CN106279206A - A kind of new synthetic method of sulbactam - Google Patents
A kind of new synthetic method of sulbactam Download PDFInfo
- Publication number
- CN106279206A CN106279206A CN201610669963.XA CN201610669963A CN106279206A CN 106279206 A CN106279206 A CN 106279206A CN 201610669963 A CN201610669963 A CN 201610669963A CN 106279206 A CN106279206 A CN 106279206A
- Authority
- CN
- China
- Prior art keywords
- acid
- sulbactam
- reaction
- water
- synthetic method
- 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.)
- Pending
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the new synthetic method of a kind of sulbactam, including by 6 aminopenicillanic acids sodium nitrite with bromine in acid condition, react in water-insoluble organic solvents, obtain the double penicillium bromo acid of product, be then passed through oxidation reaction, hydrogenation obtains sulbactam.Present invention employs water-insoluble solvent, decrease the discharge of Organic substance in water；Using the mode of step-by-step oxidation, not only decreased the consumption of potassium permanganate but also avoided and originally used ethyl acetate in a large number, manganese dioxide is carried out filtering separation by it, not only reduces the discharge of the three wastes, it is also possible to utilize as side-product；In the former technique discharge of Organic substance, abraum salt is greatly reduced, generation and the cost of material of side reaction are also greatly reduced.
Description
Technical field
The present invention relates to a kind of pharmaceutical synthesis field, be specifically related to the new synthetic method of a kind of sulbactam.
Background technology
Sulbactam (sulbactam), entitled (2S, 5R)-3 of chemistry, 3-dimethyl-7-oxygen band-4-thia-1-azabicyclo
[3.2.0] heptane-2-carboxylic acid-4,4-titanium dioxide compound.Being a kind of semisynthetic wide spectrum beta-lactamase inhibitor, it is a kind of
Competitive irreversible beta-lactamase inhibitor, share with beta-lactam antibiotic, has good synergism, in recent years
The most it is being widely used.The structure of sulbactam such as formula (I):
The traditional synthesis of sulbactam is with 6-amino-penicillanic acid as initiation material, through with sodium nitrite in acidity
Under the conditions of carry out diazo-reaction, then carry out double bromination reaction with bromine, then through potassium permanganate oxidation, finally use metal powder
End zinc powder, magnesium powder or catalytic hydrogen reduction prepare required compound sulbactam, and reaction is as shown in formula (II):
The patent documentation of such as Publication No. CN101967155A discloses a kind of preparation method of sulbactam, with 6-APA is
Raw material, under sulphuric acid or hydrobromic acid existence condition, with bromine as bromating agent, carries out double bromination reaction, then through potassium permanganate oxygen
Change, produce sulbactam with zinc powder or magnesium powder for reducing agent debrominate, three-step approach again.Oxidation stage is except taking in manganese dioxide operation
50% sulphuric acid and 20-28% hydrogen peroxide alternately add method；Reduction phase is adjusted in pH value operation and is adjusted pH with adding sodium bicarbonate
Value；In reduction phase layering extraction process, first do not take off to redness with the washing of 4-10% potassium permanganate solution at organic layer, then use
Saturated sodium-chloride water solution washs.
The patent documentation of Publication No. CN102952147A discloses the synthetic method of a kind of sulbactam, including: (1) 6-
Aminopenicillanic acid, is incubated at diazo reagent and bromine or bromide in the presence of strong acid in organic solvent
Reaction；After being reduced by unnecessary bromine, extract product to water layer；(2) in water layer product, protect after dropping oxidant
Temperature reaction: reaction adjusts pH value after terminating；Reduce unnecessary potassium permanganate, then add organic solvent extraction product to organic solvent
Layer；(3) add catalyst to organic solvent layer product and carry out hydrogenation except bromine；Reactant is extracted to organic solvent layer, distills, tie
Crystalline substance and get final product.Wherein, described organic solvent is ethyl acetate.
The patent documentation of Publication No. CN104262359A discloses the synthetic method of a kind of sulbactam, including by 6-ammonia
Base penicillanic acid forms double bromo penicillin alkanoic acid through diazotising bromination reaction, is then passed through oxidation reaction, reduction reaction obtains
Sulbactam；In described diazotising bromination reaction, 6-amino-penicillanic acid uses the form of acid solution to be continuously added to, described 6-ammonia
The acid solution of base penicillanic acid is that the hydrochloric acid of the aqueous sulfuric acid of 5-8%, the hydrobromic acid aqueous solution of 13-15% or 5-8% is water-soluble
Liquid.The present invention uses the mode of acid solution to drip 6-amino-penicillanic acid, it is to avoid dust pollution, improves the work of Field Force
Make environment. ensure that 6-amino-penicillanic acid is presented in stable salt, it is to avoid reaction of decomposing simultaneously, improve reaction
Quality, uses the method three step yield more than 70% of the present invention.
Document reports the improvement synthetic method of beta-lactamase inhibitor sulbactam, with 6-APA as raw material, through diazonium
Change, bromination, aoxidize, series reaction of reducing has synthesized sulbactam, is optimized kinds of processes condition, carry out in aqueous phase
Diazotising, bromination, carry out in ethyl acetate aoxidizing, reducing, and overall yield of reaction 70% (Study of optimization of sulbactam. chemical industry
Intermediate .2007,2:30-32).
In commercial process, all there are the following problems for the method that above-mentioned document provides: (1) reaction uses second without exception
Acetoacetic ester makees solvent, and the most whole course of reaction is strong oxidized water medium, and ethyl acetate is to be dissolved in the organic solvent of water, low temperature
Time dissolubility up to 10%, in production process, ethyl acetate can be hydrolyzed to acetic acid and ethanol the most in a large number, can enter one
Step increases the dissolubility of ethyl acetate, so under present industrial process conditions, ethyl acetate consumption is big, and useless Organic substance in water
Concentration is high, and waste water difficult treatment does not meets the requirement of green production；(2) in oxidation step, generally will be by the bromine of front step
Changing product highly basic sodium hydroxide adjusts PH to 8～9 to become sodium salt and the participation reaction that is soluble in the aqueous phase, and to add in this external oxidizing process
Enter substantial amounts of phosphoric acid or sulphuric acid to neutralize potassium hydroxide produced by course of reaction, in the process principal product due to be subject to strong
The repeated action of acid highly basic and cause product quality and yield to decline；(3) in oxidation step, potassium permanganate is generally used
As oxidant, and the by-product manganese dioxide of potassium permanganate is carried out acidic reduction it is manganese sulfate thus creates substantial amounts of useless
Salt and waste water, add the discharge of the three wastes, does not meets the requirement of green production.
Summary of the invention
In order to overcome waste water difficult treatment existing for existing sulbactam synthetic method, yield low and environmental pollution
Defect, the invention provides the new synthetic method of a kind of sulbactam, with 6-amino-penicillanic acid as raw material, exists with sodium nitrite
Carry out diazo-reaction under acid condition, then carry out double bromination reaction with bromine and generate double penicillium bromo acid；Oxidation reaction:
With hydrogen peroxide double penicillium bromo acid primary oxidations are obtained 6, the acid of 6-dibromo penam sulfoxide, further to 6,6-dibromo penicillium sp
Alkane sulfoxide acid deep oxidation in potassium permanganate aqueous phase obtains 6,6-dibromo Sulbactam；Finally to 6,6-dibromo sulbactam
Acid adds catalyst and carries out hydro-reduction.
The technical problem to be solved is achieved through the following technical solutions:
The new synthetic method of a kind of sulbactam, comprises the following steps: (1) diazotising bromination reaction: by 6-amino penicillium sp
Alkanoic acid with sodium nitrite, bromine in acid condition, reacts in water-insoluble organic solvents, obtains organic layer product
Double penicillium bromo acids；(2) oxidation reaction: (a) primary oxidation reactor: double penicillium bromo acid primary oxidations are obtained with hydrogen peroxide
To the acid of 6,6-dibromo penam sulfoxide；B () deep oxidation reacts: 6 obtained by primary oxidation reactor, 6-dibromo penam sulfoxide
Acid deep oxidation in potassium permanganate solution obtains 6,6-dibromo Sulbactam；(3) hydrogenation: with catalyst to 6,6-bis-
Bromine penicillin alkane sulfone acid hydro-reduction prepares sulbactam.
Described in step (1), water-insoluble organic solvents is dichloromethane.
Primary oxidation reactor described in step (2), course of reaction is: under the conditions of 0～5 DEG C, by concentration be 27.5～
The hydrogen peroxide of 50% is added drop-wise in the organic solvent containing double bromo penicillin alkanoic acids added with catalyst, 5～10 DEG C of conditions
Lower insulation reaction 1.5～2.5 hours, react complete and reaction suspension be centrifugally separating to obtain 6, the acid of 6-dibromo penam sulfoxide；
In the reaction of described deep oxidation, by 6,6-dibromo penam sulfoxide acid joins in pH buffer agent, adds potassium permanganate and carries out deeply
Degree oxidation, described pH buffer agent is any one in ammonium acetate, sodium acetate, ammonium chloride, and described pH buffer agent consumption is 6,6-
The 1～5% of dibromo penam sulfoxide acid amount.
The catalyst used in described step (2) primary oxidation is rudimentary organic acid or heteropolyacid salt, and described catalyst is used
Amount is the 0.1～0.5% of organic layer product weight.
Further, described rudimentary organic acid be in formic acid, acetic acid, propanoic acid, butanoic acid any one, described heteropolyacid salt is
In tungstates, molybdate, vanadate any one.
Deep oxidation described in step (2) reacts, and also includes that reaction terminates rear gained manganese dioxide aqueous suspension enters
Row solid-liquid separation, the aqueous solution obtained is directly used in hydrogenation.
Further, described solid-liquid separation uses pressure filter, centrifuge or dish-style filter to carry out solid-liquid separation.
Described in step (3), hydriding process is: adds ethyl acetate, cooling in water layer product, controls molten
Liquid pH value is 3.8～4.0, adds catalyst in 50～70min by several times, and controlling temperature is 0～5 DEG C, catalyst add after 0
～5 DEG C of insulation reaction 25～35min, filtering, filter cake water and ethyl acetate washed once respectively, and filtrate and washing liquid merge, and adjust
Joint pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stratification, and water layer glacial acetic acid ethyl ester extracts, having after merging
Machine saturated nacl aqueous solution washs, and adds activated carbon decolorizing, filters, and filtrate distillation crystallization obtains sulbactam.
Step (3) described catalyst is zinc powder or magnesium powder.
Controlling solution ph with dilute sulfuric acid in step (3) is 3.8～4.0, regulates pH to 1.5～2.0 with dilute sulfuric acid.
Compared with prior art, its remarkable advantage is the present invention:
(1) present invention have employed water-insoluble solvent in the first step, decreases the discharge of Organic substance in water.
(2) using the mode of step-by-step oxidation in second step, the most first carry out rudimentary oxidation with hydrogen peroxide, allow 6,6-dibromo is blue or green
The acid of mould alkane sulfoxide is separated from solvent, then carries out advanced oxidation with potassium permanganate at aqueous phase, has both decreased potassium permanganate
Consumption avoids again and originally used ethyl acetate in a large number, and manganese dioxide is carried out filtering separation by it, not only reduces the row of the three wastes
Put, it is also possible to utilize as side-product.
(3) present invention is in former technique Organic substance is greatly reduced, and the discharge of abraum salt is also greatly reduced the generation of side reaction
And cost of material, improve quality and the yield of final products, total recovery is 79.7～80.2%, is a new green life
Production. art.
Accompanying drawing explanation
Fig. 1 is sulbactam new synthetic method process route chart.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment, but these embodiments be intended to for explaining the present invention,
And be not considered as limiting the invention.It should be appreciated that can be to this under without departing from the spirit and scope of the present invention
The details of inventive technique scheme and form are modified and replace, but these amendments and replacement each fall within protection scope of the present invention
In.
Embodiment 1
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, the saturated aqueous solution of 0～5 DEG C of dropping sodium nitrite (12.5g, 0.14mol) and raw material 6-
The acid solution (20.0g6-aminopenicillanic acid is dissolved in the sulfuric acid solution of 20mL5%) of aminopenicillanic acid to the most above-mentioned containing
In the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino to react 30min at 10～15 DEG C
The catabolite of mould alkanoic acid), dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, water layer dichloro
Methane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, water-soluble toward addition sodium tungstate in the organic facies dichloromethane containing double penicillium bromo acids under the conditions of 0～5 DEG C
Liquid 20mL, wherein the content of sodium tungstate is the 0.5% of double penicillium bromo acid weight, slowly drips 30mL50% by constant pressure funnel
Hydrogen peroxide, control temperature 5～10 DEG C, after dripping off, be incubated 1.5 hours, filter 6, the acid of 6-dibromo penam sulfoxide is (almost calmly
Quantitative response), mother solution layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, adds
Entering is 6, and the sodium acetate of 6-dibromo penam sulfoxide acid amount 1% is cooled to less than 5 DEG C as pH buffer agent, stirring, temperature control 5～10
DEG C it is dividedly in some parts potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Dish-style filter is used to filter containing two
The reaction aqueous suspension of manganese oxide, filter cake 50mL water washs, and containing 6, the water layer of 6-dibromo Sulbactam is directly applied
React in next step.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 50min, and controlling temperature is 0～5 DEG C, pH value
It is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 25min, filter, filter cake suitable quantity of water and ethyl acetate are washed respectively
Washing once, filtrate and washing liquid merge, and dilute sulfuric acid regulation pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stratification.Water
Layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g activity
Carbon decoloring, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, and filtrate is placed in after filtration
In Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation, cooling
To 0～5 DEG C, stirring 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.2g, three step total recoverys are 79.7%, HPLC
Purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 2
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, water-soluble toward addition sodium molybdate in the organic facies dichloromethane containing double penicillium bromo acids under the conditions of 0～5 DEG C
Liquid 20mL, wherein the content of sodium molybdate is the 0.25% of double penicillium bromo acid weight, slowly drips by constant pressure funnel
The hydrogen peroxide of 50mL27.5%, controls temperature 5～10 DEG C, after dripping off, is incubated 2 hours, filter 6,6-dibromo penam sulfoxide
Acid, mother solution layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,
The ammonium chloride of 6-dibromo penam sulfoxide acid amount 2.5% is cooled to less than 5 DEG C as pH buffer agent, stirring, temperature control 5～10 DEG C points
Criticize and add potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Centrifuge is used to separate containing manganese dioxide
Reaction aqueous suspension, filter cake 50mL water washs, and containing 6, the water layer of 6-dibromo Sulbactam directly applies to down-walks instead
Should.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 60min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 30min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not Xi Di-secondary, filtrate and washing liquid merge, dilute sulfuric acid regulation pH to 1.5～2.0, and it is saturated to water layer to add sodium chloride, stand point
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.28g, three step total recoverys are
80.1%, HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 3
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid).Then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, vanadic acid sodium aqueous solution 20mL is added, its
The content of middle vanadic acid sodium is the 0.3% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 50mL35% by constant pressure funnel,
Control temperature 5～10 DEG C, after dripping off, be incubated 2.5 hours, filter 6,6-dibromo penam sulfoxide is sour (almost quantitative response),
Mother solution layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-
The ammonium acetate of dibromo penam sulfoxide acid amount 2% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C add in batches
Enter potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Dish-style filter is used to filter containing manganese dioxide
Reaction aqueous suspension, filter cake 50mL water washs, and containing 6, the water layer of 6-dibromo Sulbactam directly applies to down-walks instead
Should.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds magnesium powder by several times and amount to 14g in 70min, and controlling temperature is 0～5 DEG C, pH value
It is basically unchanged.After magnesium powder adds, 0～5 DEG C of insulated and stirred 35min, filter, filter cake suitable quantity of water and ethyl acetate are washed respectively
Washing once, filtrate and washing liquid merge, and dilute sulfuric acid regulation pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stratification.Water
Layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g activity
Carbon decoloring, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, and filtrate is placed in after filtration
In Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation, cooling
To 0～5 DEG C, stirring 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.31g, three step total recoverys are 80.2%,
HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 4
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of raw material 6-amino-penicillanic acid is supreme
Stating in the dichloromethane containing bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is without 6-ammonia for 10～15 DEG C of reaction 30min
The catabolite of base penicillanic acid).Then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, water
Layer dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, aqueous formic acid 20mL is added, wherein
Formic acid content is the 0.4% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 50mL50% by constant pressure funnel, controls temperature
Spend 5～10 DEG C, after dripping off, be incubated 1.7 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother solution divides
Layer rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6, and 6-dibromo is blue or green
The sodium acetate of mould alkane sulfoxide acid amount 1.5% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts height
Potassium manganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Use centrifuge to separate the reaction containing manganese dioxide to suspend
Aqueous solution, filter cake 50mL water washs, and containing 6, the water layer of 6-dibromo Sulbactam directly applies to next step reaction.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds magnesium powder by several times and amount to 14g in 50min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After magnesium powder adds, 0～5 DEG C of insulated and stirred 35min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not Xi Di-secondary, filtrate and washing liquid merge, dilute sulfuric acid regulation pH to 1.5～2.0, and it is saturated to water layer to add sodium chloride, stand point
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.2g, three step total recoverys are 79.7%,
HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 5
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, acetic acid aqueous solution 20mL is added, its
In, acetic acid content is the 0.1% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 50mL45% by constant pressure funnel, control
Temperature 5 processed～10 DEG C, after dripping off, be incubated 2 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother solution
Layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-dibromo
The sodium acetate of penam sulfoxide acid amount 1.5% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts
Potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Use pressure filter to separate the reaction containing manganese dioxide to hang
Swimming solution, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to down-walk instead
Should.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 55min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 35min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not washed once, filtrate and washing liquid merge, and dilute sulfuric acid regulation pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stands and divides
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.24g, three step total recoverys are
79.9%, HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 6
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, drip the saturated aqueous solution of sodium nitrite (12.5g, 0.14mol) under the conditions of 0～5 DEG C
With) acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid is to the most above-mentioned
In dichloromethane containing bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is without 6-amino for 10～15 DEG C of reaction 35min
The catabolite of penicillanic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, water layer
Extract 1 time with dichloromethane (50mL), merge organic facies, obtain the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, propionic acid solution 20mL, Qi Zhongbing are added
Acid content is the 0.5% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 30mL50% by constant pressure funnel, controls temperature
5～10 DEG C, after dripping off, be incubated 2 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother solution layering after
Apply mechanically.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-dibromo penam
The sodium acetate of sulfoxide acid 2.5% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts potassium permanganate
(9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Dish-style filter is used to filter the reaction water in suspension containing manganese dioxide
Solution, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to down-walk reaction.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, and in 60min, adding magnesium powder amounts to 14g by several times, notices that controlling temperature is 0～5 DEG C, pH
Value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 32min, filter, filter cake suitable quantity of water and ethyl acetate are respectively
Washing-secondary, filtrate and washing liquid merge, and dilute sulfuric acid regulation pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stratification.
Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g and lives
Property carbon decoloring, filter, filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, and filtrate is put after filtration
In Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation, fall
Temperature, to 0～5 DEG C, stirs 1 hour, sucking filtration, obtains white crystalline powder sulbactam 17.29g, and three step total recoverys are 80.1%,
HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 7
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid).Then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, butanoic acid aqueous solution 20mL is added, wherein
Butanoic acid content is the 0.4% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 30mL50% by constant pressure funnel, controls temperature
Spend 5～10 DEG C, after dripping off, be incubated 2.5 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother solution divides
Layer rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6, and 6-dibromo is blue or green
The ammonium acetate of mould alkane sulfoxide acid amount 1% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts Gao Meng
Acid potassium (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Use dish-style filter to filter the reaction containing manganese dioxide to hang
Swimming solution, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to next step anti-
Should.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 60min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 30min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not washed once, filtrate and washing liquid merge, and dilute sulfuric acid regulation pH to 1.5～2.0, addition sodium chloride is saturated to water layer, stands and divides
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.31g, three step total recoverys are
80.2%, HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 8
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, be added drop-wise in reactant liquor, about 1.0～1.5h drip off, 10～15 DEG C of reaction 30min (courses of reaction
Middle detection is without the catabolite of 6-amino-penicillanic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow,
Stratification, water layer dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double bromo penicillium sp of organic layer product
Alkanoic acid.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, sodium tungstate aqueous solution 20mL is added, its
Middle sodium tungstate content is the 0.45% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 30mL50% by constant pressure funnel,
Control temperature 5～10 DEG C, after dripping off, be incubated 1.5 hours, filter 6,6-dibromo penam sulfoxide is sour (almost quantitative response),
Mother solution layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-
The ammonium chloride of dibromo penam sulfoxide acid amount 4% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C add in batches
Enter potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.Centrifuge is used to separate the reaction containing manganese dioxide
Aqueous suspension, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to next step
Reaction.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds magnesium powder by several times and amount to 14g in 60min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 30min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not Xi Di-secondary, filtrate and washing liquid merge, dilute sulfuric acid regulation pH to 1.5～2.0, and it is saturated to water layer to add sodium chloride, stand point
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.28g, three step total recoverys are
80.1%, HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 9
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, vanadic acid sodium aqueous solution 20mL is added, its
The content of middle vanadic acid sodium is the 0.5% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 50mL30% by constant pressure funnel,
Control temperature 5～10 DEG C, after dripping off, be incubated 2 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother
Liquid layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-bis-
The sodium acetate of bromine penam sulfoxide acid amount 5% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts
Potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 1.8h.Dish-style filter is used to filter containing manganese dioxide
Reaction aqueous suspension, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to
Under-step reaction.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 60min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 30min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not Xi Di-secondary, filtrate and washing liquid merge, dilute sulfuric acid regulation pH to 1.5～2.0, and it is saturated to water layer to add sodium chloride, stand point
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.2g, three step total recoverys are 79.7%,
HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Embodiment 10
1, according to the reaction scheme shown in Fig. 1, dichloromethane 400mL is added in four-hole bottle, is cooled to 0 DEG C, add bromine
Element (40.0g, 0.235mol), stirring, under the conditions of 0～5 DEG C drip sodium nitrite (12.5g, 0.14mol) saturated aqueous solution and
The acid solution (being dissolved in the sulfuric acid solution of 20mL5% by 20.0g6-aminopenicillanic acid) of 6-amino-penicillanic acid contains to above-mentioned
Having in the dichloromethane of bromine, about 1.0～1.5h drip off, and (in course of reaction, detection is blue or green without 6-amino for 10～15 DEG C of reaction 30min
The catabolite of mould alkanoic acid), then dropping 1mol/L sodium sulfite solution to reactant liquor is yellow, stratification, and water layer is used
Dichloromethane (50mL) extracts 1 time, merges organic facies, obtains the double penicillium bromo acid of organic layer product.
2, under the conditions of 0～5 DEG C, in the organic facies containing double penicillium bromo acids, sodium tungstate aqueous solution 20mL is added, its
The content of middle sodium tungstate is the 0.3% of double penicillium bromo acid weight, slowly drips the hydrogen peroxide of 40mL40% by constant pressure funnel,
Control temperature 5～10 DEG C, after dripping off, be incubated 2 hours, filter 6,6-dibromo penam sulfoxide acid (almost quantitative response), mother
Liquid layering rear enclosure is used.By gained 6,6-dibromo penam sulfoxide acid adds in four-hole bottle, adds water 200mL, is incorporated as 6,6-bis-
The sodium acetate of bromine penam sulfoxide acid amount 3% is as pH buffer agent, and stirring is cooled to less than 5 DEG C, and temperature control 5～10 DEG C are dividedly in some parts
Potassium permanganate (9.5g, 0.06mol), 10～15 DEG C of insulation reaction 2h.The reaction using Filter Press to contain manganese dioxide is hanged
Swimming solution, filter cake 50mL water washs, and obtains containing 6, and the water layer of 6-dibromo Sulbactam directly applies to next step anti-
Should.
3, by upper step gained 6,6-dibromo sulbactam aqueous acid, add ethyl acetate 50mL, be cooled to 0 DEG C, use
It is 3.8～4.0 that dilute sulfuric acid controls solution ph, adds zinc powder by several times and amount to 14g in 50min, notices that controlling temperature is 0～5 DEG C,
PH value is basically unchanged.After zinc powder adds, 0～5 DEG C of insulated and stirred 30min, filter, filter cake suitable quantity of water and ethyl acetate are divided
Not Xi Di-secondary, filtrate and washing liquid merge, dilute sulfuric acid regulation pH to 1.5～2.0, and it is saturated to water layer to add sodium chloride, stand point
Layer.Water layer 100mL glacial acetic acid ethyl ester extracts, and the 100mL saturated nacl aqueous solution of the organic facies after merging washs, and adds 0.6g
Activated carbon decolorizing, filters, and filtering residue washs by appropriate ethyl acetate, and filtrate adds anhydrous calcium chloride and is dried, by filtrate after filtration
Being placed in Rotary Evaporators, control vacuum is at below-0.095MPa, and interior temperature less than 25 DEG C, until crystallization, stops evaporation,
Being cooled to 0～5 DEG C, stir 1 hour, sucking filtration, obtain white crystalline powder sulbactam 17.22g, three step total recoverys are
79.8%, HPLC purity more than 99.7%, single miscellaneous < 0.1%.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example
Property, it is impossible to being interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-mentioned
Embodiment is changed, revises, replaces and modification.
Claims (10)
1. a new synthetic method for sulbactam, comprises the following steps: (1) diazotising bromination reaction: by 6-aminopenicillanic
Acid with sodium nitrite, bromine in acid condition, is reacted in water-insoluble organic solvents, obtains organic layer product double
Penicillium bromo acid；(2) oxidation reaction: (a) primary oxidation reactor: double bromo penicillin alkanoic acid primary oxidations are obtained with hydrogen peroxide
To the acid of 6,6-dibromo penam sulfoxide；B () deep oxidation reacts: 6 obtained by primary oxidation reactor, 6-dibromo penam sulfoxide
Acid deep oxidation in potassium permanganate solution obtains 6,6-dibromo Sulbactam；(3) hydrogenation: with catalyst to 6,6-bis-
Bromine penicillin alkane sulfone acid hydro-reduction prepares sulbactam.
The new synthetic method of sulbactam the most according to claim 1, it is characterised in that water-insoluble described in step (1)
Organic solvent is dichloromethane.
The new synthetic method of sulbactam the most according to claim 1 or claim 2, it is characterised in that primary oxygen described in step (2)
Change reaction, course of reaction is: under the conditions of 0～5 DEG C, by concentration be 27.5～50% hydrogen peroxide be added drop-wise to added with catalyst
In organic solvent containing double penicillium bromo acids, insulation reaction 1.5～2.5 hours under the conditions of 5～10 DEG C, react complete will
Reaction suspension is centrifugally separating to obtain 6, the acid of 6-dibromo penam sulfoxide；In the reaction of described deep oxidation, by 6,6-dibromo penicillium sp
Alkane sulfoxide acid joins in pH buffer agent, adds potassium permanganate and carries out deep oxidation, and described pH buffer agent is ammonium acetate, acetic acid
Any one in sodium, ammonium chloride, described pH buffer agent consumption is 6, the 1～5% of 6-dibromo penam sulfoxide acid weight.
The new synthetic method of sulbactam the most according to claim 3, it is characterised in that in described step (2) primary oxidation
The catalyst used is rudimentary organic acid or heteropolyacid salt, described catalyst amount be organic layer product weight 0.1～
0.5%.
The new synthetic method of sulbactam the most according to claim 4, it is characterised in that described rudimentary organic acid be formic acid,
In acetic acid, propanoic acid, butanoic acid any one, described heteropolyacid salt be in tungstates, molybdate, vanadate any one.
The new synthetic method of sulbactam the most according to claim 5, it is characterised in that deep oxidation described in step (2)
Reaction, also includes that reaction terminates rear gained manganese dioxide aqueous suspension carries out solid-liquid separation, and the aqueous solution obtained directly is used
In hydrogenation.
The new synthetic method of sulbactam the most according to claim 6, it is characterised in that described solid-liquid separation uses filter pressing
Machine, centrifuge or dish-style filter carry out solid-liquid separation.
8. according to the new synthetic method of the arbitrary described sulbactam of claim 1 to 7, it is characterised in that hydrogen described in step (3)
Change course of reaction be: in water layer product add ethyl acetate, cooling, control solution ph be 3.8～4.0,50～
Adding catalyst in 70min by several times, controlling temperature is 0～5 DEG C, catalyst add after 0～5 DEG C of insulation reaction 25～
35min, filters, and filter cake water and ethyl acetate washed once respectively, and filtrate and washing liquid merge, and regulate pH to 1.5～2.0, add
Entering sodium chloride saturated to water layer, stratification, water layer glacial acetic acid ethyl ester extracts, and the organic facies saturated sodium-chloride after merging is molten
Liquid washs, and adds activated carbon decolorizing, filters, and filtrate distillation crystallization obtains sulbactam.
The new synthetic method of sulbactam the most according to claim 8, it is characterised in that step (3) described catalyst is zinc
Powder or magnesium powder.
The new synthetic method of sulbactam the most according to claim 9, it is characterised in that step uses dilute sulfuric acid control in (3)
Solution ph is 3.8～4.0, regulates pH to 1.5～2.0 with dilute sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610669963.XA CN106279206A (en) | 2016-08-15 | 2016-08-15 | A kind of new synthetic method of sulbactam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610669963.XA CN106279206A (en) | 2016-08-15 | 2016-08-15 | A kind of new synthetic method of sulbactam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106279206A true CN106279206A (en) | 2017-01-04 |
Family
ID=57670649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610669963.XA Pending CN106279206A (en) | 2016-08-15 | 2016-08-15 | A kind of new synthetic method of sulbactam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106279206A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312018A (en) * | 2017-07-11 | 2017-11-03 | 合肥利夫生物科技有限公司 | A kind of preparation method of the oxide of 6 penicillium bromo acid 1 |
| CN109438475A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The synthetic method of sulbactam |
| CN109705142A (en) * | 2018-12-24 | 2019-05-03 | 常州红太阳药业有限公司 | The preparation method of sulbactam |
| CN111620892A (en) * | 2020-06-05 | 2020-09-04 | 辽宁九华化工有限公司 | Method for synthesizing sulbactam acid |
| CN115494196A (en) * | 2022-09-19 | 2022-12-20 | 山东二叶制药有限公司 | Quality maintaining method for new sulbactam acid extraction process |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4393001A (en) * | 1981-03-23 | 1983-07-12 | Pfizer Inc. | Intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanates |
| CN86105952A (en) * | 1985-09-06 | 1987-03-04 | 吉斯特-布罗卡迪斯公司 | Prepare 6-amino-penicillanic acid 1 by the oxidation 6-amino-penicillanic acid, the method for 1-dioxide |
| US20040204471A1 (en) * | 2003-03-20 | 2004-10-14 | Pharmacia Corporation | Treatment and prevention of otic disorders with Cox-2 inhibitors alone or in combination with otic agents |
| CN101914104A (en) * | 2010-08-20 | 2010-12-15 | 石家庄中硕药业集团有限公司 | Preparation method of lyophilization sulbactam sodium material medicine |
| CN104262359A (en) * | 2014-09-29 | 2015-01-07 | 江西富祥药业股份有限公司 | Synthetic method of salbactam acid |
-
2016
- 2016-08-15 CN CN201610669963.XA patent/CN106279206A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4393001A (en) * | 1981-03-23 | 1983-07-12 | Pfizer Inc. | Intermediates for production of 1,1-dioxopenicillanoyloxymethyl 6-(2-amino-2-phenylacetamido)penicillanates |
| CN86105952A (en) * | 1985-09-06 | 1987-03-04 | 吉斯特-布罗卡迪斯公司 | Prepare 6-amino-penicillanic acid 1 by the oxidation 6-amino-penicillanic acid, the method for 1-dioxide |
| US20040204471A1 (en) * | 2003-03-20 | 2004-10-14 | Pharmacia Corporation | Treatment and prevention of otic disorders with Cox-2 inhibitors alone or in combination with otic agents |
| CN101914104A (en) * | 2010-08-20 | 2010-12-15 | 石家庄中硕药业集团有限公司 | Preparation method of lyophilization sulbactam sodium material medicine |
| CN104262359A (en) * | 2014-09-29 | 2015-01-07 | 江西富祥药业股份有限公司 | Synthetic method of salbactam acid |
Non-Patent Citations (1)
| Title |
|---|
| 王广生，: "《石油化工原料与产品安全手册》", 31 August 2010 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107312018A (en) * | 2017-07-11 | 2017-11-03 | 合肥利夫生物科技有限公司 | A kind of preparation method of the oxide of 6 penicillium bromo acid 1 |
| CN109438475A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The synthetic method of sulbactam |
| CN109705142A (en) * | 2018-12-24 | 2019-05-03 | 常州红太阳药业有限公司 | The preparation method of sulbactam |
| CN111620892A (en) * | 2020-06-05 | 2020-09-04 | 辽宁九华化工有限公司 | Method for synthesizing sulbactam acid |
| CN115494196A (en) * | 2022-09-19 | 2022-12-20 | 山东二叶制药有限公司 | Quality maintaining method for new sulbactam acid extraction process |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106279206A (en) | A kind of new synthetic method of sulbactam | |
| CN103709121A (en) | Preparation method for pharmaceutical grade 2-mercaptobenzothiazole and derivative DM thereof | |
| CN108264519B (en) | Preparation method and application of 6-chloropeniam sulphoxide acid diphenylmethyl ester | |
| CN102675080B (en) | Preparation method of low-carbon chain symmetric anhydride | |
| CN104262359B (en) | Synthetic method of salbactam acid | |
| CN102399182A (en) | Process for producing quinolinic acid | |
| CN1863808B (en) | Penam crystal and process for producing the same | |
| CN111808122A (en) | Method for synthesizing sulbactam acid | |
| CN102952147B (en) | Synthesizing method of sulbactam acid | |
| CN101967155B (en) | Sulbactam preparation method | |
| CN108726569B (en) | Preparation method of silver hexafluoroantimonate | |
| CN101899012B (en) | Method for improving synthesis process of Acipimox | |
| CN111153853B (en) | Preparation method of 2-chloronicotinic acid | |
| CN103980135B (en) | A kind of preparation method of 4-amino-2-fluorobenzoic acid | |
| CN106831572A (en) | A kind of preparation method of quinolinic acid | |
| CN106866441A (en) | A kind of preparation method of high-purity grade of Ferric Sodium Edetate | |
| CN105085469A (en) | Preparation method of 5-chlorothienyl-2-carboxylic acid | |
| CN109796416A (en) | A kind of synthetic method of 2- acetyl group pyrazine | |
| CN106431885B (en) | Method for synthesizing glyoxylic acid by ozonation of maleic anhydride mixed solvent | |
| CN111620892A (en) | Method for synthesizing sulbactam acid | |
| CN112830892A (en) | Synthesis method of pyridine-3-sulfonyl chloride | |
| CN107011299A (en) | A kind of method that SMIA is reclaimed in the waste liquid from SMIA | |
| CN103254214B (en) | Preparation method of 2beta-nitrine methyl penicillium alkyl diphenyl acid methyl ester | |
| CN108610322A (en) | A kind of preparation method of R- glyceraldehyde acetonides | |
| CN102432627A (en) | Method for producing p-nitrobenzyl penicillin G sulfoxide ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170104 |