WO2015198107A1 - Synthesis of metronidazole - Google Patents
Synthesis of metronidazole Download PDFInfo
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- WO2015198107A1 WO2015198107A1 PCT/IB2014/064597 IB2014064597W WO2015198107A1 WO 2015198107 A1 WO2015198107 A1 WO 2015198107A1 IB 2014064597 W IB2014064597 W IB 2014064597W WO 2015198107 A1 WO2015198107 A1 WO 2015198107A1
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- methyl
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- water
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- 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
Definitions
- the technical field of this invention concerns pharmaceutical production using "organic chemistry” science.
- the producers utilize costly and unique active ingredients to produce metronidazole synthesis which has to be imported from other countries; consequently the cost of its production rises greatly. Furthermore, this drug has side effect in the present methods of production. Overusing usual samples leads to kidney stone in the patient's body.
- the purpose of this invention is to remove the mentioned defects.
- Producing metronidazole using the new method does not require utilizing costly and unique active ingredients for the producer and production process can be done with a lower cost.
- its production using the new method has fewer side effects rather than the previous methods.
- the active ingredients which are used for metronidazole synthesis are as follows, some of them have to be made: First matter: 2- methyl, 4 and 5 dihydromidazole (2 Methyl lipidazolin, Lysidine) Second matter: N, N diacetyl anhydride amin that must be made
- distillation temperature is 185-190
- the solution can be separated bynon-aqueous organic solvent (Isopropanol - dichloroethane - difenin Oxide).
- N N diacetyl anhydride is produced.
- N 16/8 g of the second matter, N, N diacetyl anhydride, is distilled and then it is mixed with 0/7 - 3/3 gram of Raney nickel humid mixture and heated up to 170-175 c under cold weather condenser. After that we gradually heat it by a heater up to 220 c. reaction time is 60-90 minutes and depends on the catalyst amount (Palladium amount is nearly at the tip of spatula). Next, it is filtered. The solution is separated by vacuum and remaining Chrystal is dried at 40-50 c.
- the mixture is cooled down to 20 c and the remaining amount of 2 methyl imidazole which has been separated is filtered and dissociated by cold toluene. In the temperature of 40-50 c, it is dried by oven.
- the second step of fourth matter production 2 methyl 5 and 5 nitro imidazole
- the mixture is boiled for 4 hours within 130 to 132 degrees.
- the solution is cooled down to 60- 70 c by 1200 ml water which has been added and it is neutralized by 25% aqua ammonia.
- the rate of reaction is 164 g from the previous products.
- nitro imidazole mixture appropriate for fifth matter synthesis is: 1- beta hydroxyethyl 1-, 2 methyl 5 nitroimidazole (nitronidazole) without any need to be filtered.
- Fifth material 1-beta hydroxy ethyl 1-, 2 methyl 5 nitroimidazole (nitronidazole)
- the mixture will stay in 25-30c temperature for 2 hours and then it is diluted with 800 ml water and cooled down to 2-5 c and it will be kept in this temperature for 4 to 5 hours.
- the matters which were not involved in the reaction will be separated by Buchner and washed by water and dried in the oven in 60-70 c. Therefore, 5/5-10 gram of 2 methyl 4, or 5 nitroimidazole is formed again and utilized in the next stage. Since the obtained matter is acidic, it is washed and diluted with 50 ml of aqua ammonia 25% in PH-10.
- the hot mixture is cooled down to 2-5 c, kept in the same temperature, then separated by Buchner, washed by distilled water and dried in the oven within 70-80c.
- This invention is applicable for all pharmacists all over the world.
- the formula of this drug can be utilized in the pharmaceutical factories for production.
- This invention is applicable in pharmaceutical industry
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The producers utilize costly and unique active ingredients to produce metronidazole synthesis which has to be imported from other countries; consequently the cost of its production rises greatly. Furthermore, this drug has side effect in the present methods of production. Overusing usual samples leads to kidney stone in the patient's body. The purpose of this invention is to remove the mentioned defects. Producing metronidazole using the new method does not require utilizing costly and unique active ingredients for the producer and production process can be done with a lower cost. In addition, its production using the new method has fewer side effects rather than the previous methods.
Description
SYNTHESIS OF METRONIDAZOLE
Description
Technical field of invention:
The technical field of this invention concerns pharmaceutical production using "organic chemistry" science.
Technical problem:
The producers utilize costly and unique active ingredients to produce metronidazole synthesis which has to be imported from other countries; consequently the cost of its production rises greatly. Furthermore, this drug has side effect in the present methods of production. Overusing usual samples leads to kidney stone in the patient's body. The purpose of this invention is to remove the mentioned defects.
Background of the invention:
Reviewing the inventions concerning the methods of metronidazole production signifies that there has still been no method using inexpensive and simple methods as this invention. Furthermore, no progress has been made for the side effects of the available metronidazole. Presenting solutions for the technical problems followed by the detailed description of the invention.
Detailed description of the invention:
Producing metronidazole using the new method does not require utilizing costly and unique active ingredients for the producer and production process can be done with a lower cost. In addition, its production using the new method has fewer side effects rather than the previous methods.
The active ingredients which are used for metronidazole synthesis are as follows, some of them have to be made:
First matter: 2- methyl, 4 and 5 dihydromidazole (2 Methyl lipidazolin, Lysidine) Second matter: N, N diacetyl anhydride amin that must be made
Third matter: 2 methyl imidazole that must be made
Fourth matter: 2 methyl 4 Netronidazole
Fifth matter: 1 beta hydroxy ethyl 1 , 2 methyl nitroimidazole (nitronidazole)
The method for producing the second matter: N, iVdiacetyl anhydride
We add 1/5 mole 2 methyl 4 and 5 CH3COOH dihydromidazole (in a solid form or aqua solution) to the water (it can be done through a 250 ml beaker, we mix 20 ml dense acetic acid together with 80 ml water and 1/5 weighted mole in the beaker).
By adding 1.5 mole, first the solution is heated, then it is cooled by a frigid (ice) bathroom and dissolved in a 250 ml beaker with 0.5 mole of ethylenediamine (liquid) (in the form of 20-85 aqua solution). After that it is so much steamed in a reflux ( a three-neck flask, one of its neck is a condenser andthe other one is thermometer, and the other one is closed) that its temperature reaches 220-240 c. In this stage the pressure decreases and distillation is done (distillation temperature is 185-190), moreover, in addition to distillation, the solution can be separated bynon-aqueous organic solvent (Isopropanol - dichloroethane - difenin Oxide). Finally, in this process N, N diacetyl anhydride is produced.
Producing the third matter: Providing 2 methyl imidazole
First, 16/8 g of the second matter, N, N diacetyl anhydride, is distilled and then it is mixed with 0/7 - 3/3 gram of Raney nickel humid mixture and heated up to 170-175 c under cold weather condenser. After that we gradually heat it by a heater up to 220 c. reaction time is 60-90 minutes and depends on the catalyst amount (Palladium amount is nearly at the tip of spatula). Next, it is filtered. The solution is separated by vacuum and remaining Chrystal is dried at 40-50 c.
The mixture is resulted by 2 methyl imidazole. The minimum amount of its production is:
13/9-14/7 gram of imidazole (mp 139- 140) 11(86-90 c)
Based on statistics, in ideal temperature (available product): mp II- 140-143 c
The first step of fourth matter production: 2 methyl 4 nitromidazole
Mixture: 50ml of difeniloxid, and 7.5 gram nickel is heated by a heater in 190-250 c temperature in a flask (three-neck flask) with a condenser and a thermometer for an hour. The aqua mixture of nickel is cooled down to 20-30 c and then the heating continues up to 230 c and the same temperature is preserved for 2/5-3 hours so that hydrogen evolution process is completed. Then the mixture is cooled down to 155-165 c and is filtered and the catalyst (palladium) is washed in filter by the hot toluene.
The mixture is cooled down to 20 c and the remaining amount of 2 methyl imidazole which has been separated is filtered and dissociated by cold toluene. In the temperature of 40-50 c, it is dried by oven.
41/3-41/8 gram (mpl39-143 c)II of 2 methyl imidazole mixture has been obtained through the first or second method and it is going to be used in 2 methyl 4 nitroimidazole synthesis without extra filtering.
The second step of fourth matter production: 2 methyl 5 and 5 nitro imidazole
267 ml water, 352 ml of 93% sulfuric acid, 567 gram of aqua-free sulfuric sodium and 164 gram of 2 methyl imidazole are blended and heated up to the temperature of 130 c in condenser.
252 ml of HN0399% mixtureis gradually added to the hot solution by decanter drop by drop while it is stirred and heated. At the end of heating, the great evolution of nitrogen oxide occurs.
The mixture is boiled for 4 hours within 130 to 132 degrees. The solution is cooled down to 60- 70 c by 1200 ml water which has been added and it is neutralized by 25% aqua ammonia.
We continue adding ammonia up to 4-5 PH and the mixture is stirred for 30 minutes in the temperature of 30-40 c and then after 30 minutes it is deposited soit will be dissociated by Buchner and washed by water. Finally it will be dried by an oven up to 60-70 c.
The rate of reaction is 164 g from the previous products.
Based on statistics mp245c,2 methyl, 4 and 5 nitro imidazole mixture appropriate for fifth matter synthesis is: 1- beta hydroxyethyl 1-, 2 methyl 5 nitroimidazole (nitronidazole) without any need to be filtered.
Fifth material: 1-beta hydroxy ethyl 1-, 2 methyl 5 nitroimidazole (nitronidazole)
In a 2.5 liter flask, we add AC20 100ml (Acetic anhydride) to the water and wait for it to be cooled. Then we stir it and slowly add 76 ml of Phosphoric acid 85%. The temperature should not exceed 70-90 c. 63/5 gram of 2methyl, 4 and 5 nitroimidazole is added to Phosphoric acid mixture and ACOH is obtained. This mass is completely mixed with 2 methyl and 4,5nitroimidazole. Then it is cooled down to 25c. Now, 120 ml Ethylene oxide is added and after it is cooled down to 0-5 c, it will be mixed and stirred with ice for 1-1/5 hours. The mixture will stay in 25-30c temperature for 2 hours and then it is diluted with 800 ml water and cooled down to 2-5 c and it will be kept in this temperature for 4 to 5 hours. Next the matters which were not involved in the reaction will be separated by Buchner and washed by water and dried in the oven in 60-70 c. Therefore, 5/5-10 gram of 2 methyl 4, or 5 nitroimidazole is formed again and utilized in the next stage. Since the obtained matter is acidic, it is washed and diluted with 50 ml of aqua ammonia 25% in PH-10.
The hot mixture is cooled down to 2-5 c, kept in the same temperature, then separated by Buchner, washed by distilled water and dried in the oven within 70-80c.
45 gram of 1-beta hydroxy ethyl 1,2 methyl 5 nitroimidazole (metronidazole), mp 160- 161 c equals 90 pills.
Molecular structure of matter is shown on Figure 1.
The benefits of invention:
1. The low cost of its production
2. Owning fewer side effects for the patient
3. Accessibility of first materials
Practical method of the invention:
This invention is applicable for all pharmacists all over the world. The formula of this drug can be utilized in the pharmaceutical factories for production.
Industrial application:
This invention is applicable in pharmaceutical industry
Claims
1. Metronidazole synthesis by following ingredients:
a. 2- methyl, 4 and 5 dihydromidazole (2 Methyl lipidazolin, Lysidine)
b. N, N diacetyl anhydride amin
c. 2 methyl imidazole
d. 2 methyl 4 Netronidazole
e. 1 beta hydroxy ethyl 1, 2 methyl nitroimidazole (nitronidazole)
2. According to claim 1, N, Ndiacetyl anhydride producing method is:
We add some 2 methyl 4 and 5 CH3COOH dihydromidazole (in a solid form or aqua solution) to the water. Then it is cooled by a frigid (ice) bathroom and dissolved in a beaker with some of ethylenediamine. After that it is so much steamed in a reflux that its temperature reaches 220-240 c. In this stage the pressure decreases and distillation is done (distillation temperature is 185-190), moreover, in addition to distillation, the solution can be separated bynon-aqueous organic solvent (Isopropanol - dichloroethane - difenin Oxide). Finally, in this process N, N diacetyl anhydride is produced.
3. According to claim 1, 2 methyl imidazole producing method is:
First, some of the N, N diacetyl anhydride, is distilled and then it is mixed with some of Raney nickel humid mixture and heated up to 170-185 c under cold weather condenser. After that we gradually heat it by a heater up to 220 c. reaction time is 50-100 minutes and depends on the catalyst amount. Next, it is filtered. The solution is separated by vacuum and remaining Chrystal is dried at 30-60 c.
4. According to claim 1, 2 methyl 4 nitromidazole producing method is:
Mixture: some of difeniloxid, and some of nickel is heated by a heater in 180-260 c temperature in a flask with a condenser and a thermometer for an hour. The aqua mixture of nickel is cooled down to 15-35 c and then the heating continues up to 230 c and the same temperature is preserved for 2/5-3 hours so that hydrogen evolution process is completed. Then the mixture is cooled down to 150-170 c and is filtered and the catalyst (palladium) is washed in filter by the hot toluene.
The mixture is cooled down to 20 c and the remaining amount of 2 methyl imidazole which has been separated is filtered and dissociated by cold toluene. In the temperature of 40-50 c, it is dried by oven.
41/3-41/8 gram (mpl39- 143 c)II of 2 methyl imidazole mixture has been obtained through the first or second method and it is going to be used in 2 methyl 4 nitroimidazole synthesis without extra filtering.
5. According to claim 4, The second step of 2 methyl 4 nitromidazole producing method is:
Some water, some of 93% sulfuric acid, some of aqua-free sulfuric sodium and some of 2 methyl imidazole are blended and heated up to the temperature of 130 c in condenser.
Some of HN0399% mixtureis gradually added to the hot solution by decanter drop by drop while it is stirred and heated. At the end of heating, the great evolution of nitrogen oxide occurs.
The mixture is boiled for 4 hours within 120 to 140 degrees. The solution is cooled down to 50-80 c by some water which has been added and it is neutralized by 25% aqua ammonia.
We continue adding ammonia up to 3-6 PH and the mixture is stirred for 30 minutes in the temperature of 25-45 c and then after 30 minutes it is deposited soit will be dissociated by Buchner and washed by water. Finally it will be dried by an oven up to 60-70 c.
6. According to claim 1, 1-beta hydroxy ethyl 1-, 2 methyl 5 nitroimidazole (nitronidazole) producing method is:
In a flask, we add AC20 100ml (Acetic anhydride) to the water and wait for it to be cooled. Then we stir it and slowly add some of Phosphoric acid 85%. The temperature should not exceed 60- 100 c. Some of 2methyl, 4 and 5 nitroimidazole is added to Phosphoric acid mixture and ACOH is obtained. This mass is completely mixed with 2 methyl and 4,5nitroimidazole. Then it is cooled down to 25c. Now, some of Ethylene oxide is added and after it is cooled down to 0-5 c, it will be mixed and stirred with ice for 1- 1/5 hours. The mixture will stay in 20-35c temperature for 2 hours and then it is diluted with some water and cooled down to 2-5 c and it will be kept in this temperature for 4 to 5 hours. Next the matters which were not involved in the reaction will be separated by Buchner and washed by water and dried in the oven in 55-75 c. Therefore, some of 2 methyl 4, or 5 nitroimidazole is formed again and utilized in the next stage. Since the obtained matter is acidic, it is washed and diluted with 50 ml of aqua ammonia 25% in PH- 10.
The hot mixture is cooled down to 2-5 c, kept in the same temperature, then separated by Buchner, washed by distilled water and dried in the oven within 70- 80c.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IR139350140003003368 | 2014-06-24 | ||
| IR13933003368 | 2014-06-24 |
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| Publication Number | Publication Date |
|---|---|
| WO2015198107A1 true WO2015198107A1 (en) | 2015-12-30 |
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| PCT/IB2014/064597 WO2015198107A1 (en) | 2014-06-24 | 2014-09-17 | Synthesis of metronidazole |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084095A (en) * | 2017-12-21 | 2018-05-29 | 黄冈师范学院 | A kind of metronidazole synthetic method of metronidazole synthesizer and the application device |
| CN108329267A (en) * | 2018-04-16 | 2018-07-27 | 黄冈师范学院 | The method, apparatus and its application that formic acid solvent recycles in metronidazole production |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN111848524A (en) * | 2020-07-27 | 2020-10-30 | 南京甘倍加生物科技有限责任公司 | Method for synthesizing metronidazole at low temperature |
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|---|---|---|---|---|
| EP0150407A1 (en) * | 1984-01-10 | 1985-08-07 | BASF Aktiengesellschaft | Process for the preparation of 1(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity |
| US4925952A (en) * | 1988-01-15 | 1990-05-15 | Rhone-Poulenc Sante | Process for preparing 1-hydroxyalkyl-5-nitroimidazoles |
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2014
- 2014-09-17 WO PCT/IB2014/064597 patent/WO2015198107A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0150407A1 (en) * | 1984-01-10 | 1985-08-07 | BASF Aktiengesellschaft | Process for the preparation of 1(2-hydroxyethyl)-2-methyl-5-nitroimidazole of high purity |
| US4925952A (en) * | 1988-01-15 | 1990-05-15 | Rhone-Poulenc Sante | Process for preparing 1-hydroxyalkyl-5-nitroimidazoles |
Non-Patent Citations (2)
| Title |
|---|
| FASSAKHOV R KH ET AL: "Industrial synthesis of 1-(2-oxyethyl)-2-methyl-5-nitroimidazole (metronidazole)", SOVREMENNYE PROBLEMY TEKHNICHESKOI KHIMII, MATERIALY DOKLADOV VSEROSSIISKOI NAUCHNO-TEKHNICHESKOI KONFERENTSII, KAZAN, RUSSIAN FEDERATION, SEPT. 26-28, 2002,, vol. 1, 1 January 2002 (2002-01-01), pages 213, XP009182554 * |
| KRAFT M YA ET AL: "Imidazoles. 84. Synthesis of metronidazole from ethylene diamine", KHIMIKO-FARMATSEVTICHESKII ZHURNAL, IZDATEL'STVO FOLIUM, RU, vol. 23, no. 10, 1 January 1989 (1989-01-01), pages 1246 - 1248, XP009182548, ISSN: 0023-1134 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084095A (en) * | 2017-12-21 | 2018-05-29 | 黄冈师范学院 | A kind of metronidazole synthetic method of metronidazole synthesizer and the application device |
| CN108084095B (en) * | 2017-12-21 | 2023-09-19 | 黄冈师范学院 | Metronidazole synthesis device and Metronidazole synthesis method using same |
| CN108329267A (en) * | 2018-04-16 | 2018-07-27 | 黄冈师范学院 | The method, apparatus and its application that formic acid solvent recycles in metronidazole production |
| CN108329267B (en) * | 2018-04-16 | 2023-09-19 | 黄冈师范学院 | Method and device for recycling formic acid solvent in metronidazole production and application thereof |
| CN111574459A (en) * | 2020-05-15 | 2020-08-25 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN111574459B (en) * | 2020-05-15 | 2021-05-04 | 石家庄四药有限公司 | Preparation method of metronidazole |
| CN111848524A (en) * | 2020-07-27 | 2020-10-30 | 南京甘倍加生物科技有限责任公司 | Method for synthesizing metronidazole at low temperature |
| CN111848524B (en) * | 2020-07-27 | 2022-02-18 | 南京甘倍加生物科技有限责任公司 | Method for synthesizing metronidazole at low temperature |
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