CN108774112B - Preparation method of m-bromophenol - Google Patents
Preparation method of m-bromophenol Download PDFInfo
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- CN108774112B CN108774112B CN201810457321.2A CN201810457321A CN108774112B CN 108774112 B CN108774112 B CN 108774112B CN 201810457321 A CN201810457321 A CN 201810457321A CN 108774112 B CN108774112 B CN 108774112B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
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Abstract
The invention discloses a preparation method of m-bromophenol, which comprises the following steps: diazotization reaction, hydrolysis reaction and extraction, m-bromoaniline is used as a raw material, and a high-purity target product can be prepared by diazotization, catalytic hydrolysis, solvent extraction and vacuum rectification; and the process avoids using hydrobromic acid, has mild reaction conditions, is favorable for releasing nitrogen generated in hydrolysis because the hydrolysis reaction is an open system, enables the reaction balance to be carried out towards the reaction direction under hydrolysis, and is favorable for improving the reaction yield.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a preparation method of m-bromophenol.
Background
The m-bromophenol is a key intermediate for synthesizing the analgesic drug tramadol hydrochloride, and the supply of tramadol hydrochloride is increased due to the increase of cancer patients in recent years. Because tramadol hydrochloride has certain adverse reactions after being taken, the requirement on the purity of the intermediate is quite high so as to reduce the adverse reactions generated after the tramadol hydrochloride is taken as a medicament. The m-bromophenol is prepared with m-aminophenol as material and through diazotization, bromination with hydrobromic acid and cuprous bromide to obtain the target product. Because the bromination reaction is carried out according to an SN1 mechanism, the bromination can obtain higher yield, but the competition with hydroxyl still exists, so the yield of the product is generally not more than 55%, most of the product becomes resorcinol as a byproduct, and the separation difficulty and the quality of the product are difficult to improve.
Disclosure of Invention
The invention aims to provide a preparation method of m-bromophenol.
The technical scheme adopted by the invention is as follows:
a method for preparing m-bromophenol is characterized by comprising the following steps: the chemical reaction in the process is as follows:
the method comprises the following steps: step 1: diazotization reaction: adding 400mL of water 200-260 g and 260g of 98% concentrated sulfuric acid 130-260g into a reaction bottle provided with a stirrer, a thermometer and a dropping funnel, cooling, adding 69-138g of m-bromoaniline, adding 150mL of water 100-150, cooling the reaction solution to below 5 ℃, beginning to dropwise add a solution prepared by dissolving 32.2-64.4g of sodium nitrite in 90-180mL of water, controlling the diazotization temperature to be below 5 ℃, controlling the dropwise addition time to be over 25min, continuing to stir for reaction for 10min, adding 3-5g of urea to decompose excessive sodium nitrite, stirring for 10min, adding 270mL of low-temperature water at 0 ℃, and uniformly stirring for later use;
step 2: and (3) hydrolysis reaction: adding 170g of catalyst 100 and 200g of 98% concentrated sulfuric acid 130 into a reaction bottle provided with a stirrer, a thermometer, a dropping funnel and a distillation device, heating to 110 ℃ and 130 ℃, dropwise adding the diazonium salt solution obtained in the step 1, collecting a distillate from the distillation device, controlling the diazonium salt solution to be added within 3.5 hours, and collecting about 400mL of the distillate;
and step 3: and (3) extraction: distilling out a mixture of hydrolysate and water after hydrolysis reaction, extracting by using halogenated alkane, cooling, extracting by using 300mL of extraction solvent of 150-mL each time, extracting for three times, combining the extract solutions, washing by using water, washing for 200mL each time twice, washing by using 10% sodium hydroxide, using 100mL each time continuously twice, combining for next recycling, combining the liquids for use when the pH =2-3, neutralizing by using hydrochloric acid, extracting by using the extraction solvent, combining the extract solutions, distilling the extraction solvent, performing vacuum rectification at the vacuum degree of 1.6kPa, collecting the distillate of 140 ℃ of 135-DEG, and preparing the m-bromophenol.
The catalyst in the step 2 is copper sulfate or sodium sulfate.
In the reaction processes of the step 1 and the step 2, the molar ratio of the intermediate bromoaniline to the sodium nitrite to the 98% sulfuric acid to the sodium sulfate to the water is 1:1.17: 5-7: 1.5-2: 60-90.
The diazotization reaction temperature in the step 1 is 0-10 ℃.
The extraction solvent in the step 3 is selected from dichloromethane, trichloromethane, chloroethane or dichloroethane.
The invention has the advantages that: the invention uses m-bromoaniline as raw material, and can prepare high-purity target product through diazo, catalytic hydrolysis, solvent extraction and vacuum rectification; and the process avoids using hydrobromic acid, has mild reaction conditions, is favorable for releasing nitrogen generated in hydrolysis because the hydrolysis reaction is an open system, enables the reaction balance to be carried out towards the reaction direction under hydrolysis, and is favorable for improving the reaction yield.
Detailed Description
Example 1
The preparation method of the m-bromophenol comprises the following chemical reaction processes:
the method comprises the following steps: adding 400mL of water and 260g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer and a dropping funnel, adding 138g of m-bromoaniline under cooling, supplementing 150mL of water, cooling the reaction solution to below 5 ℃, starting to dropwise add a solution prepared by dissolving 64.4g of sodium nitrite in 180mL of water, controlling the diazotization temperature to be below 5 ℃, controlling the dropwise addition time to be 25min, continuing to stir for reaction for 10min, adding 5g of urea to decompose excessive sodium nitrite, stirring for 10min, adding 270mL of low-temperature water at 0 ℃, and uniformly stirring for later use;
adding 170g of sodium sulfate catalyst and 200g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer, a dropping funnel and a distillation device, heating to 125 ℃, dropwise adding the diazonium salt solution prepared in the previous step, collecting distillate by the distillation device, controlling the addition of the diazonium salt solution to be finished within 3.5 hours, and collecting about 400mL of the distillate;
cooling the distillate, extracting with 300mL of chloroform for three times, mixing the extractive solutions, washing with 200mL of water for two times; and washing with 10% sodium hydroxide, using 100mL of sodium hydroxide for each time, continuously twice, combining and reserving for the next recycling, combining the liquids, neutralizing with hydrochloric acid when the pH =3, extracting with trichloromethane, combining the extracts, evaporating the trichloromethane, performing vacuum rectification, and collecting 140 ℃ (1.6 kPa) fractions to obtain 128.8g of m-bromophenol, wherein the yield is 92.8, and the content is 99.1% (HPLC).
Example 2
The preparation method of the m-bromophenol comprises the following chemical reaction processes:
the method comprises the following steps: adding 200mL of water and 130g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer and a dropping funnel, adding 69g of m-bromoaniline under cooling, supplementing 100mL of water, cooling the reaction solution to below 5 ℃, starting to dropwise add a solution prepared by dissolving 32.2g of sodium nitrite in 90mL of water, controlling the diazotization temperature to be below 5 ℃, controlling the dropwise addition time to be 25min, continuing to stir for reaction for 10min, adding 3g of urea to decompose excessive sodium nitrite, stirring for 10min, adding 270mL of low-temperature water at 0 ℃, and uniformly stirring for later use;
adding 100g of sodium sulfate catalyst and 130g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer, a dropping funnel and a distillation device, heating to 130 ℃, dropwise adding the diazonium salt solution prepared in the previous step, collecting distillate by the distillation device, controlling the addition of the diazonium salt solution to be finished within 3.5 hours, and collecting about 200mL of the distillate;
cooling the distillate, extracting with 150mL of chloroform for three times, mixing the extractive solutions, washing with 200mL of water for two times; washing with 10% sodium hydroxide, using 100mL of sodium hydroxide for each time, continuously twice, combining and reserving for the next recycling, combining the liquids, neutralizing with hydrochloric acid when the pH =2, extracting with trichloromethane, combining the extracts, evaporating the trichloromethane, performing vacuum rectification, and collecting 135 ℃ (1.6 kPa) fractions to obtain 65.5g of m-bromophenol, the yield is 93.4, and the content is 99.0% (HPLC).
Example 3
The preparation method of the m-bromophenol comprises the following chemical reaction processes:
the method comprises the following steps: adding 300mL of water and 195g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer and a dropping funnel, cooling, adding 103.5g of m-bromoaniline, supplementing 125mL of water, cooling the reaction solution to below 5 ℃, starting to dropwise add a solution prepared by dissolving 48.3g of sodium nitrite in 135mL of water, controlling the diazotization temperature to be below 5 ℃, controlling the dropwise addition time to be 25min, continuing to stir for reaction for 10min, adding 4g of urea to decompose excessive sodium nitrite, stirring for 10min, adding 270mL of low-temperature water at 0 ℃, and uniformly stirring for later use;
adding 135g of copper sulfate catalyst and 165g of 98% concentrated sulfuric acid into a reaction bottle provided with a stirrer, a thermometer, a dropping funnel and a distillation device, heating to 120 ℃, dropwise adding the diazonium salt solution prepared in the previous step, collecting distillate by the distillation device, controlling the addition of the diazonium salt solution to be finished within 3.5 hours, and collecting about 200mL of distillate;
cooling the distillate, extracting with 225mL of dichloromethane each time for three times, mixing the extractive solutions, washing with water, 200mL each time, and washing twice; washing with 10% sodium hydroxide, each time using 100mL twice, combining for the next cycle, when the pH =2.5, combining the liquids, neutralizing with hydrochloric acid, extracting with dichloromethane, combining the extracts, evaporating dichloromethane, vacuum rectifying, collecting 138 deg.C (1.6 kPa) fractions, obtaining 65.5g of m-bromophenol, 93.4 yield and 99.0% content (HPLC).
The invention uses m-bromoaniline as raw material, and can prepare high-purity target product through diazo, catalytic hydrolysis, solvent extraction and vacuum rectification; and the process avoids using hydrobromic acid, has mild reaction conditions, is favorable for releasing nitrogen generated in hydrolysis because the hydrolysis reaction is an open system, enables the reaction balance to be carried out towards the reaction direction under hydrolysis, and is favorable for improving the reaction yield.
Claims (1)
1. A method for preparing m-bromophenol is characterized by comprising the following steps: the chemical reaction in the process is as follows:
the method comprises the following steps:
step 1: diazotization reaction: adding 400mL of water 200-260 g and 260g of 98% concentrated sulfuric acid 130-260g into a reaction bottle provided with a stirrer, a thermometer and a dropping funnel, cooling, adding 69-138g of m-bromoaniline, adding 150mL of water 100-150, cooling the reaction solution to below 5 ℃, beginning to dropwise add a solution prepared by dissolving 32.2-64.4g of sodium nitrite in 90-180mL of water, controlling the diazotization temperature to be below 5 ℃, controlling the dropwise addition time to be over 25min, continuing to stir for reaction for 10min, adding 3-5g of urea to decompose excessive sodium nitrite, stirring for 10min, adding 270mL of low-temperature water at 0 ℃, and uniformly stirring for later use;
step 2: and (3) hydrolysis reaction: adding 170g of catalyst 100 and 200g of 98% concentrated sulfuric acid 130 into a reaction bottle provided with a stirrer, a thermometer, a dropping funnel and a distillation device, heating to 110 ℃ and 130 ℃, dropwise adding the diazonium salt solution obtained in the step 1, collecting a distillate from the distillation device, controlling the diazonium salt solution to be added within 3.5 hours, and collecting about 400mL of the distillate;
and step 3: and (3) extraction: distilling out a mixture of hydrolysate and water after hydrolysis reaction, extracting by using halogenated alkane, cooling, extracting by using 300mL of extraction solvent of 150-mL each time, extracting for three times, combining the extraction solutions, washing by using water, washing for 200mL each time twice, washing by using 10% sodium hydroxide, using 100mL each time continuously twice, combining for next recycling, combining the liquids, neutralizing by using hydrochloric acid when the pH =2-3, extracting by using the extraction solvent, combining the extraction solutions, distilling out the extraction solvent, performing vacuum rectification at the vacuum degree of 1.6kPa, collecting 135-140 ℃ distillate, and preparing m-bromophenol; the molar ratio of bromoaniline, sodium nitrite, 98% sulfuric acid, sodium sulfate and water in the reaction process of the step 1 to the reaction process of the step 2 is 1:1.17: 5-7: 1.5-2: 60-90, the catalyst in the step 2 is copper sulfate or sodium sulfate, the diazotization reaction temperature in the step 1 is 0-10 ℃, and the extraction solvent in the step 3 is dichloromethane, trichloromethane, chloroethane or dichloroethane.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100999446A (en) * | 2007-01-15 | 2007-07-18 | 浙江寿尔福化学有限公司 | Production method of m-bromophonol and production device thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100999446A (en) * | 2007-01-15 | 2007-07-18 | 浙江寿尔福化学有限公司 | Production method of m-bromophonol and production device thereof |
Non-Patent Citations (2)
| Title |
|---|
| "间溴苯甲醚的合成";曹玉庆等;《中国医药工业杂志》;20050324;第36卷(第2期);第73页右栏最后一段、第74页左栏第一段 * |
| Preparation of m-bromophenol;Koelsch, C et al;《Journal of the American Chemical Society》;19390401;第61卷;第969页 * |
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Effective date of registration: 20211213 Address after: 475003 intersection of national highway 310 and Fengxian street, yuwangtai District, Kaifeng City, Henan Province Patentee after: Kaifeng Yuanrun Pharmaceutical Co.,Ltd. Address before: 226100 Qiandao intersection, Wangjiang Road, LingDian industrial concentration area, Linjiang New District, Haimen City, Nantong City, Jiangsu Province Patentee before: HAIMEN CITY CHEMGOO PHARMA Co.,Ltd. |