaction, wherein heat is released in the quenching process, the temperature of the system is controlled to be lower than 0-5 ℃, the pH = 4-5, the system is layered, a tetrahydrofuran layer is separated and is decompressed and concentrated, an aqueous layer is extracted by ethyl acetate for 2 times each time, the ethyl acetate layer and the concentrated tetrahydrofuran layer are combined, the sodium chloride aqueous solution is washed once, an organic phase is concentrated to be under no flow, n-heptane is added for heating and pulping, cooling and filtering are carried out again, and a filter cake is dried to obtain the 2-methoxycarbonylphenylboronic acid.

Further, the step 2) is specifically as follows: adding 2-methoxycarbonylphenylboronic acid and methanol into a reaction kettle, dropwise adding 25% sodium hydroxide at 45-50 ℃, keeping the temperature at 45-50 ℃ for reacting for 2 hours after dropwise adding, controlling whether raw materials remain in LC (liquid chromatography) control reaction liquid, supplementing sodium hydroxide if yes, performing aftertreatment without raw materials, distilling under reduced pressure until no liquid flows, adding acetone into obtained solid, heating to 50 ℃ for pulping, then gradually cooling to 0 ℃ for pulping for 0.5 hour, filtering to obtain the solid, and drying in the air.

Further, in step 1), the amount of butyllithium used was 1 to 1.5eq based on methyl 2-bromobenzoate, but when it exceeded 1.1 equivalents, the amount of by-products increased, and the yield decreased.

Furthermore, the dosage of the sodium hydroxide in the step 2) is at least more than 1eq, and the optimal dosage is 1-1.5eq when the dosage of the 2-methoxycarbonyl phenylboronic acid is 1-1.5 eq.

The invention has the beneficial effects that: the method for synthesizing the sodium 2-carboxylbenzenesulfonate has the advantages of easily available raw materials, simple and convenient operation, safety, environmental protection, lower cost and high yield, and is suitable for industrial production.

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the specific examples.

Example 1

Under the protection of 2-nitrogen, 280g of THF, 43g of methyl 2-bromobenzoate and trimethyl borate (1.5 eq is the molar ratio) are put into a 500mL four-port bottle, the temperature is reduced to-85 to-75 ℃, 60g of n-butyl lithium n-hexane solution is added dropwise to the bottle, the bottle is kept warm and stirred for 2 hours after the dropwise addition, 10% of hydrochloric acid is sampled for quenching, and the HPLC detection raw material is less than 6.5%. Naturally heating up, stirring and heating to-20-15 ℃, dropwise adding 99g of 10% hydrochloric acid aqueous solution to quench the reaction, wherein heat is released in the quenching process, the temperature of the system is controlled to be lower than 0-5 ℃, the pH = 4-5, the system is layered, a tetrahydrofuran layer is separated and concentrated under reduced pressure, an aqueous layer is extracted with 80g of ethyl acetate each time for 2 times, the ethyl acetate layer and the concentrated tetrahydrofuran layer are combined, 15-20 g of sodium chloride aqueous solution is washed once, an organic phase is concentrated to be under no-flow liquid, 40g of n-heptane is added for heating and pulping, cooling and filtering are carried out again, 19.4g of 2-methoxycarbonylphenylboronic acid is obtained after a filter cake is dried in the air, and the yield is 54.1.

25g of 2-methoxycarbonylphenylboronic acid and 50g of methanol are added into a 250mL reaction kettle, and 22g of 25% sodium hydroxide is dropwise added at the reaction temperature of 45-50 ℃. After the dropwise addition, the temperature is kept between 45 and 50 ℃ for 2 hours of reaction, and the LC central control reaction solution is added with sodium hydroxide if the raw materials are remained. After-treatment without the remainder of the raw materials, distilling under reduced pressure to obtain a non-flowing liquid, adding 50g of acetone into the obtained solid, heating to 50 ℃ for pulping, then gradually cooling to 0 ℃ for pulping for 0.5h, filtering to obtain a solid, and airing the solid, wherein the total amount of 25.9g, the yield is 90%, and the lc is 99.8%.

Example 2

The first step is the same as in example 1

29.5g of 2-methoxycarbonylphenylboronic acid and 60g of methanol are added into a 250mL reaction kettle, and 26.2g of 25% sodium hydroxide is dropwise added at the reaction temperature of 45-50 ℃. After the dropwise addition, the temperature is kept between 45 and 50 ℃ for 2 hours of reaction, and the LC central control reaction solution is added with sodium hydroxide if the raw materials are remained. And (3) performing after-treatment without the residual raw materials, distilling under reduced pressure to obtain a non-flowing liquid, adding 60g of mother solution acetone and new acetone which are subjected to first pulping into the obtained solid, heating to 50 ℃ for pulping, then gradually cooling to 0 ℃ for pulping for 0.5h, filtering to obtain 32g of solid, and drying in the air, wherein the yield is 95% and the lc is 99.8%.

Example 3

Under the protection of 3-nitrogen, 280g of THF, 43g of methyl 2-bromobenzoate and 49g (1.28 eq) of triisopropyl borate are put into a 500mL four-port bottle, the temperature is reduced to-85 to-75 ℃, 60g of n-butyl lithium n-hexane solution is added dropwise to the bottle, the bottle is stirred for 2 hours under the condition of heat preservation after dripping, 10% of hydrochloric acid is sampled for quenching, and the HPLC detection raw material is less than 1.6%. Naturally heating up, stirring and heating to-20-15 ℃, dropwise adding 99g of 10% hydrochloric acid aqueous solution to quench the reaction, wherein heat is released in the quenching process, the temperature of the system is controlled to be lower than 0-5 ℃, the pH value is = 4-5, the system is layered, a tetrahydrofuran layer is separated and concentrated under reduced pressure, an aqueous layer is extracted with 80g of ethyl acetate each time for 2 times, the ethyl acetate layer and the concentrated tetrahydrofuran layer are combined, 15-20 g of sodium chloride aqueous solution is washed once, an organic phase is concentrated to be not flowing liquid, 40g of n-heptane is added for heating and pulping, cooling and filtering are carried out again, 26.1g of 2-methoxycarbonylphenylboronic acid is obtained after a filter cake is dried in the air, and the yield is 72.5%.

Adding 2 times of methanol by mass, heating to 40-50 ℃, dropwise adding 1eq of 30% liquid caustic soda (sodium hydroxide aqueous solution), after dropwise adding, keeping the temperature and reacting for 3 hours, keeping the pH =8, detecting the residual situation of the raw materials by HPLC, cooling after complete reaction, concentrating under reduced pressure to obtain a non-flowing liquid, adding 30g of acetone, pulping at 0-10 ℃ for 1 hour, filtering, and drying to finally obtain 27.6g of 2-sodium carboxyphenylborate. HPLC is more than 98%, HNMR structure is in accordance.

Comparative example 1

Under the protection of nitrogen, 8.4g of magnesium chips, 20g of THF, 5g of o-bromotoluene and 1g of iodine are added into the kettle. Heating to 50-60 ℃, stirring until initiating reaction, keeping the temperature at about 55 ℃, and dropwise adding 45g of o-bromotoluene and 180g of tetrahydrofuran. After the dropwise addition, the temperature is kept for 2 h. The sample was taken to quench GC, 96.3% toluene, 3.6% o-bromotoluene.

45.6g of trimethyl borate and 80g of THF were added to the kettle under nitrogen. Controlling the temperature of the reaction system to be-10 to-15 ℃, and slowly dripping the Grignard reagent into the reaction system. After the dropwise addition, the mixture is heated to room temperature and stirred for 2 hours, the temperature is controlled to be below 0 ℃, 60g of water is dropwise added for quenching, then 100g of 10% hydrochloric acid is dropwise added for acidification, the pH is =2-3, THF is distilled under reduced pressure, 100g of ethyl acetate is added into reaction liquid, kieselguhr is added for filtering insoluble substances, liquid separation is carried out, and 300g of ethyl acetate is added into a water layer for extraction twice. And combining organic layers, evaporating to dryness under reduced pressure, adding 40g of heptane, pulping for 0.5h, filtering, and airing the solid to obtain 20g of o-tolylboronic acid product, lc99%, wherein the yield is 50%.

13.6 g of 2-methylphenylboronic acid, 150mL (50 mL of 50% NaOH +100mL of water) of sodium hydroxide solution was added, followed by heating to 50 ℃. A solution of potassium permanganate, 36 g +400mL of water, was added in six portions over a period of 1 hour. Maintained at 50 degrees for 3 hours. Then cooling to 0 deg.C, adding concentrated hydrochloric acid to adjust pH =8, filtering to remove MnO₂Then, concentrated hydrochloric acid was added to the filtrate to adjust the pH =2, the solution was evaporated to dryness, and 500mL of acetone was added. Filtering salt, evaporating the solution to dryness to obtain a crude product, adding 3g of sodium hydroxide and 50g of water, stirring for 2 hours at a room temperature, evaporating water until a large amount of solid is separated out, cooling to 0 ℃, pulping, filtering the solid, and drying in the air to obtain 12.5g of the product with the yield of 60%.

In the first step of the comparison example, the yield is up to 50% by adopting a one-pot method for reacting the methyl 2-bromobenzoate with the trimethyl borate, and the yield is up to 72.5% by adopting the triisopropyl borate, so that the yield is improved by 20%, and the possibility of nucleophilic reaction between the added n-butyl lithium and the methyl carboxylate in the raw material in a step method is avoided, thereby improving the yield. In the second step of the comparative example, 2-methylphenylboronic acid was prepared from o-bromotoluene as a raw material and trimethyl borate, and then oxidized under potassium permanganate conditions, which resulted in a lower yield than the previous method and a larger amount of waste solids.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and their concepts should be equivalent or changed within the technical scope of the present invention.

Claims

1. A method for synthesizing 2-sodium carboxyphenylboronic acid is characterized in that 1) methyl 2-bromobenzoate is used as a starting material, butyl lithium is used for removing bromine, the methyl 2-bromobenzoate reacts with triisopropyl borate or trimethyl borate by a one-pot method to obtain a product 2-methoxycarbonylphenylboronic acid, 2) the 2-methoxycarbonylphenylboronic acid is hydrolyzed in sodium hydroxide methanol solution, and acetone is used for pulping to obtain 2-sodium carboxyphenylboronic acid monohydrate.

2. The method for synthesizing sodium 2-carboxyphenylboronate as claimed in claim 1, wherein step 1) is specifically: under the protection of nitrogen, adding THF, 2-methyl bromobenzoate and trimethyl borate or triisopropyl borate, cooling to-85 to-75 ℃, dropwise adding n-butyllithium n-hexane solution, and stirring for 2 hours after dropwise adding; naturally heating up, stirring and heating up to-20-15 ℃, dropwise adding 10% hydrochloric acid aqueous solution to quench reaction, wherein heat is released in the quenching process, the temperature of the system is controlled to be lower than 0-5 ℃, the pH = 4-5, the system is layered, a tetrahydrofuran layer is separated and is decompressed and concentrated, an aqueous layer is extracted by ethyl acetate for 2 times each time, the ethyl acetate layer and the concentrated tetrahydrofuran layer are combined, the sodium chloride aqueous solution is washed once, an organic phase is concentrated to be under no flow, n-heptane is added for heating and pulping, cooling and filtering are carried out again, and a filter cake is dried to obtain the 2-methoxycarbonylphenylboronic acid.

3. The method for synthesizing sodium 2-carboxyphenylboronate as claimed in claim 1, wherein step 2) is specifically: adding 2-methoxycarbonylphenylboronic acid and methanol into a reaction kettle, dropwise adding 25% sodium hydroxide at 45-50 ℃, keeping the temperature at 45-50 ℃ for reacting for 2 hours after dropwise adding, controlling whether raw materials remain in LC (liquid chromatography) control reaction liquid, supplementing sodium hydroxide if yes, performing aftertreatment without raw materials, distilling under reduced pressure until no liquid flows, adding acetone into obtained solid, heating to 50 ℃ for pulping, then gradually cooling to 0 ℃ for pulping for 0.5 hour, filtering to obtain the solid, and drying in the air.

4. The method for synthesizing sodium 2-carboxyphenylboronate as claimed in claim 1, wherein in step 1), the amount of butyl lithium is 1 to 1.5eq based on methyl 2-bromobenzoate.

5. A process for preparing sodium 2-carboxyphenylboronate as claimed in claim 3 or 4, characterized in that: and in the step 2), the dosage of the sodium hydroxide is 1-1.5eq of that of the 2-methoxycarbonylphenylboronic acid.