KR100577874B1 - Preparing method for methyl 4-hydroxyiminovenzoate utilizing evaporated residue from DMT preparation - Google Patents

Abstract

The present invention relates to a method for preparing methyl 4-hydroxyiminobenzoate from distillation residue during DMT preparation.

A) a distillation residue generated in the process for preparing dimethyl terephthalate containing methyl 4-formylbenzoate or a mixture of an inorganic acid salt of hydroxylamine or hydroxylamine and an inorganic base in a solution in which the distillation residue is dissolved in an organic solvent. Adding and reacting;

B) adding an inorganic acid or an inorganic acid aqueous solution to the reaction mixture of step a);

C) filtering the mixture of step b) to obtain a precipitated solid component; And

D) providing a method of preparing methyl 4-hydroxyiminobenzoate, which comprises washing the filtered solid component.

By effectively recycling industrial waste and manufacturing and supplying it with low cost and high purity in a simple process, it contributes to related industries and has a great effect on the environment.

DMT, distillation residue, methyl 4-hydroxyiminobenzoate

Description

Preparation method for methyl 4-hydroxyiminovenzoate utilizing evaporated residue from DMT preparation

The present invention relates to a method for preparing methyl 4-hydroxyiminobenzoate, and more particularly, to high-purity methyl 4-hydroxyiminobenzoate from distillation residue generated in the process of preparing dimethyl terephthalate (DMT). It relates to a method of manufacturing.

Methyl 4-hydroxyiminobenzoate, a target compound of the present invention, and 4-hydroxyiminobenzoic acid, a hydrolyzate thereof, are 4- (aminomethyl) benzoic acid utilized as a fiber improving agent, a starting material for producing polymers, and an intermediate for preparing pharmaceuticals. 3859342, Japanese Patent No. 57053441) and 4- (aminomethyl) cyclohexanecarboxylic acid (UK Patent No. 2084145) are used as main raw materials, and have recently been utilized as various new drug development intermediates. For example, methyl 4-hydroxyiminobenzoate, a target compound of the present invention, and 4-hydroxyiminobenzoic acid, a hydrolyzate thereof, are widely used as hemostatic agents such as Tranexamic acid and gastric ulcer medicine, Setraxate. It is the main raw material of manufacturing. Tranexamic acid is prepared from methyl 4-hydroxyiminobenzoate or its hydrolyzate 4-hydroxyiminobenzoic acid as described in Scheme a below (Japanese Patent No. 57053441, Japanese Patent). No. 51052159, Japanese Patent No. 56012348) and setlacate are obtained by esterification from the obtained tranexamic acid or esters thereof (British Patent No. 1580783).

Scheme a

On the other hand, when manufacturing dimethyl terephthalate (DMT), the distillation residue is a by-product generated in the process of producing dimethyl terephthalate (DMT) by high-temperature esterification reaction from terephthalic acid with methanol. Ate, dimethyl terephthalate (DMT), methyl 4-toluate, benzoic acid, methyl benzoate, 4-toluic acid, monomethyl terephthalate and the like. Depending on the DMT manufacturing process, for example, methyl 4-formyl benzoate 75 to 80% by weight, dimethyl terephthalate (DMT) 10 to 16% by weight, methyl 4-toluate 3 to 4% by weight, in addition to benzoic acid, Methylbenzoate, 4-toluic acid, monomethyl terephthalate, and the like. Such distillation residues are mainly disposed of because they are not suitable for use.

According to Japanese Patent Laid-Open Publication No. 50-71614, USSR Patent No. 1268563 and US Pat. No. 1244140, methyl 4-formylbenzoate contained in the distillation residue generated in the manufacturing process of dimethyl terephthalate is used as a sulfite salt adduct. The conversion is separated and purified, and then methyl 4-formylbenzoate is recovered by hydrolysis under acidic or alkaline conditions. However, these methods have a low purity of the sulfite salt adduct of methyl 4-formylbenzoate, which is a manufacturing intermediate, and thus requires a high cost for purification of the intermediate to obtain clean methyl 4-formylbenzoate. In particular, to recover methyl 4-formylbenzoate, the sulfite salt adduct of methyl 4-formylbenzoate, which is a reaction intermediate, must be hydrolyzed under acidic or alkaline conditions. In the case of alkali hydrolysis, a large amount of wastewater of inorganic sulfite salts is generated. In addition, due to the low yield during hydrolysis, a large amount of separated filtrate is generated as wastewater with high organic content, which is economical in terms of environment and manufacturing cost.

Korean Patent Publication No. 195-0005193 and Korean Patent No. 0224964 disclose methods for preparing 4-formylbenzoic acid from DMT distillation residues, all of which obtain the target compound through high temperature reaction in a strong acid aqueous solution. Due to the generation of high concentration organic acid wastewater and the generation of large amount of sulfur dioxide, toxic gas, there are many problems in industrialization and it is difficult to use.

In Korean Patent Publication No. 2003-0070824, chlorine is added to a DMT distillation residue, followed by chlorination to synthesize methyl 4-carbamoylbenzoate by addition of ammonia, which is separated by a Hoffman reaction. It is reported that 4-aminobenzoic acid can be prepared by decomposition. However, this method is not practical because it is a costly process compared to the price of 4-aminobenzoic acid which is manufactured and supplied inexpensively in large quantities internationally.

As described above, the conventional methods of using the DMT distillation residue are recovered by separating and recovering the methyl 4-formylbenzoate contained therein from the DMT distillation residue as it is, converting to 4-formylbenzoic acid, and separating the methyl4-carbox By converting to methyl 4-carbamoylbenzoate and separating it, it is economical in terms of environment and cost, and most DMT distillation residues are incinerated.

Known methods for the preparation of methyl 4-hydroxyiminobenzoate, which is the objective compound of the present invention, are described according to WO 02/060876 from purified methyl 4-formylbenzoate (J. Heterocyclic Chem. 1982, 19.721). It was mentioned that it was prepared by referring to the method for preparing methyl 2-hydroxyiminobenzoate described in the above reference, and according to this reference, methyl 2-hydroxyiminobenzoate was prepared with hydroxylamine hydrochloride and excess 30% methanol. Reaction in aqueous solution is said to yield methyl 2-hydroxyiminobenzoate in 73% yield. However, this method is a commercially uneconomical process because it uses the expensive raw material methyl 4-formylbenzoate as a raw material, low reaction yield and a large amount of waste water.

For reference, methyl 4-formylbenzoate used as a raw material is chlorinated 4-toluic acid in Japanese Patent No. 5350133, to obtain 4- (dichloromethyl) benzoic acid, and hydrolyzed to obtain 4-formyl. Obtain benzoic acid and esterify it to afford methyl 4-formylbenzoate. However, this production method uses 4-toluoic acid, which is an expensive raw material, and requires the process of purifying mono- and tri-chloro compounds by chlorination, thereby purifying them, and purifying and esterifying them after hydrolysis. It is a process that requires a process and lacks commercial viability in terms of yield and purity.

The present invention is to provide a method for economically preparing high purity methyl 4-hydroxyiminobenzoate.

The present invention also provides a method for producing methyl 4-hydroxyiminobenzoate useful as a raw material for pharmaceutical raw materials and polymer materials from waste which is a distillation residue generated in a dimethyl terephthalate (DMT) manufacturing process.                         

The inventors of the present invention completed the present invention by synthesizing and separating high purity methyl 4-hydroxyiminobenzoate by reacting the mixture of the DMT distillation residue as it is without a separate purification process for separating the active ingredient. Was done.

According to the present invention, a) inorganic salts and inorganic bases of hydroxylamine or hydroxylamine in a distillation residue generated in the process for preparing dimethyl terephthalate containing methyl 4-formylbenzoate or the distillation residue in a solvent are dissolved. Reacting by adding a combination of these;

B) adding an inorganic acid or an inorganic acid aqueous solution to the reaction mixture of step a) and / or cooling to precipitate crystals;

C) filtering the mixture of step b) to obtain a precipitated solid component; And if necessary

D) there is provided a method of preparing methyl 4-hydroxyiminobenzoate, which comprises washing the filtered solid component.

Also provided by the present invention is a method for producing methyl 4-hydroxyiminobenzoic acid further comprising the step of hydrolyzing the methyl 4-hydroxyiminobenzoate under alkaline conditions.

The term "DMT distillation residue" or "distillation residue when producing DMT" used as a starting material in the present invention refers to a by-product of the production of dimethyl terephthalate (DMT) by high temperature esterification with methanol from terephthalic acid. Typically 75-80% by weight of methyl 4-formylbenzoate, 10-16% by weight of dimethyl terephthalate (DMT), 3-4% by weight of methyl 4-toluate, in addition to benzoic acid, methylbenzoate, 4-toluine As long as it contains a mixture consisting of acid (4-Toluic acid), monomethyl terephthalate, etc., but contains a considerable amount of methyl 4-formylbenzoate, the change of components is not so problematic.

The present invention provides the formation of Aldoxime by selective oximation reaction of methyl 4-formylbenzoate of structural formula (I) contained in the distillation residue during the production of DMT by hydroxylamine. By induction, methyl 4-formylbenzoate of formula (I) contained in the distillation residue is completely converted to methyl 4-hydroxyiminobenzoate of formula (II), which is crystallized and separated and washed to obtain raw impurities and reaction by-products. Methyl 4-hydroxyiminobenzoate of the formula (II), from which they were removed, was prepared in high purity.

For the oxime reaction of step a), it is common to prepare a distillation residue in solution using various solvents capable of dissolving the DMT distillation residue. Preferred solvents are aromatic organic solvents such as benzene, toluene and xylene, or carbon chloride solvents such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethane and trichloroethylene, or a mixed solvent thereof. More preferably, they are benzene, toluene, dichloromethane, dichloroethane, or a mixed solvent thereof. The amount of the solvent used is 1.5 to 40 times, preferably 2 to 5 times by weight relative to the distillation residue in the preparation of DMT. If the solvent is used less than 2 times, there is a problem in maintaining the purity of the product. If the solvent is used more than 5 times, it is not economical in terms of concentration and solvent recovery.

The reaction temperature may be carried out at 0 to 100 ° C. depending on the solvent and the amount of solvent used, preferably at 10 to 40 ° C. Below 10 ℃, the progress of reaction is slow and the cost increases due to the increase of solvent amount and cooling to maintain the purity of the product, and above 40 ℃, the target yield can decrease due to the formation of secondary reactants as the temperature increases. Inefficient

As the hydroxylamine, a commercially available 50% hydroxylamine aqueous solution may be used as it is, or an inorganic acid salt of hydroxylamine and an equivalent of a base corresponding to the inorganic acid thereof or an aqueous solution thereof may be used. The inorganic acid salt may be hydrochloride, sulfate, nitrate or phosphate salt of hydroxylamine, but commercially available aqueous 50% hydroxylamine solution or hydrochloride or sulfate salt of hydroxylamine may be used. At this time, as the base used may be NaOH, KOH, Na2CO3, K2CO3, NaHCO3, KHCO3, sodium acetate, potassium acetate, NaOH, Na2CO3 is preferably used economically.

In this case, the hydroxylamine or the inorganic acid salt of the hydroxylamine may be used in an amount of 1 to 1 equivalent or more based on methyl 4-formylbenzoate contained in the distillation residue during the production of DMT, and preferably 1 to 1.1 equivalents. Using less than 1 equivalent is inefficient due to unreacted reaction, and more than 1.1 equivalents may be fast in reaction but inefficient in terms of side reactant production and raw material cost.

In order to precipitate crystals in the reaction mixture of step b), the reaction mixture is cooled to 10 ° C. or lower, preferably 5 ° C. or lower, and / or separated by crystallization produced by addition of an inorganic acid. The addition of inorganic acids is advantageous in the purity, yield and reaction efficiency of the crystals. Crystals can precipitate without these steps, but are much lower in yield and purity. Preferred inorganic acids are hydrochloric acid, bromic acid or aqueous solutions thereof. The inorganic acid used at this time is generally 0.5 to 3 equivalents based on methyl 4-hydroxyiminobenzoate, and preferably 1 to 2 equivalents. If the amount of acid is less than 1 equivalent, the yield is lowered. If more than 2 equivalents are used, it is not economical because there is little additional effect in terms of yield.

Filtration of step c) is carried out using a conventional method comprising a filter cloth or filter paper.

The washing of step d) is generally performed at least once using an organic solvent or water. As is well known, the filtration of step c) and the washing of step d) may be repeated as necessary.

In step e), 4-hydroxyiminobenzoic acid of formula (III) is prepared by hydrolyzing methyl 4-hydroxyiminobenzoate of formula (II) using aqueous alkali solution as in Scheme A. As alkali used at this time, NaOH, KOH, Na2CO3, K2CO3 is preferable. The alkali to be used may be one molecular equivalent or more, but preferably 1 to 1.1 molecular equivalents. If the base is used in less than one molecule equivalent, the reaction will not be completed. If more than 1.1 molecular equivalents are used, additional raw material and neutralization costs will be incurred.

The water to be used is 2 to 20 times by weight to methyl 4-hydroxyiminobenzoate, but 3 to 5 times is preferable. Using less than 3 times affects the agitation and quality, and more than 5 times is uneconomical with a lot of waste water.

The hydrolysis reaction can be carried out at 20 to 100 ° C, but 80 to 100 ° C is preferred. Below 80 ° C, the lower the temperature, the slower the reaction rate.

Hereinafter, the present invention will be described in detail with reference to Examples, but the following Examples illustrate the present invention, and the present invention is not limited to the following Examples. In the following examples, 76 wt% of methyl 4-formylbenzoate, 16 wt% of dimethyl terephthalate (DMT), 3.5 wt% of methyl 4-toluate, and benzoic acid, methyl benzoate, and 4-tol as distillation residue in the manufacture of DMT. Experiments were carried out using a mixture consisting of 4-toluic acid and monomethyl terephthalate as a raw material. Eastman Kodak, DuPont, SK Chemicals, etc. are known to manufacture similar DMT manufacturing processes worldwide.

Example 1

50 g of the distillation residue is dissolved in 150 ml of dichloromethane, and 16.5 g (0.25 mole) of 50% hydroxylamine solution is added thereto, followed by stirring at 25 ° C for 2 hours. After confirming that methyl 4-formylbenzoate in the reaction solution was completely consumed as thin layer chromatography (silica gel 60F 254, ethyl acetate e: n-hexane = 1: 4), the reaction solution was cooled to 5 ° C. While stirring vigorously, 40 ml of 35% aqueous hydrochloric acid solution was added dropwise to the reaction solution over 20 minutes, and further stirred for 10 minutes, followed by filtration. The filtrate is washed with 50 ml of dichloromethane and the solvent is filtered off thoroughly. The filtrate was added to 70 ml of water, the solution pH was adjusted to 5-6 with 5% aqueous Na 2 CO 3 solution, stirred for 30 minutes, vacuum filtered and washed with 20 ml of water.

The white powdery solid obtained was added to 100 ml of dichloromethane and heated to reflux for 2 hours. The reaction solution was cooled to 20 ° C., filtered, washed with 20 ml of dichloromethane, and dried at 80 ° C. for 4 hours to obtain 33.9 g of methyl 4-hydroxyiminobenzoate (yield 81.7%) having a purity of 99.9%. Purity is the result of gas chromatography analysis, and the yield is the yield of methyl 4-formylbenzoate contained in the distillation residue during the preparation of the used DMT.

1 H nmr δ (DMSO-d6): 3.85 (3H, s), 7.7-7.98 (4H, m), 8.22 (1H, s), 11.6 (1H, s)

Example 2

When preparing DMT, 50 g of the distillation residue was dissolved in 1500 ml of dichloromethane and reacted in the same manner as in Example 1 to obtain a clear solution. After cooling to 5 ° C., 40 ml of 35% aqueous hydrochloric acid solution was added dropwise to the reaction solution over 20 minutes to precipitate white crystals. After stirring for 10 minutes, the solution was filtered. The filtrate is washed with 50 ml of dichloromethane and the solvent is filtered off thoroughly. The filtrate was added to 70 ml of water, the solution pH was adjusted to 5-6 with 5% aqueous Na 2 CO 3 solution, stirred for 30 minutes, vacuum filtered and washed with 20 ml of water. The filtrate was dried at 80 ° C. for 4 hours to obtain 34.85 g (yield 84.0%) of methyl 4-hydroxyiminobenzoate having a purity of 99.8%.

[Comparative Example 1]

In preparing DMT, 50 g of the distillation residue was dissolved in 150 ml of dichloromethane and reacted in the same manner as in Example 1, but the precipitated crystals were filtered at 25 ° C. without cooling. Apart from the filtrate, the filtrate was cooled to 5 ° C., and 20 ml of 35% aqueous hydrochloric acid solution was added dropwise over 20 minutes, stirred for 10 minutes, and filtered. The filtrates were washed with water in the same manner as in Example 1 and dried at 80 ° C. for 8 hours to obtain 22.9 g of methyl 4-hydroxyiminobenzoate with a purity of 99.6% (yield 55.1%) and methyl 4-hydroxy with a purity of 99.8%. 7.9 g (yield 23.6%) of roxyiminobenzoate were obtained in order.

Example 3

When preparing DMT, 50 g of distilled residue was dissolved in 150 ml of dichloromethane, and the reaction was carried out as in Example 1, and the reaction solution was cooled to 5 ° C., and the resulting solid was vacuum filtered without washing with 30 ml of dichloromethane. To 40 ml of water, stirred for 30 minutes and filtered. Apart from the filtrate, 10 ml of 35% aqueous hydrochloric acid solution was added dropwise over 10 minutes while stirring and stirring the organic layer having a water layer separated from the filtrate to 5 ° C and stirring. The resulting white crystalline powder was vacuum filtered, washed with 10 ml of dichloromethane, the filtrate was added to 15 ml of water, stirred for 30 minutes and filtered.

The filtrates were dried at 80 ° C. for 8 hours to obtain 33.1 g of methyl 4-hydroxyiminobenzoate with a purity of 96.5% (yield 79.6%) and 2.9 g of methyl 4-hydroxyiminobenzoate with a purity of 99.8% (yield 7.0%). ) Was obtained in order.

Example 4

To 20 g (0.112 mole) of methyl 4-hydroxyiminobenzoate obtained in Example 1 was added 60 ml of water and 4.9 g (0.123 mole) of NaOH, followed by stirring at 90 ° C. for 3 hours. Reaction completion was confirmed by thin layer chromatography (RP-18F 254S, water: methanol = 1: 10), and cooled to room temperature. To the clear reaction solution was added dropwise 10.9ml of 35% hydrochloric acid aqueous solution for 10 minutes to precipitate white powder, which was stirred for 30 minutes and filtered. Washed with 20 ml of water and dried for 8 hours at 80 ℃ to give 17.75 g (96% yield) of 4-hydroxyiminobenzoic acid. Purity was 99.8% by gas chromatography analysis.

1 H nmr δ (DMSO-d6): 7.7 to 7.97 (4H, m), 8.23 (1H, s), 11.57 (1H, s), 13.07 (1H, s)

Melting Point: 212.0 ~ 213.3 ℃

Methyl 4-hydroxyiminobenzoate production method according to the present invention using the distillation residue generated in the dimethyl terephthalate (DMT) manufacturing process as it is without a separate purification process, a new process that is not known before the object of the present invention Compounds can be prepared. Unlike conventional methods of separating and recovering specific components of the distillation residue in the production of DMT or methods of utilizing the distillation residue in the production of DMT, which are difficult to apply in the past, a simple process by effectively recycling industrial wastes of industrially important target compounds of the present invention As a result, manufacturing and supplying with low cost and high purity contributes to related industries and has a great effect on the environment.

Claims (6)

A) a distillation residue generated in the process for preparing dimethyl terephthalate containing methyl 4-formylbenzoate or a mixture of an inorganic acid salt of hydroxylamine or hydroxylamine and an inorganic base in a solution in which the distillation residue is dissolved in an organic solvent. Adding and reacting; B) adding an inorganic acid or inorganic acid aqueous solution to the reaction mixture of step a) and / or cooling to precipitate crystals; C) filtering the mixture of step b) to obtain a precipitated solid component; And if necessary D) washing the filtered solid component to prepare methyl 4-hydroxyiminobenzoate. The method according to claim 1, wherein the distillation residue is dissolved in an aromatic organic solvent, a carbon chloride solvent, or a mixed solvent thereof in the step a) of preparing methyl 4-hydroxyiminobenzoate. The combination according to claim 2, wherein the inorganic acid salt of hydroxylamine is a hydrochloride salt, sulfate salt, nitrate salt or phosphate salt and the inorganic salt salt is NaOH, KOH, Na2CO3, K2CO3, NaHCO3, KHCO3, sodium acetate, or potassium acetate. A method for producing methyl 4-hydroxyiminobenzoate to be used. The method according to claim 3, wherein 1 to 1.1 equivalents of the aqueous hydroxylamine solution or the inorganic acid salt of the hydroxylamine in step a) are used with respect to methyl 4-formylbenzoate contained in the distillation residue generated at the dimethyl terephthalate manufacturing plant. And to prepare a methyl 4-hydroxyiminobenzoate to carry out the reaction at 10 ~ 40 ℃. The method of claim 4, wherein in step b), methyl 4-hydroxyiminobenzoate is prepared by adding hydrochloric acid, bromic acid or an aqueous solution thereof as an inorganic acid. The method for preparing 4-hydroxyiminobenzoic acid according to claim 1, further comprising hydrolyzing in alkaline conditions.