CN104496986A - Preparation method of nalidixic acid - Google Patents
Preparation method of nalidixic acid Download PDFInfo
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- CN104496986A CN104496986A CN201410759804.XA CN201410759804A CN104496986A CN 104496986 A CN104496986 A CN 104496986A CN 201410759804 A CN201410759804 A CN 201410759804A CN 104496986 A CN104496986 A CN 104496986A
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- nalidixic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a preparation method of nalidixic acid. The preparation method is characterized in that at least three intermediates are adopted in preparation, including a first intermediate namely methyl-2-pyridyl)amino]methylene}diethyl malonate, a second intermediate namely ethyl, 4hydro-7-methyl-1,8-naphthyridine-3-carbonate, and a third intermediate namely ethyl-1,4-dihydro-7-methyl-4-oxy-1,8-naphthyridine-3-carbonate; and a relatively low temperature is adopted during preparation of the second intermediate, and bromoethane is adopted during preparation of the third intermediate. Therefore, the reaction time is saved, and the cost of reactants is reduced. More importantly, impurities are reduced as much as possible to improve the quality of a finished product.
Description
Technical field
The present invention relates to a kind of compounds process for production thereof, particularly relate to a kind of preparation method of Nalidixic Acid.
Background technology
Nalidixic Acid is first-generation Comprecin, to the part bacterial strain tool anti-microbial activity of escherichia coli, klebsiella spp, proteus, Shigella, Salmonella, enterobacter and hemophilus influenzae, anti-microbial activity also had to Diplococcus gonorrhoeae, but to gram positive coccus such as Rhodopseudomonas, acinetobacter and Staphylococcus all without anti-microbial activity.For sterilant, urine ph values change is on its effect nothing impact.For light yellow crystalline powder; Almost odorless, mildly bitter flavor.This product is dissolved in chloroform, in ethanol slightly soluble, soluble,very slightly in ether, almost insoluble in water; Dissolve in sodium hydroxide or sodium carbonate solution.The fusing point of this product is 226 ~ 231 DEG C.
It is in existing preparation process, often needs to be heated to 250 DEG C, adds the energy consumption of reaction and overall reaction times, improves the cost of preparation.Meanwhile, need during preparation to adopt sherwood oil making beating, extend the unnecessary reaction times.Further, impurity occurrence rate is higher, and impurity-eliminating effect is not good.
Summary of the invention
Object of the present invention is exactly to solve the above-mentioned problems in the prior art, provides a kind of preparation method of Nalidixic Acid.
Object of the present invention is achieved through the following technical solutions:
The preparation method of Nalidixic Acid, it comprises the following steps: 1. step, prepares intermediate one, adds 2-amino-6-picoline in reaction vessel, diethyl ethoxymethylenemalonate, heat after stirring, after 90 DEG C (positive and negative 3 degree), insulation reaction, question response stops heating completely, be cooled to room temperature, obtain crude product, adopt aftertreatment to obtain finished product intermediate one.2. step, is prepared intermediate two, in reaction vessel, is added phenyl ether, be heated to backflow, in order, temperature stirs when 200-230 DEG C, adds intermediate one, when back flow reaction to raw material no longer consumes, aftertreatment is adopted to the reaction solution obtained, obtain finished product intermediate two.3. step, prepares intermediate three, adds intermediate two, DMF successively, is heated to 40 DEG C, after stirring clarification, adds salt of wormwood, then drips monobromethane, and adopt some board monitoring reaction, to during without intermediate two, reaction terminates, and obtains intermediate three.Step 4., in a kettle., add successively the 3rd step intermediate, water, tetrahydrofuran (THF) stir clearly molten, and add sodium hydroxide in batches, carry out back flow reaction after adding, after adopting some board monitoring raw material reaction complete, tetrahydrofuran (THF) is steamed, after carrying out aftertreatment, has obtained finished product.
The preparation method of above-mentioned Nalidixic Acid, wherein: described reaction vessel is there-necked flask, alr mode is mechanical stirring.
Further, the preparation method of above-mentioned Nalidixic Acid, wherein: described step 1. in aftertreatment be, with ethyl alcohol recrystallization, by filter after filter cake ethanol carry out forced air drying 4 hours, obtain finished product intermediate one.
Further, the preparation method of above-mentioned Nalidixic Acid, wherein: described step 2. in aftertreatment be, after room temperature is down in reaction, add sherwood oil, stir and separate out solid, after filtering, after filter cake petroleum ether, filter cake is pulled an oar to during inclusion-free with methylene dichloride again, again filter, by filter cake forced air drying 6 hours at 60 DEG C, obtain finished product intermediate two.
Further, the preparation method of above-mentioned Nalidixic Acid, wherein: the 4. described aftertreatment of step is, reaction solution is overanxious, and filtrate is cooled to room temperature, regulate PH to 3, separate out solid under stirring, filter cake is washed with water, obtain finished product by after the solid forced air drying after washing.
Again further, the preparation method of above-mentioned Nalidixic Acid, wherein: the 4. described solid forced air drying of step is adopts 70 DEG C, drying 24 hours.
The advantage of technical solution of the present invention is mainly reflected in: can complete under temperature in lower when adding phenyl ether and carrying out reflux, both just can meet reaction needed during 200-230 DEG C, existing temperature of reaction of comparing is minimized, and has saved the reaction times.Meanwhile, compare the mode that tradition adopts iodoethane, adopt monobromethane to greatly reduce cost.Again can Reaction time shorten further.What is more important, adopts mode of the present invention, can reduce the appearance of impurity as far as possible, improves final product quality.Thus, space has been expanded in the technical progress for this area, and implementation result is good.
Accompanying drawing explanation
Object of the present invention, advantage and disadvantage, by for illustration and explanation for the non-limitative illustration passing through preferred embodiment below.These embodiments are only the prominent examples of application technical solution of the present invention, allly take equivalent replacement or equivalent transformation and the technical scheme that formed, all drop within the scope of protection of present invention.
Fig. 1 is the structural formula of intermediate one.
Fig. 2 is the structural formula of intermediate two.
Fig. 3 is the structural formula of intermediate three.
Embodiment
The preparation method of Nalidixic Acid as shown in Figure 1, is characterized in that comprising the following steps:
First, need to prepare intermediate one, its Chinese name is called, methyl-2-pyridyl) amino] methylene radical diethyl malonate.English name is:
Diethyl{[(6-methyl-2-pyridinyl)amino]methylene}propanedioate。Chinese is, methyl-2-pyridyl) amino] methylene radical diethyl malonate.
As shown in Figure 1, CAS is its structural formula, 13250-95-8, and molecular formula is C14H18N2O4.
The process of preparation is that in reaction vessel, add 2-amino-6-picoline, diethyl ethoxymethylenemalonate, heats after stirring.Afterwards, after 90 DEG C, carry out insulation reaction.Stopping heating etc. reacting completely, being cooled to room temperature, obtaining crude product, adopt aftertreatment to obtain finished product intermediate one.Specifically, aftertreatment adopted during this period is, with ethyl alcohol recrystallization, the filter cake ethanol after filtering is carried out forced air drying to 60 DEG C, 4 hours, obtains finished product intermediate one.
Further, for the product of this step, TLC can be adopted to monitor raw material reaction, and in TLC, the ratio of ethyl acetate and sherwood oil is 3:1.
Afterwards, carry out the preparation of intermediate two, the english name of this intermediate two is, ethyl 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate.(8-naphthyridines-3-structural carbonate formula as shown in Figure 2 for ethyl, 4 hydrogen-7-methyl isophthalic acids.Its CAS is 13250-96-9, and molecular formula is, C12H12N2O3, and molecular weight is 232.
Its actual procedure is as follows, in reaction vessel, add phenyl ether, is heated to backflow, and in order, temperature stirs when 200-230 DEG C, is good with 220 DEG C.Like this, existing temperature of reaction of comparing is minimized, and has saved the reaction times.Afterwards, add intermediate one, carry out back flow reaction 50-100 minute, after when substantially no longer consuming to raw material, aftertreatment is adopted to the reaction solution obtained, obtain finished product intermediate two.
Specifically, in order to obtain the higher intermediate of quality two, the aftertreatment that the present invention adopts is, after reaction solution is down to room temperature rapidly, add sherwood oil, stirs and separates out a large amount of yellow solid.Subsequently, filter, (reclaim filtrate) by after filter cake petroleum ether, filter cake is pulled an oar to during inclusion-free with methylene dichloride again.Relative to the making beating of traditional sherwood oil, present impurity-eliminating effect is better.Finally, again filter, by filter cake forced air drying 6 hours at 60 DEG C, obtain finished product intermediate two.Further, the TLC developping agent adopted during this period is ethyl acetate: sherwood oil=10:1, and ultraviolet develops the color.
Subsequently, carry out the preparation of intermediate three, its English name is, ethyl1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate.Chinese name is, ethyl-Isosorbide-5-Nitrae-dihydro-7-methyl-4-oxygen-1,8-naphthyridines-3-carbonic ether.Structural formula as shown in Figure 3.The CAS of this intermediate two is 33331-59-8, and molecular formula is C14H16N2O3, molecular weight 260.
During preparation, add intermediate two, DMF successively, be heated to 40 DEG C.Subsequently, stir clarification, add salt of wormwood, then drip monobromethane and be dissolved in DMF, adopt some board monitoring reaction, to during without intermediate two, reaction terminates, acquisition intermediate three.
Afterwards, adopt reactor, add the 3rd step intermediate successively, water, tetrahydrofuran (THF) stir clearly molten, and slowly add sodium hydroxide in batches.Carry out back flow reaction after adding, after adopting some board monitoring raw material reaction complete, tetrahydrofuran (THF) has been steamed, after carrying out aftertreatment, has obtained finished product.During this period, the developping agent of some board monitoring is ethyl acetate: methyl alcohol=1:3, and ultraviolet develops the color.
Meanwhile, the aftertreatment of employing is, reaction solution is overanxious, and filtrate is cooled to room temperature.Conveniently, regulating about PH to 3 (with 3 for good) by adding hydrochloric acid, under stirring, separating out yellow solid.Then, filter cake use water (1L × 3) is washed.During this period, solid is washed into faint yellow.Finally, finished product is obtained by after the solid forced air drying after washing.Further, in order to improve processing efficiency, solid forced air drying is, adopts 70 DEG C, dry 24 hours.
With regard to the present invention one preferably embodiment, for the ease of preparation, improve reaction efficiency, in intermediate one preparation process, adopt the there-necked flask of 500ml as reaction vessel, prepare the there-necked flask that intermediate two and intermediate three adopt 10l.Further, alr mode is mechanical stirring.
In conjunction with actual service condition of the present invention, if having pure DEG C of situation not up to standard in above process, can also with after sodium hydroxide neutralization, more again recall to hydrochloric acid.
" embodiment "
The preparation method of Nalidixic Acid as shown in Figure 1, is characterized in that comprising the following steps:
First, need to prepare intermediate one, its process is,
In reaction vessel, add 130g2-amino-6-picoline, 300g diethyl ethoxymethylenemalonate, heats after stirring.Afterwards, after 90 DEG C, carry out insulation reaction.Stopping heating etc. reacting completely, being cooled to room temperature, obtaining crude product.Afterwards, carry out aftertreatment, both used 500ml ethyl alcohol recrystallization, the filter cake ethanol (50ml × 2) after filtering is carried out forced air drying to 60 DEG C, after 4 hours, obtains 300g finished product intermediate one.
Afterwards, carry out the preparation of intermediate two: in reaction vessel, add 6L phenyl ether, be heated to backflow, in order, temperature stirs when 200-230 DEG C.Afterwards, add intermediate one, carry out back flow reaction 50-100 minute, after when substantially no longer consuming to raw material, aftertreatment is adopted to the reaction solution obtained.Specifically, after reaction solution is down to room temperature rapidly, add 7L sherwood oil, stir and separate out a large amount of yellow solid.
Subsequently, filter, filter cake (is reclaimed filtrate) with after 500ml petroleum ether, filter cake is pulled an oar to during inclusion-free with 8L methylene dichloride again.Finally, again filter, by filter cake forced air drying 6 hours at 60 DEG C, obtain finished product 230g intermediate two.Then, the preparation of intermediate three is carried out, add intermediate two, DMF successively, be heated to 40 DEG C.Subsequently, stir clarification, add 427g salt of wormwood, then drip 324g monobromethane be dissolved in the DMF of 500ml adopt some board monitoring reaction, to without intermediate two time, reaction terminate, acquisition intermediate three.
Afterwards, adopt the reactor of 50L, add 2kg the 3rd step intermediate, 10L water successively, 5L tetrahydrofuran (THF) stirs clearly molten, and slowly adds 368g sodium hydroxide in batches.Carry out back flow reaction after adding, after adopting some board monitoring raw material reaction complete, tetrahydrofuran (THF) has been steamed, after carrying out aftertreatment, has obtained finished product.
Meanwhile, the aftertreatment of employing is, reaction solution is overanxious, and filtrate is cooled to room temperature.Conveniently, regulating about PH to 3 (with 3 for good) by adding hydrochloric acid, under stirring, separating out yellow solid.Then, filter cake use water (1L × 3) is washed.During this period, solid is washed into faint yellow.Finally, finished product is obtained by after the solid forced air drying after washing.Further, in order to improve processing efficiency, solid forced air drying is, adopts 70 DEG C, dry 24 hours.
Moreover for the ease of preparation, improve reaction efficiency, adopt the there-necked flask of 500ml as reaction vessel in intermediate one preparation process, prepare the there-necked flask that intermediate two and intermediate three adopt 10l, final process adopts the there-necked flask of 50l.Further, alr mode is mechanical stirring.
In conjunction with actual service condition of the present invention, if having pure DEG C of situation not up to standard in above process, can also with after sodium hydroxide neutralization, more again recall to hydrochloric acid.
Can be found out by above-mentioned character express, adopt after the present invention, to add when phenyl ether carries out reflux and can complete under temperature in lower, both just can meet reaction needed during 200-230 DEG C, existing temperature of reaction of comparing is minimized, and has saved the reaction times.Meanwhile, compare the mode that tradition adopts iodoethane, adopt monobromethane to greatly reduce cost.Again can Reaction time shorten further.What is more important, adopts mode of the present invention, can reduce the appearance of impurity as far as possible, improves final product quality.
Claims (6)
1. the preparation method of Nalidixic Acid, is characterized in that comprising the following steps:
Step 1., prepare intermediate one, in reaction vessel, add 2-amino-6-picoline, diethyl ethoxymethylenemalonate, heats after stirring, after 90 DEG C, insulation reaction, question response stops heating completely, is cooled to room temperature, obtain crude product, adopt aftertreatment to obtain finished product intermediate one;
2. step, is prepared intermediate two, in reaction vessel, is added phenyl ether, be heated to backflow, in order, temperature stirs when 200-230 DEG C, adds intermediate one, when back flow reaction to raw material no longer consumes, aftertreatment is adopted to the reaction solution obtained, obtain finished product intermediate two;
3. step, prepares intermediate three, adds intermediate two, DMF successively, is heated to 40 DEG C, after stirring clarification, adds salt of wormwood, then drips monobromethane, and adopt some board monitoring reaction, to during without intermediate two, reaction terminates, and obtains intermediate three;
Step 4., in a kettle., add successively the 3rd step intermediate, water, tetrahydrofuran (THF) stir clearly molten, and add sodium hydroxide in batches, carry out back flow reaction after adding, after adopting some board monitoring raw material reaction complete, tetrahydrofuran (THF) is steamed, after carrying out aftertreatment, has obtained finished product.
2. the preparation method of Nalidixic Acid according to claim 1, is characterized in that: described reaction vessel is there-necked flask, and alr mode is mechanical stirring.
3. the preparation method of Nalidixic Acid according to claim 1, is characterized in that: described step 1. in aftertreatment be, with ethyl alcohol recrystallization, by filter after filter cake ethanol carry out forced air drying 4 hours, obtain finished product intermediate one.
4. the preparation method of Nalidixic Acid according to claim 1, it is characterized in that: described step 2. in aftertreatment be, after room temperature is down in reaction, add sherwood oil, stir and separate out solid, after filtering, after filter cake petroleum ether, filter cake is pulled an oar to during inclusion-free with methylene dichloride again, again filters, by filter cake forced air drying 6 hours at 60 DEG C, obtain finished product intermediate two.
5. the preparation method of Nalidixic Acid according to claim 1, is characterized in that: the 4. described aftertreatment of step is, reaction solution is overanxious, and filtrate is cooled to room temperature, regulate PH to 3, under stirring, separate out solid, filter cake is washed with water, obtains finished product by after the solid forced air drying after washing.
6. the preparation method of Nalidixic Acid according to claim 5, is characterized in that: the 4. described solid forced air drying of step is adopts 70 DEG C, drying 24 hours.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014167326A1 (en) * | 2013-04-09 | 2014-10-16 | Cresset Biomolecular Discovery Ltd | The local treatment of inflammatory ophthalmic diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014167326A1 (en) * | 2013-04-09 | 2014-10-16 | Cresset Biomolecular Discovery Ltd | The local treatment of inflammatory ophthalmic diseases |
| WO2014167327A1 (en) * | 2013-04-09 | 2014-10-16 | Cresset Biomolecular Discovery Ltd | The treatment of inflammatory disorders |
Non-Patent Citations (1)
| Title |
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| 夏明珠等: "1-乙基-4-氧-7-甲基-1,8-萘啶-3-羧酸的合成", 《应用化学》 * |
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Application publication date: 20150408 |