CN110845516B - Synthetic method of penicillin G sulfoxide diphenylmethyl ester - Google Patents
Synthetic method of penicillin G sulfoxide diphenylmethyl ester Download PDFInfo
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- CN110845516B CN110845516B CN201911082524.9A CN201911082524A CN110845516B CN 110845516 B CN110845516 B CN 110845516B CN 201911082524 A CN201911082524 A CN 201911082524A CN 110845516 B CN110845516 B CN 110845516B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/46—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with acyclic hydrocarbon radicals or such radicals substituted by carbocyclic or heterocyclic rings, attached to the carboxamido radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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Abstract
The invention discloses a synthetic method of penicillin G sulfoxide diphenylmethyl ester. Taking penicillin G sylvite as a starting material, esterifying the penicillin G sylvite, and then performing esterification on the penicillin G sylvite by using 2KHSO5·KHSO4·K2SO4The penicillin G sulfoxide diphenylmethyl ester is synthesized by oxidation, the product purity is over 99 percent, the total molar yield is over 95 percent, and the method is suitable for industrial production. The invention has the advantages of easily obtained raw materials, high yield, less pollution, high safety factor, easy operation and the like.
Description
Technical Field
The invention belongs to the field of synthesis of small molecular compounds, and relates to a synthesis method of penicillin G sulfoxide diphenylmethyl ester.
Background
Cephalosporin is an important antibiotic, and has the characteristics of strong antibacterial action, good curative effect, low toxicity, broad spectrum and penicillinase resistance. Therefore, the compound has wide development prospect as a first-line medicament in clinic. At present, cephalosporin and intermediates thereof such as 7-AVCA, 7-ACCA, 7-ANCA, 7-AMCA and the like are mainly prepared from 7-ACA and penicillin. However, due to the high cost of 7-ACA as a raw material [1], many people have looked at the wider source of relatively inexpensive penicillin raw material. The penicillin G sulfoxide diphenyl methyl ester is used as an important intermediate for synthesizing cephalosporin through expansion ring, and the research on the synthesis process of the penicillin G sulfoxide diphenyl methyl ester is particularly important.
Penicillin G sulfoxide diphenylmethyl ester is an important intermediate of a mother nucleus of cephalosporin antibiotics, and the molecular formula of the penicillin G sulfoxide diphenylmethyl ester is as follows: c29H28N2O5S, molecular weight 516.61, white or off-white powder in appearance, structural formula as follows:
the process for preparing penicillin sulfoxide esters from penicillin G potassium salt can be generally divided into two processes of esterification and oxidation, and esterification. Zhang Xiaofeng et al reported a synthesis method of penicillin G sulfoxide diphenyl methyl ester, which uses penicillin G potassium (3) as raw material, uses 18% peroxyacetic acid to oxidize it to obtain penicillin G sulfoxide acid (2), and uses diphenyl methanol to esterify it with dichloromethane solution to obtain penicillin G sulfoxide diphenyl methyl ester (1). However, the total yield of the method is only 77.35% (Zhang Xiaofeng, Zhongjing, Zhang hui Liang. synthesis research of penicillin G sulfoxide diphenylmethyl ester [ J ] fine chemical intermediate, 2008,38(4): 34-37).
At present, the process of penicillin G sulfoxide diphenyl methyl ester oxidation process is mainly researched in two aspects, one is that a peroxyacetic acid method is adopted, the method is high in yield, but generates a large amount of acidic wastewater and causes serious pollution, and peroxyacetic acid synthesis belongs to a high-risk process, is flammable, has the characteristics of explosiveness, strong corrosivity, strong irritation and the like, is not beneficial to operation and is low in safety factor; secondly, the method adopts the oxidation method of hydrogen peroxide and supported catalyst, and the yield of the method is low.
In conclusion, under the current situation of safety and increasingly severe environmental protection, the synthesis of penicillin G sulfoxide diphenyl methyl ester is necessary to develop an oxidation process which has high yield, is safe and environment-friendly, is easy to operate and is suitable for industrial production aiming at the defects of the prior art.
Disclosure of Invention
The invention aims to provide a method for synthesizing penicillin G sulfoxide diphenylmethyl ester, which has high yield, safety and environmental protection aiming at the defects in the prior art.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of penicillin G sulfoxide diphenylmethyl ester is characterized in that a compound 2 is oxidized by hydrogen sulfate methyl complex salt to obtain penicillin G sulfoxide diphenylmethyl ester, and the reaction route is as follows:
said compound 2 is preferably synthesized by the following route:
the synthesis of the penicillin G sulfoxide diphenylmethyl ester further preferably comprises the following steps in sequence:
using a compound 1 as a raw material, and performing esterification to obtain a compound 2:
oxidizing the hydrogen persulfate complex salt in the step (b) to obtain a compound 3:
the oxidation reaction is preferably 2KHSO5·KHSO4·K2SO4Dissolving in 2KHSO5·KHSO4·K2SO44 times of the weight of the compound 1 and 2KHSO5·KHSO4·K2SO4The molar ratio of (A) to (B) is 1: 0.6-0.8.
The oxidation reaction temperature is preferably 20-30 ℃, further preferably 20-25 ℃, and the reaction time is preferably 5-6 h.
In the esterification reaction of step (a), the reaction solvent is preferably methyl halide or ethyl halide, more preferably methyl chloride or ethyl chloride, and preferably methylene chloride.
In the esterification reaction in the step (a), the molar ratio of the compound 1 to the benzhydrol, the pyridine and the methylsulfonyl chloride is preferably 1: 1.0-1.2: 1.5-2.0: 1.1-1.4.
(a) The esterification reaction temperature is preferably 0-20 ℃, and further preferably 10-15 ℃; the reaction time is preferably 4-5 h.
Has the advantages that:
the invention takes the potassium salt of penicillin as the starting material, and penicillin G sulfoxide diphenylmethyl ester is synthesized by two steps, the product purity is more than 99 percent, the total molar yield is more than 95 percent, and the invention is suitable for industrial production. The method has the advantages of easily available raw materials, high yield, less pollution, high safety coefficient, easy operation and the like. In the oxidation step the invention uses persulfurAcid hydrogen methyl composite salt (2 KHSO)5·KHSO4·K2SO4) The hydrogen persulfate-methyl persulfate composite salt is used as the oxidizing agent, has very strong and effective non-chlorine oxidation capability, meets the requirements of safety and environmental protection in the use and treatment process, avoids the problem of environmental pollution caused by using peroxyacetic acid by using the hydrogen persulfate-methyl persulfate composite salt as the oxidizing agent, and obviously improves the yield compared with the oxidation method of hydrogen peroxide and a supported catalyst.
Detailed Description
The present disclosure is further illustrated or described below by examples, which should not be construed as limiting the scope of the present disclosure.
Example 1
(1) Synthesis of Compound 2:
adding 120ml of dichloromethane, benzhydrol (23.2g, 0.126mol) and compound 1(40g, 0.107mol) into a 500ml four-neck flask, cooling to 15 ℃, adding pyridine (16g, 0.202mol), dropwise adding methylsulfonyl chloride (16g, 0.140mol) at the temperature of 10-15 ℃, controlling the dropwise addition to be finished for 60min, and preserving the heat for 4 hours after the dropwise addition is finished. After the completion of the incubation, 135g of 5% dilute sulfuric acid was added and the mixture was washed, the organic phase was separated, the aqueous phase was extracted with 30ml of dichloromethane, the organic phases were combined to obtain a dichloromethane solution of Compound 2, and the solution was transferred to a 1000ml four-necked flask for use.
(2) Synthesis of Compound 3:
the dichloromethane solution of the compound 2 prepared in the above step was adjusted to 22 ℃. Preparing a potassium hydrogen persulfate composite salt aqueous solution: potassium hydrogen persulfate complex salt (45g, 0.073mol) was weighed in a 500ml beaker, 160ml of water was added thereto, and dissolved by stirring. And controlling the temperature to be 20-25 ℃, dropwise adding the prepared potassium hydrogen persulfate composite salt aqueous solution into the reaction solution, and controlling the dripping for 60 min. After dripping, the temperature is kept for 6 hours. Layering, separating an organic phase, performing vacuum distillation on the organic phase, adding 350ml of prepared methanol after dichloromethane is evaporated to dryness, cooling to 0 ℃ for crystallization, performing suction filtration, and performing vacuum drying on a wet product at 50-60 ℃ for 4.5h to obtain 53.1g of a compound 3, wherein the molar yield is 95.7%, and the HPLC purity is 99.54%.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (12)
1. A synthetic method of penicillin G sulfoxide diphenylmethyl ester is characterized in that a compound 2 is oxidized by hydrogen sulfate methyl complex salt to obtain penicillin G sulfoxide diphenylmethyl ester, and the reaction route is as follows:
2. the synthesis according to claim 1, characterized in that said compound 2 is synthesized by the following route:
3. a synthesis process according to claim 1 or 2, characterized in that the synthesis of penicillin G sulfoxide benzhydryl ester comprises the following steps in sequence:
using a compound 1 as a raw material, and performing esterification to obtain a compound 2:
oxidizing the hydrogen persulfate complex salt in the step (b) to obtain a compound 3:
4. the synthesis method according to claim 1, wherein the oxidation reaction uses 2KHSO5·KHSO4·K2SO4Dissolving in 2KHSO5·KHSO4·K2SO44 times of the weight of the compound 1 and 2KHSO5·KHSO4·K2SO4The molar ratio of (A) to (B) is 1: 0.6-0.8.
5. The synthesis method according to claim 1, wherein the oxidation reaction temperature is 20-30 ℃ and the reaction time is 5-6 h.
6. The synthesis method according to claim 5, wherein the oxidation reaction temperature is 20-25 ℃.
7. The synthesis process according to claim 3, wherein in the esterification reaction of step (a), the reaction solvent is methyl halide or ethyl halide.
8. The synthesis process according to claim 3, wherein in the esterification reaction of step (a), the reaction solvent is methyl chloride or ethyl chloride.
9. The method of claim 8, wherein the esterification reaction of step (a) is carried out in the presence of methylene chloride as a reaction solvent.
10. The synthesis method according to claim 3, wherein in the esterification reaction in step (a), the molar ratio of the compound 1 to the benzhydrol, the pyridine and the methylsulfonyl chloride is 1: 1.0-1.2: 1.5-2.0: 1.1-1.4.
11. The synthesis method according to claim 3, wherein the esterification reaction temperature in step (a) is 0-20 ℃ and the reaction time is 4-5 h.
12. The synthesis method according to claim 3, wherein the esterification reaction temperature in the step (a) is 10-15 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101070315A (en) * | 2007-05-11 | 2007-11-14 | 江苏工业学院 | Method for preparing omeprazole |
| CN103497206A (en) * | 2013-10-09 | 2014-01-08 | 盐城开元医药化工有限公司 | Synthesis method for cefaclor key intermediate |
| CN107298666A (en) * | 2016-04-15 | 2017-10-27 | 上海医药工业研究院 | A kind of Preparation Method And Their Intermediate of flavone compound |
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- 2019-11-07 CN CN201911082524.9A patent/CN110845516B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101070315A (en) * | 2007-05-11 | 2007-11-14 | 江苏工业学院 | Method for preparing omeprazole |
| CN103497206A (en) * | 2013-10-09 | 2014-01-08 | 盐城开元医药化工有限公司 | Synthesis method for cefaclor key intermediate |
| CN107298666A (en) * | 2016-04-15 | 2017-10-27 | 上海医药工业研究院 | A kind of Preparation Method And Their Intermediate of flavone compound |
Non-Patent Citations (2)
| Title |
|---|
| Oxidation of Thymines by Peroxosulfate Ions in Water;Toshio Itahara,等;《J.Org.Chem.》;19881231;第53卷(第15期);3421-3424 * |
| Use of Alumina for Elimination of Sulfinic Acid from β-ARYL- ANDβ-Alkylsulfonyl Carbonyl Compounds;Joelle Vidal，等;《Tetrahedron Letters》;19861231;第27卷(第32期);3733-3736 * |
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