CN104910184A - 6, 6-dibromo penicillanic acid preparation method - Google Patents
6, 6-dibromo penicillanic acid preparation method Download PDFInfo
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- CN104910184A CN104910184A CN201510205910.8A CN201510205910A CN104910184A CN 104910184 A CN104910184 A CN 104910184A CN 201510205910 A CN201510205910 A CN 201510205910A CN 104910184 A CN104910184 A CN 104910184A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/865—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 with hetero atoms or with carbon atoms 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 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses a 6, 6-dibromo penicillanic acid preparation method which is as follows: at the temperature of-20 to 0 DEG C, sodium nitrite is slowly added into a hydrobromic acid solution dissolved with bromide to produce and separate a black active solution containing nitrosyl bromide, bromide and sodium bromide; then the solution is dripped into a 6-APA hydrobromic acid solution of the temperature of-25 to 5 DEG C; after the completion of reaction, reaction liquid is filtered, and the product 6, 6-dibromo penicillanic acid is obtained by washing and vacuum drying of the filter cake. The method completely does not use an organic solvent, is simple in post-processing, improves the utilization rate of the bromide and the hydrobromic acid, ensures the safety of production and reduces the cost, and the product yield of 96.5% or higher.
Description
Technical field
The present invention relates to the method that the two bromo of a kind of 6-APA prepares 6,6-dibromo penicillanic acid, belong to medical art.
Background technology
6,6-dibromo penicillanic acid is the key intermediate in beta-lactamase inhibitor Sulbactam and Tazobactam Sodium building-up process, and it is that starting raw material obtains through two bromo-reaction preparation with 6-APA.Two bromo methods that the Ji Site Buro Cadiz of Holland described in the patent CN85101193A of China's application in 1985 are: to 6-beta-amino penicillanic acid 1, add the dichloromethane solution being dissolved with bromine, Hydrogen bromide and methyl alcohol in the suspension of 1-dioxide and methylene dichloride, then add Sodium Nitrite in batches; React complete, reduce excess bromine with sodium sulfite solution, with trichloromethane, reaction mixture is extracted, then obtain two bromination product 6,6-dibromo penicillanic acid after washing, dry and steaming desolventize.The two bromo methods described in Chinese patent CN102532164A are: in ethyl acetate and Hydrogen bromide, add bromine and Sodium Nitrite, add 6-APA more in batches, react complete, excess bromine is reduced with sodium sulfite solution, desolventize through extraction, washing and steaming again and obtain two bromination product 6,6-dibromo penicillanic acid.
There is following shortcoming in above method: (1) uses inflammable and explosive organic solvent, and neither safety cost is high again; (2) excessive bromine bisulfite sodium reduction, causes the waste of raw material and produces large amount of sewage; (3) in the larger bromine reaction system of toxicity, add solid material in batches, be unfavorable for production operation.
Summary of the invention
Instant invention overcomes above-mentioned the deficiencies in the prior art, provide a kind of preparation method of 6,6-dibromo penicillanic acid.Completely not with an organic solvent, aftertreatment is simple, and improves bromine, hydrobromic utilization ratio, ensure that the security of production and reduces cost for the method.
Two bromo-reaction equations of 6-APA (6-amino-penicillanic acid) are as follows:
Equation is answered: two bromo-reactions of 6-APA are diazotization-halogenating reaction as can be seen from above-mentioned side.The present inventor, by the combination of theory and practice, draws following viewpoint:
(1) product 6,6-dibromo penicillanic acid solubleness in water is minimum, and is solid under normal temperature, and from water, crystallization is feasible;
(2) provide in hydrionic environment at Hydrogen bromide, nitrosyl bromide is the active particle of main diazotization; Find from practice, Sodium Nitrite and Hydrogen bromide and bromine react, and can generate a kind of black living solution containing nitrosyl bromide, bromine and Sodium Bromide, and and water stratification;
(3) above-mentioned living solution density ratio water is many greatly, our inference its contain Sodium Bromide, we also infer: itself and the reason of water stratification are that in living solution, bromine is combined with bromide anion and dissolves nitrosyl bromide, the polarity of bromine and nitrosyl bromide is very little, makes the polarity of the solution of this moisture content less not reach the degree of dissolving each other with water.
(4) bromine can be combined with bromide anion and water-soluble, does not need to add organic solvent again to dissolve bromine;
(5) a small amount of impurity soluble in water can take in product by organic solvent, affects product quality.
In conjunction with production practice in above-mentioned theoretical basis, obtain technical scheme of the present invention as follows: a kind of 6, the preparation method of 6-dibromo penicillanic acid, it is characterized in that, at-20 DEG C ~ 0 DEG C, in the hydrobromic acid solution being dissolved with bromine, slowly add Sodium Nitrite, generate and isolate the black living solution containing nitrosyl bromide, bromine and Sodium Bromide; Then by the hydrobromic acid solution of the 6-APA of this solution instillation-25 DEG C ~ 5 DEG C; After having reacted, reacting liquid filtering, filter cake obtains product 6,6-dibromo penicillanic acid after washing, vacuum-drying.
Specifically comprise the following steps:
(1) in reaction vessel, add the Hydrogen bromide of concentration 35%, be cooled to-10 DEG C ~-5 DEG C, add bromine, make bromine be dissolved in hydrobromic acid solution; Control-15 DEG C ~-5 DEG C and slowly add Sodium Nitrite, control-10 DEG C ~-5 DEG C and stir 8-15 minute, leave standstill, layering; Lower floor is solution A (the black living solution containing nitrosyl bromide, bromine and Sodium Bromide), be cooled to-15 DEG C ~-10 DEG C stand-by;
(2) in reaction vessel, adding Hydrogen bromide and the purified water of concentration 35%, be down to-15 DEG C ~-10 DEG C, add 6-APA, stirring and dissolving, is B solution, control-15 DEG C ~-10 DEG C stand-by;
(3) control-15 DEG C ~-5 DEG C, solution A is instilled in B solution; Dropwise, control-10 DEG C ~-5 DEG C and stir 15-30 minute; Filter, filter cake is product 6,6-dibromo penicillanic acid, and mother liquor is C solution, control-10 DEG C ~-5 DEG C stand-by;
(4) with 20% aqueous solution of sodium bisulfite washing leaching cake, filter cake vacuum-drying is obtained product 6,6-dibromo penicillanic acid.
Preferably, in described step (1), the Hydrogen bromide of 35%, the mass ratio of bromine and Sodium Nitrite are 14-16:4.5-5.5:1, are preferably 15:5:1.
Preferably, in described step (2), the Hydrogen bromide of 35% and the mass ratio of 6-APA are 1-2:1; The Hydrogen bromide of described concentration 35% and the mass ratio of purified water are 1:2-5.
Preferably, the mass ratio of the Sodium Nitrite of described step (1) and the 6-APA of step (2) is 1:2-2.3.
Preferably, the vacuum-drying condition of described step (4) is: filter cake is laid in vacuum tightness≤-0.08MPa and 35 DEG C ~ 40 DEG C dry 1.5-4 hour.
Further, the upper strata of described step (1) add the vitriol oil enter distillation tower reclaim Hydrogen bromide.
Further, the C solution of described step (3), first detect the content of hydrogen ion, bromide anion and bromine, add bromine and Hydrogen bromide, continue the black living solution (i.e. solution A) of method preparation containing nitrosyl bromide, bromine and Sodium Bromide by step (1), to improve bromine and the hydrobromic rate of recovery.
By above-mentioned two aspect measures, ensure that bromine, hydrogen bromide etc. are reclaimed completely, saved resource.
The invention has the beneficial effects as follows:
(1) in the whole production process of the present invention completely not with an organic solvent, not only reduce cost, also avoid dissolvent residual affects product quality, also assures that the safety of production process, environmental protection simultaneously;
(2) first the present invention prepares the black living solution containing nitrosyl bromide, bromine and Sodium Bromide, and the hydrobromic acid solution then this solution being added drop-wise to 6-APA reacts, and not only accelerates speed of response, also makes reaction more complete; Yield >=96.5% of product;
(3), after having reacted, reaction solution is based on Hydrogen bromide, bromine, and product is with Precipitation; Bromine is dissolved in hydrobromic acid solution, and the bromine of trace is mingled with in the product, and removed by 20% aqueous solution of sodium bisulfite washing, aftertreatment is simple, is more suitable for suitability for industrialized production;
(4) by twice recovery measure, bromine, hydrogen bromide etc. are reclaimed completely, saved resource.
Embodiment
Embodiment:
(1) in 500ml there-necked flask, add the Hydrogen bromide 150.0g of concentration 35%, be cooled to-10 DEG C ~-5 DEG C, add bromine 50.0g; Control-15 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, control-10 DEG C ~-5 DEG C and stir 10 minutes, leave standstill 10 minutes, layering; Upper strata add the 10g vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by;
(2) in 500ml there-necked flask, add the Hydrogen bromide 31.8g of concentration 35%, purified water 100g, is down to-15 DEG C ~-10 DEG C, adds 6-APA21.6g, stirring and dissolving, is B solution, controls 15 DEG C ~-10 DEG C;
(3) controlling-15 DEG C ~-5 DEG C instills in B solution by solution A; Dropwise, control-10 DEG C ~-5 DEG C and stir 20 minutes.Filter, mother liquor is C solution, control-10 DEG C ~-5 DEG C stand-by; With 20% aqueous solution of sodium bisulfite 30g washing leaching cake; Filter cake is laid in vacuum tightness≤-0.08MPa and 35 DEG C ~-40 DEG C dryings and obtains 6,6-dibromo penicillanic acid 34.8g in 2 hours, the purity of product is 99.85%, yield 96.9%;
(4) control-10 DEG C ~-5 DEG C Hydrogen bromide 100.0g adding concentration 35% in C solution and bromine 35.0g to control-10 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, controls-10 DEG C ~-5 DEG C and stir 10 minutes, standing 10 minutes, layering; Upper strata add the appropriate vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by.
Embodiment 2:
(1) in 500ml there-necked flask, add the Hydrogen bromide 145.0g of concentration 35%, be cooled to-10 DEG C ~-5 DEG C, add bromine 49.0g; Control-15 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, control-10 DEG C ~-5 DEG C and stir 12 minutes, leave standstill 10 minutes, layering; Upper strata add the 10g vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by;
(2) in 500ml there-necked flask, add the Hydrogen bromide 33.0g of concentration 35%, purified water 110g, is down to-15 DEG C ~-10 DEG C, adds 6-APA21.6g, stirring and dissolving, is B solution, controls 15 DEG C ~-10 DEG C;
(3) controlling-15 DEG C ~-5 DEG C instills in B solution by solution A; Dropwise, control-10 DEG C ~-5 DEG C and stir 22 minutes; Filter, mother liquor is C solution, control-10 DEG C ~-5 DEG C stand-by; With 20% aqueous solution of sodium bisulfite 30g washing leaching cake; Filter cake is laid in vacuum tightness≤-0.08MPa and 35 DEG C ~-40 DEG C dryings and obtains 6,6-dibromo penicillanic acid 34.7g in 2.5 hours, the purity of product is 99.83%, yield 96.7%;
(4) control-10 DEG C ~-5 DEG C Hydrogen bromide 105.0g adding concentration 35% in C solution and bromine 36.0g to control-10 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, controls-10 DEG C ~-5 DEG C and stir 10 minutes, standing 10 minutes, layering; Upper strata add the appropriate vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by.
Embodiment 3:
(1) in 500ml there-necked flask, add the Hydrogen bromide 152.0g of concentration 35%, be cooled to-10 DEG C ~-5 DEG C, add bromine 51.0g; Control-15 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, control-10 DEG C ~-5 DEG C and stir 12 minutes, leave standstill 8 minutes, layering; Upper strata add the 10g vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by;
(2) in 500ml there-necked flask, add the Hydrogen bromide 30.0g of concentration 35%, purified water 90g, is down to-15 DEG C ~-10 DEG C, adds 6-APA21.6g, stirring and dissolving, is B solution, controls 15 DEG C ~-10 DEG C;
(3) controlling-15 DEG C ~-5 DEG C instills in B solution by solution A; Dropwise, control-10 DEG C ~-5 DEG C and stir 22 minutes; Filter, mother liquor is C solution, control-10 DEG C ~-5 DEG C stand-by; With 20% aqueous solution of sodium bisulfite 30g washing leaching cake; Filter cake is laid in vacuum tightness≤-0.08MPa and 35 DEG C ~-40 DEG C dryings and obtains 6,6-dibromo penicillanic acid 35.0g in 2.5 hours, the purity of product is 99.83%, yield 97.4%;
(4) control-10 DEG C ~-5 DEG C Hydrogen bromide 98.0g adding concentration 35% in C solution and bromine 35.0g to control-10 DEG C ~-5 DEG C and slowly add Sodium Nitrite 10.0g, controls-10 DEG C ~-5 DEG C and stir 10 minutes, standing 10 minutes, layering; Upper strata add the appropriate vitriol oil enter distillation tower reclaim Hydrogen bromide, lower floor is solution A, be down to-15 DEG C ~-10 DEG C stand-by.
Claims (7)
1. the preparation method of a dibromo penicillanic acid, is characterized in that, at-20 DEG C ~ 0 DEG C, slowly adds Sodium Nitrite, generate and isolate the black living solution containing nitrosyl bromide, bromine and Sodium Bromide in the hydrobromic acid solution being dissolved with bromine; Then by the hydrobromic acid solution of the 6-APA of this solution instillation-25 DEG C ~ 5 DEG C; After having reacted, reacting liquid filtering, filter cake obtains product 6,6-dibromo penicillanic acid after washing, vacuum-drying.
2. the preparation method of a kind of 6,6-dibromo penicillanic acid as claimed in claim 1, is characterized in that,
(1) in reaction vessel, add the Hydrogen bromide of concentration 35%, be cooled to-10 DEG C ~-5 DEG C, add bromine, make bromine be dissolved in hydrobromic acid solution; Control-15 DEG C ~-5 DEG C and slowly add Sodium Nitrite, control-10 DEG C ~-5 DEG C and stir 8-15 minute, leave standstill, layering; Lower floor is solution A, be cooled to-15 DEG C ~-10 DEG C stand-by; The mass ratio of the Hydrogen bromide of described 35%, bromine and Sodium Nitrite is 14-16:4.5-5.5:1;
(2) in reaction vessel, adding Hydrogen bromide and the purified water of concentration 35%, be down to-15 DEG C ~-10 DEG C, add 6-amino-penicillanic acid, stirring and dissolving, is B solution, control-15 DEG C ~-10 DEG C stand-by; The Hydrogen bromide of described 35% and the mass ratio of 6-amino-penicillanic acid are 1-2:1; The mass ratio of the Sodium Nitrite of described step (1) and the 6-amino-penicillanic acid of step (2) is 1:2-2.3;
(3) control-15 DEG C ~-5 DEG C, solution A is instilled in B solution; Dropwise, control-10 DEG C ~-5 DEG C and stir 15-30 minute; Filter, filter cake is product 6,6-dibromo penicillanic acid, and mother liquor is C solution, control-10 DEG C ~-5 DEG C stand-by;
(4) use aqueous solution of sodium bisulfite washing leaching cake, filter cake vacuum-drying is obtained product 6,6-dibromo penicillanic acid.
3. one 6 as claimed in claim 2, the preparation method of 6-dibromo penicillanic acid, it is characterized in that, the processing mode of the C solution of described step (3) is, first detect the content of hydrogen ion, bromide anion and bromine, add bromine and Hydrogen bromide, continue to prepare solution A by the method for step (1).
4. the preparation method of a kind of 6,6-dibromo penicillanic acid as claimed in claim 2, is characterized in that, the upper strata of described step (1) adds the vitriol oil and enters distillation tower recovery Hydrogen bromide.
5. as the preparation method of one 6, the 6-dibromo penicillanic acid in claim 2-4 as described in any one, it is characterized in that, in described step (1), the Hydrogen bromide of 35%, the mass ratio of bromine and Sodium Nitrite are 15:5:1.
6. as the preparation method of one 6, the 6-dibromo penicillanic acid in claim 2-4 as described in any one, it is characterized in that, in described step (2), the Hydrogen bromide of concentration 35% and the mass ratio of purified water are 1:2-5.
7. as the one 6 in claim 2-4 as described in any one, the preparation method of 6-dibromo penicillanic acid, it is characterized in that, the vacuum-drying of described step (4) is specially: filter cake is laid in vacuum tightness≤-0.08MPa and 35 DEG C ~ 40 DEG C dry 1.5-4 hour.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111943963A (en) * | 2020-08-19 | 2020-11-17 | 杭州瑞思新材料有限公司 | Production device and method of 6-bromopenicillanic acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0129360A1 (en) * | 1983-06-06 | 1984-12-27 | Pfizer Inc. | Process for debromination of dibromopenicillanic acid and derivatives |
| EP0093465B1 (en) * | 1982-04-19 | 1987-05-06 | Gist-Brocades N.V. | Preparation of 6-alpha-bromo- and/or 6,6-dibromo-penicillanic acid 1,1-dioxides |
| CN102020663A (en) * | 2010-11-24 | 2011-04-20 | 山东鑫泉医药中间体有限公司 | Tazobactam synthesis method |
| CN102532164A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method for sulbactam |
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2015
- 2015-04-27 CN CN201510205910.8A patent/CN104910184B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0093465B1 (en) * | 1982-04-19 | 1987-05-06 | Gist-Brocades N.V. | Preparation of 6-alpha-bromo- and/or 6,6-dibromo-penicillanic acid 1,1-dioxides |
| EP0129360A1 (en) * | 1983-06-06 | 1984-12-27 | Pfizer Inc. | Process for debromination of dibromopenicillanic acid and derivatives |
| CN102020663A (en) * | 2010-11-24 | 2011-04-20 | 山东鑫泉医药中间体有限公司 | Tazobactam synthesis method |
| CN102532164A (en) * | 2011-12-27 | 2012-07-04 | 山东鑫泉医药有限公司 | Synthesis method for sulbactam |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111943963A (en) * | 2020-08-19 | 2020-11-17 | 杭州瑞思新材料有限公司 | Production device and method of 6-bromopenicillanic acid |
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Effective date of registration: 20200304 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: Shandong Anxin Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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