CN113387824A - High-purity D-dihydro phenyl glycine methyl ester and preparation method thereof - Google Patents
High-purity D-dihydro phenyl glycine methyl ester and preparation method thereof Download PDFInfo
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- CN113387824A CN113387824A CN202110818111.3A CN202110818111A CN113387824A CN 113387824 A CN113387824 A CN 113387824A CN 202110818111 A CN202110818111 A CN 202110818111A CN 113387824 A CN113387824 A CN 113387824A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Abstract
The invention discloses high-purity D-dihydro phenyl glycine methyl ester and a preparation method thereof, belonging to the field of pharmaceutical chemicals. The preparation method changes the prior preparation process, ensures that the phenylglycine methyl ester content of the product is below 0.67 percent, and reduces the product cost to some extent due to the innovative preparation method. In addition, the production process is simple and easy to operate, the production cost is low, and the industrial production is facilitated.
Description
Technical Field
The invention relates to D-dihydro-phenyl glycine methyl ester and a preparation method thereof, in particular to high-purity D-dihydro-phenyl glycine methyl ester and a preparation method thereof, and belongs to the field of pharmaceutical chemicals.
Background
D-dihydro phenylglycine methyl ester is a side chain of the enzyme method ampicillin.
The "method for producing cefradine" of Dutch corporation, Zhonghua Dismann pharmaceutical Co., Ltd, application No. 201080057051.8. It is proposed that 0.87% of phenylglycine methyl ester in D-dihydrophenylglycine methyl ester can be produced by using inert gases such as nitrogen and the like for protection in the production process so as to prepare high-quality cephradine.
The main problems of the method are as follows: the nitrogen is filled into the methanol for degassing, the oxygen content needs to be lower than 100ppm, the cost is high, and the preparation of the enzyme method antibiotic is seriously influenced.
Disclosure of Invention
In view of the above, the invention provides a preparation method of high-purity D-dihydro-phenylglycine methyl ester, so as to solve the problems of high cost, complex process and harsh conditions of the preparation method of D-dihydro-phenylglycine methyl ester in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of high-purity D-dihydro-phenylglycine methyl ester comprises the following steps:
1) mixing and stirring D-dihydrophenylglycine and methanol uniformly, maintaining the temperature of a reaction system at 60-65 ℃, heating and refluxing, cooling to 45-55 ℃, adding a reaction reagent, and maintaining the temperature of the system after the reaction reagent is added at 45-50 ℃;
2) after adding a reaction reagent, maintaining the temperature of a reaction system at 58-62 ℃, and performing reflux reaction;
3) and after the reflux reaction is finished, carrying out post-treatment to obtain the high-purity D-dihydro-phenylglycine methyl ester.
Further, the reaction reagent is concentrated sulfuric acid or thionyl chloride, when the reaction reagent is concentrated sulfuric acid, the mass ratio of the concentrated sulfuric acid to the D-dihydro-phenylglycine in the system is 1-1.3: 1, and when the reaction reagent is thionyl chloride, the mass ratio of the thionyl chloride to the D-dihydro-phenylglycine in the system is 1-1.3: 1.
Further, the operation of adding the reaction reagent in the step 1) is as follows: slowly adding concentrated sulfuric acid in a flowing manner, or cooling the system to-10-0 ℃, and adding thionyl chloride once.
The post-treatment operation in the step 3) is that when the reaction reagent is concentrated sulfuric acid: vacuum distilling, supplementing methanol, performing reflux reaction again, and repeating the operation until the content of D-dihydro phenylglycine in the system is reduced to below 0.5%;
when the reaction reagent is thionyl chloride: and after the reflux reaction is finished, carrying out vacuum distillation, and then cooling, crystallizing, centrifuging and drying.
Further, in the above reaction system, the micro positive pressure of the reaction system is at least 0.005 MPa.
Further, the mixing ratio of the D-dihydrophenyl glycine and the methanol in the step 1) is 1 g: 4-6 mL.
Further, the heating reflux time in the step 1) is 0.5 h.
Further, the time of reflux reaction in the step 2) is 3.5-4.5 h.
The invention also provides high-purity D-dihydro phenylglycine methyl ester which is prepared by the method.
The invention has the beneficial effects that the preparation method changes the existing preparation process, so that the phenylglycine methyl ester of the product is below 0.67 percent, and the product cost is reduced to some extent due to the renovation of the preparation method. In addition, the production process is simple and easy to operate, the production cost is low, and the industrial production is facilitated.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding 20L of methanol into a 50L reaction tank, adding 5Kg of D-dihydrophenyl glycine under stirring, uniformly stirring, refluxing for 0.5h at the temperature of 60-65 ℃, cooling to 45-55 ℃, keeping the micro-positive pressure at 0.005MPa, adding 5Kg of concentrated sulfuric acid in a flowing manner, controlling the temperature to be below 50 ℃, keeping the temperature in the reactor to be 59 ℃ after finishing dropping, refluxing for 3.5h, and finishing the reaction. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 10 percent. 20L of methanol is added, and the reaction is finished after refluxing for 4 h. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 10 percent. And thus recycled three times to D-dihydrophenylglycine 0.3%.
Example 2
Adding 20L of methanol into a 50L reaction tank, adding 5Kg of D-dihydrophenyl glycine under stirring, uniformly stirring, refluxing for 1.0h at the temperature of 60-65 ℃, cooling to 45-55 ℃, keeping the micro-positive pressure at 0.007MPa, adding 5Kg of concentrated sulfuric acid in a flowing manner, controlling the temperature to be below 50 ℃, after finishing dropping, keeping the temperature in a reactor at 60 ℃, refluxing for 5h, and finishing the reaction. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 10 percent. 20L of methanol is added, and the reaction is finished after 4.5h of reflux. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 10 percent. And thus recycled three times to D-dihydrophenylglycine 0.3%.
Example 3
Adding 20L of methanol into a 50L reaction tank, adding 5Kg of D-phenylglycine under stirring, refluxing for 0.5h at the temperature of 60-65 ℃ after uniform stirring, cooling to-10-0 ℃, keeping the pressure negative, adding 5Kg of thionyl chloride at one time, maintaining the temperature in the reactor at 59 ℃ after the addition is finished, and refluxing for 3.5h, thus finishing the reaction. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 15%, cooling to 0 ℃, stirring for 30-60 min, centrifuging, and drying in vacuum at 50 ℃ for 8h to obtain 4.80Kg of D-phenylglycine methyl ester hydrochloride.
Example 4
Adding 20L of methanol into a 50L reaction tank, adding 5Kg of D-phenylglycine under stirring, uniformly stirring, refluxing for 0.5h at the temperature of 60-65 ℃, cooling to-10-0 ℃, keeping the pressure negative, adding 5Kg of thionyl chloride at one time, after the addition is finished, maintaining the temperature in the reactor at 59 ℃, refluxing for 4.5h, and finishing the reaction. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 15%, cooling to 0 ℃, stirring for 30-60 min, centrifuging, and drying in vacuum at 50 ℃ for 8h to obtain 4.82Kg of D-phenylglycine methyl ester hydrochloride.
Comparative example 1
Preparation method of D-dihydro-phenylglycine methyl ester in prior art
Adding 20L of methanol into a 50L reaction tank, adding 5Kg of D-phenylglycine under stirring, after uniformly stirring, adding 5Kg of thionyl chloride in a flowing manner, controlling the temperature to be below 50 ℃, after finishing dripping, maintaining the temperature in the reactor to be 59 ℃, refluxing for 4 hours, and finishing the reaction. Then vacuum distillation is carried out, and the vacuum degree in the reactor is maintained at 0.03 MPa. And stopping vacuum distillation after the mass content of the methanol in the solution in the reaction tank reaches 15%, cooling to 0 ℃, stirring for 30-60 min, centrifuging, and drying in vacuum at 50 ℃ for 8h to obtain 4.80Kg of D-phenylglycine methyl ester hydrochloride.
Quality results of comparative and examples are shown in the following table
TABLE 1 quality results of examples and comparative examples
| Item | Glycine methyl ester (%) | Yield (Kg) |
| Example 1 | 0.68 | 4.85 |
| Example 2 | 0.66 | 4.83 |
| Example 3 | 0.67 | 4.80 |
| Example 4 | 0.65 | 4.82 |
| Comparative example 1 | 1.5 | 4.80 |
Claims (10)
1. A preparation method of high-purity D-dihydro phenyl glycine methyl ester is characterized by comprising the following steps:
1) mixing and stirring D-dihydrophenylglycine and methanol uniformly, maintaining the temperature of a reaction system at 60-65 ℃, heating and refluxing, cooling to 45-55 ℃, adding a reaction reagent, and maintaining the temperature of the system after the reaction reagent is added at 45-50 ℃;
2) after adding a reaction reagent, maintaining the temperature of a reaction system at 58-62 ℃, and performing reflux reaction;
3) and after the reflux reaction is finished, carrying out post-treatment to obtain the high-purity D-dihydro-phenylglycine methyl ester.
2. The process for producing high purity D-dihydrophenylglycine methyl ester according to claim 1, wherein the reaction system has a slight positive pressure of at least 0.005 MPa.
3. The method for preparing high-purity D-dihydrophenyl glycine methyl ester according to claim 1, wherein the mixing ratio of D-dihydrophenyl glycine to methanol in the step 1) is 1 g: 4-6 mL.
4. The method for preparing high purity D-dihydrophenyl glycine methyl ester according to claim 1, wherein the heating reflux time in step 1) is 0.5 h.
5. The method for preparing high-purity D-dihydrophenyl glycine methyl ester according to claim 1, wherein the time of the reflux reaction in step 2) is 3.5 to 4.5 hours.
6. The process for producing high purity D-dihydrophenyl glycine methyl ester according to any one of claims 1 to 5, wherein the reaction reagent is concentrated sulfuric acid or thionyl chloride.
7. The method for preparing high-purity D-dihydrophenyl glycine methyl ester according to claim 6, wherein when the reaction reagent is concentrated sulfuric acid, the mass ratio of the concentrated sulfuric acid to the D-dihydrophenyl glycine in the system is 1-1.3: 1;
when the reaction reagent is thionyl chloride, the mass ratio of the thionyl chloride to the D-dihydrophenyl glycine in the system is 1-1.3: 1.
8. The method for producing high purity D-dihydrophenyl glycine methyl ester according to claim 6, wherein when the reaction reagent is concentrated sulfuric acid, the operation of adding the reaction reagent in step 1) is: slowly adding concentrated sulfuric acid in a flowing manner;
when the reaction reagent is thionyl chloride, the operation of adding the reaction reagent in the step 1) is as follows: cooling the system to-10-0 ℃, and adding thionyl chloride at one time.
9. The method for producing high-purity D-dihydrophenyl glycine methyl ester according to claim 6, wherein when the reaction reagent is concentrated sulfuric acid, the post-treatment is performed by: vacuum distilling, supplementing methanol, performing reflux reaction again, and repeating the operation until the content of D-dihydro phenylglycine in the system is reduced to below 0.5%;
when the reaction reagent is thionyl chloride, the post-treatment operation comprises the following steps: and after the reflux reaction is finished, carrying out vacuum distillation, and then cooling, crystallizing, centrifuging and drying.
10. A high purity D-dihydrophenylglycine methyl ester prepared by the process of any one of claims 1 to 9.
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| CN202110818111.3A CN113387824A (en) | 2021-07-20 | 2021-07-20 | High-purity D-dihydro phenyl glycine methyl ester and preparation method thereof |
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| CN202110818111.3A CN113387824A (en) | 2021-07-20 | 2021-07-20 | High-purity D-dihydro phenyl glycine methyl ester and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631764A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of amino acid methyl esters |
| CN102656274A (en) * | 2009-12-14 | 2012-09-05 | 中化帝斯曼制药有限公司荷兰公司 | Production process for cephradine |
| CN110128285A (en) * | 2019-06-24 | 2019-08-16 | 华北制药股份有限公司 | D-PG methyl ester hydrochloride/D- dihydro phenyl glycine methyl ester hydrochloride preparation method |
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2021
- 2021-07-20 CN CN202110818111.3A patent/CN113387824A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101631764A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of amino acid methyl esters |
| US20100063312A1 (en) * | 2007-03-09 | 2010-03-11 | Harold Monro Moody | Process for the preparation of amino acid methyl esters |
| CN102656274A (en) * | 2009-12-14 | 2012-09-05 | 中化帝斯曼制药有限公司荷兰公司 | Production process for cephradine |
| CN110128285A (en) * | 2019-06-24 | 2019-08-16 | 华北制药股份有限公司 | D-PG methyl ester hydrochloride/D- dihydro phenyl glycine methyl ester hydrochloride preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 叶树祥等: ""固定化青霉素酰化酶合成头孢拉定的工艺研究"", 《中国医药工业杂志》 * |
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