CN103848850B - A kind of preparation method of Sulbactam - Google Patents
A kind of preparation method of Sulbactam Download PDFInfo
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- CN103848850B CN103848850B CN201310383063.5A CN201310383063A CN103848850B CN 103848850 B CN103848850 B CN 103848850B CN 201310383063 A CN201310383063 A CN 201310383063A CN 103848850 B CN103848850 B CN 103848850B
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- sulbactam
- ethyl acetate
- dibromo
- tri
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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
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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
Abstract
The present invention discloses a kind of preparation method of Sulbactam; be characterized in utilizing tri-butyl tin hydride, as reductive agent, Sulbactam is prepared in the reduction of dibromo Sulbactam; specifically in dibromo Sulbactam ethyl acetate solution, add tri-butyl tin hydride; stoichiometric number hour; then reaction mixture is poured into water; make to be extracted with ethyl acetate, merge organic layer, then use saturated common salt water washing; Above-mentioned organic over anhydrous dried over mgso, after elimination magnesium sulfate; Add gac again, stir decolorization filtering, filter residue ethyl acetate is washed; Then mother liquor is placed in rotatory evaporator, water-bath vacuum-evaporation, crystallization to be had, stops evaporation, cooling, suction filtration, vacuum-drying, obtains Sulbactam white crystals.Reaction conditions of the present invention is gentle, and do not relate to inflammable and explosive and high malicious reagent, yield is higher than the preparation method of document, is a kind of economical and practical synthetic method, is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation of pharmaceutical chemicals, particularly relate to a kind of preparation method of new Sulbactam, belong to medicine and technical field of chemical synthesis.
Background technology
Sulbactam (sulbactam), also known as sulbactam, chemistry is by name: (2R, 5R)-3,3-dimethyl-4,4,7-trioxy--4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, molecular formula: C
6h
11nO
5s, molecular weight: 233.24.
Sulbactam is the sodium salt of Sulbactam, is a kind of white or off-white color crystalline powder; Micro-have special smell, mildly bitter flavor; Easily molten in water, slightly soluble in methyl alcohol, almost insoluble in ethanol, acetone or ethyl acetate.
Sulbactam is irreversible competitive beta-lactamase inhibitor, all has restraining effect to the β-lactamase that gram-positive and negative bacterium (except Pseudomonas aeruginosa) produce.Independent application is infected effectively to gonococcus and meningococcal surrounding; Sulbactam is combined with penicillins and cephalosporins, just obvious synergy can be produced at low concentration, be used for the treatment of the urinary tract infections caused by sensitive organism, pulmonary infection, bronchial infection, Respiratory infections, abdominal cavity and pelvic infection, biliary tract infection, septicemia, skin soft-tissue infection etc.
Sulbactam is raw material usually with 6-APA, in acid condition, take bromine as bromizating agent, carries out two bromo reaction, then through potassium permanganate oxidation, restore agent reduction-debromination, obtain through three-step reaction.
Existing is that the three-step reaction that main raw material prepares in the three-step reaction process of Sulbactam---dibromo Sulbactam reduction-debromination is prepared in the synthetic technology method of Sulbactam with 6-APA, exists following not enough:
(1) prior art mainly adopts zinc powder or magnesium powder to be that reductive agent carries out debrominate (US4554104, EP92286), require that zinc powder or magnesium powder have higher purity in process of production, simultaneously, still need and carry out pickling purifying to the surface of zinc powder or magnesium powder, to ensure the quality of product, prior art adds complex process degree, reaction process poor stability, product yield is low.In addition the zinc inevitably containing trace in product or magnesium elements, product, when carrying out purity test, is difficult to reach the People's Republic of China (PRC) 2010 pharmacopoeial requirements.
(2) bibliographical information dibromo Sulbactam reduction-debromination prepares Sulbactam second method is adopt Raney Ni to be that catalyzer carries out catalytic hydrogen reduction debrominate (Chinese patent 201110375146.0).The shortcoming of the method is that the activity of catalytic hydrogenation Raney Ni is low, needs just can carry out up to more than 7Mpa in reaction pressure.High to equipment requirements, complex technical process, investment is large, virtually adds cost.
(3) bibliographical information dibromo Sulbactam reduction-debromination prepares Sulbactam another kind method is adopt palladium carbon to be that catalyzer carries out catalytic hydrogen reduction debrominate (Chinese patent 200510102131.1).The shortcoming of the method is that the activity of catalytic hydrogenation palladium carbon is low, and high to equipment requirements, complex technical process, cost is high.
Summary of the invention
Object of the present invention is just the problems referred to above solving prior art existence, provides a kind of preparation method of simple and direct safe Sulbactam.The present invention utilizes tri-butyl tin hydride, as reductive agent, Sulbactam is prepared in the reduction of dibromo Sulbactam, reagent safety used by the method, to be easy to get, there is reaction conditions gentleness, do not relate to inflammable and explosive and high malicious reagent, yield is higher than existing preparation method and cost is low feature, be a kind of economical and practical synthetic method, be suitable for large-scale industrial production.
The preparation method of this Sulbactam provided by the invention, is characterized in that concrete reaction is as follows:
Dibromo Sulbactam Sulbactam
Namely obtain Sulbactam at dibromo Sulbactam reduction-debromination under tri-butyl tin hydride exists, its detailed process is:
Tri-butyl tin hydride is added in dibromo Sulbactam ethyl acetate solution;
React 1 ~ 4 hour under 10 DEG C – ethyl acetate backflow conditions;
Then reaction mixture is poured into water, makes to be extracted with ethyl acetate, merge organic layer, then use saturated common salt water washing;
Above-mentioned organic over anhydrous dried over mgso, after elimination magnesium sulfate;
Add gac again, stir decolorization filtering, filter residue ethyl acetate is washed;
Then mother liquor is placed in rotatory evaporator, water-bath vacuum-evaporation, crystallization to be had, stops evaporation, cooling, suction filtration, vacuum-drying, obtains Sulbactam white crystals.
In above technical scheme, reductive agent used is tri-butyl tin hydride.Reaction solvent used is ethyl acetate.
Dibromo Sulbactam is 1:1 ~ 5 with the ratio of the amount of the reactive material of tri-butyl tin hydride.Preferred temperature of reaction controls in 10 DEG C ~ ethyl acetate backflow temperature; Reaction times controlled at 2 ~ 3 hours.
Compared with prior art, the invention has the beneficial effects as follows: the present invention utilizes tri-butyl tin hydride, as reductive agent, Sulbactam is prepared in the reduction of dibromo Sulbactam, reagent safety used by the method, to be easy to get, there is reaction conditions gentleness, do not relate to inflammable and explosive and high malicious reagent, yield is higher than existing preparation method and cost is low feature, be a kind of economical and practical synthetic method, be suitable for large-scale industrial production.
Embodiment
Embodiment
Under nitrogen protection; in 1000mL three-necked bottle; by 39.1g(0.1mol) 6,6-dibromo Sulbactam 200mL acetic acid ethyl dissolutions, add tri-butyl tin hydride (58g under at room temperature stirring; 0.2mol); after reaction 2h, reaction mixture is poured into water, makes to be extracted with ethyl acetate (150mL × 3); merge organic layer, then use saturated aqueous common salt (100mL × 2) to wash.Above-mentioned organic over anhydrous dried over mgso, after elimination magnesium sulfate; Add gac again, stir decolouring 1h at 5 ~ 10 DEG C, filter, filter residue ethyl acetate is washed.Then mother liquor is placed in rotatory evaporator, water-bath vacuum-evaporation, crystallization to be had, stop evaporation, be chilled to less than 10 DEG C, suction filtration, vacuum-drying, obtain 20.2g white crystals Sulbactam, reaction yield is 86.6%.Purity is 92.1%(HPLC), mp150-152 DEG C (dec); [α]
20 d+ 250 ° (c=0.01, methyl alcohol); IR (KBr) ν: 3454,3017,2988,2977,2952,1782,1607,1464,1398,1301,1256,1232,1197,1124,1099,1013,899,750,719cm-';
1hNMR (300MHz, DMSO-d
6): δ 1.37 (3H, s, CH
3), 1.47 (3H, 8, CH
3), 3.23 (1H, dd, J=1.7,16.4Hz, 6 β-H), 3.64 (1H, dd, J=4.4,16.4Hz, 6 α-H), 4.26 (1H, S, 3-H), 5.13 (1H, dd, J=1.7,4.4Hz, 5-H).
Similarly, will change reactant molar ratio, temperature of reaction, reaction times, and obtain the embodiment of Sulbactam, result is converged and is listed in table 1.
The preparation of table 1. Sulbactam
Claims (2)
1. a preparation method for Sulbactam, is characterized in that concrete reaction is as follows:
Namely dibromo Sulbactam reduction-debromination under tri-butyl tin hydride exists obtains Sulbactam, and its detailed process is:
In dibromo Sulbactam ethyl acetate solution, add tri-butyl tin hydride, dibromo Sulbactam is 1:1 ~ 5 with the ratio of the amount of the reactive material of tri-butyl tin hydride;
React 1 ~ 4 hour under 10 DEG C – ethyl acetate backflow conditions;
Then reaction mixture is poured into water, makes to be extracted with ethyl acetate, merge organic layer, then use saturated common salt water washing;
Above-mentioned organic over anhydrous dried over mgso, after elimination magnesium sulfate;
Add gac again, stir decolorization filtering, filter residue ethyl acetate is washed;
Then mother liquor is placed in rotatory evaporator, water-bath vacuum-evaporation, crystallization to be had, stops evaporation, cooling, suction filtration, vacuum-drying, obtains Sulbactam white crystals.
2. the preparation method of Sulbactam according to claim 1, is characterized in that, temperature of reaction controls in 10 DEG C ~ ethyl acetate backflow temperature, and the reaction times controlled at 2 ~ 3 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4588527A (en) * | 1983-06-06 | 1986-05-13 | Pfizer Inc. | Process for preparing penicillanic acid 1,1-dioxide derivatives |
| US4714761A (en) * | 1979-03-05 | 1987-12-22 | Pfizer Inc. | 6,6-dihalopenicillanic acid 1,1-dioxides and process |
| US4866077A (en) * | 1987-06-24 | 1989-09-12 | H. Lundbeck A/S | 1,2,3-Triazole and tetrazole substituted piperidine or tetrahydropyridine compounds useful as acetylcholine agonists |
-
2013
- 2013-08-28 CN CN201310383063.5A patent/CN103848850B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4714761A (en) * | 1979-03-05 | 1987-12-22 | Pfizer Inc. | 6,6-dihalopenicillanic acid 1,1-dioxides and process |
| US4588527A (en) * | 1983-06-06 | 1986-05-13 | Pfizer Inc. | Process for preparing penicillanic acid 1,1-dioxide derivatives |
| US4866077A (en) * | 1987-06-24 | 1989-09-12 | H. Lundbeck A/S | 1,2,3-Triazole and tetrazole substituted piperidine or tetrahydropyridine compounds useful as acetylcholine agonists |
Non-Patent Citations (3)
| Title |
|---|
| 6,6-二溴青霉烷砜酸三种脱溴方法的初步比较;陆导仁等;《医药工业》;19871231;第18卷(第7期);第325-326页 * |
| Stereoselective Reduction of (Pivaloyloxy)methyl Mixed 6,6-Dihalogenopenicillanates and their (1 R)-Sulphoxides and Sulphones by Tributyltin Hydride;Diego U. Belinzoni，et al.;《Journal of chemical research,synopses》;19881231;第178页 * |
| STEREOSELECTIVE SYNTHESIS OF 6β-SUBSTITUTED PENICILLANATES;Jules A.Aimetti,et al，;《Tetrahedron Letters》;19791231;第20卷(第48期);第4631-4634页 * |
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