CN102863434A - Synthetic method of nifuratel - Google Patents
Synthetic method of nifuratel Download PDFInfo
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- CN102863434A CN102863434A CN2012104010592A CN201210401059A CN102863434A CN 102863434 A CN102863434 A CN 102863434A CN 2012104010592 A CN2012104010592 A CN 2012104010592A CN 201210401059 A CN201210401059 A CN 201210401059A CN 102863434 A CN102863434 A CN 102863434A
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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: the 5-[(methylthio group) methyl]-3-[[(5-nitro-2-furans) methylene radical] amino]-the 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, effect with the polyinfection of significant treatment vagina, it is active equivalent with metronidazole that it kills trichomonad, have simultaneously anti-microbial effect, can also effectively kill chlamydia trachomatis and mycoplasma, candidiasis is also had certain activity.Oral and the vagina administration of nifuratel shows that its tolerance is good, and is equivalent to curative ratio and penbritin, the Pyocianil of bacterial vaginitis also without the resistance phenomenon, and adverse reaction rate significantly is lower than penbritin, Pyocianil.Nifuratel is a broad-spectrum antibiotics, especially the common disease substance of gynecological infection such as Gram-positive and negative bacteria, trichomonad, mould, chlamydozoan and mycoplasma there is strong killing action, 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.M 4544(1966); CA 66:59221a, its chemical equation is as follows:
Above-mentioned two kinds of methods there is no the difference of essence, all are take epoxy chloropropane as starting raw material, only are that response hierarchy is slightly different when preparation 3-methylthio group-2-hydroxyl-propyl hydrazine.But above-mentioned synthetic method all is 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 purpose of the present invention, the present invention adopts following technical scheme:
A kind of synthetic method of nifuratel may further comprise the steps:
Step 1, epoxy chloropropane is added in the reaction flask, at 0～10 ℃ of lower sodium methyl mercaptide that slowly drips, drip finish after, reaction is 3 hours under the room temperature, underpressure distillation is collected cut and is got the 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 the there-necked flask, under 90～95 ℃, splashes into the 2-(methylthiomethyl)-oxirane, dripped the Bi Jixu insulation reaction 2 hours, underpressure distillation is collected cut and is got 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, reacting by heating gets N-amino-5-methylthiomethyl-2-oxazolidone under the alkali existence condition; The mol ratio of wherein said 3-methylthio group-2-hydroxyl-propyl hydrazine and methylcarbonate is 1: 1 ~ 1:1.2;
Step 4, get the 5-Nitrofulral diacetate and add ethanol and under the diluted acid existence condition, be hydrolyzed to get the 5-nitryl furfural; The mol ratio of wherein said ethanol and 5-Nitrofulral diacetate is 1:0.05;
Step 5, under the lucifuge condition, N-amino-5-methylthiomethyl-2-oxazolidone is mixed with the 5-nitryl furfural, 15-30 ℃ stir 2 hours after, left standstill 2 hours, filter, the filter cake washing with alcohol drying, get the nifuratel crude product, recrystallization purifying gets the 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 the 2-(methylthiomethyl with sodium methyl mercaptide generation substitution reaction)-oxirane, the 2-(methylthiomethyl)-and oxirane and hydrazine hydrate generation hydrazinolysis reaction 3-methylthio group-2-hydroxyl-propyl hydrazine, then carry out ring-closure reaction under 3-methylthio group-2-hydroxyl-propyl hydrazine and the methylcarbonate alkali existence condition and obtain N-amino-5-methylthiomethyl-2-oxazolidone.The 5-nitryl furfural condensation that N-amino-5-methylthiomethyl-2-oxazolidone and the hydrolysis of 5-Nitrofulral diacetate obtain generates the 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, avoided the use of sodium Metal 99.5, guarantees production safety.Improved simultaneously the yield of nifuratel, the product foreign matter content that has reduced has improved the purity of nifuratel sterling.
As preferably, the described collection cut of step 1 is for collecting 42-60 ℃ of cut.
As preferably, the described underpressure distillation of step 2 is for being concentrated into first thickness, again-0.095 ~-distill under the 0.1MPa vacuum tightness.
As preferably, the described diluted acid of step 3 is dilute sulphuric acid.
As preferably, the reaction conditions of the described hydrolysis of step 4 is heating reflux reaction 30 minutes.
As preferably, the described recrystallization purifying of step 5 is specially under the lucifuge condition, gets the nifuratel crude product, press g/mL, add the Glacial acetic acid of 10 times of volumes of nifuratel crude product, be heated to and boil, charcoal absorption, filtered while hot, filtrate is left standstill crystallization, filter after being cooled to room temperature, filter cake with washing with alcohol to the product redfree, water, washing with alcohol are drying to obtain after draining again.
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, avoided the use of sodium Metal 99.5, guarantees production safety.Propose simultaneously reaction and easily occur, the nifuratel yield that process is easily controlled, synthesized 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, used solvent and to participate in the equal recoverable cost of raw material of reaction low, and 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 this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is, all similarly replace and change apparent to those skilled in the art, and they all are deemed to be included in the present invention.Method of the present invention is described by preferred embodiment, and the related personnel obviously can change or suitably change and combination method as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
In order further to understand the present invention, the present invention is described in detail below in conjunction with embodiment.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 the described substitution reaction of 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 (%) |
| 7～22℃ | Yellow 23.7 |
| 0～10℃ | Colourless 52.5 |
| 50～75℃ | Yellow 11.0 |
| 15～25℃ | Yellow 32.6 |
| -3～5℃ | Colourless 58.6 |
| 0～5℃ | Colourless 58.0 |
By table 1 result as seen, in the building-up process of nifuratel, the described substitution reaction temperature of step 1 is higher, and the yellow impurities of generation is more, intermediate 2-(methylthiomethyl)-the oxirane yield is lower.Therefore temperature of reaction is defined as 0～10 ℃.Further detect the reactant of the rear raffinate of distillation and sodium methyl mercaptide, do not obtain the 2-(methylthiomethyl)-oxirane, illustrate to 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: the control temperature is 0～10 ℃; Drip sodium methyl mercaptide solution, continue reaction 3 hours; Underpressure distillation is collected 42-60 ℃ of cut and is got 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 the intermediate 3-methylthio group that the present invention further prepares-2-hydroxyl-propyl hydrazine 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
By table 2 result as seen, 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 reaction solution first under lower temperature and vacuum tightness, boil off hydrazine hydrate and water after, under condition of high vacuum degree, distill out again the high 3-methylthio group of purity-2-hydroxyl-propyl hydrazine.
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 different hydrolysising solvents on the preparation of intermediate 5-nitryl furfural and on the impact of end product, the results are shown in Table 3.
Table 3 different solvents is on the impact of the preparation of intermediate 5-nitryl furfural
| Hydrolysising solvent | The 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 |
By table 3 result as seen, compare with dilute hydrochloric acid, the 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 determines the technique that adopts the 5-Nitrofulral diacetate to be hydrolyzed in dilute sulphuric acid.
Embodiment 5: nifuratel synthetic
1,2-(methylthiomethyl)-preparation of oxirane (intermediate 1)
The 130ml epoxy chloropropane is added in the reaction flask, after ice bath, stirring are cooled to 0～10 ℃, slowly drip 500ml sodium methyl mercaptide (dripping off in 1～2 hour).After drip finishing, remove ice bath, reaction is 3 hours under the room temperature.Separatory, get oil reservoir with anhydrous sodium sulfate drying, filtration.Filtrate steams colourless cut with 60～70 ℃ heating in water bath, decompression, collects 42-60 ℃ of cut.Get the 2-(methylthiomethyl)-oxirane (intermediate 1) 90g.
2, the preparation of 3-methylthio group-2-hydroxyl-propyl hydrazine (intermediate 2)
The 230ml hydrazine hydrate is added in the 500ml there-necked flask, be heated to 90 ℃.Splash into the 60g2-(methylthiomethyl)-oxirane (temperature control dripped off in 90～95 ℃, 1～2 hour).Dripped the Bi Jixu insulation reaction 2 hours.Be concentrated into first thickness, again-0.095 ~-distill under the 0.1MPa vacuum tightness, regather water white transparency shape liquid.Get 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 backflow.React after 2 hours, stopping to reflux steams solvent, and adding 57ml ethanol is for subsequent use.
4,5-nitryl furfural (intermediate 4) preparation
126ml ethanol, 63ml water, the 7ml vitriol oil are added in the reaction flask, add again the 31.6g5-Nitrofulral diacetate.Be heated to backflow, stopped heating after 30 minutes is cooled to room temperature for subsequent use.
5, the preparation of nifuratel crude product
To add under the N-amino-5-methylthiomethyl-2-oxazolidone lucifuge of preparation in the solution of 5-nitryl furfural of preparation, 15-30 ℃ is stirred and stops after 2 hours stirring, leaving standstill 2 hours, filters, the filter cake washing with alcohol, and drying gets 15g nifuratel crude product.
6, the purifying of nifuratel crude product
Get the 15g crude product and add the 150ml Glacial acetic acid, be heated to and boil, added again the 1g charcoal absorption 5～10 minutes; Filtered while hot, filtrate is left standstill crystallization, filters after being cooled to room temperature.Filter cake with washing with alcohol to the product redfree, use a small amount of water, washing with alcohol again.Drain rear in 50～60 ℃ of dry 7.8g nifuratels that get.(operating process lucifuge)
Embodiment 6: the amplification test that nifuratel is synthetic
Carried out scale-up according to embodiment 5 described synthetic methods, charging capacity reaches kilogram levels in the 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 shown in table 4 and 5.
Table 4 laboratory sample prepares the result
The analytical results of table 5 laboratory sample
From above-mentioned experimental result as can be known, 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, and this explanation uses nifuratel synthetic method of the present invention can produce sustainedly and stably the product that meets quality standard in the laboratory.
Embodiment 6: the pilot scale amplification test that nifuratel is synthetic
On a large amount of lab scale experimental basis, we have carried out nifuratel scale-up and middle trial production, and (lot number: 070901,070902,071001,071002,071003) production technique checking, experimental result is 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
By above-mentioned experimental result as can be known, in the building-up process of nifuratel, its quality product and yield are within span of control, show and use nifuratel synthetic method route maturation of the present invention, stable, can produce the product that meets quality standard, and good circulation ratio and reliability are arranged, be applicable to suitability for industrialized production.
The explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle 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 claim of the present invention.
Claims (6)
1. the synthetic method of a nifuratel is characterized in that, may further comprise the steps:
Step 1, epoxy chloropropane is added in the reaction flask, at 0～10 ℃ of lower sodium methyl mercaptide that slowly drips, drip finish after, reaction is 3 hours under the room temperature, underpressure distillation is collected cut and is got the 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 the there-necked flask, under 90～95 ℃, splashes into the 2-(methylthiomethyl)-oxirane, dripped the Bi Jixu insulation reaction 2 hours, underpressure distillation is collected cut and is got 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, reacting by heating gets N-amino-5-methylthiomethyl-2-oxazolidone under the alkali existence condition; The mol ratio of wherein said 3-methylthio group-2-hydroxyl-propyl hydrazine and methylcarbonate is 1:1 ~ 1:1.2;
Step 4, get the 5-Nitrofulral diacetate and add ethanol and under the diluted acid existence condition, be hydrolyzed to get the 5-nitryl furfural; The mol ratio of wherein said ethanol and 5-Nitrofulral diacetate is 1:0.05;
Step 5, under the lucifuge condition, N-amino-5-methylthiomethyl-2-oxazolidone is mixed with the 5-nitryl furfural, 15-30 ℃ stir 2 hours after, left standstill 2 hours, filter, the filter cake washing with alcohol drying, get the nifuratel crude product, recrystallization purifying gets the 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. described synthetic method according to claim 1 is characterized in that, the described collection cut of step 1 is for collecting 42-60 ℃ of cut.
3. described synthetic method according to claim 1 is characterized in that, the described underpressure distillation of step 2 is for being concentrated into first thickness, again-0.095 ~-distill under the 0.1MPa vacuum tightness.
4. described synthetic method according to claim 1 is characterized in that, the described diluted acid of step 3 is dilute sulphuric acid.
5. described synthetic method according to claim 1 is characterized in that, the reaction conditions of the described hydrolysis of step 4 is heating reflux reaction 30 minutes.
6. described synthetic method according to claim 1 is characterized in that, the described recrystallization purifying of step 5 is specially under the lucifuge condition, get the nifuratel crude product, press g/mL, add the Glacial acetic acid of 10 times of volumes of nifuratel crude product, be heated to and boil, charcoal absorption, filtered while hot, filtrate is left standstill crystallization, filter after being cooled to room temperature, to the product redfree, water, washing with alcohol are drying to obtain after draining filter cake again with washing with alcohol.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN103664923A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Preparation method for nifuratel |
| CN103755696A (en) * | 2014-01-21 | 2014-04-30 | 北京安汀医药生物科技有限公司 | Synthetic method of nifuratel |
| CN104402874A (en) * | 2013-12-02 | 2015-03-11 | 四川摩尔生物制药有限公司 | Preparation method of compound nifuratel as shown in formula E |
| CN105820145A (en) * | 2015-01-07 | 2016-08-03 | 成都青山利康药业有限公司 | Method for preparing 5-nitro-2-furaldehyde and nifuratel |
| CN107987069A (en) * | 2017-11-28 | 2018-05-04 | 北京朗依制药有限公司 | The preparation process of anti-infectives Nifuratel |
| CN108084174A (en) * | 2017-11-28 | 2018-05-29 | 北京朗依制药有限公司 | The preparation method of Nifuratel |
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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 |
| CN104402874A (en) * | 2013-12-02 | 2015-03-11 | 四川摩尔生物制药有限公司 | Preparation method of compound nifuratel as shown in formula E |
| CN103664923A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Preparation method for nifuratel |
| 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 |
| CN103755696A (en) * | 2014-01-21 | 2014-04-30 | 北京安汀医药生物科技有限公司 | Synthetic method of nifuratel |
| CN105820145A (en) * | 2015-01-07 | 2016-08-03 | 成都青山利康药业有限公司 | Method for preparing 5-nitro-2-furaldehyde and 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 |
| CN107987069A (en) * | 2017-11-28 | 2018-05-04 | 北京朗依制药有限公司 | The preparation process of anti-infectives Nifuratel |
| CN108084174A (en) * | 2017-11-28 | 2018-05-29 | 北京朗依制药有限公司 | The preparation method of 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 |
| 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 |
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Owner name: SHANDONG LUOXIN PHARMACY GROUP CO., LTD. Free format text: FORMER NAME: SHANDONG LUOXIN PHARMACY STOCK CO., LTD. |
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| CP01 | Change in the name or title of a patent holder |
Address after: Seven of 276017 Shandong province Linyi city Luozhuang District Patentee after: Shandong Luo Xin Pharmaceutical Group Plc Address before: Seven of 276017 Shandong province Linyi city Luozhuang District Patentee before: SHANDONG LUOXIN PHARMACY STOCK Co., LTD. |