CN108250218B - Process for preparing penicillanic acid diphenyl methyl ester sulfoxide - Google Patents
Process for preparing penicillanic acid diphenyl methyl ester sulfoxide Download PDFInfo
- Publication number
- CN108250218B CN108250218B CN201711448985.4A CN201711448985A CN108250218B CN 108250218 B CN108250218 B CN 108250218B CN 201711448985 A CN201711448985 A CN 201711448985A CN 108250218 B CN108250218 B CN 108250218B
- Authority
- CN
- China
- Prior art keywords
- borohydride
- benzhydryl
- penicillanoate
- producing
- sulfoxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D499/86—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 only atoms other than nitrogen atoms 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
-
- 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
- C07D499/04—Preparation
-
- 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
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of penicillanic acid diphenyl methyl ester sulfoxide, which takes 6-bromo-penicillanic acid as an initial raw material and is prepared by oxidation, esterification one-pot reaction and reduction reaction. The reducing agent adopted in the reduction reaction is one or two of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride. The oxidation and esterification one-pot reaction is that the catalyst is firstly oxidized and then esterified with benzophenone hydrazone, the catalyst oxidation system is oxygen and alkali metal halide, and the alkali metal halide is potassium iodide or sodium iodide. Compared with zinc powder, the reduction system of the invention can obtain higher reduction reaction yield, is more environment-friendly and is suitable for industrial mass production. The catalytic oxidation system of the invention has the advantages of higher yield, lower production cost and higher safety, thereby being further suitable for industrial mass production.
Description
Technical Field
The invention belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a preparation method of penicillanic acid diphenylmethyl ester sulfoxide.
Background
Tazobactam is a broad-spectrum and efficient β -lactamase inhibitor of penicillanic sulfone acids, and has the advantages of less toxic side effect, strong enzyme inhibiting activity, high stability and the like, so that tazobactam is judged as the most promising β -lactamase inhibitor in the industry, and penicillanic acid diphenyl methyl ester sulfoxide is an important intermediate for synthesizing tazobactam.
The existing route for synthesizing penicillanic acid diphenyl methyl ester sulfoxide is mainly prepared by taking 6-aminopenicillanic acid (6-APA) as an initial raw material through bromination, oxidation, esterification and reduction (documents 1 to 6).
For the above bromination reaction, monobromination is mostly used and dibromination is rarely used in the prior art (documents 1 and 5).
For the above oxidation reaction, the prior art mainly includes two oxidation systems of hydrogen peroxide (documents 2 to 6) and peracetic acid (document 1). The disadvantage of peroxyacetic acid oxidation systems is that: the product is easily oxidized and thus the yield is not high (the yield of document 1 is only about 70.2%). The yield of the hydrogen peroxide oxidation system is significantly improved compared to the peroxyacetic acid system, but this high yield is either based on that obtained in hexafluoroisopropanol, an organic solvent that is highly toxic and also not inexpensive, leading to lower safety (document 2); or obtained on the basis of adding a catalyst such as molybdenum acetylacetonate, which is relatively expensive, resulting in a relatively high production cost (document 4); still others are oxidative esterification products rather than bromination products.
For the above reduction reaction, zinc powder is basically used for reduction in the prior art, on one hand, zinc powder reduction is not environment-friendly, on the other hand, except that the yield can be improved to 93% by adopting ultrasonic assistance in the document 2, the yield of reduction reaction in other documents is not high and is basically not more than 80% [ the applicant can not reach the claimed 92% after many times of experiments according to the method in the document 4 ].
Document 1: "improvement of synthesis process of penicillanic acid diphenylmethyl ester sulfoxide", Yanghui, J.antibiotics, Vol.26, No. 4, p.309-310, 2001, 8 months.
Document 2: "Synthesis of Benzhydrylmethyl Penicillilanoate sulfoxide", Xuweiliang et al, Fine chemical engineering, Vol.20, No. 11, p.700-701, month 11 2003.
Document 3: "search for Synthesis method of Benzylpenicillanic acid sulfoxide", Lizhou Qing et al, Hebei chemical engineering, 29 th 11 th, 37 th, 63 th, 2006, 11 months.
Document 4: chinese patent document CN101935324A, published 2011, 1/5.
Document 5: chinese patent document CN102020663A, published 2011, 4 months and 20 days.
Document 6: chinese patent document CN106967089A, published 2017, 7 and 21.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of penicillanic acid diphenylmethyl ester sulfoxide, which has the advantages of low production cost, high safety, environmental friendliness and high yield.
The technical scheme for realizing the purpose of the invention is as follows: a process for preparing diphenyl methyl penicillanic acid sulfoxide from 6-bromopenicillanic acid includes oxidizing, esterifying and reducing.
In order to obtain higher yield of reduction reaction, the reducing agent adopted in the reduction reaction is borohydride.
The molar ratio of the borohydride to the oxidation and esterification product (namely 6-bromopenicillanic acid diphenylmethyl ester sulfoxide) is 1: 1-4: 1, and the preferential ratio is 2: 1.
The borohydride is one or two of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride.
In order to further obtain higher reduction reaction yield, the borohydride is preferably sodium borohydride.
The reduction reaction is carried out in an organic solvent; the organic solvent is one or more of tetrahydrofuran, methanol, ethanol, isopropanol and diethyl ether, and preferably ethanol.
The oxidation and esterification one-pot reaction is carried out by firstly carrying out catalytic oxidation and then carrying out esterification reaction with benzophenone hydrazone.
The catalytic oxidation system is oxygen + alkali metal halide.
The molar ratio of the alkali metal halide to the 6-bromopenicillanic acid is 0.01: 1-0.1: 1, and preferably 0.04: 1.
The alkali metal halide is one or two of sodium iodide, potassium iodide, lithium iodide, sodium bromide, potassium bromide, lithium bromide and sodium chloride.
The alkali metal halide is preferably potassium iodide or sodium iodide for better yield and product purity.
The invention has the following positive effects:
(1) compared with zinc powder, the reduction system of the invention can obtain higher reduction reaction yield, is more environment-friendly and is suitable for industrial mass production.
(2) The catalytic oxidation system of the invention has the advantages of higher yield, lower production cost and higher safety, thereby being further suitable for industrial mass production.
Detailed Description
(examples)
This example illustrates the bromination of 6-aminopenicillanic acid to produce 6-bromopenicillanic acid by the following method:
adding 800mL of 12wt% dilute sulfuric acid into a reaction bottle, adding 64.8g of 6-aminopenicillanic acid (0.3 mol), 88.1g of 48wt% hydrobromic acid and 120mL of 95vol% ethanol under stirring, cooling to 2-5 ℃, dropwise adding 17.5wt% sodium nitrite solution (31 g of sodium nitrite dissolved in 146g of water), and keeping the temperature (2-5 ℃) after dropwise addition until the reaction is completed.
After the reaction, filtration was performed, the filtrate was extracted with dichloromethane (200 mL × 3), the organic layers were combined, washed once with 30mL water, and the solvent was recovered by concentration under reduced pressure to obtain 80.2g of 6-bromopenicillanic acid, the yield was 95.5%, and the HPLC purity was 98.1%.
(example 1)
The embodiment is a method for preparing 6-bromopenicillanic acid diphenylmethyl sulfoxide by oxidizing and esterifying 6-bromopenicillanic acid in one-pot reaction, and the specific method comprises the following steps:
70g of 6-bromopenicillanic acid (0.25 mol) is added into a reaction bottle, then 238mL of acetic acid, 0.55g of manganese acetate and 1.66g of potassium iodide (0.01 mol) are added, the temperature is reduced to 4 ℃, oxygen is continuously introduced into the reaction bottle, and the reaction is carried out for 6 hours.
Then 52.9g of benzophenone hydrazone (0.27 mol) was added into the reaction flask, 18mL of 10wt% diluted sulfuric acid was added dropwise, and the mixture was reacted at 0 ℃ for 1 hour, and then heated to 25 ℃ for 1 hour.
After the reaction is finished, concentrating under reduced pressure to recover the solvent, adding 160mL of ethyl acetate and 60mL of water into the residue, stirring for 30min, standing for layering, washing the ethyl acetate layer with 30mL of 5wt% sodium bicarbonate once, washing with 30mL of saturated saline once, concentrating under reduced pressure to recover the solvent to 1/3 volume, adding 50mL of petroleum ether, slowly cooling the mixed material to 5-10 ℃, and filtering to obtain 108.5g of 6-bromopenicillanic acid diphenylmethyl ester sulfoxide, wherein the yield is 93.9%, the HPLC purity is 98.5%, and the melting point is 130.8-132.9 ℃.
(examples 2 to 5)
The preparation method of each example is basically the same as that of example 1 except for the differences shown in Table 1.
Comparative example 1
Comparative example 1 was prepared substantially the same as example 1, except as shown in table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Comparative example 1 | |
| Alkali metal halide | Potassium iodide 1.66g | Sodium iodide 1.50g | Lithium iodide 1.34g | Potassium bromide 1.19g | Sodium bromide 1.03g | / |
| 6-Bromopenicillanic acid diphenylmethyl sulfoxide | 108.5g | 108.3g | 103.3g | 103.6g | 103.9g | 85.5g |
| Yield of | 93.9% | 93.8% | 89.4% | 89.7% | 90.0% | 74.0% |
| HPLC purity | 98.5% | 98.2% | 97.9% | 98.0% | 97.8% | 95.8% |
| Melting Point | 130.8～132.9℃ | 130.7～133.1℃ | 130.5～132.9℃ | 130.5～133.0℃ | 130.4～132.9℃ | 128.9～131.7℃ |
(example 6)
This example is a specific method for preparing penicillanic acid diphenylmethyl ester sulfoxide by 6-bromopenicillanic acid diphenylmethyl ester sulfoxide reduction, which is as follows:
adding 92.4g of 6-bromopenicillanic acid diphenylmethyl sulfoxide (0.2 mol) into a reaction bottle, adding 400mL of ethanol, cooling to 0-5 ℃, adding 15.2g of sodium borohydride (0.4 mol) into the reaction bottle in three times (at intervals of 10 minutes), stirring and reacting at 0-5 ℃ for 30min, and then heating to 25 ℃ and stirring and reacting for 1 h.
After the reaction is finished, cooling to 5-10 ℃, dropwise adding 50mL of 1M hydrochloric acid into a reaction bottle, concentrating under reduced pressure to recover ethanol, extracting with ethyl acetate (100 mL × 3), combining organic layers, washing with 50mL of water, concentrating under reduced pressure to recover ethyl acetate until the volume of the material is about 100mL, adding 50mL of n-hexane, stirring and cooling to 10-15 ℃, and crystallizing to obtain 71.3g of penicillanic acid diphenyl methyl ester sulfoxide, wherein the yield is 93.1%, the HPLC purity is 99.5%, and the melting point is 151.0-152.8 ℃.
(examples 7 to 12)
The preparation method of each example is basically the same as that of example 6 except for the differences shown in Table 2.
TABLE 2
| Example 6 | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 | |
| Organic solvent | 400mL of ethanol | 400mL of ethanol | 400mL of ethanol | 400mL of ethanol | 400mL of ethanol | 400mL of methanol | 400mL of tetrahydrofuran |
| Reducing agent | Sodium borohydride 15.2g | Sodium borohydride 30.4g | Sodium borohydride 7.6g | Potassium borohydride 21.6g | 8.8g of lithium borohydride | Sodium borohydride 15.2g | Sodium borohydride 15.2g |
| Penicillanic acid diphenylmethyl ester Sulfoxide | 71.3g | 71.5g | 67.1g | 67.8g | 67.1g | 69.0g | 68.6g |
| Yield of | 93.1% | 93.3% | 87.6% | 88.5% | 87.6% | 90.1% | 89.6% |
| HPLC purity | 99.5% | 99.6% | 99.3% | 99.3% | 99.2% | 98.8% | 98.6% |
| Melting Point | 151.0～152.8 ℃ | 151.2～153.2 ℃ | 150.7～153.2 ℃ | 150.8～153.3 ℃ | 150.7～153.1 ℃ | 150.5～ 152.7℃ | 150.4～152.9 ℃ |
Claims (10)
1. A method for preparing penicillanic acid diphenyl methyl ester sulfoxide, it regards 6-bromo penicillanic acid as the initial raw materials, through oxidizing, esterifying one pot reaction and reduction reaction to get final product; the method is characterized in that: the reducing agent adopted in the reduction reaction is borohydride.
2. The process for producing benzhydryl penicillanoate sulfoxide according to claim 1, wherein: the borohydride is one or two of lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride.
3. The process for producing benzhydryl penicillanoate sulfoxide according to claim 2, wherein: the borohydride is sodium borohydride.
4. The process for producing benzhydryl penicillanoate sulfoxide according to claim 1, wherein: the reduction reaction is carried out in an organic solvent; the organic solvent is one or more of tetrahydrofuran, methanol, ethanol, isopropanol and diethyl ether.
5. The process for producing benzhydryl penicillanoate sulfoxide according to claim 4, wherein: the organic solvent is ethanol.
6. The process for the preparation of benzhydryl penicillanic acid sulfoxide according to any one of claims 1 to 5, characterized in that: the oxidation and esterification one-pot reaction is that the catalyst is firstly oxidized and then the esterification reaction is carried out with benzophenone hydrazone; the catalytic oxidation system is oxygen + alkali metal halide.
7. The process for producing benzhydryl penicillanoate sulfoxide according to claim 6, wherein: the molar ratio of the alkali metal halide to the 6-bromopenicillanic acid is 0.01: 1-0.1: 1.
8. The process for producing benzhydryl penicillanoate sulfoxide according to claim 7, wherein: the molar ratio of the alkali metal halide to the 6-bromopenicillanic acid is 0.04: 1.
9. The process for producing benzhydryl penicillanoate sulfoxide according to claim 6, wherein: the alkali metal halide is one or two of sodium iodide, potassium iodide, lithium iodide, sodium bromide, potassium bromide, lithium bromide and sodium chloride.
10. The process for producing benzhydryl penicillanoate sulfoxide according to claim 9, wherein: the alkali metal halide is potassium iodide or sodium iodide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711448985.4A CN108250218B (en) | 2017-12-27 | 2017-12-27 | Process for preparing penicillanic acid diphenyl methyl ester sulfoxide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711448985.4A CN108250218B (en) | 2017-12-27 | 2017-12-27 | Process for preparing penicillanic acid diphenyl methyl ester sulfoxide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108250218A CN108250218A (en) | 2018-07-06 |
| CN108250218B true CN108250218B (en) | 2020-07-03 |
Family
ID=62724410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711448985.4A Active CN108250218B (en) | 2017-12-27 | 2017-12-27 | Process for preparing penicillanic acid diphenyl methyl ester sulfoxide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108250218B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101935324B (en) * | 2010-09-08 | 2012-09-05 | 景德镇市富祥药业有限公司 | Method for preparing penicillanic acid sulfoxide diphenyl methyl ester |
| CN102503956A (en) * | 2011-11-21 | 2012-06-20 | 江西华邦药业有限公司 | Preparation method of penicillanic acid sulphoxide diphenylmethyl ester |
-
2017
- 2017-12-27 CN CN201711448985.4A patent/CN108250218B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN108250218A (en) | 2018-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114133350A (en) | Preparation method of anti-neocorolla drug Paxlovid intermediate | |
| EP2802562B1 (en) | Process for the preparation of travoprost | |
| CN111205176A (en) | Synthetic method of 3, 5-dihalogen-2-pentanone | |
| CN114539048B (en) | Carlong anhydride intermediate and preparation method of Carlong anhydride | |
| CN103087074A (en) | Method of semi-synthesizing artemisinin | |
| CN108250218B (en) | Process for preparing penicillanic acid diphenyl methyl ester sulfoxide | |
| KR20110098760A (en) | Process for preparing zanamivir and intermediates for use in the process | |
| CN111560005B (en) | Preparation method of 2-thiopheneacetyl chloride | |
| CN106749335B (en) | A kind of preparation method and application of halogenated oxygen cephalo-type intermediate | |
| CN106520892B (en) | The preparation method of 7-AVCA | |
| KR20020068518A (en) | Penicillin crystal and process for producing the same | |
| CN108947919A (en) | A kind of novel processing step and its key intermediate of gout suppressant Lesinurad | |
| CN114736151B (en) | Preparation method of Pa Luo Weide key intermediate and structural formula of compound | |
| CN114163380B (en) | Alvacpam intermediate and preparation method and application thereof | |
| KR20010072702A (en) | Process for the preparation of fluorobenzyl derivatives | |
| CN111620876B (en) | Synthetic method of Rudesiwei key intermediate | |
| CN113416142B (en) | Preparation method of 5-ALA intermediate 5-bromolevulinate | |
| CN112898152B (en) | Preparation method of ethoxy diethyl methylene malonate | |
| CN109678738B (en) | Method for synthesizing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formate | |
| CN113773182A (en) | Method for synthesizing 6, 8-dichloro caprylic acid ester | |
| CN115385837A (en) | Method for preparing astaxanthin through canthaxanthin oxidation | |
| CN113461615B (en) | Preparation method of 4-fluoro-1H-pyrazole | |
| CN109265385A (en) | A kind of synthesis technology of chiral catalyst | |
| CN110950919B (en) | Synthetic method of sofosbuvir | |
| CN109956958B (en) | Synthesis method of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |