CN103819489B - A kind of preparation method of benzhydryl s-oxopenicillanate - Google Patents
A kind of preparation method of benzhydryl s-oxopenicillanate Download PDFInfo
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- CN103819489B CN103819489B CN201410099381.3A CN201410099381A CN103819489B CN 103819489 B CN103819489 B CN 103819489B CN 201410099381 A CN201410099381 A CN 201410099381A CN 103819489 B CN103819489 B CN 103819489B
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- benzhydryl
- oxopenicillanate
- haloalkane
- bromine
- aliphatic alcohols
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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
-
- 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
Abstract
The invention discloses a kind of preparation method of benzhydryl s-oxopenicillanate, belong to medical art.It is using haloalkane as reaction solvent, lower aliphatic alcohols is as catalyzer, the hydrogen that generates is reacted for reductive agent with a kind of more active metal-powder and ammonium acetate solution, 6-bromine benzhydryl s-oxopenicillanate is reduced, after filtration, obtains benzhydryl s-oxopenicillanate after concentrating under reduced pressure and the removal of impurities of hexanaphthene high temperature.The present invention adopts haloalkane replace expensive and easily form the tetrahydrofuran (THF) of explosive peroxides, and the method has simple, with low cost, dangerous little, the reaction yield of aftertreatment and content advantages of higher.
Description
Technical field
The present invention relates to a kind of Tazobactam Sodium important intermediate 3, the preparation method of 2-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4--oxide compound (hereinafter referred to as benzhydryl s-oxopenicillanate), belongs to medical art.
Background technology
Tazobactam Sodium (tazobactam), chemical name: 3-methyl-7-oxo-3-(1H-1,2,3,-triazole-1-methylene radical)-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4,4-dioxide, structural formula is as follows, is novel penicillanic acid sulfones β mono-lactamase restrainer of Japanese roc drugmaker exploitation.Its structure increases a triazole ring on the basis of Sulbactam, and press down enzyme effect to improve, it is β mono-lactamase restrainer of current clinical effectiveness the best, has the features such as stability is high, activity is low, toxicity is low, Inhibiting enzyme activity is strong.1992, the compound medicine Tazobactam Sodium/piperacillin (1:8) of Tazobactam Sodium, first in France's listing, was used for the treatment of various bacteria and infects.
At present, the synthesis of Tazobactam Sodium is different according to adopted starting material, mainly contains three synthesis techniques, respectively with: Sulbactam, potassium penicillin G and 6-amino-penicillanic acid (6-APA) are for raw starting material.Wherein, especially with 6-amino-penicillanic acid (6-APA) for starting raw material synthesis Tazobactam Sodium research the most active.This operational path mainly comprises the 10 step reactions such as bromo, list oxidation, esterification, reduction, cracking open loop, chloromethylation, azide, dual oxide, cyclization, deprotection, and obtain Tazobactam Sodium, every single step reaction is all relatively simple, is easy to realize suitability for industrialized production.Its reaction process (see reaction equation 1):
The preparation technology of existing benzhydryl s-oxopenicillanate is normally according to the method preparation described in document " synthesis of benzhydryl s-oxopenicillanate " (volume o. 11th in " fine chemistry industry " November the 20th in 2003): be dissolved in tetrahydrofuran (THF) by 6-bromine benzhydryl s-oxopenicillanate, prepare by reacting with zinc powder and ammonium acetate solution (see in reaction equation 1 III to IV reaction process).Reaction terminates, and with diatomite elimination zinc powder, organic layer is concentrated into dry, adds chloroform and dissolves, use saturated common salt water washing, dry, filters.Filtrate decompression evaporate to dryness, benzhydryl s-oxopenicillanate (yield 93%) is obtained with the mixed solution recrystallization of ethyl acetate and normal hexane, above-mentioned post-reaction treatment is complicated, and using tetrahydrofuran (THF) as reaction solvent, this solvent is expensive, easy formation superoxide and exploding, toxicity is comparatively large, and smell is pungent.
Summary of the invention
For the above-mentioned deficiency of prior art, the invention provides a kind of preparation method of new benzhydryl s-oxopenicillanate.The method has simple, with low cost, dangerous little, the yield of aftertreatment and content advantages of higher.
Technical scheme of the present invention is as follows: a kind of preparation method of benzhydryl s-oxopenicillanate, is characterized in that, using haloalkane as reaction solvent, lower aliphatic alcohols, as catalyzer, reacts with a kind of more active metal-powder and ammonium acetate solution the H generated
+for reductive agent, with 6-bromine benzhydryl s-oxopenicillanate in-10 DEG C ~ 25 DEG C insulation reaction 1 ~ 2 hour; After having reacted, cross and filter zinc powder, stratification; By haloalkane layer evaporated under reduced pressure, products therefrom hexanaphthene 40 DEG C ~ 50 DEG C stirs 0.5-1.5 hour, filters, and dries and obtains benzhydryl s-oxopenicillanate.
Its reaction process as shown in the reaction equation 2.
Described haloalkane is monochloro methane, methylene dichloride, trichloromethane, tetracol phenixin, ethylene dichloride etc.The consumption of haloalkane is 1 ~ 20 times of 6-bromine benzhydryl s-oxopenicillanate quality, and preferred methylene chloride is 10 times.
Described lower aliphatic alcohols is methyl alcohol, ethanol, Virahol, propyl carbinol, ethylene glycol, glycerol etc.0.05 ~ 1 times of the consumption 6-bromine benzhydryl s-oxopenicillanate quality of described lower aliphatic alcohols, the consumption of preferred lower aliphatic alcohols is 0.1 times.
Described metal-powder is magnesium powder, aluminium powder, iron powder, zinc powder etc.
Reaction mechanism of the present invention is: using halo alkanes as reaction solvent, the hydrogen that generates is reacted for reductive agent with a kind of more active metal-powder and ammonium acetate solution, hydrogen transference in aqueous phase is completed reduction reaction to organic phase as the carrier of hydrogen by lower aliphatic alcohols, thus play katalysis, as shown in Figure 1.
The invention has the beneficial effects as follows: the present invention adopts lower aliphatic alcohols as catalyzer, the tetrahydrofuran (THF) that halo alkanes explodes as reaction solvent expensive, the easy formation superoxide of replacement, toxicity is comparatively large, smell is pungent, the method has aftertreatment simple, with low cost, dangerous little, the yield of product, content advantages of higher.
Accompanying drawing explanation
Fig. 1 is reaction mechanism schematic diagram of the present invention.
Embodiment
Below in conjunction with embodiment, the present invention will be further described, but be not limited thereto.
This patent raw materials used 6-bromine benzhydryl s-oxopenicillanate is according to the method preparation described in document " synthesis of benzhydryl s-oxopenicillanate " (volume o. 11th in " fine chemistry industry " November the 20th in 2003), the 6-bromine benzhydryl s-oxopenicillanate Diethyl ether recrystallization obtained, content >=99.5%.
Embodiment 1:
6-bromine benzhydryl s-oxopenicillanate 20.0g is dropped into successively, methylene dichloride 200g, dehydrated alcohol 2.0g, water 60g, ammonium acetate 20.0g in 500ml there-necked flask.Ice bath cools, and at-5 ~ 0 DEG C, gradation adds zinc powder 11.1g.Finish ,-5 ~ 0 DEG C is reacted 1 hour, with diatomite elimination zinc powder, and stratification.By dichloromethane layer evaporated under reduced pressure, products therefrom 40g hexanaphthene 50 DEG C stirs and carries out high temperature removal of impurities in 1 hour, filters (filter cake is penicillanic acid benzhydryl ester), dries to obtain finished product 16.35g, yield 98.6%(content 99.70%).
Embodiment 2 ~ 3:
Operate by embodiment 1, methylene dichloride is changed successively into the trichloromethane of identical weight, tetracol phenixin, content and the yield of products obtained therefrom are as shown in table 1.
Embodiment 4 ~ 5:
Operate by embodiment 1, dehydrated alcohol is changed successively into the anhydrous methanol of identical weight, Virahol, content and the yield of products obtained therefrom are as shown in table 1.
Contrast experiment 1:
Operate by embodiment 1, but do not add aliphatic alcohols material and carry out catalysis, react and carry out in single solvent methylene dichloride.6-bromine benzhydryl s-oxopenicillanate 20.0g is dropped into successively, methylene dichloride 200g, water 60g, ammonium acetate 20.0g in 500ml there-necked flask.Ice bath cools, and at-5 ~ 0 DEG C, gradation adds zinc powder 11.1g.Finish ,-5 ~ 0 DEG C is reacted 1 hour, with diatomite elimination zinc powder, and stratification.By dichloromethane layer evaporated under reduced pressure, products therefrom 40g hexanaphthene 50 DEG C stirs 1 hour, filters, dries to obtain finished product 13.31g, yield 80.3%(content 94.70%).
Simultaneous test 2:
6-bromine benzhydryl s-oxopenicillanate 20.0g is dropped into successively, tetrahydrofuran (THF) 150ml, water 100g, ammonium acetate 30.0g in 500m1 there-necked flask.Ice bath cools, and at 0 DEG C ~ 5 DEG C, gradation adds zinc powder 14.0g.Finish, room temperature reaction 3 hours under ultrasonic wave, with diatomite elimination zinc powder, stratification.Organic layer is concentrated into dry, adds chloroform and dissolves, use saturated common salt water washing, anhydrous magnesium sulfate drying, evaporated under reduced pressure.The mixed solution recrystallization of products therefrom use ethyl acetate and normal hexane, obtains finished product 15.42g, yield 93.0%(content 95.36%).
Table 1 the present invention and existing methodical yield and comparision contents table
Result shows by experiment: when carrying out in the single halogenated alkyl solvent of reaction, and does not add aliphatic alcohols material when carrying out catalysis, and the content of synthesis yield and product all significantly reduces.As can be seen here, aliphatic alcohols material as the carrier of hydrogen, achieves the transfer of hydrogen between aqueous phase and organic phase, serves good katalysis in this type of reaction.The relative traditional method content of preparation method of the present invention and yield all improve simultaneously.
Claims (1)
1. a preparation method for benzhydryl s-oxopenicillanate, is characterized in that, using haloalkane as reaction solvent, lower aliphatic alcohols, as catalyzer, reacts with zinc powder and ammonium acetate solution the H generated
+for reductive agent, with 6-bromine benzhydryl s-oxopenicillanate in-10 DEG C ~ 25 DEG C insulation reaction 1 ~ 2 hour; After having reacted, cross and filter zinc powder, stratification; By haloalkane layer evaporated under reduced pressure, products therefrom hexanaphthene 40 DEG C ~ 50 DEG C stirs 0.5-1.5 hour, filters, and dries and obtains benzhydryl s-oxopenicillanate; Described haloalkane is monochloro methane, methylene dichloride, trichloromethane, tetracol phenixin or ethylene dichloride, and the consumption of described haloalkane is 10 times of 6-bromine benzhydryl s-oxopenicillanate quality; Described lower aliphatic alcohols is methyl alcohol, ethanol, Virahol, propyl carbinol, ethylene glycol or glycerol, and the consumption of described lower aliphatic alcohols is 0.1 times of 6-bromine benzhydryl s-oxopenicillanate quality.
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| CN108997375A (en) * | 2018-08-10 | 2018-12-14 | 潍坊奥通药业有限公司 | A kind of preparation method of 6,6- dihydro penicillanic acid benzhydryl ester-S- sulfoxide |
| US11110444B2 (en) | 2019-12-30 | 2021-09-07 | Industrial Technology Research Institute | Chiral catalyst and heterogeneous chiral catalyst comprising the same |
Citations (5)
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| CN1845929A (en) * | 2003-09-03 | 2006-10-11 | 大塚化学株式会社 | Process for producing penicillanic acid compound |
| WO2009027732A1 (en) * | 2007-08-24 | 2009-03-05 | Astrazeneca Ab | 5-6-bicyclic heteroaromatic compounds with antibacterial activity |
| 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 |
| CN103044447A (en) * | 2013-01-16 | 2013-04-17 | 江西富祥药业股份有限公司 | Preparation method of benzhydryl s-oxopenicillanate |
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Patent Citations (5)
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|---|---|---|---|---|
| CN1845929A (en) * | 2003-09-03 | 2006-10-11 | 大塚化学株式会社 | Process for producing penicillanic acid compound |
| WO2009027732A1 (en) * | 2007-08-24 | 2009-03-05 | Astrazeneca Ab | 5-6-bicyclic heteroaromatic compounds with antibacterial activity |
| 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 |
| CN103044447A (en) * | 2013-01-16 | 2013-04-17 | 江西富祥药业股份有限公司 | Preparation method of benzhydryl s-oxopenicillanate |
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| 青霉烷酸二苯甲酯亚砜合成工艺改进;杨辉;《中国抗生素杂志》;20010831;第26卷(第4期);第309-310页，参见第3节 * |
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Effective date of registration: 20181210 Address after: 250105 Dongjia Town 849, Licheng District, Jinan City, Shandong Province Co-patentee after: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. Patentee after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Address before: 250105 Dongjia Town 849, Licheng District, Jinan City, Shandong Province Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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Address after: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20200304 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: Shandong Anxin Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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