CN108250218A - The preparation method of benzhydryl s-oxopenicillanate - Google Patents
The preparation method of benzhydryl s-oxopenicillanate Download PDFInfo
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- CN108250218A CN108250218A CN201711448985.4A CN201711448985A CN108250218A CN 108250218 A CN108250218 A CN 108250218A CN 201711448985 A CN201711448985 A CN 201711448985A CN 108250218 A CN108250218 A CN 108250218A
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- benzhydryl
- oxopenicillanate
- preparation
- borohydride
- sodium
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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
- C07D499/86—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
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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
- C07D499/04—Preparation
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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
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
Abstract
The invention discloses a kind of preparation methods of benzhydryl s-oxopenicillanate, it is using 6 penicillium bromo acids as starting material, and oxidized, esterification one pot reaction and reduction reaction are made.The reducing agent that reduction reaction uses is one or both of lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride.Oxidation, esterification one pot reaction are first through catalysis oxidation, again with Benzophenonehydrazones progress esterification, and catalytic oxidation system is oxygen+alkali halide, and alkali halide is potassium iodide or sodium iodide.The reduction system of the present invention can obtain higher reduction reaction yield, and more friendly to environment, be suitble to industrialized production compared to zinc powder.The oxidized catalyst precursor of the present invention ties up to while obtaining higher yields that production cost is relatively low, safety is higher, so as to be further adapted for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical intermediate preparing technical fields, and in particular to a kind of system of benzhydryl s-oxopenicillanate
Preparation Method.
Background technology
Tazobactam Sodium is a kind of beta-lactamase inhibitor of the sulbactam acids of broad-spectrum high efficacy, because of its toxic side effect
Less, the advantages that Inhibiting enzyme activity is strong, stability is high is chosen as in the industry most promising beta-lactamase inhibitor, penicillanic acid two
Benzene methyl sulfoxide is then the important intermediate for synthesizing Tazobactam Sodium.
The route of existing synthesis benzhydryl s-oxopenicillanate is mainly with 6-amino-penicillanic acid（6-APA）For starting
Raw material is made through bromination, oxidation and esterification, reduction（1~document of document 6）.
For above-mentioned bromination reaction, the prior art is mostly using single bromination, and minority is using double brominations（Document 1, document 5）.
For above-mentioned oxidation reaction, the prior art mainly includes hydrogen peroxide（2~document of document 6）And Peracetic acid（Document
1）Two kinds of oxidation systems.The shortcomings that Peracetic acid oxidation system, is：Easy peroxidating, it is not high so as to cause yield（Document 1
Yield only has 70.2% or so）.Hydrogen peroxide oxidation system is significantly improved compared to Peracetic acid system yield, and still, this is in high yield
Be based on being obtained in the higher and price in toxicity also not low organic solvent hexafluoroisopropanol, so as to cause safety compared with
It is low（Document 2）；It is to be obtained based on the catalyst such as acetylacetone acid molybdenum for adding in higher price, so as to cause being produced into
This is higher（Document 4）；Also be then oxidative esterification product rather than brominated product.
For above-mentioned reduction reaction, the prior art is substantially using zinc powder reduction, on the one hand, zinc powder reduction to environment not
Close friend, on the other hand, other than yield can be increased to 93% by document 2 using ultrasonic wave auxiliary, remaining document reduction reaction is received
Rate is not high, and substantially no more than 80%【According to document 4 method applicant by test of many times be also unable to reach its claim 92%
More than】.
Document 1：" benzhydryl s-oxopenicillanate improvement in synthesis ", Yang Hui,《Chinese antibiotic magazine》, volume 26
4th phase, the 309-310 pages, in August, 2001.
Document 2：" synthesis of benzhydryl s-oxopenicillanate ", Xu Weiliang etc.,《Fine chemistry industry》, the o. 11th of volume 20,
The 700-701 pages, in November, 2003.
Document 3：" synthetic method of benzhydryl s-oxopenicillanate is explored ", Li Guoqing etc.,《Hebei chemical industry》, volume 29
O. 11th, page 37,63, in November, 2006.
Document 4：Chinese patent literature CN101935324A, publication date on January 5th, 2011.
Document 5：Chinese patent literature CN102020663A, publication date on April 20th, 2011.
Document 6：Chinese patent literature CN106967089A, publication date on July 21st, 2017.
Invention content
It is an object of the invention to solve the above problems, provide a kind of production cost is relatively low, safety is higher, to environment friend
Good, the especially higher benzhydryl s-oxopenicillanate of yield preparation method.
Realizing the technical solution of the object of the invention is：A kind of preparation method of benzhydryl s-oxopenicillanate, it be with
6- penicillium bromo acids are starting material, and oxidized, esterification one pot reaction and reduction reaction are made.
In order to obtain higher reduction reaction yield, the reducing agent that above-mentioned reduction reaction uses is boron hydride.
The boron hydride and oxidation, esterification products（Namely 6- penicillium bromo acid benzhydryl ester sulfoxides）Molar ratio be
1: 1~4: 1, preferably 2: 1.
The boron hydride is one or both of lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride.
In order to further obtain higher reduction reaction yield, the boron hydride is preferably sodium borohydride.
The reduction reaction carries out in organic solvent；The organic solvent is tetrahydrofuran, methanol, ethyl alcohol, different
It is one or more in propyl alcohol, ether, preferably ethyl alcohol.
The oxidation, esterification one pot reaction are first to carry out esterification with Benzophenonehydrazones through catalysis oxidation, again.
The catalytic oxidation system is oxygen+alkali halide.
The molar ratio of the alkali halide and 6- penicillium bromo acids is 0.01: 1~0.1: 1, preferably 0.04: 1.
The alkali halide is sodium iodide, in potassium iodide, lithium iodide, sodium bromide, potassium bromide, lithium bromide, sodium chloride
It is one or two kinds of.
In order to obtain preferable yield and product purity, the alkali halide is preferably potassium iodide or iodate
Sodium.
The good effect that the present invention has：
（1）The reduction system of the present invention can obtain higher reduction reaction yield, and more friendly to environment compared to zinc powder
It is good, it is suitble to industrialized production.
（2）The oxidized catalyst precursor of the present invention ties up to while obtaining higher yields that production cost is relatively low, safety is higher, from
And it is further adapted for industrialized production.
Specific embodiment
（Example）
This example prepares 6- penicillium bromo acids for 6-amino-penicillanic acid bromination, and specific method is as follows：
The dilute sulfuric acid 800mL of 12wt% is added in into reaction bulb, is added with stirring the 6-amino-penicillanic acid of 64.8g（0.3mol）、
The ethyl alcohol 120mL of the hydrobromic acid 88.1g and 95vol% of 48wt% are cooled to 2~5 DEG C, and 17.5wt% sodium nitrite solutions are added dropwise
（31g sodium nitrites are dissolved in 146g water）, drip off heat preservation（2~5 DEG C）It reacts to complete.
After reaction, it filters, filtrate is extracted with dichloromethane（200mL×3）, merge organic layer, one washed with 30mL
It is secondary, recycling design is concentrated under reduced pressure, obtains 6- penicillium bromo acid 80.2g, yield 95.5%, HPLC purity is 98.1%.
（Embodiment 1）
The present embodiment is the oxidation of 6- penicillium bromo acids, esterification one pot reaction prepares 6- penicillium bromo acid benzhydryl ester sulfoxides,
Specific method is as follows：
By the 6- penicillium bromo acids of 70g（0.25mol）It is added in reaction bulb, then adds in 238mL acetic acid, 0.55g acetic acid
Manganese and 1.66g potassium iodide（0.01mol）, 4 DEG C are cooled to, oxygen is continually fed into reaction bulb, reacts 6h.
Then the Benzophenonehydrazones of 52.9g are added in into reaction bulb（0.27mol）, the dilute sulfuric acid 18mL of 10wt% is added dropwise, it is first
1h is reacted at 0 DEG C, then is warming up to 25 DEG C of reaction 1h.
After reaction, recycling design is concentrated under reduced pressure, the ethyl acetate of 160mL and the water of 60mL are added in into residue,
Stratification after 30min is stirred, ethyl acetate layer washed once with 5wt% sodium bicarbonates 30mL, then with 30mL saturated salt solutions
It washed once, recycling design is concentrated under reduced pressure to 1/3 volume, adds in 50mL petroleum ethers, mixed material is slowly cooled to 5~10
DEG C, filtering obtains 6- penicillium bromo acid benzhydryl ester sulfoxide 108.5g, yield 93.9%, and HPLC purity is 98.5%, fusing point
130.8~132.9 DEG C.
（2~embodiment of embodiment 5）
The preparation method of each embodiment is substantially the same manner as Example 1, and difference is shown in Table 1.
（Comparative example 1）
The preparation method of comparative example 1 is substantially the same manner as Example 1, and difference is still shown in Table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Comparative example 1 | |
| Alkali halide | Potassium iodide 1.66g | Sodium iodide 1.50g | Lithium iodide 1.34g | Potassium bromide 1.19g | Sodium bromide 1.03g | / |
| 6- penicillium bromo acid benzhydryl ester sulfoxides | 108.5g | 108.3g | 103.3g | 103.6g | 103.9g | 85.5g |
| Yield | 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% |
| Fusing point | 130.8~132.9 DEG C | 130.7~133.1 DEG C | 130.5~132.9 DEG C | 130.5~133.0 DEG C | 130.4~132.9 DEG C | 128.9~131.7 DEG C |
（Embodiment 6）
The present embodiment prepares benzhydryl s-oxopenicillanate, specific method for 6- penicillium bromo acid benzhydryl ester sulfoxide reductions
It is as follows：
By the 6- penicillium bromo acid benzhydryl ester sulfoxides of 92.4g（0.2mol）It is added in reaction bulb, adds in 400mL ethyl alcohol,
0~5 DEG C is cooled to, in three times（Interval 10 minutes）Sodium borohydride 15.2g is added in into reaction bulb（0.4mol）, add first 0
~5 DEG C are stirred to react 30min, then heat to 25 DEG C and are stirred to react 1h.
After reaction, 5~10 DEG C are cooled to, the hydrochloric acid 50mL of 1M is added dropwise into reaction bulb, recycling ethyl alcohol is concentrated under reduced pressure,
It is extracted with ethyl acetate（100mL×3）, organic layer is primary with 50mL water washings after merging, then recycling ethyl acetate is concentrated under reduced pressure
It is about 100mL to volume of material, adds in 50mL n-hexanes, stirring is cooled to 10~15 DEG C, crystallizes to obtain penicillanic acid benzhydryl ester
Sulfoxide 71.3g, yield 93.1%, HPLC purity are 99.5%, and fusing point is 151.0~152.8 DEG C.
（7~embodiment of embodiment 12）
The preparation method of each embodiment is substantially the same manner as Example 6, and difference is shown in Table 2.
Table 2
| Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | |
| Organic solvent | 400mL ethyl alcohol | 400mL ethyl alcohol | 400mL ethyl alcohol | 400mL ethyl alcohol | 400mL ethyl alcohol | 400mL methanol | 400mL tetrahydrofurans |
| Reducing agent | Sodium borohydride 15.2g | Sodium borohydride 30.4g | Sodium borohydride 7.6g | Potassium borohydride 21.6g | Lithium borohydride 8.8g | Sodium borohydride 15.2g | Sodium borohydride 15.2g |
| Benzhydryl s-oxopenicillanate | 71.3g | 71.5g | 67.1g | 67.8g | 67.1g | 69.0g | 68.6g |
| Yield | 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% |
| Fusing point | 151.0~152.8 DEG C | 151.2~153.2 DEG C | 150.7~153.2 DEG C | 150.8~153.3 DEG C | 150.7~153.1 DEG C | 150.5~152.7 DEG C | 150.4~152.9 DEG C |
Claims (10)
1. a kind of preparation method of benzhydryl s-oxopenicillanate, it is using 6- penicillium bromo acids as starting material, through oxygen
Change, esterification one pot reaction and reduction reaction are made；It is characterized in that：The reducing agent that above-mentioned reduction reaction uses is hydroboration
Object.
2. the preparation method of benzhydryl s-oxopenicillanate according to claim 1, it is characterised in that：The hydroboration
Object is one or both of lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride.
3. the preparation method of benzhydryl s-oxopenicillanate according to claim 2, it is characterised in that：The hydroboration
Object is sodium borohydride.
4. the preparation method of benzhydryl s-oxopenicillanate according to claim 1, it is characterised in that：The reduction is anti-
It should carry out in organic solvent；The organic solvent for tetrahydrofuran, methanol, ethyl alcohol, isopropanol, one kind in ether or
It is a variety of.
5. the preparation method of benzhydryl s-oxopenicillanate according to claim 4, it is characterised in that：It is described organic molten
Agent is ethyl alcohol.
6. the preparation method of the benzhydryl s-oxopenicillanate according to one of claim 1 to 5, it is characterised in that：Institute
State oxidation, esterification one pot reaction is first to carry out esterification with Benzophenonehydrazones through catalysis oxidation, again；The catalytic oxidation system
For oxygen+alkali halide.
7. the preparation method of benzhydryl s-oxopenicillanate according to claim 6, it is characterised in that：The alkali metal
The molar ratio of halide and 6- penicillium bromo acids is 0.01: 1~0.1: 1.
8. the preparation method of benzhydryl s-oxopenicillanate according to claim 7, it is characterised in that：The alkali metal
The molar ratio of halide and 6- penicillium bromo acids is 0.04: 1.
9. the preparation method of benzhydryl s-oxopenicillanate according to claim 6, it is characterised in that：The alkali metal
Halide is sodium iodide, one or two kinds of in potassium iodide, lithium iodide, sodium bromide, potassium bromide, lithium bromide, sodium chloride.
10. the preparation method of benzhydryl s-oxopenicillanate according to claim 9, it is characterised in that：The alkali gold
It is potassium iodide or sodium iodide to belong to halide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101935324A (en) * | 2010-09-08 | 2011-01-05 | 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
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101935324A (en) * | 2010-09-08 | 2011-01-05 | 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 |
Non-Patent Citations (5)
| Title |
|---|
| RONALD G.MICETICH: "synthesis of 2β-Azidomethylpenicillin-1,1-Dioxides and 3β-Azido-3a-methylcepham-1,1-Dioxides", 《SYNTHESIS》 * |
| 曹琳等: "β-内酰胺酶抑制剂他唑巴坦的合成", 《化学工业与工程》 * |
| 段行信主编: "《实用精细有机合成手册》", 31 January 2000, 化学工业出版社 * |
| 白国义等: "他唑巴坦合成中1,3-偶极环加成反应的研究", 《精细化工》 * |
| 陆导仁等: "新酶抑制剂他唑巴坦的合成", 《浙江医科大学学报》 * |
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