CN103254214B - Preparation method of 2beta-nitrine methyl penicillium alkyl diphenyl acid methyl ester - Google Patents
Preparation method of 2beta-nitrine methyl penicillium alkyl diphenyl acid methyl ester Download PDFInfo
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- CN103254214B CN103254214B CN201310205379.5A CN201310205379A CN103254214B CN 103254214 B CN103254214 B CN 103254214B CN 201310205379 A CN201310205379 A CN 201310205379A CN 103254214 B CN103254214 B CN 103254214B
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Abstract
The invention discloses a preparation method of 2beta-nitrine methyl penicillium alkyl diphenyl acid methyl ester, belonging to the technical field of medicines. The preparation method comprises the following steps of: carrying out insulation reaction on 2beta-chloromethyl penicillium alkyl diphenyl acid methyl ester and nitrine sodium aqueous solution by taking dichloromethane as a reaction solvent and taking polyethylene glycol substance as a phase transfer catalyst, and at the end of the reaction, adding an alkaline catalyst to carry out reflux reaction for a period of time; at the end of the reaction, sanding for layering and removing a water layer; and brine-washing, drying, filtering, decompressing and concentrating an organic phase till the organic phase is dry, thus obtaining yellow oily liquid 2beta-nitrine methyl penicillium alkyl diphenyl acid methyl ester. According to the preparation method disclosed by the invention, the dichloromethane is used for replacing difficultly recycled N,N-dimethylformamide. The preparation method disclosed by the invention has the advantages that raw materials are easily available, the cost is low, the environment is hardly damaged, good reaction selectivity and high yield are achieved, and the product purity is high.
Description
Technical field
The present invention relates to a kind of Tazobactam Sodium important intermediate (2S, 3S, 5R) preparation method of-3-azido-methyl-3-methyl-7-oxygen-4-thia-1-azabicyclo [3.2.0] heptane-2-diphenylmethyl carboxylate (hereinafter referred to as 2 β-azido-methyl penicillanic acid benzhydryl ester), belongs to medical art.
Background technology
Tazobactam Sodium (tazobactam), chemical name: 3-methyl-7-oxo-3-(1H-1,2,3,-triazole-1-methylene radical)-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-4,4-dioxide is the novel penicillanic acid sulfones beta-lactamase inhibitor of Japanese roc drugmaker exploitation.Its structure increases a triazole ring on the basis of Sulbactam, and press down enzyme effect to improve, it is the beta-lactamase inhibitor of current clinical effectiveness the best, has the features such as stability is high, activity is low, toxicity is low, Inhibiting enzyme activity is strong.1992, the compound medicine Tazobactam Sodium/piperacillin (1:8) of Tazobactam Sodium, first in France's listing, was used for the treatment of various bacteria and infects.
At present, the synthesis of Tazobactam Sodium is different according to adopted starting material, mainly contains three synthesis techniques, respectively with: Sulbactam, potassium penicillin G and 6-amino-penicillanic acid (6-APA) are for raw starting material.Wherein, especially with 6-amino-penicillanic acid (6-APA) for starting raw material synthesis Tazobactam Sodium research the most active.This operational path mainly comprises the 10 step reactions such as bromo, list oxidation, esterification, reduction, cracking open loop, chloromethylation, azide, dual oxide, cyclization, deprotection, and obtain Tazobactam Sodium, every single step reaction is all relatively simple, is easy to realize suitability for industrialized production.Its reaction process (see reaction equation 1):
The preparation technology of existing 2 β-azido-methyl penicillanic acid benzhydryl ester is normally according to the method preparation described in patent EP0097446A1: 2 β-chloromethyl penicillanic acid benzhydryl ester is dissolved in N, in dinethylformamide (DMF), prepare (Blocked portion see in reaction equation 1) by reacting with sodium azide.Reaction terminates, and pours in cold water, add extraction into ethyl acetate by reaction feed liquid.Ethyl acetate layer purified water is washed, dry, filters.Filtrate reduced in volume obtains yellow oily liquid 2 β-azido-methyl penicillanic acid benzhydryl ester to dry.
Above-mentioned reaction is using DMF as reaction solvent, and because DMF dissolves each other in organic phase and aqueous phase, this reaction is homogeneous reaction, and reaction is easily carried out.But exactly because DMF has the characteristic of dissolving each other in organic phase and aqueous phase, the more difficult removing of DMF in last handling process, causes in material residual high, affects next step reaction.Meanwhile, the part be dissolved in water is difficult to recycle, and causes waste water to be difficult to process, causes environmental pollution.
Summary of the invention
For the above-mentioned deficiency of prior art, the invention provides a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester preparation method newly.The method has that raw material is easy to get, with low cost, environmental hazard is little, good reaction selectivity, yield advantages of higher.
Technical scheme of the present invention is as follows: the preparation method of a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester, it is characterized in that, take methylene dichloride as reaction solvent, take polyethylene glycol substances as phase-transfer catalyst, 2 β-chloromethyl penicillanic acid benzhydryl ester and sodium azide aqueous solution, in-5 ~ 0 DEG C of insulation reaction 2-5 hour, then add catalyzer alkaloids back flow reaction 4 ~ 10 hours at 40-45 DEG C; After reaction terminates, be cooled to-5 ~ 0 DEG C, stratification, water layer discarded; Organic phase is washed through salt, dry, filter and be evaporated to dry after obtain yellow oily liquid 2 β-azido-methyl penicillanic acid benzhydryl ester.Its reaction process as shown in the reaction equation 2.
The mol ratio of described phase-transfer catalyst and raw material 2 β-chloromethyl penicillanic acid benzhydryl ester is (0.01 ~ 0.10): 1;
The mol ratio of described catalyzer alkaloids and raw material 2 β-chloromethyl penicillanic acid benzhydryl ester is (0.01 ~ 0.05): 1;
Described 2 β-chloromethyl penicillanic acid benzhydryl ester and sodium azide mol ratio are 1:(1 ~ 3), preferred 1:1.5;
Described phase-transfer catalyst is polyethylene glycols: as Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, polyethylene glycol-800, cetomacrogol 1000, Macrogol 2000 etc.;
Described catalyzer can be organic bases such as quinoline, pyridine, triethylamine, also can be the alkali-metal carbonates such as salt of wormwood, calcium carbonate, sodium carbonate, magnesiumcarbonate, saleratus;
The consumption of described reaction solvent methylene dichloride is 10 ~ 20 times of 2 β-chloromethyl penicillanic acid benzhydryl ester quality, and preferred methylene chloride is 15 times.
Reaction mechanism of the present invention is: using methylene dichloride as reaction solvent, because methylene dichloride and water do not dissolve each other, reacts for two-phase reaction system, and choosing polyethylene glycol substances is phase-transfer catalyst, and reaction is easily carried out; Substituting DMF with methylene dichloride and alkaloids for catalyzer (by improving temperature and the polarity adding alkaline matter regulation system, improve speed of response and selectivity) simultaneously, improve content and the yield of product.
The invention has the beneficial effects as follows: the present invention adopts methylene dichloride to replace the difficult N reclaimed, dinethylformamide, the method has the advantages such as raw material is easy to get, with low cost, environmental hazard is little, good reaction selectivity, yield high (>=94.0%), purity good (>=98.0%).
Embodiment
Below in conjunction with embodiment, the present invention will be further described, but be not limited thereto.
Raw materials used 2 β of this patent-chloromethyl penicillanic acid benzhydryl ester is by the method preparation described in patent JP1110689A, 2 β obtained-chloromethyl penicillanic acid benzhydryl ester oily matter obtains with Diethyl ether recrystallization after GF254 silica gel chromatography is separated, content >=98.0%.
Embodiment 1:
2 β-chloromethyl penicillanic acid benzhydryl ester 40.2g(0.1mol is dropped into successively in 500ml there-necked flask), methylene dichloride 380ml, polyoxyethylene glycol (200) 2.0g (0.01mol).Be cooled to-5 ~ 0 DEG C, drip by sodiumazide 19.5g(0.3mol) and the solution that is mixed with of 30ml water.Finish, at-5 ~ 0 DEG C of insulation reaction 3h.Add salt of wormwood 0.69g(0.005mol), be warming up to 40 ~ 45 DEG C of back flow reaction 5h.Reaction terminates, and is cooled to-5 ~ 0 DEG C, stratification, water layer discarded.Organic phase 70ml saturated nacl aqueous solution washes material one time, adds 10g anhydrous sodium sulfate drying in organic phase, filters.Filtrate reduced in volume, to dry, obtains yellow oily liquid 2 β-azido-methyl penicillanic acid benzhydryl ester 39.5g, yield 96.7%(content 98.3%).
Embodiment 2 ~ 3:
Operate by embodiment 1, Macrogol 200 is changed successively into the poly(oxyethylene glycol) 400 of same molar weight, Polyethylene Glycol-600, purity and the yield of products obtained therefrom are as shown in table 1.
Embodiment 4 ~ 5:
Operate by embodiment 1, catalyzer salt of wormwood is changed successively into calcium carbonate, the saleratus of same molar weight, purity and the yield of products obtained therefrom are as shown in table 1.
Contrast experiment:
In 500ml there-necked flask, drop into 2 β-chloromethyl penicillanic acid benzhydryl ester 5.13g, DMF 155ml successively, drip the solution be mixed with by sodiumazide 5g and 53ml water.Finish, incubation at room temperature reaction 4h.Reaction terminates, and will react feed liquid and import in cold water, and add extraction into ethyl acetate.Ethyl acetate layer purified water is washed, anhydrous magnesium sulfate drying, filters.Filtrate reduced in volume, to dry, obtains yellow oily liquid 2 β-azido-methyl penicillanic acid benzhydryl ester 4.79g, yield 91.9%(content 90.3%).
Table 1 the present invention and existing methodical yield and purity comparison sheet
Claims (7)
1. the preparation method of 2 β-azido-methyl penicillanic acid benzhydryl ester, it is characterized in that, take methylene dichloride as reaction solvent, take polyethylene glycol substances as phase-transfer catalyst, 2 β-chloromethyl penicillanic acid benzhydryl ester and sodium azide aqueous solution, in-5 ~ 0 DEG C of insulation reaction 2-5 hour, then add catalyzer alkaloids back flow reaction 4 ~ 10 hours at 40-45 DEG C; After reaction terminates, be cooled to-5 ~ 0 DEG C, stratification, water layer discarded; Organic phase is washed through salt, dry, filter and be evaporated to dry after obtain yellow oily liquid 2 β-azido-methyl penicillanic acid benzhydryl ester; The mol ratio of described phase-transfer catalyst and raw material 2 β-chloromethyl penicillanic acid benzhydryl ester is (0.01 ~ 0.10): 1; The mol ratio of described catalyzer and raw material 2 β-chloromethyl penicillanic acid benzhydryl ester is (0.01 ~ 0.05): 1.
2. the preparation method of a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester as claimed in claim 1, it is characterized in that, described phase-transfer catalyst is Macrogol 200, poly(oxyethylene glycol) 400, Polyethylene Glycol-600, polyethylene glycol-800, cetomacrogol 1000 or Macrogol 2000.
3. the preparation method of a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester as claimed in claim 1, it is characterized in that, described catalyzer is quinoline, pyridine, triethylamine, salt of wormwood, calcium carbonate, sodium carbonate, magnesiumcarbonate or saleratus.
4. as the preparation method of a kind of 2 β in claim 1-3 as described in any one-azido-methyl penicillanic acid benzhydryl ester, it is characterized in that, the mol ratio of described 2 β-chloromethyl penicillanic acid benzhydryl ester and sodium azide is 1:1 ~ 3.
5. the preparation method of a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester as claimed in claim 4, it is characterized in that, the mol ratio of described 2 β-chloromethyl penicillanic acid benzhydryl ester and sodium azide is 1:1.5.
6. as the preparation method of a kind of 2 β in claim 1-3 as described in any one-azido-methyl penicillanic acid benzhydryl ester, it is characterized in that, the consumption of described methylene dichloride is 10 ~ 20 times of 2 β-chloromethyl penicillanic acid benzhydryl ester quality.
7. the preparation method of a kind of 2 β-azido-methyl penicillanic acid benzhydryl ester as claimed in claim 6, it is characterized in that, the consumption of described methylene dichloride is 15 times of 2 β-chloromethyl penicillanic acid benzhydryl ester quality.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0097446A1 (en) * | 1982-06-21 | 1984-01-04 | Taiho Pharmaceutical Company Limited | Penicillin derivatives and process for preparation of the same |
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin 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 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0097446A1 (en) * | 1982-06-21 | 1984-01-04 | Taiho Pharmaceutical Company Limited | Penicillin derivatives and process for preparation of the same |
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin 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 |
Non-Patent Citations (3)
| Title |
|---|
| Narsihma Reddy. B,等.An improved synthesis of Tazobactam and its related impurities.《Der Pharmacia Lettre》.2012,第4卷(第2期),第674-682页,尤其参见其第679页合成路线1. * |
| 曹琳,等.β-内酰胺酶抑制剂他唑巴坦的合成.《化学工业与工程》.2002,第19卷(第3期),第219-224,273页,尤其参见其第222页. * |
| 胡月华,等.他唑巴坦的合成新方法.《安徽师范大学学报》.2003,第26卷(第1期),第48-50页,尤其参见其49页第1.8节. * |
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Address after: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee after: Shandong Anshun Pharmaceutical Co.,Ltd. Patentee after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Co-patentee before: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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