CN102863434B - Synthetic method of nifuratel - Google Patents
Synthetic method of nifuratel Download PDFInfo
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- CN102863434B CN102863434B CN201210401059.2A CN201210401059A CN102863434B CN 102863434 B CN102863434 B CN 102863434B CN 201210401059 A CN201210401059 A CN 201210401059A CN 102863434 B CN102863434 B CN 102863434B
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Abstract
The invention belongs to the field of medicine synthesis, and discloses a synthetic method of nifuratel. The synthetic method of nifuratel is to carry out ring closing reaction under the alkaline condition of sodium methoxide, therefore, the metallic sodium can be avoided being used, and the safety in production can be ensured; meanwhile, the reaction is easy to generate, the process is easy to control, high yield of the synthesized nifuratel is achieved, few impurities are generated, and the quality is stable; and moreover, the synthetic method of nifuratel is simple in operation, and the raw material is easy to obtain; the used solvent and the raw material out of the reaction can be recycled along with low cost; no waste liquid is generated in each step of the reaction; the pollution is greatly reduced; and the synthetic method is suitable for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate in particular to a kind of synthetic method of nifuratel.
Background technology
Nifuratel (Cefditoren Pivoxil) chemistry is by name: 5-[(methylthio group) methyl]-3-[[(5-nitro-2-furans) methylene radical] amino]-2-oxazolidone, molecular formula is C10H11N3O5S, and molecular weight is 285.28, and chemical structural formula is as follows:
Nifuratel is that Italian Poli Industria Chimica S.p.A company develops listing the sixties, itrofurans Antibiotics medicine, there is the effect of significant treatment vagina polyinfection, it kills trichomonad activity and metronidazole equivalence, there is anti-microbial effect simultaneously, can also effectively kill chlamydia trachomatis and mycoplasma, candidiasis is also had to certain activity.Nifuratel is oral shows that with vagina administration its tolerance is good, also without resistance phenomenon, and the curative ratio to bacterial vaginitis and penbritin, Pyocianil equivalence, and adverse reaction rate is significantly lower than penbritin, Pyocianil.Nifuratel is a broad-spectrum antibiotics, especially the common disease substance of gynecological infection is had to strong killing action as Gram-positive and negative bacteria, trichomonad, mould, chlamydozoan and mycoplasma, to by bacterium, trichomonad, the microbial vulva of mould and beads, vaginal infection and leucorrhea increasing and urinary system infection, digestive tube loeschiasis and giardiasis have good therapeutic action.
At present according to bibliographical information, nifuratel synthetic mainly contains following two kinds of methods:
Method one: referring to belgian patent Belg pat.635608 (1963); CA61:16069c, its chemical equation is as follows:
Method two: referring to French Patent Fr.M4544(1966); CA66:59221a, its chemical equation is as follows:
Above-mentioned two kinds of methods there is no essential difference, are all take epoxy chloropropane as starting raw material, are only that response hierarchy is slightly different in the time of preparation 3-methylthio group-2-hydroxyl-propyl hydrazine.But above-mentioned synthetic method is all to carry out in the alkaline environment of methyl alcohol-sodium methylate, and in the production of industrially scalable, owing to having used sodium Metal 99.5, can bring the danger of blast.Above-mentioned synthetic method reactivity and yield are all lower in addition, and product impurity is many, purity is low.
Summary of the invention
In view of this, the object of the invention is to for problems of the prior art, provide that a kind of yield is high, impurity is few, the synthetic method of stay-in-grade nifuratel.
For realizing object of the present invention, the present invention adopts following technical scheme:
A synthetic method for nifuratel, comprises the following steps:
Step 1, epoxy chloropropane is added in reaction flask, slowly drip sodium methyl mercaptide at 0～10 ℃, after dripping and finishing, react 3 hours under room temperature, underpressure distillation, collects cut and obtains 2-(methylthiomethyl)-oxirane; The mol ratio of wherein said epoxy chloropropane and sodium methyl mercaptide is 1:5;
Step 2, hydrazine hydrate is added in there-necked flask, at 90～95 ℃, splashes into 2-(methylthiomethyl)-oxirane, drip Bi Jixu insulation reaction 2 hours, underpressure distillation, collects cut and obtains 3-methylthio group-2-hydroxyl-propyl hydrazine; Wherein said hydrazine hydrate and 2-(methylthiomethyl) mol ratio of-oxirane is 1:1～1.1:1;
Step 3, get 3-methylthio group-2-hydroxyl-propyl hydrazine and add methylcarbonate, under alkali existence condition, reacting by heating obtains N-amino-5-methylthiomethyl-2-oxazolidone; The mol ratio of wherein said 3-methylthio group-2-hydroxyl-propyl hydrazine and methylcarbonate is 1:1～1:1.2;
Step 4, get 5-Nitrofulral diacetate and add ethanol under diluted acid existence condition, to be hydrolyzed to obtain 5-nitryl furfural; The mol ratio of wherein said ethanol and 5-Nitrofulral diacetate is 1:0.05;
Step 5, under lucifuge condition, N-amino-5-methylthiomethyl-2-oxazolidone is mixed with 5-nitryl furfural, stir after 2 hours at 15-30 ℃, leave standstill 2 hours, filtration, filter cake washing with alcohol, dry, obtain nifuratel crude product, recrystallization purifying obtains nifuratel sterling; The mol ratio of wherein said N-amino-5-methylthiomethyl-2-oxazolidone and 5-nitryl furfural is 1:1～1:1.05.
Preparation method of the present invention is take epoxy chloropropane as reaction raw materials, generate 2-(methylthiomethyl with sodium methyl mercaptide generation substitution reaction)-oxirane, 2-(methylthiomethyl)-oxirane reacts 3-methylthio group-2-hydroxyl-propyl hydrazine with hydrazine hydrate generation hydrazinolysis, and then under 3-methylthio group-2-hydroxyl-propyl hydrazine and methylcarbonate alkali existence condition, carry out ring-closure reaction and obtain N-amino-5-methylthiomethyl-2-oxazolidone.N-amino-5-methylthiomethyl-2-oxazolidone and 5-Nitrofulral diacetate are hydrolyzed the 5-nitryl furfural condensation obtaining and generate nifuratel crude product, and last recrystallization purifying obtains nifuratel.Synthetic method of the present invention is carried out ring-closure reaction under the alkaline condition of sodium methylate, has avoided the use of sodium Metal 99.5, guarantees production safety.Improved the yield of nifuratel, the product foreign matter content having reduced, has improved the purity of nifuratel sterling simultaneously.
As preferably, collect cut for collecting 42-60 ℃ of cut described in step 1.
As preferably, underpressure distillation, for being first concentrated into thickness, then is distilled under-0.095～-0.1MPa vacuum tightness described in step 2.
As preferably, diluted acid is dilute sulphuric acid described in step 4.
As preferably, the reaction conditions of hydrolysis is heating reflux reaction 30 minutes described in step 4.
As preferably, recrystallization purifying is specially under lucifuge condition described in step 5, gets nifuratel crude product, press g/mL, add the Glacial acetic acid of 10 times of volumes of nifuratel crude product, be heated to boil, charcoal absorption, filtered while hot, filtrate leaves standstill crystallization, filter after being cooled to room temperature, filter cake by washing with alcohol to product redfree, water, washing with alcohol again, is drying to obtain after draining.
Can find out from above-mentioned technical scheme, the invention provides a kind of synthetic method of nifuratel.The synthetic method of nifuratel of the present invention is carried out ring-closure reaction under the alkaline condition of sodium methylate, has avoided the use of sodium Metal 99.5, guarantees production safety.Propose reaction simultaneously and easily occur, process easily controls, synthetic nifuratel yield is high, impurity is few, steady quality.And the synthetic method of nifuratel of the present invention is simple to operate, and raw material is easy to get, solvent used and not participate in the equal recoverable cost of raw material of reaction low, each step reaction does not have waste liquid substantially, greatly reduces pollution, is more suitable for suitability for industrialized production.
Embodiment
The embodiment of the invention discloses a kind of synthetic method of nifuratel.Those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, and related personnel obviously can change method as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
In order further to understand the present invention, below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1: the optimization of process conditions of the synthetic method step 1 of nifuratel
In the building-up process of nifuratel, the present invention investigates the temperature of substitution reaction described in the synthetic method step 1 of nifuratel to reaction solution color and 2-(methylthiomethyl) impact of-oxirane yield, the results are shown in Table 1.
The processing condition of table 1 step 1
| Temperature of reaction | Reaction solution color yield (%) |
| 7～22C | Yellow 23.7 |
| 0～lOC | Colourless 52.5 |
| 50～75C | Yellow 11.0 |
| 15～25C | Yellow 32.6 |
| -3～5C | Colourless 58.6 |
| 0～5C | Colourless 58.0 |
From table 1 result, in the building-up process of nifuratel, substitution reaction temperature is higher described in step 1, and the yellow impurities of generation is more, intermediate 2-(methylthiomethyl)-oxirane yield is lower.Therefore temperature of reaction is defined as to 0～10 ℃.The reactant that further detects the rear raffinate of distillation and sodium methyl mercaptide, does not obtain 2-(methylthiomethyl)-oxirane, illustrate and drip sodium methyl mercaptide solution, continue reaction 3 hours, epoxy chloropropane reacts completely in reaction solution.Consider the influence factor of each side, the processing condition of the synthetic method step 1 of nifuratel are preferably: controlling temperature is 0～10 ℃; Drip sodium methyl mercaptide solution, continue reaction 3 hours; Underpressure distillation is collected 42-60 ℃ of cut and is obtained intermediate 2-(methylthiomethyl)-oxirane.
Embodiment 2: the optimization of process conditions of the synthetic method step 2 of nifuratel
In the building-up process of nifuratel, the post-treating method of intermediate 3-methylthio group-2-hydroxyl-propyl hydrazine that the present invention further prepares is studied, and the results are shown in Table 2.
The processing condition of the aftertreatment of table 2 3-methylthio group-2-hydroxyl-propyl hydrazine
From table 2 result, in the building-up process of nifuratel, if reaction solution without molecular distillation, final nifuratel quality product can be subject to more impact.Therefore determine that reaction solution is first at lower temperature and vacuum tightness, boil off after hydrazine hydrate and water, then under condition of high vacuum degree, distill out 3-methylthio group-2-hydroxyl-propyl hydrazine that purity is high.
Embodiment 4: the optimization of process conditions of the synthetic method step 3 of nifuratel
In the building-up process of nifuratel, the present invention has investigated the preparation of different hydrolysising solvents on intermediate 5-nitryl furfural and the impact on end product, the results are shown in Table 3.
The impact of the preparation of table 3 different solvents on intermediate 5-nitryl furfural
| Hydrolysising solvent | Result |
| Dilute hydrochloric acid | Be difficult to obtain 5-nitryl furfural solution, the nifuratel of trial-production off quality |
| Dilute sulphuric acid | The 5-nitryl furfural solution that is easy to get, the nifuratel of trial-production up-to-standard |
From table 3 result, compared with dilute hydrochloric acid, 5-Nitrofulral diacetate refluxes, is hydrolyzed 30 minutes and is easy to obtain 5-nitryl furfural solution in dilute sulphuric acid, and final nifuratel quality product is also qualified, therefore determine the technique that adopts 5-Nitrofulral diacetate to be hydrolyzed in dilute sulphuric acid.
Embodiment 5: nifuratel synthetic
1,2-(methylthiomethyl) preparation of-oxirane (intermediate 1)
130ml epoxy chloropropane is added in reaction flask, and ice bath, stirring are cooled to after 0～10 ℃, slowly drip 500ml sodium methyl mercaptide (dripping off for 1～2 hour).Drip finish after, remove ice bath, under room temperature, react 3 hours.Separatory, get anhydrous sodium sulfate drying for oil reservoir, filtration.Filtrate steams colourless cut with heating in water bath, the decompression of 60～70 ℃, collects 42-60 ℃ of cut.Obtain 2-(methylthiomethyl)-oxirane (intermediate 1) 90g.
2, the preparation of 3-methylthio group-2-hydroxyl-propyl hydrazine (intermediate 2)
230ml hydrazine hydrate is added in 500ml there-necked flask, be heated to 90 ℃.Splash into 60g2-(methylthiomethyl)-oxirane (temperature control drips off for 90～95 ℃, 1～2 hour).Drip Bi Jixu insulation reaction 2 hours.First be concentrated into thickness, then distill under-0.095～-0.1MPa vacuum tightness, regather water white transparency shape liquid.Obtain overhead product 19g.
3, the preparation of N-amino-5-methylthiomethyl-2-oxazolidone (intermediate 3)
In there-necked flask, add 19g3-methylthio group-2-hydroxyl-propyl hydrazine, 12g methylcarbonate, 10ml sodium methoxide solution (concentration 19%), be heated to reflux.React after 2 hours, stopping refluxing steams solvent, adds 57ml ethanol for subsequent use.
4,5-nitryl furfural (intermediate 4) preparation
126ml ethanol, 63ml water, the 7ml vitriol oil are added in reaction flask, then add 31.6g5-Nitrofulral diacetate.Be heated to reflux, after 30 minutes, stop heating, be cooled to room temperature for subsequent use.
5, the preparation of nifuratel crude product
To under N-amino-5-methylthiomethyl-2-oxazolidone lucifuge of preparation, add in the solution of 5-nitryl furfural of preparation, 15-30 ℃ of stirring stops after 2 hours stirring, leaving standstill 2 hours, and filtration, filter cake washing with alcohol are dry, obtain 15g nifuratel crude product.
6, the purifying of nifuratel crude product
Get 15g crude product and add 150ml Glacial acetic acid, be heated to boil, then add 1g charcoal absorption 5～10 minutes; Filtered while hot, filtrate leaves standstill crystallization, filters after being cooled to room temperature.Filter cake by washing with alcohol to product redfree, use a small amount of water, washing with alcohol again.After draining, be dried to obtain 7.8g nifuratel in 50～60 ℃.(operating process lucifuge)
Embodiment 6: the amplification test that nifuratel is synthetic
Carried out scale-up according to synthetic method described in embodiment 5, charging capacity reaches kilogram levels in 5-Nitrofulral diacetate.Intermediate 1,2,4 reaction process are used 50L jacketed type normal-pressure reaction kettle, and intermediate 3 adopts the there-necked flask of 5L to be prepared, and its processing parameter and embodiment 5 are basically identical.Experimental result is as shown in table 4 and 5.
Table 4 laboratory sample is prepared result
The analytical results of table 5 laboratory sample
From above-mentioned experimental result, in the building-up process of nifuratel, its processing parameter, quality product and yield are within span of control, and product has determined that through structural identification product structure is correct, this explanation uses nifuratel synthetic method of the present invention can produce sustainedly and stably the product that meets quality standard in laboratory.
Embodiment 6: the pilot scale amplification test that nifuratel is synthetic
In a large amount of lab scale experimental basis, we have carried out nifuratel scale-up and middle trial production (lot number: 070901,070902,071001,071002,071003) production technique checking, experimental result is as shown in table 6 and table 7 in the workshop that meets GMP.
The raw material usage quantity of table 6 scale-up and middle trial production and product preparation amount
The analytical results of table 7 scale-up and middle trial production
From above-mentioned experimental result, in the building-up process of nifuratel, its quality product and yield are within span of control, show to use nifuratel synthetic method route maturation of the present invention, stable, can produce the product that meets quality standard, and there are good circulation ratio and reliability, are applicable to suitability for industrialized production.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (6)
1. a synthetic method for nifuratel, is characterized in that, comprises the following steps:
Step 1, epoxy chloropropane is added in reaction flask, slowly drip sodium methyl mercaptide at 0～10 ℃, after dripping and finishing, react 3 hours under room temperature, underpressure distillation, collects cut and obtains 2-(methylthiomethyl)-oxirane; The mol ratio of wherein said epoxy chloropropane and sodium methyl mercaptide is 1:5;
Step 2, hydrazine hydrate is added in there-necked flask, at 90～95 ℃, splashes into 2-(methylthiomethyl)-oxirane, drip Bi Jixu insulation reaction 2 hours, underpressure distillation, collects cut and obtains 3-methylthio group-2-hydroxyl-propyl hydrazine; Wherein said hydrazine hydrate and 2-(methylthiomethyl) mol ratio of-oxirane is 1:1～1.1:1;
Step 3, get 3-methylthio group-2-hydroxyl-propyl hydrazine and add methylcarbonate, under alkali existence condition, reacting by heating obtains N-amino-5-methylthiomethyl-2-oxazolidone; The mol ratio of wherein said 3-methylthio group-2-hydroxyl-propyl hydrazine and methylcarbonate is 1:1～1:1.2;
Step 4, get 5-Nitrofulral diacetate and add ethanol under diluted acid existence condition, to be hydrolyzed to obtain 5-nitryl furfural; The mol ratio of wherein said ethanol and 5-Nitrofulral diacetate is 1:0.05;
Step 5, under lucifuge condition, N-amino-5-methylthiomethyl-2-oxazolidone is mixed with 5-nitryl furfural, stir after 2 hours at 15-30 ℃, leave standstill 2 hours, filtration, filter cake washing with alcohol, dry, obtain nifuratel crude product, recrystallization purifying obtains nifuratel sterling; The mol ratio of wherein said N-amino-5-methylthiomethyl-2-oxazolidone and 5-nitryl furfural is 1:1～1:1.05.
2. synthetic method according to claim 1, is characterized in that, collects cut for collecting 42-60 ℃ of cut described in step 1.
3. synthetic method according to claim 1, is characterized in that, underpressure distillation, for being first concentrated into thickness, then is distilled under-0.095～-0.1MPa vacuum tightness described in step 2.
4. synthetic method according to claim 1, is characterized in that, diluted acid is dilute sulphuric acid described in step 4.
5. synthetic method according to claim 1, is characterized in that, the reaction conditions of hydrolysis is heating reflux reaction 30 minutes described in step 4.
6. synthetic method according to claim 1, is characterized in that, recrystallization purifying is specially under lucifuge condition described in step 5, get nifuratel crude product, by g/mL, add the Glacial acetic acid of 10 times of volumes of nifuratel crude product, be heated to boil, charcoal absorption, filtered while hot, filtrate leaves standstill crystallization, after being cooled to room temperature, filter, filter cake is by washing with alcohol to product redfree, then water, washing with alcohol, be drying to obtain after draining.
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| CN103232445A (en) * | 2013-05-02 | 2013-08-07 | 中国医药研究开发中心有限公司 | Method for preparing nifuratel |
| CN103396413A (en) * | 2013-08-14 | 2013-11-20 | 盐城凯利药业有限公司 | Preparation method of nifuratel |
| CN104402874B (en) * | 2013-12-02 | 2016-08-03 | 四川摩尔生物制药有限公司 | A kind of preparation method of the compound nifuratel as shown in formula E |
| CN103664923B (en) * | 2013-12-23 | 2016-05-11 | 湖南方盛制药股份有限公司 | The preparation method of Nifuratel |
| CN103755696B (en) * | 2014-01-21 | 2016-05-11 | 北京安汀医药生物科技有限公司 | A kind of synthetic method of Nifuratel |
| CN105820145B (en) * | 2015-01-07 | 2019-01-29 | 成都青山利康药业有限公司 | A kind of preparation method of 5- nitryl furfural and Nifuratel |
| CN107987069B (en) * | 2017-11-28 | 2020-07-03 | 北京金城泰尔制药有限公司 | Preparation process of anti-infective nifuratel |
| CN108084174B (en) * | 2017-11-28 | 2020-04-17 | 北京金城泰尔制药有限公司 | Preparation method of nifuratel |
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| CN101037434A (en) * | 2006-03-16 | 2007-09-19 | 韩志强 | Production method of nifuratel |
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