CN102952147B - Synthesizing method of sulbactam acid - Google Patents
Synthesizing method of sulbactam acid Download PDFInfo
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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, particularly relate to a kind of synthetic method of sulbactam, belong to the synthesis field of sulbactam.
Background technology
The chemical name of sulbactam: 4-sulphur-1-mixes dicyclo [β, 2,0] heptane-2-carboxylic acid-dimethyl-7-oxygen-4.4-dioxide; Its structural formula is as follows:
The physico-chemical property of sulbactam: this product is off-white color or light yellow crystalline powder, soluble in water, alcohol, ester are insoluble in ether; The purposes of medicine: sulbactam is that head is satisfied the first-selected enzyme inhibitors of class antibacterials and penicillins antibacterials.Belong to atypia Beta-lactam medicine, because head the long-term a large amount of of class and penicillin medicine that satisfy use, create β-lactamase and create antibiotic resistance, and Sulbactam and head satisfy class and penicillin medicine compatibility use after by suppressing β-lactamase to produce, solve a difficult problem for 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 DEG C under being stirred by methylene dichloride, suck bromine, drip sulfuric acid water, control temperature is no more than 10 DEG C, mark time control temperature adds Sodium Nitrite, be incubated 20 minutes, gradation slowly adds 6-APA, add again in 10 DEG C of reactions 0.5 hour, below 14 DEG C, 10% aqueous solution of sodium bisulfite is dripped to bromine decoloration after insulation terminates, leave standstill and separate dichloromethane layer, stirring cooling caustic lye of soda adjusts crowd pH to be 7, static layering, methylene dichloride water extraction twice, in water layer (I) i.e. suction oxidation pot.Methylene dichloride Distillation recovery is applied mechanically.Yield 80%; Existing problems: this two-step reaction have employed methylene dichloride, and to be solvent bring solvent recuperation difficulty with lower step oxidation solvent is inconsistent, and dichloromethane layer is destroyed after remaining bromide distillation yield is reduced.
Described oxidizing reaction mainly comprises: first bromination water layer (I) is chilled to less than 10 DEG C, dripping potassium permanganate acidic aqueous solution (potassium permanganate+phosphoric acid+water) temperature first prepared controls at 5-10 DEG C, again in 10 DEG C of reactions 30 minutes after adding, add ethyl acetate and be cooled to 5 DEG C, pH to 1.25 is adjusted with 30% hydrochloric acid, 10% aqueous solution of sodium bisulfite is dripped in 5-10 DEG C, drop to potassium permanganate decoloration, and reaction solution is light yellow, add refined salt, make its saturated (adding as unsaturated), stratification, aqueous layer with ethyl acetate extracts twice (250kg × 2), the process of water layer suction treating pond, merge methacrylate layer (II), two step yields 90%.Main existing problems are: a large amount of phosphoric acid salt using phosphoric acid to produce is comparatively large to the pollution of environment, and sodium-chlor consumption is more, and wastewater treatment is difficult, is not suitable with suitability for industrialized production.
Described hydrogenation mainly comprises: sucked in hydrogenation pot by methacrylate layer (II), adds damping fluid and palladium charcoal leads to nitrogen replacement, more logical hydrogen, and in keeping, temperature inhales hydrogen below 15 DEG C.Filtration after completing, acidifying layering, extraction decolouring, be distilled to when a lot of crystallisate appears in liquid material and put to whizzer rejection filter, dry vinyl acetic monomer drip washing, discharging after drying, drying.Receiving excellent rate is 90%.The problem also existed is: 1. owing to being debromination, and make catalyzer with palladium charcoal very easily poisoning, bring and apply mechanically and reclaim difficulty, cost is higher.2. device security coefficient requirements is high, uses high-pressure hydrogenation still.
Summary of the invention
Technical problem to be solved by this invention overcomes that yield existing for existing sulbactam synthetic method is low, cost is high, the defect of contaminate environment, provides a kind of new sulbactam synthetic method.
Technical problem to be solved by this invention is achieved through the following technical solutions:
A synthetic method for sulbactam, comprises the following steps: (1) diazotization and bromination reaction: 6-amino-penicillanic acid is deposited in case at diazo reagent and bromine or bromide at strong acid, in organic solvent, carry out insulation reaction; After being reduced by unnecessary bromine, with mineral alkali abstraction reaction product to water layer, obtain water layer reaction product; (2) oxidizing reaction: by water layer reaction product, carries out insulation reaction after dripping the oxygenant be made up of potassium permanganate, acid and water; Reaction terminates rear adjust pH to strongly-acid; Reduce unnecessary potassium permanganate, by organic solvent extraction reaction product to organic solvent layer, obtain organic solvent layer product; (3) hydrogenation: organic solvent layer product is added catalyzer and carry out hydrogenation except bromine; Reactant is extracted into organic solvent layer, is distilled to dry, refining, to obtain final product; Wherein, described organic solvent is preferably ethyl acetate;
Catalyzer described in step (3) is preferably Raney's nickel, magnesium powder or zinc powder.
Diazo reagent described in 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, sodium carbonate or calcium carbonate.
The temperature of step (1) or the insulation reaction described in step (2) is preferably 4-15 DEG C, and the insulation reaction time is preferably 20-40 minute.
In step (1), the mol ratio of 6-amino-penicillanic acid and Sodium Nitrite is preferably 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.
In step (2), the mol ratio of 6-amino-penicillanic acid and potassium permanganate is preferably 1: 1-2.
Add water after the cooling of organic solvent layer product in step (3), then add catalyzer and carry out hydrogenation except bromine; Preferred further, add catalyzer again when the compound system of organic solvent layer product, organic solvent and water is cooled to 0-15 DEG C, the pH value simultaneously controlling 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 organic solvent of the present invention to the four-step reaction of the synthetic method of existing sulbactam is optimized, and finds the organic solvent of ethyl acetate as four-step reaction the solvent consumption of whole reaction is greatly reduced and effectively improves the total recovery of product.The synthetic method of sulbactam of the present invention can fully utilize the byproduct (metal-salt etc. after bromine, potassium permanganate oxidation, hydrogenolysis reducing) in reaction, and the inventive method has the advantages such as yield is high, cost is low, cleaner production.
Accompanying drawing explanation
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 embodiments are only exemplary, do not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
Embodiment 1
1, 1000kg ethyl acetate is added in 1500L reactor, then stir and be chilled to 0 DEG C, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid gets 43.2kg+ water 200kg), control temperature is no more than 5 DEG C, be chilled to 4 DEG C, divide and add 57.6kg Sodium Nitrite for several times, control temperature is no more than 5 DEG C, be incubated 20 minutes, then 6-APA 90kg is slowly added in 4 DEG C of gradation, add again in 10 DEG C of reactions 0.5 hour, 10% aqueous solution of sodium bisulfite is dripped to bromine decoloration at 5 DEG C after insulation terminates, reaction solution is light yellow, treat can stop stirring without yellow gas effusion, stratification, lower aqueous layer ethyl acetate extracts secondary (400kg × 2), water layer after extraction reclaims bromine, combined ethyl acetate layer stirs cooling to neutralization pot, pH is adjusted to be 7 with caustic lye of soda, static layering, ethyl acetate washed with water extracts twice (200kg × 2), in water layer i.e. (I) 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 less than 10 DEG C, drip the potassium permanganate acidic aqueous solution first prepared, temperature controls at 5 DEG C, again in 10 DEG C of reactions 30 minutes after adding, add 500kg ethyl acetate and be cooled to 5 DEG C, pH to 1.25 is adjusted with 30% hydrochloric acid, hydrogen peroxide solution is dripped in 5 DEG C, drop to potassium permanganate decoloration, and reaction solution is light yellow for terminal repetition measurement pH, if pH value is higher than 1.25, pH to 1.25 is adjusted again with 30% hydrochloric acid, add 50kg refined salt and stir 20 minutes, make its saturated (adding as unsaturated), stratification, aqueous layer with ethyl acetate extracts twice (250kg × 2), water layer enters and reclaims manganese salt, combined ethyl acetate layer, (II), yield 91%
3, (II) is extracted into 3000L to reduce in pot, is cooled to less than 0 DEG C to start to add ethyl acetate (applying mechanically) and water.Open emptying valve, open and stir cooling.Treat that Nei Wenda to 0 DEG C of beginning gradation adds Zn, and dropping sulfuric acid keeps pH to be no more than 5 simultaneously, until the not obvious rising of temperature and pH value decline time, be incubated 10 minutes, then 10 DEG C are cooled, adjust pH to 1.25, filter layering, aqueous layer with ethyl acetate (500kg) extracts once, water layer reclaims zinc salt, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, wash once with 100kg saturated brine, divide only and add activated carbon decolorizing, to decolour rear filtration, then filter to still pot distill liquid material substantially dry time crystallisate is put to whizzer rejection filter, with the ethyl ester acetic acid drip washing of about 50kg after drying, discharging after drying.And at vacuum tightness≤-0.085Mpa, bath temperature in the bipyramid of 28-35 DEG C dry 3 hours, dries.Yield 92%.
The total recovery of product is 77%.
Embodiment 2
1, 1000kg ethyl acetate is added in 1500L reactor, then stir and be chilled to 0 DEG C, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid gets 43.2kg+ water 200kg), control temperature is no more than 5 DEG C, be chilled to 4 DEG C, divide and add 57.6kg Sodium Nitrite for several times, control temperature is no more than 5 DEG C, be incubated 30 minutes, then 6-APA 90kg is slowly added in 8 DEG C of gradation, add again in 10 DEG C of reactions 40 minutes, 10% aqueous solution of sodium bisulfite is dripped to bromine decoloration at 10 DEG C after insulation terminates, reaction solution is light yellow, treat can stop stirring without yellow gas effusion, stratification, lower aqueous layer ethyl acetate extracts secondary (400kg × 2), water layer after extraction reclaims bromine, combined ethyl acetate layer stirs cooling to neutralization pot, pH is adjusted to be 7 with caustic lye of soda, static layering, ethyl acetate water extraction twice (200kg × 2), in water layer i.e. (I) 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 less than 10 DEG C, drip the potassium permanganate acidic aqueous solution first prepared, temperature controls at 8 DEG C, again in 8 DEG C of reactions 40 minutes after adding, add 500kg ethyl acetate and be cooled to 5 DEG C, pH to 1.25 is adjusted with 30% hydrochloric acid, 10% aqueous solution of sodium bisulfite is dripped in 5 DEG C, drop to potassium permanganate decoloration, and reaction solution is light yellow for terminal repetition measurement pH, if pH value is higher than 1.25, pH to 1.25 is adjusted again with 30% hydrochloric acid, add 50kg refined salt and stir 20 minutes, make its saturated (adding as unsaturated), stratification, aqueous layer with ethyl acetate extracts twice (250kg × 2), water layer reclaims manganese salt, combined ethyl acetate layer (II), yield 91%.
3, (II) being extracted into 3000L reduces in pot, 0 DEG C is cooled to start add damping fluid and add Raney's nickel, use nitrogen replacement air, use hydrogen exchange nitrogen again, insulation is below 15 DEG C, logical H-H reaction, after not inhaling hydrogen, be incubated 2 hours, then cooling 10 DEG C press filtration after nitrogen replacement hydrogen, adjust pH to 1.25, filter layering, aqueous layer with ethyl acetate (500kg) extracts once, water layer takes out treating pond process, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, wash once with 100kg saturated brine, divide only and add activated carbon decolorizing, to decolour rear filtration, then be extracted into still pot distill liquid material substantially dry time crystallisate is put to whizzer rejection filter, with the vinyl acetic monomer drip washing of about 50kg after drying, discharging after drying.And at vacuum tightness≤-0.085Mpa, bath temperature in the bipyramid of 28-35 DEG C dry 3 hours, dries.90％。
The total recovery of product is 75%.
Embodiment 3
1, 1000kg ethyl acetate is added in 1500L reactor, then stir and be chilled to 0 DEG C, suck bromine 150kg, drip aqueous sulfuric acid (sulfuric acid gets 43.2kg+ water 200kg), control temperature is no more than 5 DEG C, be chilled to 4 DEG C, divide and add 57.6kg Sodium Nitrite for several times, control temperature is no more than 5 DEG C, be incubated 30 minutes, then 6-APA 90kg is slowly added in 10 DEG C of gradation, add again in 10 DEG C of reactions 0.4 hour, 10% aqueous solution of sodium bisulfite is dripped to bromine decoloration at 14 DEG C after insulation terminates, reaction solution is light yellow, treat can stop stirring without yellow gas effusion, stratification, lower aqueous layer ethyl acetate extracts secondary (400kg × 2), water layer after extraction reclaims bromine, combined ethyl acetate layer stirs cooling to neutralization pot, pH is adjusted to be 7 with caustic lye of soda, static layering, ethyl acetate water extraction twice (200kg × 2), in bromination water layer (I) 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 less than 10 DEG C, drip the potassium permanganate acidic aqueous solution first prepared, temperature controls at 10 DEG C, again in 10 DEG C of reactions 30 minutes after adding, add 500kg ethyl acetate and be cooled to 5 DEG C, pH to 1.25 is adjusted with 30% hydrochloric acid, 10% aqueous solution of sodium bisulfite is dripped in 5 DEG C, drop to potassium permanganate decoloration, and reaction solution is light yellow for terminal repetition measurement pH, if pH value is higher than 1.25, pH to 1.25 is adjusted again with 30% hydrochloric acid, add 50kg refined salt and stir 20 minutes, make its saturated (adding as unsaturated), stratification, aqueous layer with ethyl acetate extracts twice (250kg × 2), water layer suction process water vat, combined ethyl acetate layer.Obtain product (II); Yield 91%.
3, product (II) is extracted into 3000L to reduce in pot, is cooled to less than 0 DEG C to start to add ethyl acetate (reclaimed in above-mentioned steps) and water.Open emptying valve, open and stir cooling.Treat that Nei Wenda to 0 DEG C of beginning gradation adds magnesium powder, and dropping sulfuric acid keeps pH to be no more than 5 simultaneously, until the not obvious rising of temperature and pH value decline time, be incubated 15 minutes, then 10 DEG C are cooled, adjust pH to 1.25, filter layering, aqueous layer with ethyl acetate (500kg) extracts once, water layer takes out treating pond process, combined ethyl acetate, and a collection of mother liquor to be applied mechanically of suction, wash once with 100kg saturated brine, divide only and add activated carbon decolorizing, to decolour rear filtration, then suction filtration to still pot distill liquid material substantially dry time, crystallisate is put to whizzer rejection filter, with the vinyl acetic monomer drip washing of about 50kg after drying, discharging after drying.And at vacuum tightness≤-0.085Mpa, bath temperature in the bipyramid of 28-35 DEG C dry 3 hours, dries.Yield 92%.
The total recovery 77% of product.
The former synthetic method comparison example of sulbactam:
Methylene dichloride 900KG is joined under stirring in reactor and be chilled to 0 DEG C, suck bromine 200KG, drip sulfuric acid water (sulfuric acid 43.2KG+200KG), control temperature is no more than 10 DEG C, divide and add Sodium Nitrite 57.6KG for several times, control temperature is incubated 20 minutes, at 4-10 DEG C, gradation slowly adds 6-APA90KG, add again in less than 10 DEG C reactions 0.5 hour, below 14 DEG C, 10% aqueous solution of sodium bisulfite is dripped to bromine decoloration after insulation terminates, leave standstill to divide and get dichloromethane layer, stirring cooling caustic lye of soda adjusts crowd pH to be 7, static layering, methylene dichloride water extraction twice, in combining water layer (I) i.e. suction oxidation pot.Methylene dichloride Distillation recovery is applied mechanically.Two step yields 80%;
First bromination water layer (I) is chilled to less than 10 DEG C, dripping potassium permanganate acidic aqueous solution (the potassium permanganate 87.6+ phosphatase 24 8.3+ water 800) temperature first prepared controls at 5-10 DEG C, again in 10 DEG C of reactions 30 minutes after adding, add ethyl acetate and be cooled to 5 DEG C, pH to 1.25 is adjusted with 30% hydrochloric acid, 10% aqueous solution of sodium bisulfite is dripped in 5-10 DEG C, drop to potassium permanganate decoloration, and reaction solution is light yellow, add refined brine 690KG to make its saturated (adding as unsaturated), stratification, aqueous layer with ethyl acetate extracts twice (250kg × 2), water layer reclaims, combined ethyl acetate layer (II), yield 90%,
Ethyl acetate layer (II) is sucked in hydrogenation pot, is cooled to 5 DEG C, add damping fluid and palladium charcoal 10KG, logical nitrogen replacement, more logical hydrogen, in keeping, temperature inhales hydrogen below 15 DEG C.Filtration after completing, with 30% hcl acidifying layering, extraction, decolour, to be distilled to liquid material substantially dry, put by crystallisate to whizzer rejection filter, dries vinyl acetic monomer drip washing, discharging after drying, dry.Yield is 90%.
The total recovery 65% of product.
Claims (4)
1. a synthetic method for sulbactam, comprises the following steps: (1) diazotization and bromination reaction: 6-amino-penicillanic acid is deposited in case at Sodium Nitrite and bromine at strong acid, in organic solvent, carry out insulation reaction, and described strong acid is sulfuric acid; After being reduced by unnecessary bromine, with mineral alkali abstraction reaction product to water layer, obtain water layer reaction product; (2) oxidizing reaction: by water layer reaction product, carries out insulation reaction after dripping the oxygenant be made up of potassium permanganate, acid and water; Reaction terminates rear adjust pH to strongly-acid; Reduce unnecessary potassium permanganate, then use organic solvent extraction reaction product to organic solvent layer, obtain organic solvent layer product; (3) hydrogenation: add water after organic solvent layer product is cooled, add catalyzer and carry out hydrogenation except bromine, add catalyzer again when wherein the compound system of organic solvent layer product, organic solvent and water is cooled to 0-15 DEG C, the pH value simultaneously controlling reaction system is no more than 7; Reactant is extracted into organic solvent layer, and decolouring, distillation, crystallization, to obtain final product; It is characterized in that: described organic solvent is ethyl acetate;
Wherein the temperature of step (1) or the insulation reaction described in step (2) is 4-15 DEG C, and the insulation reaction time is 20-40 minute;
Described highly acid pH value wherein in step (1) or (2) is 1-1.25;
In step (1), the mol ratio of 6-amino-penicillanic acid and Sodium Nitrite is 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;
In step (2), the mol ratio of 6-amino-penicillanic acid and potassium permanganate is 1:1-2.
2. according to synthetic method according to claim 1, it is characterized in that: the catalyzer described in step (3) is Raney's nickel, magnesium powder or zinc powder.
3. according to synthetic method according to claim 1, it is characterized in that: the diazo reagent described in step (1) is Sodium Nitrite; Described mineral alkali is the carbonate of sodium hydroxide or metal; Wherein, the carbonate of described metal comprises salt of wormwood, Quilonum Retard, sodium carbonate or calcium carbonate.
4. in accordance with the method for claim 1, it is characterized in that: the described reductive agent in step (2) is sodium bisulfite, S-WAT or hydrogen peroxide.
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| CN110393719B (en) * | 2018-08-28 | 2021-09-28 | 广东金城金素制药有限公司 | Cefoperazone sodium and sulbactam sodium composition pharmaceutical preparation and new indications for treating infectious endocarditis |
| CN109438475A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The synthetic method of sulbactam |
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| US4234579A (en) * | 1977-06-07 | 1980-11-18 | Pfizer Inc. | Penicillanic acid 1,1-dioxides as β-lactamase inhibitors |
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| CN1263530A (en) * | 1998-04-09 | 2000-08-16 | 大塚化学株式会社 | Process for producing halogenated beta-lactam compound |
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| CZ279076B6 (en) * | 1990-05-04 | 1994-12-15 | Vyzk Ustav Farm Biochem Sp | Process for preparing semi-synthetic antibiotic sulbactam |
| EP1041075B1 (en) * | 1999-03-03 | 2005-02-02 | Astur Pharma S.A. | Procedure for the preparation of dioxopenicillanic acid derivatives |
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| US4234579A (en) * | 1977-06-07 | 1980-11-18 | Pfizer Inc. | Penicillanic acid 1,1-dioxides as β-lactamase inhibitors |
| US4276285A (en) * | 1977-06-07 | 1981-06-30 | Pfizer Inc. | Combinations of penicillanic acid 1,1-dioxide with 7-(D-2-[4-ethylpiperazin-2,3-dione-1-carboxamido]-2-[4-hydroxyphenyl]acetamido)-3-([1-methyl-5-tetrazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid |
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Effective date of registration: 20170703 Address after: 222523 Jiangsu city of Lianyungang province guannaxian heap ditch town (Chemical Industrial Park) Patentee after: LIANYUNGANG HENGFEI PHARMACEUTICAL CO., LTD. Address before: Taizhou City, Zhejiang province 318000 Jiaojiang road outside No. 258 Patentee before: Taizhou Xinyou Pharmaceutical & Chemical Co., Ltd. |