CN108203411A - A kind of method of high-pressure synthesis metronidazole - Google Patents
A kind of method of high-pressure synthesis metronidazole Download PDFInfo
- Publication number
- CN108203411A CN108203411A CN201611203338.2A CN201611203338A CN108203411A CN 108203411 A CN108203411 A CN 108203411A CN 201611203338 A CN201611203338 A CN 201611203338A CN 108203411 A CN108203411 A CN 108203411A
- Authority
- CN
- China
- Prior art keywords
- pressure
- ethylene oxide
- metronidazole
- passed
- amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960000282 metronidazole Drugs 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 238000006396 nitration reaction Methods 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 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 description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 238000004140 cleaning Methods 0.000 claims description 5
- 230000000630 rising effect Effects 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 2
- 208000004881 Amebiasis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010011668 Cutaneous leishmaniasis Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 208000000291 Nematode infections Diseases 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 208000007456 balantidiasis Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods of high-pressure synthesis metronidazole, it solves the problems, such as that the utilization rate of prior art ethylene oxide is low, it is characterised in that：Using at elevated pressures, ethylene oxide is more soluble in the characteristic of nitration mixture solvent, and metronidazole synthetic reaction is allowed to be carried out in enclosed system with pressure, and ethylene oxide more than arrival liquid level is made also to be soluble in participating in reaction in solution.The beneficial effects of the invention are as follows：Not only the utilization rate of ethylene oxide had been improved, but also has alleviated its pollution to environment.
Description
First, technical field
The invention belongs to organic synthesis, resource reclaim and field of environment protection, more particularly to a kind of high-pressure synthesis metronidazole
Method.
2nd, background technology
Metronidazole is white or yellowish crystallization or crystalline powder, for treating enteron aisle and parenteral amcbiasis (such as
Amebic abscess, pleura amcbiasis etc.).It can also be used to treat trichomoniasis, balantidiasis and cutaneous Leishmaniasis, wheat
That imperial nematode infections of ground etc..It is also widely used in the treatment of anaerobic infection at present, anti-anaerobism is used as by the World Health Organization (WHO)
The choice drug of bacterium.
Metronidazole synthesize using the mixed acid of formic acid and sulfuric acid as solvent, 2- 5-nitro imidazoles be precursor compound, ring
Oxidative ethane is hydroxylation agent.Since ethylene oxide boiling point is 10.8 DEG C, and reaction temperature is 90 DEG C, so it is to join in a gaseous form
With reacting.Current technology is passed through ethylene oxide to reaction kettle bottom, has little time more than the ethylene oxide arrival liquid level of dissolving to arrange
Go out outside kettle, be no longer participate in reacting.Utility model patent metronidazole hydroxylation reaction kettle (201020227836.2), by autoclave body height with
The increase of the ratio between internal diameter；Utility model patent metronidazole hydroxylation reaction kettle ethylene oxide access equipment (201020247143.X), changes
The kind distribution situation for being passed through gas；A kind of Processes and apparatus for improving metronidazole raw materials for production utilization rate of ethylene oxide of patent of invention
(201310215220.1), using the measure of three kettles series winding and multi-stage condensing.Although above three patent all increases to some extent
Add ethylene oxide and the catalytic chance of material, but since they are all to open wide in system to be reacted in normal pressure, so
Still there are a large amount of ethylene oxide for having little time reaction to be discharged outside kettle as tail gas, so that the utilization rate of ethylene oxide is relatively low.
3rd, invention content
It is an object of the invention to be directed to existing metronidazole production technology there are the shortcomings that, a kind of high-pressure synthesis first nitre is provided
The method of azoles.
The present invention technical characteristic be：Using at elevated pressures, ethylene oxide is more soluble in the characteristic of nitration mixture solvent, allows
Metronidazole synthetic reaction carries out in enclosed system with pressure, and ethylene oxide more than arrival liquid level is made also to be soluble in participating in instead in solution
It should.Its operating procedure is as follows：
1) into pressure-resistant reaction kettle, a certain amount of formic acid, sulfuric acid and 2- 5-nitro imidazoles are added in；
2) after cleaning checks pressure safety valve, sealing kettle cover is covered, selectively replaces pressure-resistant reaction kettle with ethylene oxide
The air of interior superjacent；
3) according to the voltage endurance capability of pressure-resistant reaction kettle, pressure control value is set；
4) it selectively stirs；
5) ethylene oxide slowly is passed through to pressure-resistant reactor bottom, when temperature and pressure rising is very fast, turns down and be passed through
Amount of ethylene oxide when pressure is close to pressure control value, further turns or suspends being passed through amount of ethylene oxide down, when temperature is relatively low, and presses
When power is far from pressure control value, slightly tunes up and be passed through amount of ethylene oxide；
6) lead to and finish, insulation reaction 1-12 hours detaches to obtain metronidazole product.
The beneficial effects of the invention are as follows：It reaches ethylene oxide more than liquid level also to be soluble in participating in reaction in solution, both improve
The utilization rate of ethylene oxide, and alleviate its pollution to environment.
5th, specific embodiment
Below by embodiment, the present invention is further illustrated.
Embodiment 1：
1) into pressure-resistant reaction kettle, input itrated compound 150kg, formic acid 105kg and sulfuric acid 95kg；
2) after cleaning checks pressure safety valve, sealing kettle cover is covered；
3) pressure control value (gauge pressure) is set as 1.013 × 106Pa；
4) ethylene oxide 54kg slowly is passed through to pressure-resistant reactor bottom, when temperature and pressure rising is very fast, turned down
Amount of ethylene oxide is passed through, when pressure is close to pressure control value, further turns or suspend being passed through amount of ethylene oxide down, when temperature is relatively low,
And pressure far from pressure control value when, slightly tune up and be passed through amount of ethylene oxide；
5) lead to and finish, keep the temperature 89-93 DEG C, react 1-12 hours, detach to obtain metronidazole product.
Embodiment 2：
1) into pressure-resistant reaction kettle, input itrated compound 150kg, formic acid 105kg and sulfuric acid 95kg；
2) after cleaning checks pressure safety valve, sealing kettle cover is covered, is replaced in pressure-resistant reaction kettle on solution with ethylene oxide
The air of side；
3) pressure control value (gauge pressure) is set as 0.5 × 105Pa；
4) it stirs；
5) ethylene oxide 54kg slowly is passed through to pressure-resistant reactor bottom, when temperature and pressure rising is very fast, turned down
Amount of ethylene oxide is passed through, when pressure is close to pressure control value, further turns or suspend being passed through amount of ethylene oxide down, when temperature is relatively low,
And pressure far from pressure control value when, slightly tune up and be passed through amount of ethylene oxide；
6) lead to and finish, keep the temperature 89-93 DEG C, react 1-12 hours, detach to obtain metronidazole product.
Embodiment 3：
1) into pressure-resistant reaction kettle, input itrated compound 150kg, formic acid 105kg and sulfuric acid 95kg；
2) after cleaning checks pressure safety valve, sealing kettle cover is covered,；
3) pressure control value (gauge pressure) is set as 1.013 × 105Pa；
4) it stirs；
5) ethylene oxide 54kg slowly is passed through to pressure-resistant reactor bottom, when temperature and pressure rising is very fast, turned down
Amount of ethylene oxide is passed through, when pressure is close to pressure control value, further turns or suspend being passed through amount of ethylene oxide down, when temperature is relatively low,
And pressure far from pressure control value when, slightly tune up and be passed through amount of ethylene oxide；
6) lead to and finish, keep the temperature 89-93 DEG C, react 1-12 hours, detach to obtain metronidazole product.
Above-mentioned 3 embodiments, the yield of metronidazole higher than current technology, the utilization rate of ethylene oxide all reach 50% with
On.
Claims (1)
1. a kind of method of high-pressure synthesis metronidazole, technical characteristic are：Using at elevated pressures, ethylene oxide is more soluble in
The characteristic of nitration mixture solvent allows metronidazole synthetic reaction to be carried out in enclosed system with pressure, makes ethylene oxide more than arrival liquid level
It also is soluble in participating in reaction in solution.Its operating procedure is as follows：
1) into pressure-resistant reaction kettle, a certain amount of formic acid, sulfuric acid and 2- 5-nitro imidazoles are added in；
2) after cleaning checks pressure safety valve, sealing kettle cover is covered, is selectively replaced with ethylene oxide molten in pressure-resistant reaction kettle
Air above liquid；
3) according to the voltage endurance capability of pressure-resistant reaction kettle, pressure control value is set；
4) it selectively stirs；
5) ethylene oxide slowly is passed through to pressure-resistant reactor bottom, when temperature and pressure rising is very fast, turns down and be passed through epoxy
Ethane amount when pressure is close to pressure control value, further turns or suspends being passed through amount of ethylene oxide down, when temperature is relatively low, and pressure is remote
During from pressure control value, slightly tune up and be passed through amount of ethylene oxide；
6) lead to and finish, insulation reaction 1-12 hours detaches to obtain metronidazole product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611203338.2A CN108203411A (en) | 2016-12-19 | 2016-12-19 | A kind of method of high-pressure synthesis metronidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611203338.2A CN108203411A (en) | 2016-12-19 | 2016-12-19 | A kind of method of high-pressure synthesis metronidazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108203411A true CN108203411A (en) | 2018-06-26 |
Family
ID=62603244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611203338.2A Pending CN108203411A (en) | 2016-12-19 | 2016-12-19 | A kind of method of high-pressure synthesis metronidazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108203411A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4241060A (en) * | 1977-08-19 | 1980-12-23 | Hoffmann-La Roche Inc. | Nitroimidazoles and compositions thereof |
| CN201783324U (en) * | 2010-06-25 | 2011-04-06 | 黄冈银河阿迪药业有限公司 | Ethylene oxide filling device of metronidazole hydroxylation reactor |
| CN102911122A (en) * | 2012-11-08 | 2013-02-06 | 兰亚朝 | Metronidazole preparation method |
| CN103342681A (en) * | 2013-05-31 | 2013-10-09 | 黄冈银河阿迪药业有限公司 | Process and device for improving utilization rate of ethylene oxide of metronidazole production raw materials |
| CN104177297A (en) * | 2013-05-20 | 2014-12-03 | 东港市宏达制药有限公司 | Clean production method for synthesizing metronidazole by using bulk drugs |
| CN105348200A (en) * | 2015-12-23 | 2016-02-24 | 武汉武药制药有限公司 | Environment-friendly method for metronidazole synthesis |
-
2016
- 2016-12-19 CN CN201611203338.2A patent/CN108203411A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4241060A (en) * | 1977-08-19 | 1980-12-23 | Hoffmann-La Roche Inc. | Nitroimidazoles and compositions thereof |
| CN201783324U (en) * | 2010-06-25 | 2011-04-06 | 黄冈银河阿迪药业有限公司 | Ethylene oxide filling device of metronidazole hydroxylation reactor |
| CN102911122A (en) * | 2012-11-08 | 2013-02-06 | 兰亚朝 | Metronidazole preparation method |
| CN104177297A (en) * | 2013-05-20 | 2014-12-03 | 东港市宏达制药有限公司 | Clean production method for synthesizing metronidazole by using bulk drugs |
| CN103342681A (en) * | 2013-05-31 | 2013-10-09 | 黄冈银河阿迪药业有限公司 | Process and device for improving utilization rate of ethylene oxide of metronidazole production raw materials |
| CN105348200A (en) * | 2015-12-23 | 2016-02-24 | 武汉武药制药有限公司 | Environment-friendly method for metronidazole synthesis |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180626 |