CN111909046A - D-phenylglycine methyl ester phosphate crystal, preparation method and solution - Google Patents
D-phenylglycine methyl ester phosphate crystal, preparation method and solution Download PDFInfo
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- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
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Abstract
The invention discloses a D-phenylglycine methyl ester phosphate crystal, a preparation method and a solution, wherein the preparation method comprises the following steps: step a, adding D-phenylglycine and methanol into a reaction tank, uniformly stirring, and then adding phosphoric acid in a flowing manner; b, after the phosphoric acid is fed completely, carrying out reflux reaction; and c, after the reflux reaction in the step b is finished, carrying out vacuum dehydration, and repeating the following operations for n times: adding methanol, continuing to perform reflux reaction, and performing vacuum dehydration after the reflux reaction is finished; and D, adjusting the pH value to be acidic, adding D-phenylglycine methyl ester phosphate seed crystals for crystallization, and drying to obtain the D-phenylglycine methyl ester phosphate crystals. Solves the problems of low conversion rate of subsequent enzymatic synthesis and serious corrosion to equipment in the related technology.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to D-phenylglycine methyl ester phosphate crystals, a preparation method and a solution.
Background
Currently, the side chains of enzymatic ampicillin, cephalexin and cefaclor are prepared based on hydrochloride or hemisulfate of D-phenylglycine methyl ester, such as the synthesis method of D-phenylglycine methyl ester hydrochloride mentioned in the document "synthesis of cefaclor active side chain phenylglycine methyl ester hydrochloride", and the synthesis method of hemisulfate of D-phenylglycine methyl ester mentioned in the patent document CN 107074742A.
The main problems of the method are as follows: no matter the preparation of D-phenylglycine methyl ester hydrochloride or hemisulfate, on one hand, the conversion rate of the subsequent enzyme synthesis is low and is only 96%, and on the other hand, the subsequent enzyme synthesis has serious corrosion to metal-containing equipment such as a stainless steel tank and the like, so that enamel equipment is needed in the production process, the difficulty of manufacturing the special-shaped stirring paddle is high, the stirring rotating speed is low, the mass transfer and heat transfer of a reaction tank are inferior to those of the metal-containing equipment such as the stainless steel tank and the like, and the reaction effect is poor, so that the production amplification is seriously influenced.
Disclosure of Invention
The invention aims to provide D-phenylglycine methyl ester phosphate crystals, a preparation method and a solution, which are used for solving the problems of low conversion rate of subsequent enzymatic synthesis and severe corrosion to equipment in the related art.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, there is provided a crystalline D-phenylglycine methyl ester phosphate having an X-ray powder diffraction pattern, expressed in 2 θ, including features at 5.70. + -. 0.20, 7.18. + -. 0.20, 12.34. + -. 0.20, 14.52. + -. 0.20, 18.78. + -. 0.20, 19.82. + -. 0.20, 21.96. + -. 0.20, 24.18. + -. 0.20, 25.02. + -. 0.20, 26.08. + -. 0.20, 28.12. + -. 0.20, 28.86. + -. 0.20, 29.46. + -. 0.20, 30.00. + -. 0.20, 31.62. + -. 0.20, 31.88. + -. 0.20, 32.80. + -. 0.20, 35.48. + -. 0.20, 38.32. + -. 0.20 degrees.
In a second aspect, there is provided a solution whose components include crystals of D-phenylglycine methyl ester phosphate as described in the first aspect.
In one possible implementation, the solution may be an aqueous solution.
In a third aspect, a process for the preparation of crystals of D-phenylglycine methyl ester phosphate as described in the first aspect, which process comprises:
step a, adding D-phenylglycine and methanol into a reaction tank, uniformly stirring, and then adding phosphoric acid in a flowing manner;
b, after the phosphoric acid is fed completely, carrying out reflux reaction;
and c, after the reflux reaction in the step b is finished, carrying out vacuum dehydration, and repeating the following operations for n times: adding methanol, continuing to perform reflux reaction, and performing vacuum dehydration after the reflux reaction is finished;
and D, adjusting the pH value to be acidic, adding D-phenylglycine methyl ester phosphate seed crystals for crystallization, and drying to obtain the D-phenylglycine methyl ester phosphate crystals.
In one possible implementation, in step a: the temperature in the reaction tank is less than or equal to 40 ℃.
In one possible implementation, in step a: the ratio of D-phenylglycine to methanol is 1 g: 4-7 mL. Optionally, the ratio of the D-phenylglycine to the methanol is 1 g: 4 mL.
In one possible implementation, in step a: the weight ratio of the phosphoric acid to the D-phenylglycine is 1: 0.8 to 1.5. Optionally, the weight ratio of the phosphoric acid to the D-phenylglycine is 1: 1.
in one possible implementation, in step b: the temperature in the reaction tank is 75-80 ℃. Optionally, in step b: the temperature in the reaction tank was 75 ℃.
In one possible implementation, in step b: the time of the reflux reaction is 2-4 h. Optionally, the reflux reaction time is 2 h.
In one possible implementation, in step b: the value of n is 3-6. Optionally, in step b: the value of n is 5.
In one possible implementation, in step c: and when water is removed in vacuum, the vacuum degree in the reaction tank is 0.04-0.06 Mpa. Optionally, in step c: and when water is removed in vacuum, the vacuum degree in the reaction tank is 0.05 Mpa.
In one possible implementation, in step c: the time for carrying out the reflux reaction is 40-60 min. Optionally, in step c: the time for carrying out the reflux reaction was 60 min.
In one possible implementation, in step c: the temperature for the reflux reaction is 84 to 86 ℃. Optionally, in step c: the temperature at which the reflux reaction was carried out was 83 ℃.
In a possible implementation manner, the step d includes: adding water, adding ammonia water to adjust the pH value to acidity, cooling for the first time, adding D-phenylglycine methyl ester phosphate crystal seed crystals for crystallization, cooling for the second time, stirring, centrifuging, and drying to obtain the D-phenylglycine methyl ester phosphate crystals.
In one possible implementation, in step d: the weight of water added was the same as the weight of the D-phenylglycine.
In one possible implementation, in step d: the pH value is 2.4-2.6. Optionally, in step d: the pH was 2.5.
In one possible implementation, in step d: the temperature is reduced to-5 to 15 ℃ for the first time. Optionally, in step d: the temperature is reduced to 5 ℃ for the first time.
In one possible implementation, in step d: the weight of the D-phenylglycine methyl ester phosphate seed crystal is 1-2% of that of the D-phenylglycine. Optionally, in step d: the weight of the D-phenylglycine methyl ester phosphate seed crystals was 2% of the weight of the D-phenylglycine.
In one possible implementation, in step d: and cooling to 5-10 ℃ for the second time. Optionally, in step d: and the temperature is reduced to 5 ℃ for the second time.
In one possible implementation, in step d: the stirring time is 30-60 min. Optionally, in step d: the stirring time was 40 min.
In one possible implementation, in step d: the temperature during drying is 45-50 ℃. In the step d: the temperature during drying was 50 ℃.
In one possible implementation, in step d: the drying time is 6-8 h. Optionally, in step d: the drying time was 8 h.
In a fourth aspect, there is provided the use of crystals of D-phenylglycine methyl ester phosphate for the preparation of ampicillin, cefaclor or cephalexin, comprising acylating said D-phenylglycine methyl ester phosphate with 6-aminopenicillanic acid, 7-aminodesacetoxycephalosporanic acid or 7-amino-3-chloro-cephem acid, respectively, in the presence of a penicillin acylase.
The invention has the following beneficial effects:
because a stable pH range is required in a reaction system of side chains of the enzymatic ampicillin, cefalexin and cefaclor, in the technical scheme of the invention, because the phosphate is trivalent salt, compared with monovalent hydrochloride and divalent sulfate, the phosphate has stronger buffering capacity and is beneficial to maintaining the stability of the PH range of the reaction system, thereby improving the conversion rate of the subsequent enzymatic synthesis, in addition, compared with the preparation of D-phenylglycine methyl ester hydrochloride and sulfate, phosphoric acid is adopted in the preparation process of the D-phenylglycine methyl ester phosphate, the corrosion to metal-containing equipment such as a stainless steel tank is very low, so that the limit of enamel equipment can be eliminated, and the metal-containing equipment such as the stainless steel tank is adopted, so that the reaction effect can be greatly improved, thereby improving the conversion rate of enzymatic synthesis, being beneficial to production amplification and further bringing remarkable economic benefit.
In addition, in the process of implementing the present invention, the inventors found that no seed crystal is added in the preparation process of hydrochloride and sulfate of D-phenylglycine methyl ester, and the crystallization effect is good, but when preparing D-phenylglycine methyl ester phosphate, the control of the crystallization of D-phenylglycine methyl ester phosphate is very difficult, and the same good crystallization effect cannot be achieved all the time.
These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter.
Drawings
In order to more clearly illustrate the embodiments of the present invention or technical solutions in related arts, the drawings used in the description of the embodiments or related arts will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a crystal electron microscope image of D-phenylglycine methyl ester phosphate provided by an embodiment of the present invention;
FIG. 2 is an X-ray powder diffraction pattern of crystals of D-phenylglycine methyl ester phosphate provided by an embodiment of the present invention.
Detailed Description
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
The D-phenylglycine methyl ester phosphate crystal, the preparation method and the raw materials or auxiliary materials used in the solution provided by the invention can be purchased from the market.
EXAMPLE 1 preparation of crystals of D-phenylglycine methyl ester phosphate
Adding 80L of methanol into a 200L reaction tank, adding 20Kg of D-phenylglycine under stirring, and after uniformly stirring, adding 20Kg of phosphoric acid in a flowing manner, wherein the temperature is controlled below 40 ℃. After the feeding is finished, the temperature in the reaction tank is maintained at 75 ℃, reflux reaction is carried out for 2 hours, and the reflux reaction is finished. And then carrying out vacuum dehydration, and adopting a reduced pressure distillation mode, specifically, maintaining the vacuum degree in the reaction tank at 0.04-0.06 MPa, and stopping reduced pressure distillation after the mass content of methanol in the solution in the reaction tank reaches 2%. And then adding 60L of methanol, continuing to perform reflux reaction for 1h, after the reflux reaction is finished, performing reduced pressure distillation, cooling and crystallizing after the mass content of the methanol in the solution in the reaction tank reaches 2%, repeating the steps for 5 times, and finally performing reduced pressure distillation until the residual 25L is obtained. And then adding 20L of water, adding ammonia water to adjust the pH value to 2.5, cooling to 5 ℃ for the first time, adding 400g of D-phenylglycine methyl ester phosphate seed crystal for crystallization, cooling to 5 ℃ for the second time, stirring for 30-60 min, centrifuging, and drying in vacuum at 50 ℃ for 8h to obtain 30Kg of D-phenylglycine methyl ester phosphate crystal.
An electron microscope image of the D-phenylglycine methyl ester phosphate crystals obtained in this example is shown in fig. 1, and the D-phenylglycine methyl ester phosphate crystals were analyzed by a radiation diffraction analyzer. The type and detection conditions of the powder X-ray diffractometer are as follows in Table 1:
TABLE 1 type of powder X-ray diffractometer and detection conditions
An X-ray powder diffraction pattern of the D-phenylglycine methyl ester phosphate crystal is shown in fig. 2, in which the abscissa 2 θ represents the diffraction angle and the ordinate cps represents the diffraction intensity, and fig. 2 includes characteristic peaks at 5.70, 7.18, 12.34, 14.52, 18.78, 19.82, 21.96, 24.18, 25.02, 26.08, 28.12, 28.86, 29.46, 30.00, 31.62, 31.88, 32.80, 35.48, and 38.32 degrees.
EXAMPLE 2 preparation of cephalexin
20g 7-aminodesacetoxycephalosporanic acid (7-ADCA) were suspended in 100mL of water and the temperature was controlled at 25 ℃. The mixture was stirred for 5 minutes while maintaining the pH at 7.0 by adding 15% aqueous ammonia solution, and 10g of immobilized enzyme was added. Next, 25g of D-phenylglycine methyl ester phosphate crystals were added at a constant rate over 90 min. Once all of the D-phenylglycine methyl ester phosphate was crystallized by addition, the pH was maintained at 7.0 by addition of either a 15% aqueous ammonia solution or a 30% aqueous sulfuric acid solution. After 230min, the pH was adjusted to 5.8 by adding 30% aqueous sulfuric acid. During the reaction, samples were taken and analyzed by High Performance Liquid Chromatography (HPLC), and the analysis results are shown in table 2.
TABLE 2 results of sampling analysis for the preparation of cephalexin based on D-phenylglycine methyl ester phosphate crystallization
Conversion rate: 100 Cefalexin mol/(Cefalexin mol +7-ADCA mol)
For comparison, the above protocol for the preparation of cephalexin was repeated using D-phenylglycine methyl ester hydrochloride crystals instead of D-phenylglycine methyl ester phosphate crystals. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 3.
TABLE 3 results of sampling analysis for the preparation of cefalexin based on D-phenylglycine methyl ester hydrochloride
Conversion rate: 100 Cefalexin mol/(Cefalexin mol +7-ADCA mol)
For comparison, the above protocol for the preparation of cephalexin was repeated using D-phenylglycine methyl ester hemisulfate crystals instead of D-phenylglycine methyl ester phosphate crystals. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 4.
TABLE 4 results of sampling analysis of the preparation of cephalexin based on D-phenylglycine methyl ester hemisulfate crystals
Conversion rate: 100 Cefalexin mol/(Cefalexin mol +7-ADCA mol)
As can be seen from tables 2, 3 and 4, when cephalexin was prepared based on the D-phenylglycine methyl ester phosphate crystals, the D-phenylglycine methyl ester hydrochloride crystals and the D-phenylglycine methyl ester hemisulfate crystals after 90min, the amounts of 7-ADCA in the samples corresponding to the D-phenylglycine methyl ester phosphate crystals were 12.35mg/mL, 16.57mg/mL and 17.32mg/mL in this order, which indicates that the amount of 7-ADCA in the samples corresponding to the D-phenylglycine methyl ester phosphate crystals was the smallest, that is, the enzymatic synthesis rate corresponding to the D-phenylglycine methyl ester phosphate crystals was the fastest. After 130min, when cefalexin is prepared based on D-phenylglycine methyl ester phosphate crystals, D-phenylglycine methyl ester hydrochloride crystals and D-phenylglycine methyl ester hemisulfate crystals, the 7-ADCA separated out from the corresponding samples is 3.41mg/mL, 5.62mg/mL and 6.49mg/mL, at the moment, the amount of 7-ADCA in the samples corresponding to the D-phenylglycine methyl ester phosphate crystals is still minimum, and the enzymatic synthesis conversion rate of 98.9% when cefalexin is prepared based on the D-phenylglycine methyl ester phosphate crystals is higher than that of 95.8% and 96.1% when cefalexin is prepared based on the D-phenylglycine methyl ester hydrochloride crystals and the D-phenylglycine methyl ester hemisulfate crystals.
From the above analysis it can be seen that the use of D-phenylglycine methyl ester phosphate crystals gives significantly better results with respect to cephalexin formation than the use of D-phenylglycine methyl ester hydrochloride crystals and sulphate crystals.
EXAMPLE 3 preparation of ampicillin
20g 6-aminopenicillanic acid (6-APA) were suspended in 100mL water and the temperature was controlled at 25 ℃. The mixture was stirred for 5 minutes while maintaining the pH at 7.0 by adding 15% aqueous ammonia solution, and 10g of immobilized enzyme was added. Next, 25g of D-phenylglycine methyl ester phosphate crystals were added at a constant rate over 90 min. Once all of the D-phenylglycine methyl ester phosphate was added to crystallize, while maintaining the pH at 7.0 by adding a 15% aqueous ammonia solution or adding a 30% aqueous sulfuric acid solution. After 230 minutes, the pH was adjusted to 5.8 by addition of 30% aqueous sulfuric acid. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 5.
TABLE 5 results of sampling analysis for ampicillin preparation based on D-phenylglycine methyl ester phosphate crystallization
For comparison, the above ampicillin preparation protocol was repeated using D-phenylglycine methyl ester hydrochloride crystals instead of D-phenylglycine methyl ester phosphate crystals. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 6.
TABLE 6 results of sampling analysis for ampicillin preparation based on D-phenylglycine methyl ester hydrochloride crystallization
For comparison, the above ampicillin preparation protocol was repeated using D-phenylglycine methyl ester hemisulfate crystals instead of D-phenylglycine methyl ester phosphate crystals. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 7.
TABLE 7 results of sampling analysis for ampicillin preparation based on D-phenylglycine methyl ester hemisulfate crystallization
As is apparent from tables 5, 6 and 7, when ampicillin was produced based on the D-phenylglycine methyl ester phosphate crystals, the D-phenylglycine methyl ester hydrochloride crystals and the D-phenylglycine methyl ester hemisulfate crystals after 90 minutes, 6-APA separated in the corresponding samples was 10.21mg/mL, 15.57mg/mL and 17.32mg/mL in this order, which indicated that the amount of 6-APA in the sample corresponding to the D-phenylglycine methyl ester phosphate crystals was the smallest, that is, the enzymatic synthesis rate corresponding to the D-phenylglycine methyl ester phosphate crystals was the fastest. After 130min, when ampicillin is prepared based on D-phenylglycine methyl ester phosphate crystals, D-phenylglycine methyl ester hydrochloride crystals and D-phenylglycine methyl ester hemisulfate crystals, 6-APA separated in corresponding samples is 2.06mg/mL, 4.58mg/mL and 5.12mg/mL, at this time, the amount of 6-APA in the samples corresponding to the D-phenylglycine methyl ester phosphate crystals is still minimum, and the enzymatic synthesis conversion rate of 98.8% when ampicillin is prepared based on the D-phenylglycine methyl ester phosphate crystals is higher than 96.8% and 96.2% when ampicillin is prepared based on the D-phenylglycine methyl ester hydrochloride crystals and the D-phenylglycine methyl ester hemisulfate crystals.
From the above analysis, it is clear that the use of D-phenylglycine methyl ester phosphate crystals also gives significantly better results with respect to ampicillin formation than the use of D-phenylglycine methyl ester hydrochloride crystals and sulphate crystals.
Example 4 preparation of cefaclor
20g 7-amino-3-chloro-cephem acid (7-ACCA) was suspended in 100mL water and the temperature was controlled at 25 ℃. The mixture was stirred for 5 minutes while maintaining the pH at 7.0 by adding 15% aqueous ammonia solution, and 10g of immobilized enzyme was added. Next, 25g of D-phenylglycine methyl ester phosphate crystals were added at a constant rate over 90 min. Once all of the D-phenylglycine methyl ester phosphate was crystallized by addition, the pH was maintained at 7.0 by addition of 15% aqueous ammonia or by addition of 30% aqueous sulfuric acid. After 230min, the pH was adjusted to 5.8 by adding 30% aqueous sulfuric acid. During the reaction, samples were taken and analyzed by HPLC, and the analysis results are shown in Table 8.
TABLE 8 results of sampling analysis for preparation of cefaclor based on D-phenylglycine methyl ester phosphate crystals
For comparison, the above-described protocol for the preparation of cefaclor was repeated using crystals of D-phenylglycine methyl ester hydrochloride instead of crystals of D-phenylglycine methyl ester phosphate, and the analytical results are shown in Table 9.
TABLE 9 results of sample analysis for preparation of cefaclor based on D-phenylglycine methyl ester hydrochloride crystallization
For comparison, the above-described protocol for the preparation of cefaclor was repeated using crystals of D-phenylglycine methyl ester hemisulfate instead of crystals of D-phenylglycine methyl ester phosphate, and the results of the analysis are shown in Table 10.
TABLE 10 results of sample analysis for the preparation of cefaclor based on D-phenylglycine methyl ester hemisulfate salt crystals
As can be seen from tables 8, 9 and 10, when cefaclor was prepared based on crystals of D-phenylglycine methyl ester phosphate, crystals of D-phenylglycine methyl ester hydrochloride and crystals of D-phenylglycine methyl ester hemisulfate after 90min, the amounts of 7-ACCA separated in the corresponding samples were 9.27mg/mL, 14.52mg/mL and 16.69mg/mL in this order, which indicated that the amount of 7-ACCA in the samples corresponding to the crystals of D-phenylglycine methyl ester phosphate was the smallest, i.e., the enzymatic synthesis rate corresponding to the crystals of D-phenylglycine methyl ester phosphate was the fastest. After 130min, when cefaclor is prepared based on D-phenylglycine methyl ester phosphate crystals, D-phenylglycine methyl ester hydrochloride crystals and D-phenylglycine methyl ester hemisulfate crystals, the 7-ACCA separated in the corresponding samples is 1.78mg/mL, 3.63mg/mL and 4.61mg/mL, at this time, the amount of 7-ACCA in the samples corresponding to the D-phenylglycine methyl ester phosphate crystals is still minimum, and the enzymatic synthesis conversion rate when cefaclor is prepared based on the D-phenylglycine methyl ester phosphate crystals is 99.2% higher than the enzymatic synthesis conversion rate when cefaclor is prepared based on the D-phenylglycine methyl ester hydrochloride crystals and the D-phenylglycine methyl ester hemisulfate crystals is 95.1% and 94.1%.
From the above analysis it can be seen that the use of D-phenylglycine methyl ester phosphate crystals also gives significantly better results with respect to cefaclor formation than the use of D-phenylglycine methyl ester hydrochloride crystals and sulphate crystals.
Although alternative embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are illustrative and not to be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments within the scope of the present invention, and that such changes, modifications, substitutions and alterations should also be construed as within the scope of the present invention.
Claims (10)
1. A D-phenylglycine methyl ester phosphate crystal characterized by an X-ray powder diffraction pattern, expressed in terms of 2 Θ, comprising characteristic peaks at 5.70 ± 0.20, 7.18 ± 0.20, 12.34 ± 0.20, 14.52 ± 0.20, 18.78 ± 0.20, 19.82 ± 0.20, 21.96 ± 0.20, 24.18 ± 0.20, 25.02 ± 0.20, 26.08 ± 0.20, 28.12 ± 0.20, 28.86 ± 0.20, 29.46 ± 0.20, 30.00 ± 0.20, 31.62 ± 0.20, 31.88 ± 0.20, 32.80 ± 0.20, 35.48 ± 0.20, 38.32 ± 0.20 degrees.
2. A solution comprising the crystalline D-phenylglycine methyl ester phosphate according to claim 1 as a component.
3. The solution of claim 2, wherein the solution is an aqueous solution.
4. A process for the preparation of crystals of D-phenylglycine methyl ester phosphate according to claim 1, which comprises:
step a, adding D-phenylglycine and methanol into a reaction tank, uniformly stirring, and then adding phosphoric acid in a flowing manner;
b, after the phosphoric acid is fed completely, carrying out reflux reaction;
and c, after the reflux reaction in the step b is finished, carrying out vacuum dehydration, and repeating the following operations for n times: adding methanol, continuing to perform reflux reaction, and performing vacuum dehydration after the reflux reaction is finished;
and D, adjusting the pH value to be acidic, adding D-phenylglycine methyl ester phosphate seed crystals for crystallization, and drying to obtain the D-phenylglycine methyl ester phosphate crystals.
5. A process for the preparation of crystals of D-phenylglycine methyl ester phosphate according to claim 4 wherein in step a: the temperature in the reaction tank is less than or equal to 40 ℃, and/or the ratio of the D-phenylglycine to the methanol is 1 g: 4-7 mL, and/or the weight ratio of the phosphoric acid to the D-phenylglycine is 1: 0.8 to 1.5.
6. A process for the preparation of crystals of D-phenylglycine methyl ester phosphate according to claim 4 wherein in step b: the temperature in the reaction tank is 75-80 ℃, and/or the reflux reaction time is 2-4 h, and/or the value of n is 3-6.
7. A process for the preparation of crystals of D-phenylglycine methyl ester phosphate according to claim 4 wherein in step c: when the water is removed in vacuum, the vacuum degree in the reaction tank is 0.04-0.06 Mpa, and/or the time of reflux reaction is 40-60 min, and/or the temperature of reflux reaction is 84-86 ℃.
8. The method of preparing D-phenylglycine methyl ester phosphate crystals as claimed in claim 4, wherein the step D, comprises:
adding water, adding ammonia water to adjust the pH value to acidity, cooling for the first time, adding D-phenylglycine methyl ester phosphate crystal seed crystals for crystallization, cooling for the second time, stirring, centrifuging, and drying to obtain the D-phenylglycine methyl ester phosphate crystals.
9. A process for the preparation of crystals of D-phenylglycine methyl ester phosphate according to claim 8 wherein in step D: the weight of the added water is the same as that of the D-phenylglycine, and/or the pH value is 2.4-2.6 and/or the temperature is reduced to-5-15 ℃ for the first time, and/or the weight of the D-phenylglycine methyl ester phosphate seed crystal is 1-2% of that of the D-phenylglycine, and/or the temperature is reduced to 5-10 ℃ for the second time, and/or the stirring time is 30-60 min, and/or the drying temperature is 45-50 ℃, and/or the drying time is 6-8 h.
Use of crystals of D-phenylglycine methyl ester phosphate for the preparation of ampicillin, cefaclor or cephalexin, comprising acylation of said D-phenylglycine methyl ester phosphate with 6-aminopenicillanic acid, 7-aminodesacetoxycephalosporanic acid or 7-amino-3-chloro-cephem acid, respectively, in the presence of a penicillin acylase.
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| CN114105795A (en) * | 2022-01-28 | 2022-03-01 | 天津市职业大学 | Synthesis method of amoxicillin production intermediate |
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