阅读说明：本技术 一种适于工业化生产的d-对羟基苯甘氨酸甲酯盐酸盐的制备方法 (Preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production ) 是由 李晓晖 张志海 杨明高 陈威 于 2021-08-20 设计创作，主要内容包括：本发明公开了一种适于工业化生产的D-对羟基苯甘氨酸甲酯盐酸盐的制备方法,涉及一种适于工业化生产的D-对羟基苯甘氨酸甲酯盐酸盐的制备方法。本方法第一步反应以乙醛酸甲酯和苯酚为原料,以廉价的S-(-)-芳基乙胺为手性诱导试剂,反应得到(R)-2-(4-羟基苯基)-2-(((S)-1-芳基乙基)氨基)乙酸甲酯盐酸盐(中间体1)。本方法第二步反应为中间体1在Pd/C催化条件下氢解保护基团。本发明提供的方法主要特点有：1,工艺简单,仅有两步化学反应,生产效率高；2,使用廉价的手性诱导试剂S-(-)-芳基乙胺替代昂贵拆分试剂手性樟脑磺酸或手性苯乙磺酸,大大降低了原料和生产成本。(The invention discloses a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production, and relates to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production. In the first step of the reaction, methyl glyoxylate and phenol are used as raw materials, cheap S- (-) -aryl ethylamine is used as a chiral induction reagent, and (R) -2- (4-hydroxyphenyl) -2- (((S) -1-aryl ethyl) amino) methyl acetate hydrochloride (an intermediate 1) is obtained through the reaction. The second step of the reaction of the method is that the intermediate 1 is subjected to hydrogenolysis protection group under the Pd/C catalysis condition. The method provided by the invention is mainly characterized in that: 1, the process is simple, only two steps of chemical reactions are carried out, and the production efficiency is high; and 2, the cheap chiral inducing reagent S- (-) -aryl ethylamine is used for replacing an expensive resolution reagent chiral camphor sulfonic acid or chiral phenethyl sulfonic acid, so that the raw material and production cost are greatly reduced.)

1. A preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production is characterized by carrying out reaction preparation according to the following reaction formula:

2. the method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 1, which is suitable for industrial production, comprising the steps of:

in the first step, methyl glyoxylate and phenol are used as raw materials, S-aryl ethylamine is used as a chiral induction reagent, and an intermediate 1(R) -2- (4-hydroxyphenyl) -2- (((S) -1-aryl ethyl) amino) methyl acetate hydrochloride is obtained through reaction; the reaction process of the step is as follows: the methyl glyoxylate and chiral arylamine form imine, and then Friedel-Crafts reaction is carried out under the catalytic action of a catalyst to obtain an intermediate 1;

the second step is that the intermediate 1 is subjected to hydrogenolysis deprotection under the catalysis of Pd/C to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

3. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production according to claim 2, wherein in the first step, the Friedel-Crafts reaction step is:

adding organic solvent with a molar ratio of 1: reacting 0.9-1: 1.2 of methyl glyoxylate with S-aryl ethylamine at the temperature of 10-50 ℃, adding phenol or anisole and a catalyst into the reaction solution after the reaction is finished, wherein the molar ratio of the methyl glyoxylate to the phenol or the anisole to the catalyst is 1: 0.9: 0.05-1: 1.2: 0.2; then continuing to react at 10-50 ℃; and (3) adding a hydrogen chloride solution after the reaction is finished, heating to 70-80 ℃ or refluxing, then cooling to 0-40 ℃ for crystallization, performing suction filtration, and drying the solid to obtain the intermediate 1.

4. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production according to claim 2, wherein in the second step, the deprotection reaction step is:

adding the intermediate 1 and a Pd/C catalyst into a solvent, wherein the using amount of the catalyst is 2-15% of the weight of the intermediate, carrying out deprotection at 20-60 ℃ by using a reducing agent through catalytic hydrogenolysis, cooling to-10-40 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, and drying the solid to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

5. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 3, which is suitable for industrial production, comprising: in the Friedel-Crafts reaction, the organic solvent is at least one of toluene, chlorobenzene, dichloromethane, xylene, dichloroethane, ethyl acetate and tetrahydrofuran.

6. The process for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 1 or 2, which is suitable for industrial production, characterized in that: in the Friedel-Crafts reaction, the catalyst is Bronsted acid or Lewis acid.

7. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 6, which is suitable for industrial production, comprising: the Bronsted acid or the Lewis acid is at least one of methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, chiral phosphoric acid, trifluoromethanesulfonic acid or indium trifluoromethanesulfonate.

8. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 3, which is suitable for industrial production, comprising: the hydrogen chloride solution is at least one of hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrochloric acid and hydrogen chloride isopropanol solution.

9. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 4, which is suitable for industrial production, comprising: the reducing agent can be at least one of hydrogen, formic acid, ammonium formate or sodium formate.

10. The method for preparing D-p-hydroxyphenylglycine methyl ester hydrochloride according to claim 4, which is suitable for industrial production, comprising: the solvent is at least one of water, methanol, ethanol, isopropanol or ethyl acetate.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production.

Background

D-p-hydroxyphenylglycine methyl ester hydrochloride (CAS: 57591-61-4) is a key intermediate in the enzymatic process of broad-spectrum antibiotic amoxicillin (amoxicillin). Compared with a chemical synthesis process, the enzymatic process has great advantages in the aspects of environmental protection, energy consumption and production efficiency, so that the enzymatic production of amoxicillin drives the market demand of the intermediate D-p-hydroxyphenylglycine methyl ester hydrochloride. D-p-hydroxyphenylglycine methyl ester hydrochloride (CAS: 57591-61-4) has the following structure:

for p-hydroxyphenylglycine resolution process, a large number of patents report related resolution methods. Chinese patent CN100494165C reports that racemic p-hydroxyphenylglycine is resolved under catalysis of 2-nitro-benzaldehyde, respectively, by using (+) -3-bromo-8-camphorsulfonic acid ammonium salt as a resolving agent to obtain D-p-hydroxyphenylglycine. Chinese patent CN101613297 reports that D-p-hydroxyphenylglycine-p-toluenesulfonate complex salt is obtained by resolving racemic DL-p-hydroxyphenylglycine by using p-toluenesulfonic acid as a resolving agent, filtrate is recycled and reused, DL-p-hydroxyphenylglycine is continuously added for resolution, and L-p-hydroxyphenylglycine-p-toluenesulfonate complex salt is obtained by filtering. The resolution technology can respectively obtain two kinds of p-hydroxyphenylglycine with different configurations. Chinese patent CN102757356A reports that D-phenylethanesulfonic acid is used as a resolving agent to resolve racemic DL-p-hydroxyphenylglycine, the obtained resolved double salt is dissociated to obtain D-p-hydroxyphenylglycine, and the filtrate is recycled and used in a dynamic kinetic resolution process. The process technology realizes integration of racemization and resolution, the conversion rate is kept above 80%, and the production efficiency is high. Chinese patent CN103524366B reports that phenol and 2-hydroxy glycine are reacted in the presence of acid catalyst, R-configurational isomer double salt is separated from S-configurational isomer double salt by first chiral resolution, then S-configurational isomer is resolved after racemization, R-configurational isomer double salt is further obtained, and R-p-hydroxy phenylglycine is obtained after the double salt is dissociated.

D-p-hydroxyphenylglycine and methanol are esterified to obtain p-hydroxyphenylglycine methyl ester hydrochloride, and the related reported technologies are as follows: chinese patent CN103641729A reports that D-p-hydroxyphenylglycine is used as a starting material and reacts with methanol or a hydrogen chloride methanol solution in the presence of trimethylchlorosilane to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride after treatment, and the product purity is high. Chinese patent CN104744281A reports that D-p-hydroxyphenylglycine is used as a starting material and reacts with methanol in the presence of an acyl halide reagent or acid to produce D-p-hydroxyphenylglycine methyl ester hydrochloride.

As can be seen from the patent report technology, the prior art schemes basically adopt the steps of firstly preparing racemic DL-p-hydroxyphenylglycine, then obtaining D-p-hydroxyphenylglycine through resolution, and finally obtaining D-p-hydroxyphenylglycine methyl ester hydrochloride through esterification reaction with methanol (shown as the following formula).

However, the technical problems in the prior art are not solved, and firstly, the prior art has long route, five steps of processes (no need of recycling a resolving agent) are needed for obtaining the D-p-hydroxyphenylglycine hydrochloride from phenol as a starting material, the process route is long, the production period is long, the production efficiency is low, and the product yield is low. Secondly, the prior art generates a large amount of wastewater in the step of synthesizing racemic DL-p-hydroxyphenylglycine, and although a wastewater treatment mode is reported in patent CN109354261A, the treatment mode has high energy consumption and low efficiency, and the generation of solid waste cannot be avoided. Thirdly, in the existing resolution technology, aryl sulfonic acid or camphor sulfonic acid is used as a resolving agent, and the resolving agent is expensive, so that the raw material and production cost of the product are high.

Disclosure of Invention

Based on the defects of the prior art, the technical problem to be solved by the invention is to provide a new process route (shown as the following formula) for synthesizing D-p-hydroxyphenylglycine methyl ester hydrochloride, and the process is mainly characterized by comprising the following steps of: 1, the operation is simple, only two steps of chemical reactions are carried out, and the production efficiency is high; 2, the three wastes are less generated, and the organic solvent can be recycled and reused; 3, the very cheap chiral induction reagent S- (-) -phenethylamine is used, so that the cost is greatly reduced. The new process route for synthesizing the D-p-hydroxyphenylglycine methyl ester hydrochloride is as follows:

in order to solve the technical problems, the invention provides a preparation method of D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production, which is prepared by the reaction according to the following reaction formula:

as the optimization of the technical scheme, the preparation method of the D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production further comprises part or all of the following technical characteristics:

as an improvement of the technical scheme, the preparation method of the D-p-hydroxyphenylglycine methyl ester hydrochloride suitable for industrial production comprises the following steps:

in the first step, methyl glyoxylate and phenol are used as raw materials, cheap S-aryl ethylamine is used as a chiral induction reagent, and an intermediate 1(R) -2- (4-hydroxyphenyl) -2- (((S) -1-aryl ethyl) amino) methyl acetate hydrochloride is obtained through reaction; the reaction process of the step is as follows: the methyl glyoxylate and chiral arylamine form imine, then Friedel-Crafts reaction is carried out under the catalytic action of a catalyst, and the chirality of d amino acid ester group is induced to generate during the Friedel-Crafts reaction due to the introduction of chiral arylamine group, so that an intermediate 1 is obtained;

the reaction equation of the first step process is as follows:

the second step is that the intermediate 1 is subjected to hydrogenolysis deprotection under the catalysis of Pd/C to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

The reaction equation of the first step process is as follows:

as an improvement of the technical scheme, in the first step, the Friedel-Crafts reaction step is as follows:

adding organic solvent with a molar ratio of 1: reacting 0.9-1: 1.2 of methyl glyoxylate with S-aryl ethylamine at the temperature of 10-50 ℃, adding phenol or anisole and a catalyst into the reaction solution after the reaction is finished, wherein the molar ratio of the methyl glyoxylate to the phenol or the anisole to the catalyst is 1: 0.9: 0.05-1: 1.2: 0.2; then continuing to react at 10-50 ℃; and (3) adding a hydrogen chloride solution after the reaction is finished, heating to 70-80 ℃ or refluxing, then cooling to 0-40 ℃ for crystallization, performing suction filtration, and drying the solid to obtain the intermediate 1.

As an improvement of the above technical scheme, in the second step, the deprotection reaction step is:

adding the intermediate 1 and a Pd/C catalyst into a solvent, wherein the using amount of the catalyst is 2-15% of the weight of the intermediate, carrying out deprotection at 20-60 ℃ by using a reducing agent through catalytic hydrogenolysis, cooling to-10-40 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, and drying the solid to obtain D-p-hydroxyphenylglycine methyl ester hydrochloride.

As an improvement of the above technical scheme, in the Friedel-Crafts reaction, the organic solvent is at least one of toluene, chlorobenzene, dichloromethane, xylene, dichloroethane, ethyl acetate and tetrahydrofuran, and toluene is preferred.

As an improvement of the technical scheme, in the Friedel-Crafts reaction, the catalyst is a Bronsted acid or a Lewis acid.

As an improvement of the technical scheme, the Bronsted acid or the Lewis acid is at least one of methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, chiral phosphoric acid, trifluoromethanesulfonic acid or indium trifluoromethanesulfonate.

As an improvement of the technical scheme, the hydrogen chloride solution is at least one of hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrochloric acid and hydrogen chloride isopropanol solution, and hydrogen chloride methanol solution is preferred

As a modification of the above technical solution, the reducing agent may be at least one of hydrogen, formic acid, ammonium formate or sodium formate, preferably formic acid.

As an improvement of the technical scheme, the solvent is at least one of water, methanol, ethanol, isopropanol or ethyl acetate, and preferably methanol.

Compared with the prior art, the technical scheme of the invention has the following beneficial effects: according to the synthesis method provided by the invention, the glyoxylic acid methyl ester and the cheap chiral arylamine are directly adopted to form imine, then the imine and the phenol are subjected to Friedel-Crafts reaction, and the R-configuration product is generated by introducing the chiral arylamine, so that the use of an expensive resolving agent is avoided, the cost and three wastes are reduced, and the production efficiency is improved. The total yield of the two-step reaction is 66%, and the chiral purity of the D-methyl p-toluenesulfonate hydrochloride is more than 99%.

The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.

FIG. 1 shows a hydrogen spectrum of D-p-hydroxyphenylglycine methyl ester hydrochloride prepared in example 7;

FIG. 2 shows an HPLC chromatogram of D-p-hydroxyphenylglycine methyl ester hydrochloride prepared in example 7; wherein, RT is 5.21min L-p-hydroxyphenylglycine methyl ester hydrochloride, and RT is 12.24min D-p-hydroxyphenylglycine methyl ester hydrochloride.

Detailed Description

Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.

Example 1 Synthesis of intermediate 1

Adding 500 ml of toluene into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 36.4 g of S-phenethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 5.2 g (0.03mol) of p-toluenesulfonic acid and 33.8 g of phenol (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride methanol solution (10%) after the reaction is finished, heating to 70-80 ℃, then cooling to 20-30 ℃, carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 70.3 g of solid with the yield of 73%.

Example 2 Synthesis of intermediate 1

Adding 500 ml of dichloromethane into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 36.4 g of S-phenethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 2.9 g (0.03mol) of methanesulfonic acid and 33.8 g of phenol (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride ethanol solution (10%) after the reaction is finished, heating to reflux, then cooling to 20-30 ℃, and carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 59.7 g of solid with the yield of 62%.

Example 3 Synthesis of intermediate 1

Adding 500 ml of dimethylbenzene into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 36.4 g of S-phenethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 3.4 g (0.03mol) of trifluoroacetic acid and 33.8 g of phenol (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride methanol solution (10%) after the reaction is finished, heating to 70-80 ℃, then cooling to 20-30 ℃, and carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 73.2 g of solid with the yield of 76%.

Example 4 Synthesis of intermediate 1

Adding 500 ml of dichloromethane into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 36.4 g of S-phenethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 8.4 g (0.015mol) of indium trifluoromethanesulfonate and 33.8 g of phenol (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride isopropanol solution (10%) after the reaction is finished, heating to reflux, then cooling to 20-30 ℃, carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 61.6 g of solid with the yield of 64%.

Example 5 Synthesis of intermediate 1

Adding 500 ml of toluene into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 51.3 g of S-naphthylethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 3.4 g (0.03mol) of trifluoroacetic acid and 33.8 g of phenol (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride methanol solution (10%), heating to 70-80 ℃, then cooling to 20-30 ℃, carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 85.7 g of solid, wherein the yield is 77%.

Example 6 Synthesis of intermediate 1

Adding 500 ml of toluene into a 1L three-necked bottle, then adding 60 ml of toluene solution of methyl glyoxylate (50% concentration, 0.3mol) and 36.4 g of S-phenethylamine (0.3mol), stirring for 2 hours at 20-30 ℃, then adding 3.4 g of trifluoroacetic acid (0.03mol) and 33.8 g of anisole (0.36mol), stirring for 12 hours at 20-30 ℃, adding 150 ml of hydrogen chloride methanol solution (10%) after the reaction is finished, heating to 70-80 ℃, then cooling to 20-30 ℃, carrying out suction filtration to obtain an intermediate 1, and carrying out vacuum drying for 8 hours at 50 ℃ to obtain 72.4 g of solid with the yield of 72%.

EXAMPLE 7 Synthesis of p-hydroxyphenylglycine methyl ester hydrochloride

Adding 500 ml of methanol into a 1L three-necked bottle, then replacing 164 g (0.2mol) of an intermediate and 6.4 g of 10% palladium carbon with nitrogen for three times, then replacing 3 times with hydrogen, pressurizing to 1Mpa with hydrogen, heating to 20-30 ℃, stirring for 4 hours, cooling to 5-15 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, and carrying out vacuum drying on the obtained solid at 50 ℃ for 8 hours to obtain 39.5 g of solid p-hydroxyphenylglycine methyl ester hydrochloride, wherein the yield is 91%.

Fig. 1 is a hydrogen spectrum and fig. 2 is an HPLC spectrum of D-p-hydroxyphenylglycine methyl ester hydrochloride prepared in this example (RT ═ 5.21min is L-p-hydroxyphenylglycine methyl ester hydrochloride, RT ═ 12.24min is D-p-hydroxyphenylglycine methyl ester hydrochloride), and the specific data are shown in table 1 below.

TABLE 1 HPLC data for D-p-hydroxyphenylglycine methyl ester hydrochloride

EXAMPLE 8 Synthesis of p-hydroxyphenylglycine methyl ester hydrochloride

Adding 500 ml of methanol into a 1L three-necked bottle, then heating to reflux the intermediate 164 g (0.2mol) and 10% palladium carbon 6.4 g, keeping the reflux temperature for reaction for 8 hours, then cooling to 5-15 ℃ for crystallization, carrying out suction filtration to obtain a solid, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain 38.6 g of solid p-hydroxyphenylglycine methyl ester hydrochloride with the yield of 89%.

EXAMPLE 9 Synthesis of p-hydroxyphenylglycine methyl ester hydrochloride

Adding 500 ml of methanol into a 1L three-necked bottle, then replacing 174 g (0.2mol) of an intermediate and 6.4 g of 10% palladium carbon by nitrogen for three times, then replacing 3 times by hydrogen, pressurizing to 1Mpa by hydrogen, heating to 20-30 ℃, stirring for 4 hours, cooling to 5-15 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, and carrying out vacuum drying on the obtained solid at 50 ℃ for 8 hours to obtain 39.7 g of solid p-hydroxyphenylglycine methyl ester hydrochloride, wherein the yield is 92%.

EXAMPLE 10 Synthesis of p-methoxyphenylglycine methyl ester hydrochloride

Adding 500 ml of methanol into a 1L three-necked bottle, then carrying out nitrogen displacement three times on 167 g (0.2mol) of an intermediate and 6.4 g of 10% palladium carbon, then carrying out hydrogen displacement 3 times, pressurizing to 1Mpa with hydrogen, heating to 20-30 ℃, stirring for 4 hours, cooling to 5-15 ℃ after the reaction is finished, crystallizing, carrying out suction filtration, carrying out vacuum drying on the obtained solid at 50 ℃ for 8 hours, and obtaining 39.9 g of solid p-methoxyphenylglycine methyl ester hydrochloride with the yield of 93%.

The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.

While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.