CN102911122A - Metronidazole preparation method - Google Patents
Metronidazole preparation method Download PDFInfo
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- CN102911122A CN102911122A CN2012104435164A CN201210443516A CN102911122A CN 102911122 A CN102911122 A CN 102911122A CN 2012104435164 A CN2012104435164 A CN 2012104435164A CN 201210443516 A CN201210443516 A CN 201210443516A CN 102911122 A CN102911122 A CN 102911122A
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- metronidazole
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- oxyethane
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 title claims abstract description 95
- 229960000282 metronidazole Drugs 0.000 title claims abstract description 94
- 238000002360 preparation method Methods 0.000 title claims abstract description 68
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 235000019253 formic acid Nutrition 0.000 claims abstract description 29
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 75
- 239000012043 crude product Substances 0.000 claims description 49
- 238000002425 crystallisation Methods 0.000 claims description 42
- 230000008025 crystallization Effects 0.000 claims description 42
- 239000007788 liquid Substances 0.000 claims description 41
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 41
- 239000012452 mother liquor Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 238000006396 nitration reaction Methods 0.000 claims description 31
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 25
- 239000008213 purified water Substances 0.000 claims description 19
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 18
- 238000006386 neutralization reaction Methods 0.000 claims description 18
- 230000033444 hydroxylation Effects 0.000 claims description 16
- 238000005805 hydroxylation reaction Methods 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 8
- 238000009413 insulation Methods 0.000 claims description 8
- 230000003068 static effect Effects 0.000 claims description 8
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 230000002378 acidificating effect Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 3
- 239000001117 sulphuric acid Substances 0.000 abstract description 3
- 235000011149 sulphuric acid Nutrition 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract 4
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 abstract 2
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 abstract 1
- 239000008186 active pharmaceutical agent Substances 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000003921 oil Substances 0.000 description 47
- 239000000126 substance Substances 0.000 description 16
- 229910017053 inorganic salt Inorganic materials 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 241001046548 Anaerobium Species 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 206010058674 Pelvic Infection Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- -1 nitro glyoxaline Chemical compound 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicine manufacturing techniques, in particular to a metronidazole API preparation method, and solves the problems that a current metronidazole preparation method is high in cost and low in yield. The method comprises the following steps: (1), acid mixing, adding 100 parts (by weight) of formic acid of concentration of 95-99 percent in a reaction kettle for stirring to a temperature of 20 DEG C, then adding 25-35 parts (by weight) of concentrated sulphuric acid, so as to prepare the mixed acid for further use; (2), synthesis reaction, adding 100-120 parts (by weight) of reaction raw materials 2-methyl-5-nitroimidazole into a reaction tank, and adding the mixed acid prepared in the step 1, stirring to a temperature of 75-80 DEG C, completely dissolving the 2-methyl-5-nitroimidazole, and maintaining 10-20 minutes. According to the invention, the design is reasonable; and the mixed acid is adopted to provide an acidic condition, an applicable reaction raw material ratio and an appropriate control reaction parameter, so as to allow the yield of the nitroimidazole to reach 65-70 percent.
Description
Technical field
The present invention relates to medical manufacturing technology field, be specially a kind of preparation method of metronidazole.
Background technology
Metronidazole has another name called Metronidazole plain BP.98 99, metronidazole, metronidazole, Metronidazole etc., and chemistry Metronidazole (2-methyl-5-nitroimidazole-1-ethanol) by name is the nitro glyoxaline synthetic antibacterial drug.Very extensive in clinical application, have wide spectrum anaerobe resistant and antiprotozoal effect, clinically be mainly used in prevention and treatment anaerobism microbial infection, such as respiratory tract, digestive tube, abdominal cavity and pelvic infection, the endocarditis that the infection at the positions such as skin soft tissue, bone and osteoarthrosis and bacteroides fragilis cause, cerebral abscess, septicemia and meningitis etc. are widely used in prevention in addition and the treatment oral cavity anaerobium infects.The nitro of metronidazole is reduced into amino and has the anaerobe resistant effect in oxygen-free environment, then invalid to aerophil or facultative aerobe.
As shown in Figure 2, to be raw material 2-5-nitro imidazole issue intercrescence with oxyethane at acidic conditions becomes reaction, generates the reaction formula of metronidazole (Metronidazole).In the prior art, mostly just adopt formic acid that acidic conditions is provided, but, the problem that this kind formic acid method suitability for industrialized production metronidazole bulk drug exists is, in a large amount of generations of industry, can consume a large amount of formic acid, and the price of formic acid is relatively more expensive, thereby so that production cost is high, simultaneously, the existence of a large amount of formic acid is all very unfavorable to volume of equipment rate and solvent recuperation energy consumption in the building-up reactions.In addition, 2-5-nitro imidazole and oxyethane also are difficult to reaction thoroughly in formic acid, cause the transformation efficiency of 2-5-nitro imidazole lower, and the yield of metronidazole is also lower so, usually about 50%; And in the process of preparation metronidazole, the unreasonable yield that also can affect metronidazole of the control of reaction parameter, reaction raw materials proportioning further increases industrialized cost.
Therefore, be necessary the production method of existing formic acid method production metronidazole bulk drug is done some improvement, reduce industrial production cost.
Summary of the invention
One object of the present invention is that there is the problem that cost is high, yield is low in the method that solves the standby metronidazole bulk drug of existing formic acid legal system; Another object of the present invention is by reasonable control reaction parameter, improves the yield of metronidazole, and a kind of preparation method who produces the metronidazole bulk drug is provided.
The present invention adopts following technical scheme to realize:
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: formic acid 100 weight parts of concentration 95%～99% are put in the reactor, added vitriol oil 25-35 weight part, it is for subsequent use to make nitration mixture;
(2), building-up reactions: reaction raw materials 2-5-nitro imidazole 100-120 weight part is put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 75-80 ℃, dissolve rear insulation 10～20 minutes fully until the 2-5-nitro imidazole, add oxyethane 90～100 weight parts, the vitriol oil 7～9 weight parts, generate hydroxylation liquid after the reaction;
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 25～35 ℃, and it is 2.0～2.5 that the dropping liquid caustic soda is neutralized to pH value, then be cooled to 15～20 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, and it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, it is 10.0～11.0 that the dropping liquid caustic soda is neutralized to the pH value, then controls temperature and carry out crystallization under 20～25 ℃, after to be crystallized the finishing, centrifugal rejection filter, collecting filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, and it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.0～7.0 with sulfuric acid after, control temperature static crystallization under 40 ℃ of conditions, after to be crystallized the finishing, rejection filter is dried, and namely obtains the metronidazole crude product;
(6), decolouring crystallization: in bleacher, add purified water, the metronidazole crude product, the gac that add successively afterwards step (5) preparation, decolour after 30 minutes, press filtration adds bicarbonate of ammonia to crystallizer, stirred crystallization, after to be crystallized the finishing, centrifugal rejection filter, oven dry, namely obtain the metronidazole highly finished product, the weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
The described vitriol oil is the general industry vitriol oil, refers to the sulphuric acid soln of concentration (the concentration here refers to the mass percent of sulfuric acid in the aqueous solution of sulfuric acid) more than or equal to 70%.
The sulfuric acid of described neutralization usefulness adopts the used sulphuric acid soln of common laboratory.
Described liquid caustic soda can adopt the used sodium hydroxide of common laboratory or potassium hydroxide solution.
The water of the described purified water hyoscine that to be tap water make through distillation method, ion exchange method, reverse osmosis method or other suitable methods does not contain any additive.
Described oxyethane is a kind of organic compound, and chemical formula is C
2H
4O for the simplest a kind of cyclic ethers, belongs to heterocyclic compound, is important petroleum chemicals.Oxyethane is colourless transparent liquid at low temperatures, is colourless gas with irritating smell at normal temperatures.When adding oxyethane in the present invention, all be by pipeline oxyethane to be put in the retort with the form of gas.
The chemical formula of described formic acid is CH
2OH is colourless transparent liquid.
Described reactor, retort, time nitre tank, crystallizer, bleacher all are production units commonly used in this area.
Described crystallization, centrifugal, rejection filter etc. all are the routine techniques means in this area.
Issuing intercrescence with oxyethane at acidic conditions at the 2-5-nitro imidazole becomes reaction to produce in the process of metronidazole (Metronidazole), the present invention adopts nitration mixture to replace purely utilizing formic acid as the acidic conditions of reaction, the ratio of formic acid and the vitriol oil is suitable in the nitration mixture, if formic acid too much then produce waste, formic acid does not then have due effect very little, in the situation that drops into same reaction substrate, if purely use formic acid, the usage quantity of formic acid will be 5 times of the used formic acid consumption of the present invention, and, the price of the vitriol oil is cheap more a lot of than formic acid, can find out, technical scheme of the present invention has been saved the usage quantity of formic acid greatly, reduce cost, be beneficial to suitability for industrialized production.And the nitration mixture that uses formic acid and the vitriol oil to prepare has also promoted the thorough reaction of 2-5-nitro imidazole and oxyethane simultaneously, has further improved the yield of metronidazole.
Be beneficial to twice neutralization reaction of step (3) and (4), once under the slant acidity condition, separate out completely 2-5-nitro imidazole of unreacted, once under the meta-alkalescence condition, separate out completely 2-5-nitro imidazole of unreacted, accomplished the abundant recovery to reaction substrate 2-5-nitro imidazole, save the use of reaction raw materials, also further reduced production cost.
In the preparation of metronidazole highly finished product, control the pH value of reaction solution by utilizing bicarbonate of ammonia, and at normal temperatures, the metronidazole raw product is dissolved in the purified water control metronidazole raw product, purified water, gac, the ratio that bicarbonate of ammonia is suitable after fully stirring, so that the sufficient crystallization of metronidazole, not only further improve the yield of metronidazole, and, conventional heating for dissolving means do not adopted, also saved the consumption of energy, be conducive to save production cost.
Preferably, in step (2), oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: added equably oxyethane for the first time in 40～70 minutes, be incubated after 10～15 minutes, add the vitriol oil first time; Afterwards, in 40～70 minutes, add equably oxyethane for the second time, be incubated after 10～15 minutes, add the vitriol oil for the second time; Afterwards, in 60～70 minutes, add equably for the third time oxyethane, be incubated after 10～15 minutes, add for the third time the vitriol oil; Afterwards, in 50～70 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
Issuing intercrescence with oxyethane in the nitration mixture condition at the 2-5-nitro imidazole becomes reaction to generate in the process of metronidazole (Metronidazole), oxyethane divides four times, the vitriol oil to divide to join in the reaction solution for three times, purpose is the control synthesising reacting speed, make mild the carrying out of reaction, and can promote reaction thoroughly, finally generate more metronidazole, further improved the yield of metronidazole.
Use method of the present invention, utilize nitration mixture that acidic conditions, suitable reaction raw materials proportioning, suitable control reaction parameter are provided, so that the transformation efficiency of 2-5-nitro imidazole can reach 65-70%, the yield of metronidazole can reach the 65-70% of theoretical amount, the metronidazole crude product is behind recrystallizing and refining, and the quality of metronidazole highly finished product meets China's pharmacopeia requirement fully.
The yield here refers in chemical reaction or relevant chemical industry are produced, the ratio of the product production of the actual production that input unit's quantity raw material obtains and the product production of Theoretical Calculation.
The present invention is reasonable in design, and there is the problem that cost is high, yield is low in the method that has solved the standby metronidazole of existing formic acid legal system.
Description of drawings
Fig. 1 is the block diagram of the method for the invention.
To be the 2-5-nitro imidazole issue intercrescence with oxyethane at acidic conditions to Fig. 2 becomes reaction.
Embodiment
The below is elaborated to specific embodiments of the invention.
Embodiment 1
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 97% (every part of 1kg, as follows be) is put in the reactor, added 30 parts of the vitriol oils, it is for subsequent use to make nitration mixture;
(2), building-up reactions: 120 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 75 ℃, dissolve rear insulation 15 minutes fully until the 2-5-nitro imidazole, add 98 parts in oxyethane, 8 parts of the vitriol oils, generate hydroxylation liquid after the reaction;
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 28 ℃, and it is 2.0 that dropping sodium hydroxide (NaOH) is neutralized to pH value, then be cooled to 15 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, it is 10.5 that dropping sodium hydroxide is neutralized to the pH value, then controls temperature and carry out crystallization under 23 ℃, after to be crystallized the finishing, centrifugal rejection filter, collecting filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.0 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 3.5 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
Embodiment 2
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 95% (every part of 10kg, as follows be) is put in the reactor, and the control temperature adds 27 parts of the vitriol oils between 20～25 ℃, and it is for subsequent use to make nitration mixture; The main purpose of control temperature between 20～25 ℃ is that the vitriol oil splashes and hurts sb.'s feelings when preventing from preparing nitration mixture when adding the vitriol oil;
(2), building-up reactions: 115 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 80 ℃, dissolve rear insulation 10 minutes fully until the 2-5-nitro imidazole, add 95 parts in oxyethane, 7 parts of the vitriol oils, generate hydroxylation liquid after the reaction;
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 25 ℃, and it is 2.3 that dropping sodium hydroxide (NaOH) is neutralized to pH value, then be cooled to 17 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, and dripping sodium hydroxide, to be neutralized to the pH value be 10.3, then control temperature and carry out crystallization at 20 ℃, after to be crystallized the finishing, centrifugal rejection filter, the collection filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.5 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 3 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
Embodiment 3
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 98% (every part of 5kg, as follows be) is put in the reactor, and the control temperature adds 25 parts of the vitriol oils between 20～25 ℃, and it is for subsequent use to make nitration mixture;
(2), building-up reactions: 110 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 76 ℃, dissolve rear insulation 17 minutes fully until the 2-5-nitro imidazole, add 100 parts in oxyethane, 8.5 parts of the vitriol oils, generate hydroxylation liquid after the reaction; Wherein, oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: added equably oxyethane for the first time in 40 minutes, be incubated after 15 minutes, add the vitriol oil first time; Afterwards, in 50 minutes, add equably oxyethane for the second time, be incubated after 10 minutes, add the vitriol oil for the second time; Afterwards, in 60 minutes, add equably for the third time oxyethane, be incubated after 10 minutes, add for the third time the vitriol oil; Afterwards, in 50 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 30 ℃, and it is 2.2 that dropping sodium hydroxide (NaOH) is neutralized to pH value, then be cooled to 20 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, and dripping sodium hydroxide, to be neutralized to the pH value be 10, then control temperature and carry out crystallization at 22 ℃, after to be crystallized the finishing, centrifugal rejection filter, the collection filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 7.0 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 4.5 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
After testing, the yield of metronidazole is about 66%.
Embodiment 4
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 96% (every part of 2kg, as follows be) is put in the reactor, and the control temperature adds 33 parts of the vitriol oils between 20～25 ℃, and it is for subsequent use to make nitration mixture;
(2), building-up reactions: 116 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 80 ℃, dissolve rear insulation 18 minutes fully until the 2-5-nitro imidazole, add 93 parts in oxyethane, 9 parts of the vitriol oils, generate hydroxylation liquid after the reaction; Wherein, oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: added equably oxyethane for the first time in 60 minutes, be incubated after 13 minutes, add the vitriol oil first time; Afterwards, in 40 minutes, add equably oxyethane for the second time, be incubated after 15 minutes, add the vitriol oil for the second time; Afterwards, in 65 minutes, add equably for the third time oxyethane, be incubated after 12 minutes, add for the third time the vitriol oil; Afterwards, in 70 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 30 ℃, and it is 2.2 that dropping sodium hydroxide (NaOH) is neutralized to pH value, then be cooled to 20 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, and dripping sodium hydroxide, to be neutralized to the pH value be 10, then control temperature and carry out crystallization at 22 ℃, after to be crystallized the finishing, centrifugal rejection filter, the collection filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 7.0 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 4.5 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
After testing, the yield of metronidazole is about 70%.
Embodiment 5
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 99% (every part of 15kg, as follows be) is put in the reactor, and the control temperature adds 35 parts of the vitriol oils between 20～25 ℃, and it is for subsequent use to make nitration mixture;
(2), building-up reactions: 118 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 78 ℃, dissolve rear insulation 20 minutes fully until the 2-5-nitro imidazole, add 90 parts in oxyethane, 7.5 parts of the vitriol oils, generate hydroxylation liquid after the reaction; Wherein, oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: added equably oxyethane for the first time in 50 minutes, be incubated after 12 minutes, add the vitriol oil first time; Afterwards, in 70 minutes, add equably oxyethane for the second time, be incubated after 12 minutes, add the vitriol oil for the second time; Afterwards, in 65 minutes, add equably for the third time oxyethane, be incubated after 15 minutes, add for the third time the vitriol oil; Afterwards, in 60 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 35 ℃, and it is 2.1 that dropping sodium hydroxide (NaOH) is neutralized to pH value, then be cooled to 16 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, and dripping sodium hydroxide, to be neutralized to the pH value be 10.1, then control temperature and carry out crystallization at 24 ℃, after to be crystallized the finishing, centrifugal rejection filter, the collection filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.4 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 4 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
After testing, the yield of metronidazole is about 68%.
Embodiment 6
A kind of preparation method of metronidazole comprises the steps:
(1), nitration mixture: 100 parts in the formic acid of concentration 95% (every part of 20kg, as follows be) is put in the reactor, and the control temperature adds 32 parts of the vitriol oils between 20～25 ℃, and it is for subsequent use to make nitration mixture;
(2), building-up reactions: 117 parts of reaction raw materials 2-5-nitro imidazoles are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 77 ℃, dissolve rear insulation 12 minutes fully until the 2-5-nitro imidazole, add 96 parts in oxyethane, 8 parts of the vitriol oils, generate hydroxylation liquid after the reaction; Wherein, oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: added equably oxyethane for the first time in 50 minutes, be incubated after 10 minutes, add the vitriol oil first time; Afterwards, in 70 minutes, add equably oxyethane for the second time, be incubated after 13 minutes, add the vitriol oil for the second time; Afterwards, in 70 minutes, add equably for the third time oxyethane, be incubated after 14 minutes, add for the third time the vitriol oil; Afterwards, in 65 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 27 ℃, and it is 2 that dropping potassium hydroxide (KOH) is neutralized to pH value, then be cooled to 19 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, and dripping potassium hydroxide, to be neutralized to the pH value be 10.7, then control temperature and carry out crystallization at 21 ℃, after to be crystallized the finishing, centrifugal rejection filter, the collection filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, washes with water to neutrality, and behind the chemical examination inorganic salt qualified (meeting national relevant regulations), it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.3 with sulfuric acid after, control temperature in static crystallization below 40 ℃ (about 5 hours), after to be crystallized the finishing, rejection filter, oven dry namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
After testing, the yield of metronidazole is about 68%.
Claims (5)
1. the preparation method of a metronidazole is characterized in that: comprise the steps:
(1), nitration mixture: formic acid 100 weight parts of concentration 95%～99% are put in the reactor, added the vitriol oil 25～35 weight parts, it is for subsequent use to make nitration mixture;
(2), building-up reactions: reaction raw materials 2-5-nitro imidazole 100～120 weight parts are put in the retort, the nitration mixture that adds step (1) preparation, the control temperature is at 75～80 ℃, dissolve rear insulation 10～20 minutes fully until the 2-5-nitro imidazole, add oxyethane 90～100 weight parts, vitriol oil 7-9 weight part, generate hydroxylation liquid after the reaction;
(3), once neutralization: the hydroxylation liquid of step (2) preparation is dropped into back in the nitre tank, and the control temperature is at 25～35 ℃, and it is 2.0～2.5 that the dropping liquid caustic soda is neutralized to pH value, then be cooled to 15～20 ℃ and carry out crystallization, after to be crystallized the finishing, centrifugal rejection filter is collected filtered liquid and is back that the nitre mother liquor is for subsequent use; This crystallisate is completely 2-5-nitro imidazole of unreacted, and it is synthetic to be used for next time;
(4), secondary neutralization: the nitre mother liquor that returns of step (3) preparation is joined back in the nitre tank, it is 10.0～11.0 that the dropping liquid caustic soda is neutralized to the pH value, then controls temperature and carry out crystallization under 20～25 ℃, after to be crystallized the finishing, centrifugal rejection filter, collecting filtered liquid is the crude product mother liquor; This crystallisate is completely 2-5-nitro imidazole of unreacted, and it is synthetic to be used for next time;
(5), metronidazole crude product preparation: the crude product mother liquor of step (4) preparation is dropped into back in the nitre tank, be neutralized to pH value 6.0～7.0 with sulfuric acid after, control temperature in static crystallization below 40 ℃, after to be crystallized the finishing, rejection filter is dried, and namely obtains the metronidazole crude product;
(6), decolouring crystallization: add purified water in bleacher, add successively afterwards metronidazole crude product, the gac of step (5) preparation, decolour after 30 minutes, press filtration is to crystallizer, add bicarbonate of ammonia, stirred crystallization is after to be crystallized the finishing, centrifugal rejection filter, oven dry namely obtains the metronidazole highly finished product; The weight ratio of described purified water, metronidazole crude product, gac, bicarbonate of ammonia is 500:100:3:10.
2. the preparation method of metronidazole according to claim 1, it is characterized in that: in step (2), oxyethane divides four times, the vitriol oil to divide to join in the retort for three times, be specially: in 40～70 minutes, add equably oxyethane for the first time, be incubated after 10～15 minutes, add the vitriol oil for the first time; Afterwards, in 40～70 minutes, add equably oxyethane for the second time, be incubated after 10～15 minutes, add the vitriol oil for the second time; Afterwards, in 60～70 minutes, add equably for the third time oxyethane, be incubated after 10～15 minutes, add for the third time the vitriol oil; Afterwards, in 50～70 minutes, add equably oxyethane the 4th time; The ratio that adds amount of ethylene oxide for four times is 4:4:2:1, and the ratio of three adding vitriol oil amounts is 2:3:1.
3. the preparation method of metronidazole according to claim 1 and 2 is characterized in that: in the nitration mixture process of step (1), control temperature when adding the vitriol oil at 20～25 ℃.
4. the preparation method of metronidazole according to claim 1 and 2, it is characterized in that: described liquid caustic soda is sodium hydroxide.
5. the preparation method of metronidazole according to claim 3, it is characterized in that: described liquid caustic soda is sodium hydroxide.
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| CN103483265A (en) * | 2013-09-05 | 2014-01-01 | 湖北省宏源药业有限公司 | Metronidazole production method |
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