CN110776443A - Preparation method of p-methylsulfonyl phenyl serine ethyl ester - Google Patents
Preparation method of p-methylsulfonyl phenyl serine ethyl ester Download PDFInfo
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- CN110776443A CN110776443A CN201811531880.XA CN201811531880A CN110776443A CN 110776443 A CN110776443 A CN 110776443A CN 201811531880 A CN201811531880 A CN 201811531880A CN 110776443 A CN110776443 A CN 110776443A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0215—Sulfur-containing compounds
- B01J31/0222—Sulfur-containing compounds comprising sulfonyl groups
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Abstract
The invention discloses a preparation method of p-methylsulfonylphenylserine ethyl ester, which comprises the following steps: 1) carrying out esterification reaction on p-methylsulfonylphenylserine copper salt, ethanol and a water-carrying agent under the catalysis of activated carbon-immobilized p-toluenesulfonic acid, carrying out reflux reaction, continuously removing water generated in the reaction in the reflux reaction process through a water separator, filtering when the reaction is finished, and recovering the activated carbon-immobilized p-toluenesulfonic acid for reuse; 2) and recovering ethanol in the reacted substances, adding a saturated sodium sulfide solution into the residues to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain the p-methylsulfonylphenylserine ethyl ester. Concentrated sulfuric acid is not needed in the reaction process, so that strong-acid wastewater is completely avoided, and the environment is protected; avoids the danger possibly generated in the sulfuric acid transportation and production process, is safer and is beneficial to improving the operation efficiency.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of p-methylsulfonylphenylserine ethyl ester.
Background
P-methylsulfonylphenylserine ethyl ester, white to white-like crystal, molecular formula C
12H
17NO
5S, is slightly soluble in water and is dissolved in an organic solvent. The p-methylsulfonylphenylserine ethyl ester is an important intermediate for synthesizing broad-spectrum antibiotics thiamphenicol, florfenicol and other medicaments, and the molecular structure is as follows:
thiamphenicol, the English/Latin name, Thiamphenicol, another name, Thiamphenicol, Methylsulfone Chloramphenicol. Is white crystalline powder; no bad smell. Can be used for treating respiratory tract infection, urinary tract infection, and intestinal infection caused by sensitive bacteria such as Haemophilus influenzae, Escherichia coli, and Salmonella. It is an analog of chloramphenicol, with antibacterial activity and range similar to chloramphenicol. At present, the domestic production mostly adopts a p-methylsulfonylbenzaldehyde route, wherein the p-methylsulfonylphenylserine ethyl ester is a key intermediate of the process route.
The existing synthesis methods have defects more or less, or the product yield is low, or the corrosivity in the reaction process is too high, or the cost is too high. The existing technical routes need to be improved both in terms of environmental friendliness and cost.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a preparation method of p-methylsulfonylphenylserine ethyl ester, which has high yield and is environment-friendly.
In order to solve the technical problems, the technical scheme provided by the invention is as follows: a preparation method of p-methylsulfonylphenylserine ethyl ester comprises the following steps:
a preparation method of p-methylsulfonylphenylserine ethyl ester comprises the following steps:
1) carrying out esterification reaction on p-methylsulfonylphenylserine copper salt, ethanol and a water-carrying agent under the catalysis of activated carbon-immobilized p-toluenesulfonic acid, carrying out reflux reaction, continuously removing water generated by the reaction in the reflux reaction process through a water separator, (4h later, sampling and detecting), filtering while hot after the reaction is finished, and recovering the activated carbon-immobilized p-toluenesulfonic acid for reuse;
2) recovering ethanol in the reacted substances, adding a saturated sodium sulfide solution into the residues to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain p-methylsulfonylphenylserine ethyl ester;
the preparation method of the active carbon immobilized p-toluenesulfonic acid catalyst comprises the following steps: leaching the activated carbon by using 12-15 Wt.% of dilute nitric acid, washing the activated carbon to be neutral, soaking the activated carbon by using distilled water, refluxing the soaked activated carbon by using deionized water for 1-2 hours, filtering the activated carbon under reduced pressure, drying the activated carbon in vacuum at 80-90 ℃ for 1-2 hours, refluxing and adsorbing the obtained clean activated carbon and a p-toluenesulfonic acid aqueous solution with the mass fraction of 30-35% for 12-15 hours, filtering the activated carbon under reduced pressure, and drying the activated carbon in the air; and finally, activating for 1-1.5 h at the temperature of 150 ℃ and 2 ℃ to obtain the activated carbon immobilized p-toluenesulfonic acid catalyst.
The molar ratio of the p-methylsulfonylphenylserine copper salt to the ethanol is 1.0: 1.2 to 1.5.
The active carbon immobilized p-toluenesulfonic acid has an immobilization amount of 50 cm 0.5%; the dosage of the activated carbon-supported p-toluenesulfonic acid is 2-5% of the mass of the p-methylsulfonylphenylserine ethyl ester.
In the step 1), the water-carrying agent is benzene, toluene, xylene, n-hexane or cyclohexane.
More preferably, the water-carrying agent is toluene.
In the step 1), the mass ratio of the p-methylsulfonylphenylserine copper salt to the water-carrying agent is 1: 0.6 to 2.0.
The progress of the reaction was monitored by HPLC; when the percentage of the p-methylsulfonylphenylserine copper salt calculated by the area normalization method is less than 1%, the reaction is ended.
Recovering ethanol by vacuum distillation process, wherein the vacuum degree is controlled to be more than-0.095 MPa and the temperature of the reacted substances is controlled to be less than 50 ℃ in the recovery process.
And (3) cooling the solution to 0-5 ℃ to ensure the quality of the target product, simultaneously reducing the solubility of the target product in water, reducing the dissolution of the target product, reducing loss and improving the yield, and finally obtaining the target product through suction filtration separation, ice water washing and drying.
Has the advantages that: the method adopts the active carbon-immobilized p-toluenesulfonic acid as the catalyst, the p-toluenesulfonic acid not only has all advantages of concentrated sulfuric acid, but also is an organic acid, has no oxidability, has weaker carbonization effect than the concentrated sulfuric acid, has simpler process, and has the advantages of high activity, no corrosion to equipment, little pollution and the like when being used as the catalyst of esterification reaction. Concentrated sulfuric acid is not needed in the reaction process, so that the generation of strong-acid wastewater is completely avoided, and the environment is protected; avoids the danger possibly generated in the sulfuric acid transportation and production process, is safer and is beneficial to improving the operation efficiency.
The average yield of the method reaches 96 percent, and the product purity is more than 99 percent.
Detailed Description
Example 1
1) Carrying out esterification reaction on 100.0g of p-methylsulfonylphenylserine copper salt, 20.6g of ethanol and 70g of water-carrying agent toluene under the catalysis of 2.4g of activated carbon-immobilized p-toluenesulfonic acid (the immobilization amount of the p-methylsulfonylphenylserine copper salt is 50 cm 0.5 percent), carrying out reflux reaction, continuously removing water generated in the reaction process through a water separator in the reflux reaction process, and monitoring the reaction progress through HPLC (high performance liquid chromatography); when the percentage content of the p-methylsulfonylphenylserine copper salt calculated by the area normalization method is less than 1%, the reaction is finished, the solution is filtered when the solution is hot, and the active carbon-supported p-toluenesulfonic acid is recovered for reuse;
the preparation method of the active carbon immobilized p-toluenesulfonic acid catalyst comprises the following steps: leaching the activated carbon by using 12-15 Wt.% of dilute nitric acid, washing the activated carbon to be neutral, soaking the activated carbon by using distilled water, refluxing the soaked activated carbon by using deionized water for 1-2 hours, filtering the activated carbon under reduced pressure, drying the activated carbon in vacuum at 80-90 ℃ for 1-2 hours, refluxing and adsorbing the obtained clean activated carbon and a p-toluenesulfonic acid aqueous solution with the mass fraction of 30-35% for 12-15 hours, filtering the activated carbon under reduced pressure, and drying the activated carbon in the air; finally, activating for 1-1.5 h at the temperature of 150 ℃ and 2 ℃ to obtain an activated carbon immobilized p-toluenesulfonic acid catalyst;
2) recovering ethanol in the reacted substances, adding a saturated sodium sulfide solution into the residues to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain 95.2g of p-methylsulfonylphenylserine ethyl ester; yield: 96.0 percent and the purity of the product is 99.1 percent.
Recovering ethanol by vacuum distillation process, wherein the vacuum degree is controlled to be more than-0.095 MPa and the temperature of the reacted substances is controlled to be less than 50 ℃ in the recovery process.
1HNMR，δ：1.118(t，J＝4.2,3H,C-CH
3)；3.176(s，3H,S-CH
3)；3.316(s,2H,NH
2)；3.500(d,J＝2.4,1H,O-CH)；4.026(m,J＝4.2,2H,CH
2)；4.922(s,1H,N-CH)；5.763(s,1H,OH)；7.580(d,J＝5.1,2H,Ar-H)；7.843(d,J＝4.8,2H,Ar-H)。
Example 2
1)100.0g of p-methylsulfonylphenylserine copper salt, 23.8g of ethanol and 150g of toluene as a water-carrying agent, 2g of recovered activated carbon-immobilized p-toluenesulfonic acid (the immobilization amount is 50 seconds 0.5 percent), 1.8g of new activated carbon-immobilized p-toluenesulfonic acid (the immobilization amount is 50 seconds 0.5 percent) for catalytic esterification reaction and reflux reaction, wherein water generated in the reaction is continuously removed through a water separator in the reflux reaction process, and the reaction progress is monitored through HPLC; when the percentage content of the p-methylsulfonylphenylserine copper salt calculated by the area normalization method is less than 1%, the reaction is finished, the solution is filtered when the solution is hot, and the active carbon-supported p-toluenesulfonic acid is recovered for reuse;
the recovered activated carbon-supported p-toluenesulfonic acid catalyst in the embodiment 1 is activated for 1-1.5 hours at the temperature of 150 ℃ and 2 ℃ and is reused;
2) recovering ethanol in the reacted substances, adding a saturated sodium sulfide solution into the residues to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain 95.4g of p-methylsulfonylphenylserine ethyl ester; yield: 96.2 percent and the purity of the product is 99.4 percent.
Recovering ethanol by vacuum distillation process, wherein the vacuum degree is controlled to be more than-0.095 MPa and the temperature of the reacted substances is controlled to be less than 50 ℃ in the recovery process.
Example 3
1) Carrying out catalytic esterification reaction and reflux reaction on 100.0g of p-methylsulfonylphenylserine copper salt, 22.3g of ethanol, 200g of water-carrying agent toluene and 3.5g of new activated carbon-immobilized p-toluenesulfonic acid (the solid loading amount is 0.5% of 50%), continuously removing water generated in the reaction process through a water separator in the reflux reaction process, and monitoring the reaction progress through HPLC; when the percentage content of the p-methylsulfonylphenylserine copper salt calculated by the area normalization method is less than 1%, the reaction is finished, the solution is filtered when the solution is hot, and the active carbon-supported p-toluenesulfonic acid is recovered for reuse;
2) recovering ethanol in the reacted substances, adding a saturated sodium sulfide solution into the residues to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain 96.6g of p-methylsulfonylphenylserine ethyl ester; yield: 96.5 percent and the purity of the product is 99.3 percent.
Recovering ethanol by vacuum distillation process, wherein the vacuum degree is controlled to be more than-0.095 MPa and the temperature of the reacted substances is controlled to be less than 50 ℃ in the recovery process.
Claims (8)
1. A preparation method of p-methylsulfonylphenylserine ethyl ester comprises the following steps:
1) carrying out esterification reaction on p-methylsulfonylphenylserine copper salt, ethanol and a water-carrying agent under the catalysis of activated carbon-immobilized p-toluenesulfonic acid, continuously removing generated water through a water separator in the reflux reaction process, filtering when the reaction is finished, and recycling the activated carbon-immobilized p-toluenesulfonic acid for reuse;
2) recovering ethanol in the reacted substances, then adding a saturated sodium sulfide solution into the residue to remove copper ions, adding activated carbon for decolorization, filtering, dropwise adding ammonia water into the obtained filtrate, adjusting the pH value to 8.5-9.0, cooling the solution to 0-5 ℃, filtering, and drying to obtain p-methylsulfonylphenylserine ethyl ester;
the preparation method of the active carbon immobilized p-toluenesulfonic acid catalyst comprises the following steps: leaching the activated carbon by using 12-15 Wt.% of dilute nitric acid, washing the activated carbon to be neutral, soaking the activated carbon by using distilled water, refluxing the soaked activated carbon by using deionized water for 1-2 hours, filtering the activated carbon under reduced pressure, drying the activated carbon in vacuum at 80-90 ℃ for 1-2 hours, refluxing and adsorbing the obtained clean activated carbon and a p-toluenesulfonic acid aqueous solution with the mass fraction of 30-35% for 12-15 hours, filtering the activated carbon under reduced pressure, and drying the activated carbon in the air; and finally, activating for 1-1.5 h at the temperature of 150 ℃ and 2 ℃ to obtain the activated carbon immobilized p-toluenesulfonic acid catalyst.
2. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: the molar ratio of the p-methylsulfonylphenylserine copper salt to the ethanol is 1.0: 1.2 to 1.5.
3. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: the active carbon immobilized p-toluenesulfonic acid has an immobilization amount of 50 cm 0.5%; the dosage of the activated carbon-supported p-toluenesulfonic acid is 2-5% of the mass of the p-methylsulfonylphenylserine ethyl ester.
4. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: in the step 1), the water-carrying agent is benzene, toluene, xylene, n-hexane or cyclohexane.
5. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 4, wherein the preparation method comprises the following steps: the water-carrying agent is toluene.
6. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: in the step 1), the mass ratio of the p-methylsulfonylphenylserine copper salt to the water-carrying agent is 1: 0.6 to 2.0.
7. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: the progress of the reaction was monitored by HPLC; when the percentage of the p-methylsulfonylphenylserine copper salt calculated by the area normalization method is less than 1%, the reaction is ended.
8. The preparation method of p-methylsulfonylphenylserine ethyl ester according to claim 1, wherein the preparation method comprises the following steps: recovering ethanol by vacuum distillation process, wherein the vacuum degree is controlled to be more than-0.095 MPa and the temperature of the reacted substances is controlled to be less than 50 ℃ in the recovery process.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115518685A (en) * | 2022-09-19 | 2022-12-27 | 浙江工业大学 | Carbon-supported p-toluenesulfonic acid catalyst and preparation method and application thereof |
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