CN115894311A - Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate - Google Patents
Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate Download PDFInfo
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Abstract
The invention belongs to the technical field of veterinary drug preparation. Specifically, the invention relates to a preparation method of a florfenicol and thiamphenicol intermediate (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate. The (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid ethyl ester is obtained by esterification of optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid under the action of concentrated sulfuric acid or solid acid serving as a catalyst.
Description
Technical Field
The invention belongs to the technical field of veterinary drug preparation. Specifically, the invention relates to a preparation method of florfenicol and thiamphenicol intermediates.
Background
Ethyl (2r, 3s) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate is of the formula:
the (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate is a key intermediate for synthesizing veterinary drugs florfenicol and thiamphenicol, and the florfenicol serving as a veterinary broad-spectrum antibiotic has wide application in the aspects of clinic and agriculture, and the demand of the florfenicol is increased year by year. At present, a synthesis method of ethyl 2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate (CN 112321467A) uses p-methylsulfonylbenzaldehyde and ethyl 2-haloacetate to prepare ethyl (2S, 3R) -2-halo-3-hydroxy-3- (4-methylsulfonyl) phenyl propionate under the action of a catalyst A, halogen atoms are substituted by azide, and then catalytic hydrogenation reduction is carried out to prepare ethyl (2S, 3R) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate; and (CN 110776443A) carrying out esterification reaction on 2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic copper salt, ethanol and a water-carrying agent under the catalysis of activated carbon immobilized p-toluenesulfonic acid, adding a sodium sulfide solution to remove copper ions after the esterification reaction is finished, adding activated carbon to decolor, adjusting the pH to 8.5-9.0, and cooling and crystallizing to obtain racemized ethyl 2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate. The method has the defects of low efficiency, complex operation, high cost, harm to the environment and the like, and particularly, a large amount of sulfuric acid and copper ions are required to be introduced into a chemical synthesis system, a large amount of acidic high-concentration wastewater containing heavy metal ions is generated in the whole process, the pollution of the copper ions to the product is required to be removed by adopting sulfur ions subsequently, the process is complex, the environmental pollution is serious, and the method is a key bottleneck for limiting the product productivity.
Therefore, the traditional mainstream process of the product is completed by 2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid and glycine under the condition that copper ions participate in activation, so the process prepares the copper salt of 2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid, so a large amount of copper-containing waste water is inevitably generated in the subsequent esterification process, and the problem that the copper salt is remained in the product is solved, which is a key pollution problem in the traditional chemical process production process of the product. Chiral pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid can be obtained by adopting a biological enzyme catalysis method, but a corresponding esterification process needs to be developed, so that the remarkable advantages that copper-containing wastewater is not generated, and the use amount of sulfuric acid can be greatly reduced without consuming sulfuric acid by copper ions; however, the key point to be solved by the process is to ensure that the chiral center of the esterification process is not racemized, and simultaneously avoid significant hydrolysis in the product purification process.
Therefore, a method for preparing (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate which is simple to operate, green and efficient needs to be explored and developed, and the method has more environmental protection and market advantages.
Disclosure of Invention
Aiming at the defects of the prior art, the inventor researches and discovers that optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid is directly adopted to replace p-methylsulfonylphenylserine copper salt for direct esterification, so that the generation of a large amount of high-concentration heavy metal wastewater is avoided. The method of the invention respectively adopts sulfuric acid, solid acid and the like as catalysts to research the amount of the sulfuric acid and the type of the solid acid, wherein the sulfuric acid is adopted as the catalyst, only 1 equivalent of the sulfuric acid as a substrate is needed to be added for catalytic reaction to achieve the esterification rate close to 95 percent, and the sulfuric acid which is 3 to 4 times of the substrate is needed to be added for reaction in the traditional copper salt esterification process, so the amount of the added sulfuric acid is greatly reduced compared with the amount of the sulfuric acid in the copper salt synthesis method, the reaction time is short, the yield is high, and simultaneously, the whole reaction process and the process control of product treatment, including the setting of temperature, system PH control and other parameters, are greatly optimized and compared, and the racemization of the product can be ensured not to occur.
The solid acid is further adopted as the catalyst, so that the method has the advantages that the subsequent product treatment can be simplified, the acid catalyst and the product can be separated by filtering after the reaction is finished, the discharge of acid-containing wastewater is avoided, the alkali amount for subsequent pH adjustment is obviously reduced, and the product hydrolysis phenomenon in the pH adjustment process is reduced; meanwhile, the catalyst can be repeatedly used, has the advantages of high environmental protection and emission reduction, and can ensure that the racemization of the product does not occur in the whole reaction process and the process control of product treatment.
In addition, because the product (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate is unstable, the purification process is optimized, and parameters and conditions such as pH adjusting temperature, pH range, concentration temperature, activated carbon amount, decoloring time, drying temperature and the like are mainly included, so that the hydrolysis and racemization of the product can be reduced to the maximum extent in the treatment process according to the process parameters, and the maximum product yield can be realized.
Therefore, the invention firstly provides a preparation method of (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate, which is obtained by esterification of optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid under the action of acid. Wherein the e.e of the optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propanoic acid is >98% and the water content is <0.3%.
Specifically, the acid is concentrated sulfuric acid or solid acid. Preferably, the concentrated sulfuric acid is 1-4N, the solid acid is p-toluenesulfonic acid, solid acid resin, and the super-strong solid acid is SO 4 2- /M x O y Specifically including SO 4 2- /Fe 2 O 3 ；SO 4 2- /ZrO 2 ；SO 4 2- /TiO 2 ；SO 4 2- /TiO 2 -ZrO 2 Etc., more preferably catalyst grade strong acid type nuclear grade ion exchange resin.
In a specific embodiment, the catalyst is added into absolute ethyl alcohol, then (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid is added into a reaction bottle, mechanical stirring is carried out, and water bath heating is carried out until the temperature in the bottle reaches 90 ℃ so as to carry out reaction.
Wherein the amount of the catalyst is 1 to 2 times equivalent to (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propanoic acid.
Further, the method also comprises a subsequent purification step. Specifically, after the reaction is finished, cooling to below 10 ℃, and filtering to separate solid acid resin; washing the resin with absolute ethyl alcohol, combining filtrates, concentrating the filtrate to 40-50 ℃ (preferably 45 ℃) by using a rotary evaporator until a solid is generated, cooling to room temperature, adding water, stirring to completely dissolve, adding 1% activated carbon, stirring and filtering at room temperature, leaching with water, discarding a filter cake, adjusting the pH of the filtrate to 8-8.5 (preferably 8.2) by using ammonia water continuously until a white solid is generated; stirring and filtering at the temperature below 20 ℃, leaching with water, and freeze-drying a filter cake by using a freeze dryer to obtain the freeze-dried powder.
And a step of recovering the solvent, wherein when concentrated sulfuric acid is used as the catalyst, after the reaction is finished, the pH of the reaction solution is adjusted to be less than 5.5 by using ammonia water under the condition that the temperature is lower than 45 ℃, and the excessive ethanol is recovered by decompressing and concentrating by using a rotary evaporator.
Further, the solid acid is recycled, namely the solid acid is recovered after the reaction is finished and is used for the subsequent catalytic reaction.
Drawings
FIG. 1 shows the reaction profile of example 2.
FIG. 2 pH temperature adjustment optimization.
FIG. 3 solvent recovery pH optimization.
Figure 4 solvent recovery temperature optimization.
Figure 5 product drying temperature optimization.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art.
Example 1
Taking four three-neck flasks, respectively adding 30ml of absolute ethyl alcohol, respectively and slowly dropwise adding 2.0, 4.0, 6.0 and 8.0ml of concentrated sulfuric acid into ice water, respectively weighing 10.0g of solid (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid (e.e >98 percent and the water content is less than 0.3 percent), and slowly adding the solid into a sulfuric acid ethanol solution in the three-neck flask; and opening the mechanical stirring, heating in a water bath to the temperature of 90 ℃ in the bottle, keeping the reflux state of the reaction system, and starting timing. The reaction conversion was measured and the data are shown in the table below.
Example 2: preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, slowly dropwise adding 20.0ml of concentrated sulfuric acid into ice water, weighing 100.0g of solid (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid (e.e is more than 98 percent, and the water content is less than 0.3 percent), and slowly adding the solid into a sulfuric acid ethanol solution in the three-neck flask; adding stirring, reflux condenser tube and temperature probe into three-mouth bottle, starting mechanical stirring, heating in water bath to 90 deg.C, and timing. The reaction reached 94.96% conversion over about 5 hours, as shown in FIG. 1.
Example 3: temperature optimization during pH adjustment during product purification
The product purification process after the reaction is finished comprises a pH adjusting process, local over-alkali is found to exist, and the condition that even the local over-alkali does not cause obvious hydrolysis of the product at a proper temperature is ensured, so the temperature of the two-step pH adjusting process in the product purification process is optimized, the reaction liquid in the example 2 is averagely divided into four parts, the pH adjustment is carried out under the conditions of 0, 10, 25 and 40 ℃, and then the proportion of the hydrolysis product in the reaction liquid after the pH adjustment is measured, and the experimental result shows that the hydrolysis product cannot be obviously increased when the temperature is lower than 10 ℃ (the result is shown in figure 2).
Example 4: PH optimization during solvent recovery in product purification
Heating is needed in a solvent recovery process included in a product purification process after the reaction is finished, the duration is long, so that the pH of a feed liquid system is controlled in a proper range, the product cannot be hydrolyzed, the reaction is prepared according to the method in example 2, the temperature is reduced to below 10 ℃ after the reaction is finished, the reaction is averagely divided into four parts, ammonia water is respectively used for adjusting the pH of a reaction solution to 3, 4, 5.5 and 6.5, a rotary evaporator is used for reducing the pressure and concentrating to recover excessive ethanol, and the temperature is 30 ℃; the results of the experiments show that a pH higher than 5.5 leads to a significant increase in the hydrolysis products (see FIG. 3).
Example 5: solvent recovery temperature optimization during product purification
In the product purification process after the reaction is finished, the solvent recovery speed is low at 30 ℃ and the efficiency is low, so the solvent recovery effect at a higher temperature under the condition of pH5.5 is further considered, referring to the preparation reaction by the method in example 2, after the reaction is finished, the temperature is reduced to below 10 ℃, the solvent is averagely divided into three parts, ammonia water is respectively used for adjusting the pH of the reaction solution to 5.5, the temperature is respectively set to be 30 ℃, 45 ℃ and 65 ℃, a rotary evaporator is used for carrying out reduced pressure concentration to recover excessive ethanol, and the experimental result shows that the hydrolysis product cannot be obviously increased when the temperature is lower than 45 ℃ (the result is shown in figure 4).
Example 6
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, slowly dropwise adding 21.7ml of concentrated sulfuric acid into ice water, weighing 105.0g of solid (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid (e.e is more than 98 percent, and the water content is less than 0.3 percent), and slowly adding the solid into a sulfuric acid ethanol solution in the three-neck flask; adding stirring, reflux condenser tube and temperature probe into three-mouth bottle, starting mechanical stirring, heating in water bath to 90 deg.C, and timing. The reaction time was about 5 hours and the conversion was found to reach 95.46%.
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
The experiment was optimized according to examples 3-5, with the optimal conditions selected, in this example the following purification steps and parameters were used:
after the reaction is finished, cooling to below 10 ℃, adjusting the pH of the reaction solution to 5.5 by using ammonia water, and performing reduced pressure concentration by using a rotary evaporator to recover excessive ethanol at the temperature of 45 ℃; then when the concentration is finished (solid is generated), adding 100ml of water, stirring until the water is completely dissolved, adding 1% (1.0 g) of activated carbon, stirring for 1 hour at room temperature, filtering, and removing a filter cake; and then adjusting the pH of the filtrate to 8.2 with ammonia water at the temperature of below 10 ℃, separating out solids, stirring for 30min at the temperature of 10 ℃, filtering, wherein a filter cake of a product contains higher water content and can cause hydrolysis and dissolution of the product in a long-time heating and drying process, so that the drying temperature is optimized, the filter cake is divided into three parts, and the three parts are dried by vacuum drying at the negative pressure conditions of 30 ℃, 45 ℃ and 60 ℃ and 0.08 MPa respectively. The experimental results show that temperatures below 30 ℃ do not result in a significant increase in the hydrolysis products (see figure 5 for results).
Example 7
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, adding 50 g of catalyst grade strong acid type nuclear grade ion exchange resin (T-62 MP DRY), weighing 100 g of (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid (e.e >98%, water content is less than 0.3%) and slowly adding into the reaction flask; adding stirring, reflux condenser tube and temperature probe into three-mouth bottle, starting mechanical stirring, heating in water bath to 90 deg.C, and timing. The conversion rate of reaction for 12 hours reaches 89%, which is calculated according to the proportion of the product in the detection result to the total amount of the initial substrate.
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
After the reaction is finished, the temperature is reduced to below 10 ℃, and the solid acid resin is filtered and separated. Washing the resin with 20 ml of absolute ethyl alcohol, combining filtrates, concentrating the filtrate by using a rotary evaporator (45 ℃) until a solid is generated, cooling to room temperature, adding 300ml of water, stirring to dissolve completely, adding 1% (1.0 g) of activated carbon, stirring for 1 hour at room temperature, filtering, rinsing with 10ml of water, discarding a filter cake, and continuously adjusting the pH of the filtrate to 8.2 by using ammonia water at 10 ℃ to generate a white solid. Stirring at 20 deg.C below for 30min, filtering, rinsing with 10ml water, and lyophilizing the filter cake with lyophilizer.
89.76g of the product is finally obtained, the purity is 98.25%, the e.e is more than 98%, and the total yield is 81.0%.
Meanwhile, the solid acid resin is repeatedly used for 5 times, the reaction activity and the yield are not obviously reduced, and the results are as follows:
| number of |
1 | 2 | 3 | 4 | 5 |
| Conversion rate% | 89.00 | 90.05 | 88.67 | 91.33 | 88.76 |
| Yield% | 81.02 | 80.46 | 82.09 | 82.01 | 80.36 |
Example 8
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, and adding super-strong solid acid SO 4 2- /Fe 2 O 3 15 g, 100 g (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propanoic acid (e.e.>98% of water<0.3%) was added to the reaction flask; adding stirring, reflux condenser tube and temperature probe into three-mouth bottle, starting mechanical stirring, heating in water bath to 90 deg.C, and timing. The reaction is carried out for 3 hours, and the conversion rate reaches 93 percent
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
The product was purified as in example 7. 90.86g of the product was finally obtained with a purity of 98.43%, an e.e >98%, and a total yield of 82.0%.
Example 9
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, and adding super-strong solid acid SO 4 2- /ZrO 2 15 g, reaction procedure and purification method of product refer to example 8. The reaction is carried out for 3 hours, and the conversion rate reaches 95 percent
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
The product was purified as in example 7. 92.34g of product was finally obtained with a purity of 98.76%, e.e >98% and a total yield of 83.3%.
Example 10
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, and adding super-strong solid acid SO 4 2- /TiO 2 15 g, procedures for reaction and purification of product refer to example 8. The reaction was carried out for 3 hours, and the conversion rate reached 95%.
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
The product was purified as in example 7. 94.41g of the product was finally obtained with a purity of 98.01%, an e.e >98%, and a total yield of 85.2%.
Example 11
1. Preparation of ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
Adding 300ml of absolute ethyl alcohol into a three-neck flask, and adding super-strong solid acid SO 4 2- /TiO 2 -ZrO 2 18 g, procedures for reaction and purification of product refer to example 7. After 3 hours of reaction, the conversion rate reached 93%.
2. Purification of Ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate
The product was purified as in example 7. 88.87g of product was finally obtained with a purity of 98.28%, an e.e >98% and a total yield of 80.2%.
Claims (10)
1. A preparation method of (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) ethyl propionate is characterized in that optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid is esterified under the action of concentrated sulfuric acid or solid acid serving as a catalyst to obtain the ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate.
2. The method of claim 1, wherein the optically pure (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid has an e.e >98% and a moisture <0.3%.
3. The method of claim 1, wherein the concentrated sulfuric acid is 1-4N, the solid acid is p-toluenesulfonic acid, a solid acid resin, a super-solid acid, and the super-solid acid is SO 4 2- /M x O y 。
4. The method of claim 1, wherein the ultra-strong solid acid is selected from the group consisting of SO 4 2- /Fe 2 O 3 ；SO 4 2- /ZrO 2 ；SO 4 2- /TiO 2 ；SO 4 2- /TiO 2 -ZrO 2 (ii) a The solid acid resin is selected from catalytic strong acid type nuclear grade ion exchange resin.
5. The method according to claim 1, wherein the reaction is carried out by adding the catalyst to absolute ethanol, adding (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionic acid, stirring, and heating in a water bath to an internal temperature of 90 ℃.
6. The method of claim 5, wherein the catalyst is used in an amount of 1 to 2 equivalents to (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propanoic acid.
7. The method of claim 1, further comprising the step of subsequently purifying the ethyl (2R, 3S) -2-amino-3-hydroxy-3- (4- (methylsulfonyl) phenyl) propionate.
8. The method according to claim 1, wherein the subsequent purification is in particular: when solid acid is adopted as a catalyst, cooling to below 10 ℃ after the reaction is finished, and filtering to separate solid acid resin; washing the resin with absolute ethyl alcohol, combining filtrates, concentrating the filtrate to 40-50 ℃ by using a rotary evaporator until solids are generated, cooling to room temperature, adding water, stirring for complete dissolution, adding 1% active carbon, stirring and filtering at room temperature, leaching with water, discarding a filter cake, adjusting the filtrate to be below 10 ℃, and adjusting the pH value to 8-8.5 by using ammonia water until white solids are generated; stirring and filtering at the temperature below 20 ℃, leaching with water, and freeze-drying a filter cake by using a freeze dryer to obtain the freeze-dried powder.
9. The method according to claim 8, wherein in the case of using concentrated sulfuric acid as a catalyst, after completion of the reaction, the pH of the reaction solution is adjusted to 5.5 or less using ammonia water at a temperature of less than 45 ℃ and the excess ethanol is recovered by concentration under reduced pressure using a rotary evaporator.
10. The method of claim 1, wherein the solid acid is recycled by recovering the solid acid after the reaction is completed for use in a subsequent catalytic reaction.
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| CN102442930A (en) * | 2011-11-02 | 2012-05-09 | 江苏宇翔化工有限公司 | Preparation method of DL-p-methylsulfonylphenyl serine ethyl ester |
| CN104860853A (en) * | 2015-05-20 | 2015-08-26 | 河南师范大学 | Preparation method of p-methyl sulfone phenyl ethyl serinate |
| CN108033903A (en) * | 2017-12-28 | 2018-05-15 | 山东汉兴医药科技有限公司 | Synthesis process for D L-p-methylsulfonylphenylserine ethyl ester with water esterification |
| CN114014787A (en) * | 2022-01-10 | 2022-02-08 | 苏州开元民生科技股份有限公司 | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester |
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