CN102952147A - Synthesizing method of sulbactam acid - Google Patents
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Abstract
The invention discloses a synthesizing method of sulbactam acid. The method comprises the steps that: (1) under the existence of a strong acid, 6-aminopenicillanic acid, a diazotization reagent, and bromine or bromide are subjected to an insulation reaction in an organic solvent; excessive bromine is reduced; and a reaction product is extracted to a water layer; (2) an oxidant is dropped into the water-layer reaction product, and an insulation reaction is carried out; when the reaction is finished, a pH value is regulated; excessive potassium permanganate is reduced; an organic solvent is added, such that a reaction product is extracted to an organic solvent layer; (3) a catalyst is added into the organic-solvent layer product, such that hydrogenation bromine-removing is carried out; a reaction product is extracted to an organic-solvent layer; and distillation and crystallization are carried out. The organic solvent is ethyl acetate. According to the invention, ethyl acetate is adopted as the organic solvent in a four-step reaction, such that solvent consumption of the whole reaction is greatly reduced, and product total yield is effectively improved. With the method provided by the invention, by-product in the reaction can be comprehensively utilized, and advantages such as high yield, low cost, clean production, and the like are provided.
Description
Technical field
The present invention relates to a kind of synthetic method of beta-lactamase inhibitor, relate in particular to a kind of synthetic method of sulbactam, belong to the synthetic field of sulbactam.
Background technology
The chemical name of sulbactam: 4-sulphur-1-dicyclo [β, 2,0] heptane-2-carboxylic acid-dimethyl-7-oxygen-4.4-dioxide of mixing; Its structural formula is as follows:
The physico-chemical property of sulbactam: this product is off-white color or light yellow crystalline powder, and soluble in water, pure, ester is insoluble in ether; The purposes of medicine: sulbactam is the first-selected enzyme inhibitors of a full class antibacterials and penicillins antibacterials.Belong to the atypia Beta-lactam medicine, because long-term a large amount of use of a full class and penicillin medicine, produce β-lactamase and produced Antibiotic resistance, and Sulbactam produces by suppressing β-lactamase after using with a full class and penicillin medicine compatibility, has solved the difficult problem of antibiotic resistance.It is domestic and international most popular beta-lactamase inhibitor.
The former synthetic method of sulbactam mainly comprises: (1) diazotization reaction, (2) bromination reaction, (3) oxidizing reaction, (4) hydrogenation.Wherein, described diazotization reaction and bromination reaction comprise: be chilled to 0 ℃ under methylene dichloride is stirred, suck bromine, drip sulfuric acid water, the control temperature is no more than 10 ℃, mark time control temperature adds Sodium Nitrite, be incubated 20 minutes, gradation slowly adds 6-APA, adds again in 10 ℃ of reactions 0.5 hour, after finishing, insulation dripping 10% aqueous solution of sodium bisulfite below 14 ℃ to the bromine decoloration, leave standstill and tell dichloromethane layer, stirring cooling is 7 with caustic lye of soda accent crowd pH, static layering, methylene dichloride water extraction twice, water layer (I) is in the suction oxidation pot.The methylene dichloride Distillation recovery is applied mechanically.Yield 80%; Existing problems: it is that the inconsistent solvent recuperation of having brought of solvent and lower step oxidation solvent is difficult that this two-step reaction has adopted methylene dichloride, and the destroyed yield that makes reduces after the residual bromide distillation of dichloromethane layer.
Described oxidizing reaction mainly comprises: first bromination water layer (I) is chilled to below 10 ℃, drip potassium permanganate acidic aqueous solution (potassium permanganate+phosphoric acid+water) temperature for preparing first and be controlled at 5-10 ℃, reacted 30 minutes in 10 ℃ again after adding, add ethyl acetate and be cooled to 5 ℃, transfer pH to 1.25 with 30% hydrochloric acid, drip 10% aqueous solution of sodium bisulfite in 5-10 ℃, drop to the potassium permanganate decoloration, and reaction solution is light yellow, add refined salt, make its saturated (adding as unsaturated), standing demix, water layer is processed with twice of ethyl acetate extraction (250kg * 2), water layer suction treating pond, merge methacrylate layer (II), two step yields 90%.Main existing problems are: the phosphoric acid salt that uses in a large number phosphoric acid to produce is larger to the pollution of environment, and the sodium-chlor consumption is more, and wastewater treatment is difficult, is not suitable with suitability for industrialized production.
Described hydrogenation mainly comprises: methacrylate layer (II) is sucked in the hydrogenation pot, add the logical nitrogen replacement of damping fluid and palladium charcoal, lead to hydrogen again, temperature is being inhaled hydrogen below 15 ℃ in keeping.Filtration after finishing, acidifying layering, extraction decolouring are distilled to and put when a lot of crystallisate appears in liquid material to the whizzer rejection filter, dry vinyl acetic monomer drip washing, discharging after drying, drying.Receiving excellent rate is 90%.The problem that exists is: 1. owing to being debromination, making catalyzer with the palladium charcoal and very easily poison, brought and applied mechanically and reclaim difficulty, cost is higher.2. the requirement of device security coefficient is high, use the high-pressure hydrogenation still.
Summary of the invention
Technical problem to be solved by this invention is to overcome that the existing yield of existing sulbactam synthetic method is low, cost is high, the defective of contaminate environment, and a kind of new sulbactam synthetic method is provided.
Technical problem to be solved by this invention is achieved through the following technical solutions:
A kind of synthetic method of sulbactam may further comprise the steps: (1) diazotization and bromination reaction: 6-amino-penicillanic acid carries out insulation reaction in the situation that diazo reagent and bromine or bromide exist at strong acid in organic solvent; After unnecessary bromine reduction, to water layer, obtain the water layer reaction product with mineral alkali abstraction reaction product; (2) oxidizing reaction: in the water layer reaction product, carry out insulation reaction after dripping the oxygenant that is formed by potassium permanganate, acid and water; Adjust pH was to strongly-acid after reaction finished; Reduce unnecessary potassium permanganate, to organic solvent layer, obtain the organic solvent layer product with the organic solvent extraction reaction product; (3) hydrogenation: the organic solvent layer product is added catalyzer carry out hydrogenation except bromine; Reactant is extracted into organic solvent layer, is distilled to driedly, refining, and get final product; Wherein, described organic solvent is preferably ethyl acetate;
Catalyzer described in the step (3) is preferably Raney's nickel, magnesium powder or zinc powder.
Diazo reagent described in the step (1) can be Sodium Nitrite; Described mineral alkali is the carbonate of sodium hydroxide or metal; Wherein, the carbonate of described metal includes but not limited to salt of wormwood, Quilonum Retard, yellow soda ash or calcium carbonate.
The temperature of the insulation reaction described in step (1) or the step (2) is preferably 4-15 ℃, and the insulation reaction time is preferably 20-40 minute.
The mol ratio of 6-amino-penicillanic acid and Sodium Nitrite is preferably 1 in the step (1): 1-3; The mol ratio of 6-amino-penicillanic acid and sulfuric acid is preferably 1: 2-3; The mol ratio of 6-amino-penicillanic acid and bromine is preferably 1: 1-3; The mol ratio of 6-amino-penicillanic acid and mineral alkali is preferably 1: 1-13.
The mol ratio of 6-amino-penicillanic acid and potassium permanganate is preferably 1 in the step (2): 1-2.
Add water after the cooling of organic solvent layer product in the step (3), add again catalyzer and carry out hydrogenation except bromine; Further preferred, when being cooled to 0-15 ℃, the compound system of organic solvent layer product, organic solvent and water adds again catalyzer, and the pH value of controlling simultaneously reaction system is no more than 7.
Described highly acid pH value in step (2) or (3) is 1-1.25, is preferably 1.25.
Reductive agent during step (2) is described is sodium bisulfite, S-WAT and hydrogen peroxide.
The present invention is optimized the organic solvent of the four-step reaction of the synthetic method of existing sulbactam, find as the organic solvent of four-step reaction the solvent consumption of whole reaction to be greatly reduced the ethyl acetate and Effective Raise the total recovery of product.The synthetic method of sulbactam of the present invention can fully utilize the byproduct (metal-salt behind bromine, potassium permanganate oxidation, the hydrogenolysis reducing etc.) in the reaction, and the inventive method has the advantages such as yield is high, cost is low, cleaner production.
Description of drawings
The process route chart of Fig. 1 sulbactam synthetic method.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment only are exemplary, scope of the present invention are not consisted of any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can make amendment or replace the details of technical solution of the present invention and form, but these modifications and replacing all fall within the scope of protection of the present invention.
1, in the 1500L reactor, add the 1000kg ethyl acetate, then stir and be chilled to 0 ℃, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid is got 43.2kg+ water 200kg), the control temperature is no more than 5 ℃, be chilled to 4 ℃, divide to add the 57.6kg Sodium Nitrite for several times, the control temperature is no more than 5 ℃, is incubated 20 minutes, then slowly add 6-APA 90kg in 4 ℃ of gradation, add in 10 ℃ of reactions 0.5 hour again, drip 10% aqueous solution of sodium bisulfite to the bromine decoloration at 5 ℃ after insulation finishes, it is light yellow that reaction solution is, treat to stop to stir without yellow gas effusion, standing demix, lower aqueous layer reclaims bromine with ethyl acetate extraction secondary (400kg * 2), the water layer after the extraction, combined ethyl acetate layer to neutralization pot stirs cooling, transferring pH with caustic lye of soda is 7, static layering, ethyl acetate layer twice of water extraction (200kg * 2), water layer is that lower batch of ethyl acetate is applied mechanically in (I) suction oxidation pot.Yield 92%.
2, the bromination water layer (I) of oxidizing reaction pot is chilled to below 10 ℃, drip the potassium permanganate acidic aqueous solution for preparing first, temperature is controlled at 5 ℃, reacted 30 minutes in 10 ℃ again after adding, add the 500kg ethyl acetate and be cooled to 5 ℃, transfer pH to 1.25 with 30% hydrochloric acid, drip hydrogen peroxide solution in 5 ℃, drop to the potassium permanganate decoloration, and reaction solution is the light yellow terminal point repetition measurement pH that is, is higher than 1.25 such as the pH value, transfer pH to 1.25 with 30% hydrochloric acid again, add 50kg refined salt and stirred 20 minutes, make its saturated (adding as unsaturated), standing demix, water layer twice of ethyl acetate extraction (250kg * 2), water layer enters and reclaims manganese salt, the combined ethyl acetate layer, (II); Yield 91%
3, (II) is extracted in the 3000L reduction pot, is cooled to begin to add ethyl acetate (applying mechanically) and water below 0 ℃.Open the emptying valve, open and stir cooling.Treat that Nei Wenda to 0 ℃ of beginning gradation adds Zn, and drip simultaneously sulfuric acid and keep pH to be no more than 5, when treating that the not obvious rising of temperature and pH value descend, be incubated 10 minutes, then cool off 10 ℃, transfer pH to 1.25, filter layering, water layer extracts once with ethyl acetate (500kg), water layer reclaims zinc salt, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, with the washing of 100kg saturated brine once, add activated carbon decolorizing after minute clean, filtration after decolouring is finished, then filter is distilled liquid material to still pot and crystallisate is put to the whizzer rejection filter when substantially dried, with the approximately ethyl ester acetic acid drip washing of 50kg, dry rear discharging after drying.And vacuum tightness≤-0.085Mpa, bath temperature in 28-35 ℃ bipyramid dry 3 hours, oven dry.Yield 92%.
The total recovery of product is 77%.
Embodiment 2
1, in the 1500L reactor, add the 1000kg ethyl acetate, then stir and be chilled to 0 ℃, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid is got 43.2kg+ water 200kg), the control temperature is no more than 5 ℃, be chilled to 4 ℃, divide to add the 57.6kg Sodium Nitrite for several times, the control temperature is no more than 5 ℃, is incubated 30 minutes, then slowly add 6-APA 90kg in 8 ℃ of gradation, add in 10 ℃ of reactions 40 minutes again, drip 10% aqueous solution of sodium bisulfite to the bromine decoloration at 10 ℃ after insulation finishes, it is light yellow that reaction solution is, treat to stop to stir without yellow gas effusion, standing demix, lower aqueous layer reclaims bromine with ethyl acetate extraction secondary (400kg * 2), the water layer after the extraction, combined ethyl acetate layer to neutralization pot stirs cooling, transferring pH with caustic lye of soda is 7, static layering, ethyl acetate twice of water extraction (200kg * 2), water layer is that lower batch of ethyl acetate is applied mechanically in (I) suction oxidation pot.Yield 92%.
2, the bromination water layer (I) of oxidizing reaction pot is chilled to below 10 ℃, drip the potassium permanganate acidic aqueous solution for preparing first, temperature is controlled at 8 ℃, reacted 40 minutes in 8 ℃ again after adding, add the 500kg ethyl acetate and be cooled to 5 ℃, transfer pH to 1.25 with 30% hydrochloric acid, drip 10% aqueous solution of sodium bisulfite in 5 ℃, drop to the potassium permanganate decoloration, and reaction solution is the light yellow terminal point repetition measurement pH that is, is higher than 1.25 such as the pH value, transfers pH to 1.25 with 30% hydrochloric acid again, adding 50kg refined salt stirred 20 minutes, make its saturated (adding as unsaturated), standing demix, water layer twice of ethyl acetate extraction (250kg * 2), water layer reclaims manganese salt, combined ethyl acetate layer (II); Yield 91%.
3, (II) is extracted in the 3000L reduction pot, being cooled to 0 ℃ begins to add damping fluid and adds Raney's nickel, use the nitrogen replacement air, use again hydrogen exchange nitrogen, insulation is below 15 ℃, and logical H-H reaction is not after inhaling hydrogen, be incubated 2 hours, then cool off 10 ℃ with press filtration behind the nitrogen replacement hydrogen, transfer pH to 1.25, filter layering, water layer extracts once with ethyl acetate (500kg), water layer is taken out treating pond and is processed, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, with the washing of 100kg saturated brine once, add activated carbon decolorizing after minute clean, then filtration after decolouring is finished is extracted into still pot and distills liquid material and crystallisate is put to the whizzer rejection filter when substantially dried, with the approximately vinyl acetic monomer drip washing of 50kg, dry rear discharging after drying.And vacuum tightness≤-0.085Mpa, bath temperature in 28-35 ℃ bipyramid dry 3 hours, oven dry.90％。
The total recovery of product is 75%.
Embodiment 3
1, in the 1500L reactor, add the 1000kg ethyl acetate, then stir and be chilled to 0 ℃, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid is got 43.2kg+ water 200kg), the control temperature is no more than 5 ℃, be chilled to 4 ℃, divide to add the 57.6kg Sodium Nitrite for several times, the control temperature is no more than 5 ℃, is incubated 30 minutes, then slowly add 6-APA 90kg in 10 ℃ of gradation, add in 10 ℃ of reactions 0.4 hour again, drip 10% aqueous solution of sodium bisulfite to the bromine decoloration at 14 ℃ after insulation finishes, it is light yellow that reaction solution is, treat to stop to stir without yellow gas effusion, standing demix, lower aqueous layer reclaims bromine with ethyl acetate extraction secondary (400kg * 2), the water layer after the extraction, combined ethyl acetate layer to neutralization pot stirs cooling, transferring pH with caustic lye of soda is 7, static layering, ethyl acetate twice of water extraction (200kg * 2), in bromination water layer (I) the suction oxidation pot, lower batch of ethyl acetate is applied mechanically.Yield 92%.
2, the bromination water layer (I) of oxidizing reaction pot is chilled to below 10 ℃, drip the potassium permanganate acidic aqueous solution for preparing first, temperature is controlled at 10 ℃, reacted 30 minutes in 10 ℃ again after adding, add the 500kg ethyl acetate and be cooled to 5 ℃, transfer pH to 1.25 with 30% hydrochloric acid, drip 10% aqueous solution of sodium bisulfite in 5 ℃, drop to the potassium permanganate decoloration, and reaction solution is the light yellow terminal point repetition measurement pH that is, is higher than 1.25 such as the pH value, transfers pH to 1.25 with 30% hydrochloric acid again, adding 50kg refined salt stirred 20 minutes, make its saturated (adding as unsaturated), standing demix, water layer twice of ethyl acetate extraction (250kg * 2), water vat, combined ethyl acetate layer are processed in the water layer suction.Obtain product (II); Yield 91%.
3, product (II) is extracted in the 3000L reduction pot, is cooled to begin to add ethyl acetate (reclaiming in the above-mentioned steps) and water below 0 ℃.Open the emptying valve, open and stir cooling.Treat that Nei Wenda to 0 ℃ of beginning gradation adds the magnesium powder, and drip simultaneously sulfuric acid and keep pH to be no more than 5, when treating that the not obvious rising of temperature and pH value descend, be incubated 15 minutes, then cool off 10 ℃, transfer pH to 1.25, filter layering, water layer extracts once with ethyl acetate (500kg), and water layer is taken out treating pond and processed, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, with the washing of 100kg saturated brine once, add activated carbon decolorizing, filtration after decolouring is finished after dividing only, then suction filtration distills liquid material when substantially dried to still pot, crystallisate is put to the whizzer rejection filter, with the approximately vinyl acetic monomer drip washing of 50kg, dried rear discharging after drying.And vacuum tightness≤-0.085Mpa, bath temperature in 28-35 ℃ bipyramid dry 3 hours, oven dry.Yield 92%.
The total recovery 77% of product.
The former synthetic method comparison example of sulbactam:
Methylene dichloride 900KG joined in the reactor be chilled to 0 ℃ under stirring, suck bromine 200KG, drip sulfuric acid water (sulfuric acid 43.2KG+200KG), the control temperature is no more than 10 ℃, divide and add Sodium Nitrite 57.6KG for several times, control temperature insulation 20 minutes, at 4-10 ℃, gradation slowly adds 6-APA90KG, adds again in reaction below 10 ℃ 0.5 hour, after finishing, insulation dripping 10% aqueous solution of sodium bisulfite below 14 ℃ to the bromine decoloration, leave standstill and minute get dichloromethane layer, stirring cooling, to transfer crowd pH with caustic lye of soda be 7, static layering, methylene dichloride water extraction twice, combining water layer (I) is in the suction oxidation pot.The methylene dichloride Distillation recovery is applied mechanically.Two step yields 80%;
First bromination water layer (I) is chilled to below 10 ℃, drip potassium permanganate acidic aqueous solution (the potassium permanganate 87.6+ phosphatase 24 8.3+ water 800) temperature for preparing first and be controlled at 5-10 ℃, reacted 30 minutes in 10 ℃ again after adding, add ethyl acetate and be cooled to 5 ℃, transfer pH to 1.25 with 30% hydrochloric acid, drip 10% aqueous solution of sodium bisulfite in 5-10 ℃, drop to the potassium permanganate decoloration, and reaction solution is light yellow, adds refined brine 690KG and makes its saturated (adding as unsaturated), standing demix, water layer twice of ethyl acetate extraction (250kg * 2), water layer reclaims, combined ethyl acetate layer (II), yield 90%;
Ethyl acetate layer (II) is sucked in the hydrogenation pot, be cooled to 5 ℃, add damping fluid and palladium charcoal 10KG, logical nitrogen replacement leads to hydrogen again, and temperature is being inhaled hydrogen below 15 ℃ in keeping.Filtration after finishing is with 30% hcl acidifying layering, extraction, to decolour, be distilled to liquid material substantially dried, and crystallisate is put to the whizzer rejection filter, dries vinyl acetic monomer drip washing, discharging after drying, drying.Yield is 90%.
The total recovery 65% of product.
Claims (10)
1. the synthetic method of a sulbactam may further comprise the steps: (1) diazotization and bromination reaction: 6-amino-penicillanic acid carries out insulation reaction in the situation that diazo reagent and bromine or bromide exist at strong acid in organic solvent; After unnecessary bromine reduction, to water layer, obtain the water layer reaction product with mineral alkali abstraction reaction product; (2) oxidizing reaction: in the water layer reaction product, carry out insulation reaction after dripping the oxygenant that is formed by potassium permanganate, acid and water; Adjust pH was to strongly-acid after reaction finished; Reduce unnecessary potassium permanganate, use again the organic solvent extraction reaction product to organic solvent layer, obtain the organic solvent layer product; (3) hydrogenation: the organic solvent layer product is added catalyzer carry out hydrogenation except bromine; Reactant is extracted into organic solvent layer, decolouring, distillation, crystallization, and get final product; It is characterized in that: described organic solvent is ethyl acetate.
2. according to synthetic method claimed in claim 1, it is characterized in that: the catalyzer described in the step (3) is Raney's nickel, magnesium powder or zinc powder.
3. according to synthetic method claimed in claim 1, it is characterized in that: the diazo reagent described in the step (1) is Sodium Nitrite; Described mineral alkali is the carbonate of sodium hydroxide or metal; Wherein, the carbonate of described metal includes but not limited to salt of wormwood, Quilonum Retard, yellow soda ash or calcium carbonate.
4. according to synthetic method claimed in claim 1, it is characterized in that: the temperature of the insulation reaction described in step (1) or the step (2) is 4-15 ℃, and the insulation reaction time is 20-40 minute.
5. according to synthetic method claimed in claim 1, it is characterized in that: the mol ratio of 6-amino-penicillanic acid and Sodium Nitrite is 1 in the step (1): 1-3; The mol ratio of 6-amino-penicillanic acid and sulfuric acid is 1: 2-3; The mol ratio of 6-amino-penicillanic acid and bromine is 1: 1-3; The mol ratio of 6-amino-penicillanic acid and mineral alkali is 1: 1-13.
6. according to synthetic method claimed in claim 1, it is characterized in that: the mol ratio of 6-amino-penicillanic acid and potassium permanganate is 1 in the step (2): 1-2.
7. according to synthetic method claimed in claim 1, it is characterized in that: add water after the cooling of organic solvent layer product in the step (3), add again catalyzer and carry out hydrogenation except bromine.
8. according to synthetic method claimed in claim 6, it is characterized in that: add catalyzer when the compound system of organic solvent layer product, organic solvent and water is cooled to 0-15 ℃ in the step (3), the pH value of controlling simultaneously reaction system is no more than 7 again.
9. according to synthetic method claimed in claim 1, it is characterized in that: the described highly acid pH value in step (2) or (3) is 1-1.25.
10. it is characterized in that in accordance with the method for claim 1: the described reductive agent in the step (2) is sodium bisulfite, S-WAT or hydrogen peroxide.
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| 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 |
| CN110393719A (en) * | 2018-08-28 | 2019-11-01 | 广东金城金素制药有限公司 | The new indication of cefoperazone sodium sulbactam sodium pharmaceutical preparation treatment infectious endocarditis |
| 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 |
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| 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 |
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