CN101519411B - Method for preparing phenylboronic acid-2-methyl formate - Google Patents
Method for preparing phenylboronic acid-2-methyl formate Download PDFInfo
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Abstract
The invention relates to a method for preparing phenylboronic acid-2-methyl formate. A starting material is a commercial raw material on the market or easy-to-prepare bromobenzoic acid methyl ester; aThe invention relates to a method for preparing phenylboronic acid-2-methyl formate. A starting material is a commercial raw material on the market or easy-to-prepare bromobenzoic acid methyl ester; and under a condition of low temperature, n-butyl lithium is dripped into a mixture of the main raw material of bromobenzoic acid methyl ester and a boric acid ester compound to form the phenylboronic nd under a condition of low temperature, n-butyl lithium is dripped into a mixture of the main raw material of bromobenzoic acid methyl ester and a boric acid ester compound to form the phenylboronic acid-2-methyl formate through hydrolysis. The method has the advantages of readily available raw materials, high reaction purity and yield, stable process conditions, simple operation and suitability acid-2-methyl formate through hydrolysis. The method has the advantages of readily available raw materials, high reaction purity and yield, stable process conditions, simple operation and suitability for large-scale production and provides a new thought and means for preparing the phenylboronic acid-2-methyl formate. for large-scale production and provides a new thought and means for preparing the phenylboronic acid-2-methyl formate.
Description
(1) technical field:
The present invention relates to a kind of method for preparing phenylboronic acid-2-methyl formate.
(2) background technology:
Phenylboronic acid-2-methyl formate is the important intermediate of preparation novel antihypertensive medicament and partner treatment diabetic nephropathy drugs Losartan; Simultaneously also be important organic synthesis intermediate and medicine, pesticide intermediate, be widely used in Suzuki cross-coupling reaction, amino acid whose asymmetric synthesis, aminocompound catalyzer etc., also be widely used in simultaneously synthesizing of medicine and synthesizing of asymmetric catalyst, aspect carbohydrate transmitter, separating substances purifying, the controlled drug delivery system very important application arranged also.Therefore, develop a kind of high benefit, the phenylboronic acid-2-methyl formate synthesis technique is significant cheaply.
Present stage, the method for preparing the phenylo boric acid compounds mainly contains following several:
1. grignard reagent method: react with magnesium chips and make Grignard reagent by replacing the o-bromobenzoic acid methyl esters, carry out nucleophilic substitution with the boron alkyl acid esters then, with after acidic hydrolysis gets substituted benzene boric acid, the product that this method obtains is because the side reaction of grignard reagent attack methyl-formiate causes yield low, and preparation Grignard reagent complex operation.
2. palladium Catalytic Oxygen boryl method, this method is at PdCl
2(dppf) under (dppf is two (diphenylphosphine) ferrocene) catalyst, make aryl halide or aryl three fluoro methane sulfonates and boryl reagent react, obtain corresponding borate ester, hydrolysis gets phenylo boric acid then.This method mild condition, but need to use expensive catalyzer, and recovery is difficult, be used for actual production and also need to seek appropriate catalyst, reaches to reduce cost; And in some cases, issuable heavy metal contamination also is serious problems.
At present existing bibliographical information is used grignard reagent method [Organic Letters, 2006; 8 (2): 305-307. and Appl.Organometal.Chem.2007; 21:234-238.] and palladium Catalytic Oxygen boryl [Organic Letters, 2007,9 (18), 3683-3685; ] be prepared into phenylboronic acid-2-methyl formate.
Traditional organolithium reagent method is to replace o-bromobenzoic acid methyl esters elder generation and lithium alkylide generation lithium-bromine permutoid reaction, obtain replacing lithium benzene, react with boric acid ester compound then, get corresponding substituted benzene boric acid through hydrolysis, but the side reaction of n-Butyl Lithium attack o-bromobenzoic acid methyl esters functional group can take place simultaneously.
(3) summary of the invention:
Technical problem to be solved by this invention is to provide a kind of method for preparing phenylboronic acid-2-methyl formate; this method raw material is easy to get; the reaction purity and yield is higher; stable process conditions; simple to operate; be applicable to large-scale production, for the preparation phenylboronic acid-2-methyl formate provides a kind of new thinking and method.
For solving the problems of the technologies described above technical scheme of the present invention:
A kind of method for preparing phenylboronic acid-2-methyl formate, selecting the o-bromobenzoic acid methyl esters of on market business-like raw material or preparation easily for use is initial feed, under cryogenic condition, n-Butyl Lithium is splashed in the mixture of main raw material o-bromobenzoic acid methyl esters and boric acid ester compound, be prepared into phenylboronic acid-2-methyl formate through hydrolysis, reaction process is referring to Fig. 2; The concrete preparation process of reaction process is as follows:
(1) feed intake: in reactor, add ether solvent, o-bromobenzoic acid methyl esters and boric acid ester compound start stirring; The amount ratio scope of o-bromobenzoic acid methyl esters and ether solvent is 1g/5～15mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.0～1.3eq;
(2) drip n-butyllithium solution: system is cooled to-88～-82 ℃, and drips n-butyllithium solution down, drip and finish, in-88～-82 ℃ of insulations down in-88～-82 ℃; Wherein the mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1: 1.05～1.40eq; Soaking time is 2～4h;
(3) termination reaction: drip the weak acid termination reaction, stop finishing, system is risen again to-35～30 ℃, continue again to transfer to pH=1～2 with dilute hydrochloric acid;
(4) aftertreatment: acid adjustment is finished, and system continues to transfer pH=5～6 with saturated sodium bicarbonate solution, leaves standstill separatory, and organic phase is washed through salt, and drying is filtered, concentrate, crystallization, suction filtration, in 40～45 ℃ down baking expect product.
Ether solvent comprises ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, or methyl tertiary butyl ether in the above-mentioned steps (1); Boric acid ester compound comprises the boric acid isopropyl ester, trimethyl borate or triethyl borate; The amount ratio scope of o-bromobenzoic acid methyl esters and ether solvent is 1g/5～10mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.0～1.2eq; The mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1: 1.05～1.1eq in the step (2); Soaking time is 2～3h; Weak acid comprises formic acid, acetate, citric acid in the step (3).
Ether solvent comprises tetrahydrofuran (THF) or 2-methyltetrahydrofuran in the above-mentioned steps (1); Boric acid ester compound comprises boric acid isopropyl ester or trimethyl borate; The amount ratio of o-bromobenzoic acid methyl esters and ether solvent is 1g/7mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.2eq; The mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1 in the step (2): 1.1eq; Soaking time is 3h; Weak acid comprises acetate or citric acid in the step (3).
Ether solvent is a tetrahydrofuran (THF) in the above-mentioned steps (1); Boric acid ester compound is the boric acid isopropyl ester; Weak acid is acetate in the step (3).
Superiority of the present invention:
1, traditional organolithium reagent method is substituted phenyl-bromide elder generation and lithium alkylide generation lithium-bromine permutoid reaction, obtains replacing lithium benzene, with the boric acid ester compound reaction, gets corresponding substituted benzene boric acid through hydrolysis then.The present invention is combined into a step (one kettle way) with the first two steps of traditional organolithium reagent method, being about to n-Butyl Lithium directly splashes in the mixture of main raw material o-bromobenzoic acid methyl esters and boric acid ester compound, hydrolysis gets phenylboronic acid-2-methyl formate then, and the side reaction of n-Butyl Lithium attack o-bromobenzoic acid methyl esters has been avoided in this invention;
2, the raw material of this patent employing all is easy to get; The raw materials used raw material that is business-like raw material or easily prepares can satisfy needs of scale production;
3, this patent reaction purity and yield is higher, and stable process conditions is simple to operate, possesses the ability of large-scale production;
(4) description of drawings:
Fig. 1: the chemical reaction step schema of the synthetic method of synthetic phenylboronic acid-2-methyl formate.
Fig. 2: the chemical reaction process schema of the synthetic method of synthetic phenylboronic acid-2-methyl formate.
Can understand the technical scheme of foregoing invention more intuitively in conjunction with Fig. 1 and/or Fig. 2.
(5) embodiment:
(, be owing to certain the floating of carrying out meeting appearance of temperature in single test with reaction process for the interval range that occurs in the embodiment; The statement of pH value test result also is the routine statement in the synthetic field of chemical industry.)
Embodiment 1:
In the 72L reaction flask, disposable adding 19.9kg tetrahydrofuran (THF) (1g/7ml), 3.2kg o-bromobenzoic acid methyl esters (1.0eq) and 3.36kg boric acid isopropyl ester (1.2eq), reinforced finishing started stirring, system is cooled to-88～-82 ℃, and in-88～-82 ℃ of following 2.5M n-Butyl Lithium 4.6kg (1.1eq) that drip, drip and finish, system reacts completely behind-88～-82 ℃ of following insulation reaction 3h.System stops with acetate, stop finishing, system is risen again to-35～-30 ℃, dilute hydrochloric acid with 18% is transferred system pH=1～2, continue to transfer pH=5～6 with saturated sodium bicarbonate solution then, leave standstill separatory, water extracts with isopropyl acetate, organic phase merges washes through salt, anhydrous sodium sulfate drying filters, after filtrate is concentrated to a certain degree, in system, add sherwood oil, again with-2～2 ℃ of system coolings, and in-2～2 ℃ of stirring and crystallizing, suction filtration, filter cake dries by the fire down in 40～45 ℃ expects, gets product 1.78kg.Yield 66.5%, liquid chromatography purity (HPLC): 99.5%.
Embodiment 2:
In the 20L reaction flask, add 8.17kg methyl tertiary butyl ether (1g/5ml), disposable adding 2.15kg o-bromobenzoic acid methyl esters (1.0eq) and 1.90kg triethyl borate (1.3eq), reinforced finishing, system is cooled to-88～-82 ℃, and drips 2.5M n-Butyl Lithium 3.36kg (1.2eq) under-88～-82 ℃, drips and finishes, the 2h afterreaction is complete, use the acetate termination reaction, stop finishing, system is risen again to-35～-30 ℃, transfer system pH=1～2 with dilute hydrochloric acid, transfer system pH=5～6 with saturated sodium bicarbonate solution again, leave standstill separatory, organic phase is washed through salt, anhydrous sodium sulfate drying, filter, concentrate, the cooling crystallization, suction filtration, in 40～45 ℃ down baking expect product 0.94kg.Yield 52.2%, liquid chromatography purity (HPLC): 98.0%.
Embodiment 3:
In the 350L reactor, disposable suction 101.48kg 2-methyltetrahydrofuran (1g/10ml) in system, add 11.8kg o-bromobenzoic acid methyl esters (1.0eq) and 5.7kg trimethyl borate (1.0eq), reinforced finishing started stirring, and system is cooled to-88～-82 ℃, and in-88～-82 ℃ of following 2.5M n-Butyl Lithium 16.2kg (1.05eq) that drip, drip and finish, HPLC tracks to reaction and finishes (3h), uses the citric acid termination reaction, stop finishing, system is risen again to-35～-30 ℃, and transfer system pH=1～2, continue accent system pH=5～6 with saturated sodium bicarbonate solution again with dilute hydrochloric acid, leave standstill separatory, organic phase is washed through salt, and anhydrous sodium sulfate drying filters, concentrate, the cooling crystallization, suction filtration, in 40～45 ℃ down baking expect product 5.76kg.Yield 58.2%, liquid chromatography purity (HPLC): 99.1%.
Embodiment 4:
In the 350L reactor, add 2-methyltetrahydrofuran 172kg (1g/5ml), disposable adding 40kg o-bromobenzoic acid methyl esters (1.0eq) and 23.2kg trimethyl borate (1.2eq), reinforced finishing, system is cooled to-88～-82 ℃, and in-88～-82 ℃ of following 2.5M n-Butyl Lithium 62.4kg (1.2eq) that drip, drip and finish, HPLC tracks to reaction and finishes (3h), uses the acetate termination reaction, stop finishing, system is risen again to-35～-30 ℃, transfer system pH=1～2, transfer system pH=5～6 with 5% sodium hydrogen carbonate solution again with dilute hydrochloric acid, leave standstill separatory, organic phase is washed through salt, and anhydrous sodium sulfate drying filters, concentrate, the cooling crystallization, suction filtration, in 40～45 ℃ down baking expect product 19.8kg, yield 59.1%, liquid chromatography purity (HPLC): 98.6%.
Embodiment 5:
In the 1000L reactor, disposable suction 516.6kg tetrahydrofuran (THF) (1g/15ml), add 38.7kg o-bromobenzoic acid methyl esters (1.0eq) and 44.1kg boric acid isopropyl ester (1.3eq), reinforced finishing started stirring, and system is cooled to-88～-82 ℃, and in-88～-82 ℃ of following 2.5M n-Butyl Lithium 70.5kg (1.4eq) that drip, drip and finish, HPLC tracks to reaction and finishes (4h), uses the acetate termination reaction, stop finishing, system is risen again to-35～-30 ℃, and transfer system pH=1～2, continue accent system pH=5～6 with saturated sodium bicarbonate solution again with dilute hydrochloric acid, leave standstill separatory, organic phase is washed through salt, and anhydrous sodium sulfate drying filters, concentrate, the cooling crystallization, suction filtration, in 40～45 ℃ down baking expect product 20.5kg.Yield 63.4%, liquid chromatography purity (HPLC): 99.1%.
This shows, the disclosed method for preparing phenylboronic acid-2-methyl formate can obtain the high target product of purity among the present invention, purity is stabilized in more than 98.0%, the raw material that synthetic method adopts is easy to get, stable process conditions, chemical reaction condition gentleness, yield 52.2%～66.5%, simple to operate in the whole process of production, pollute lower, for the preparation phenylboronic acid-2-methyl formate provides a kind of new thinking and method.
Claims (4)
1. method for preparing phenylboronic acid-2-methyl formate, it is characterized in that: the o-bromobenzoic acid methyl esters of selecting easy preparation for use is an initial feed, under cryogenic condition, n-Butyl Lithium is splashed in the mixture of main raw material o-bromobenzoic acid methyl esters and boric acid ester compound, be prepared into phenylboronic acid-2-methyl formate through hydrolysis; The concrete preparation process of reaction process is as follows:
(1) feed intake: in reactor, add ether solvent, o-bromobenzoic acid methyl esters and boric acid ester compound start stirring; The amount ratio scope of o-bromobenzoic acid methyl esters and ether solvent is 1g/5～15mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.0～1.3eq;
(2) drip n-butyllithium solution: system is cooled to-88～-82 ℃, and drips n-butyllithium solution down, drip and finish, in-88～-82 ℃ of insulations down in-88～-82 ℃; Wherein the mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1: 1.05～1.40eq; Soaking time is 2～4h;
(3) termination reaction: drip the weak acid termination reaction, stop finishing, system is risen again to-35～30 ℃, continue again to transfer to pH=1～2 with dilute hydrochloric acid;
(4) aftertreatment: acid adjustment is finished, and system continues to transfer pH=5～6 with saturated sodium bicarbonate solution, leaves standstill separatory, and organic phase is washed through salt, and drying is filtered, concentrate, crystallization, suction filtration, in 40～45 ℃ down baking expect product.
2. a kind of method for preparing phenylboronic acid-2-methyl formate according to claim 1 is characterized in that: ether solvent is selected from ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, or methyl tertiary butyl ether in the step (1); Boric acid ester compound is selected from the boric acid isopropyl ester, trimethyl borate or triethyl borate; The amount ratio scope of o-bromobenzoic acid methyl esters and ether solvent is 1g/5～10mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.0～1.2eq; The mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1: 1.05～1.1eq in the step (2); Soaking time is 2～3h; Weak acid is selected from formic acid, acetate, citric acid in the step (3).
3. a kind of method for preparing phenylboronic acid-2-methyl formate according to claim 2 is characterized in that: ether solvent is selected from tetrahydrofuran (THF) or 2-methyltetrahydrofuran in the step (1); Boric acid ester compound is selected from boric acid isopropyl ester or trimethyl borate; The amount ratio of o-bromobenzoic acid methyl esters and ether solvent is 1g/7mL; The mol ratio of o-bromobenzoic acid methyl esters and boric acid ester compound is 1: 1.2eq; The mol ratio of o-bromobenzoic acid methyl esters and n-Butyl Lithium is 1 in the step (2): 1.1eq; Soaking time is 3h; Weak acid is selected from acetate or citric acid in the step (3).
4. a kind of method for preparing phenylboronic acid-2-methyl formate according to claim 3 is characterized in that: ether solvent is a tetrahydrofuran (THF) in the step (1); Boric acid ester compound is the boric acid isopropyl ester; Weak acid is acetate in the step (3).
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| CN102731542B (en) * | 2012-06-18 | 2015-03-11 | 台州市华南医化有限公司 | Preparation method of p-bromophenyl-boric acid |
| CN102746329A (en) * | 2012-07-02 | 2012-10-24 | 盛世泰科生物医药技术(苏州)有限公司 | Method for synthesizing 4-(1-hydroxy-1, 3-dihydro-benzo[c][1, 2]boric acid-6-phenol)nitrile benzene |
| TWI480283B (en) * | 2013-07-31 | 2015-04-11 | Taiwan Biotech Co Ltd | Process for preparing 4-borono-l-phenylalanine |
| CN111171062A (en) * | 2020-01-07 | 2020-05-19 | 大连双硼医药化工有限公司 | Method for synthesizing 2-carboxyl sodium phenylboronate |
| CN111961073B (en) * | 2020-09-08 | 2023-05-02 | 天津凯莱英制药有限公司 | Continuous synthesis method of arylboronic acid |
| CN113121579B (en) * | 2021-04-19 | 2023-06-06 | 河北松辰医药科技有限公司 | Synthesis method of 3- (6-phenylhexyl) phenylboronic acid and derivative thereof |
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