CN106946659B - Preparation method of pentafluorophenol - Google Patents
Preparation method of pentafluorophenol Download PDFInfo
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- 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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- C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
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Abstract
The invention relates to the field of organic synthesis, in particular to a preparation method of pentafluorophenol. The invention provides a preparation method of pentafluorophenol, which comprises the following steps: (1) hofmann rearrangement reaction: carrying out rearrangement reaction on the compound of the formula II in the presence of alkali and a halogenated reagent to prepare a compound of a formula III; (2) diazo hydrolysis reaction: diazotizing the compound shown in the formula III and a nitroso compound, and hydrolyzing in the presence of a catalyst to obtain the compound shown in the formula I. The preparation method of pentafluorophenol provided by the invention has the advantages of easily available raw materials, short whole reaction synthesis route, mild reaction conditions, simple and convenient product purification operation, high product purity, stable quality, low cost of the whole reaction route, and suitability for industrial large-scale popularization and use.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of pentafluorophenol.
Background
Pentafluorophenol is an important chemical intermediate and is widely applied to the fields of medicines and electronic materials.
The pentafluroxyphenol is mainly used for preparing pentafluroxyphenyl active ester for polypeptide synthesis, thereby promoting the formation of peptide bond. The reaction rate for the formation of peptide bonds is very slow by activating the carboxyl group as an alkyl ester of an amino acid protecting group. And phenyl ester has higher reaction activity. If there is a substituent with strong electronegativity on the benzene ring, the rate of aminolysis will be about the same as that of the anhydride. Since one of the most important requirements for peptide bond formation is high efficiency of reaction and no side reaction, the pentafluorphenol esters have been widely used in polypeptide synthesis. The pentafluoride phenol ester can be used for solid phase synthesis of polypeptide and can also be used for liquid phase synthesis.
In particular to the preparation of a new medicine Sofosbuvir (Sofosbuvir) which is successfully developed by the international medicine Gilead and is used for treating hepatitis C.
Hepatitis c, a viral hepatitis caused by Hepatitis C Virus (HCV) infection, is mainly transmitted by blood transfusion, acupuncture, drug inhalation, etc., and can cause chronic inflammation, necrosis and fibrosis of the liver, and some patients can develop cirrhosis and even hepatocellular carcinoma, seriously endangering human health and life.
According to the data published by the world health organization, about 1.8 million people worldwide are infected with hepatitis c virus, and about 3.5 million new hepatitis c viruses are found every year. It is presumed that the hepatitis C virus carriers in China are about 4500 ten thousand, which account for one fourth of the total number of the whole world.
It is known that the hepatitis C patients in China are more born in the 60's of the last century and are in the age range of fifty years. The reason is that on one hand, the current sanitary conditions are poor, and the infection rate is high when the infants receive medical behaviors such as blood transfusion, acupuncture and the like in a crude rural clinic; on the other hand, the lack of the vaccine for hepatitis C virus leads to a tendency of concentrated outbreak in a short time as soon as the sanitary conditions are insufficient to cause the spread. Therefore, high-end drugs for treating hepatitis C are in great demand in the domestic medical market.
Sofosbuvir (also known as Sofosbuvir, the english name Sofosbuvir, trade name Sovaldi) is a new drug developed by gilide corporation for the treatment of chronic hepatitis c and is approved by the U.S. Food and Drug Administration (FDA) to be marketed in the united states at 12/6 d in 2013 and by the european drug administration (EMEA) at 16 d 1/2014. Has not yet been marketed in China. The medicine is the first medicine which can safely and effectively treat certain types of hepatitis C without combining interferon.
In 10 months 2014, the FDA approved the current latest hepatitis C treatment drug of Gilidide company, namely, a dual compound preparation Harvoni (R) (ledipasvir 90mg/sofosbuvir 400mg), the compound preparation adopts a simple administration mode of taking the compound preparation one tablet in one day all orally, the treatment period is about 8 weeks, and the effective cure rate of the compound preparation to the hepatitis C type 1 patient in clinical experiments reaches more than 95 percent.
2016.6/29 days, American FDA announced approval of oral anti-hepatitis C drugs
(sofosbuvir 400mg/velpatasvir 100mg) was used singly in all adult chronic hepatitis C Virus type 1-6 (HCV) infections.
The above three drugs currently occupy most of the hepatitis c treatment market. Also, Gilead corporation is brought billions of dollars in annual revenue. The successful development of sofosbuvir is undoubtedly the most significant drug discovery in recent years.
Therefore, in the pharmaceutical market, pentafluorophenol necessary for the synthesis of sofosbuvir is also the focus of research and development of various pharmaceutical companies and chemical enterprises. Meanwhile, as an important raw material for liquid crystal materials, the product is also receiving attention from more and more suppliers of liquid crystal raw materials.
At present, the following methods are reported internationally for the preparation of pentafluorophenol.
1) Alkaline hydrolysis of hexafluorobenzene. The method is described in Journal of Organic Chemistry; vol.56; nb.26; (1991) (ii) a p.7350-7354, and the like.
2) Alkaline hydrolysis of bromopentafluorobenzene. According to the method, bromopentafluorobenzene reacts under the catalysis of copper salt and under the alkaline condition at high temperature and high pressure, and pentafluorophenol is generated after acidification. Is reported in CN 102887817.
3) Pentafluorobromobenzene is used for preparing pentafluorophenylboronic acid, and then pentafluorophenol is obtained through oxidation. This method is reported in CN1847210 and JP 2004082548.
The main defects of the preparation process are as follows:
1. hexafluorobenzene is adopted as a raw material, so that the raw material cost is high, and a plurality of byproducts are generated.
2. The bromopentafluorobenzene is adopted as a raw material, high temperature and high pressure are not beneficial to large-scale production, and the production cost is high.
3. The scheme of synthesizing pentafluorophenylboronic acid by using bromopentafluorobenzene and then oxidizing to obtain pentafluorophenol has the advantages that although the raw material cost is low, the process route is long, an expensive Grignard reagent is required, and the production cost is increased.
Therefore, a method for preparing pentafluorophenol is urgently needed in the art.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a process for the preparation of pentafluorophenol, which solves the problems of the prior art.
In order to achieve the above objects and other related objects, the present invention provides a method for preparing pentafluorophenol, comprising the steps of:
(1) hofmann rearrangement reaction: carrying out rearrangement reaction on the compound of the formula II in the presence of alkali and a halogenating reagent to prepare the compound of the formula III, wherein the reaction equation is as follows:
(2) diazo hydrolysis reaction: diazotizing a compound shown in the formula III and a nitroso compound, and hydrolyzing in the presence of a catalyst to obtain a compound shown in the formula I, wherein the reaction equation is as follows:
in some embodiments of the present invention, in the step (1), the reaction is performed in a reaction solvent, and the reaction solvent is water and/or an organic solvent.
In some embodiments of the present invention, in the step (1), the organic solvent is selected from one or more of acetonitrile, methanol, ethanol, isopropanol, and propanol.
In some embodiments of the present invention, in the step (1), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.5.
In some embodiments of the present invention, in the step (1), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.3.
In some embodiments of the present invention, in the step (1), the mass ratio of the reaction solvent to the compound of formula II is 2 to 20: 1.
in some embodiments of the present invention, in the step (1), the mass ratio of the reaction solvent to the compound of formula II is 5 to 15: 1.
in some embodiments of the present invention, in the step (1), the alkali is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
In some embodiments of the invention, in the step (1), the molar ratio of the base to the compound of formula II is 2 to 5: 1.
in some embodiments of the invention, in step (1), the molar ratio of the base to the compound of formula II is 3 to 4.5: 1.
in some embodiments of the invention, in step (1), the halogenating agent is selected from the group consisting of chlorine, bromine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), Dibromohydantoin (DBH), and combinations of one or more thereof.
In some embodiments of the invention, in step (1), the halogenating agent is selected from chlorine and/or bromine.
In some embodiments of the present invention, in the step (1), the molar ratio of the halogenated reagent to the compound II is 0.5-2: 1.
in some embodiments of the present invention, in the step (1), the molar ratio of the halogenated agent to the compound II is 1.0 to 1.5: 1.
in some embodiments of the present invention, in the step (1), the reaction temperature is-10 to 100 ℃.
In some embodiments of the present invention, in the step (1), the reaction temperature is 0 to 80 ℃.
In some embodiments of the present invention, in the step (1), the reaction temperature is 70 to 80 ℃.
In some embodiments of the present invention, in the step (1), the post-treatment method of the reaction is: extracting, and desolventizing the organic phase to obtain the compound shown in the formula III.
In some embodiments of the present invention, in the step (2), the reaction is performed in a reaction solvent, and the reaction solvent is water and/or an organic solvent.
In some embodiments of the present invention, in the step (2), the organic solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, and methyl isoamyl ether.
In some embodiments of the present invention, in the step (2), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.5.
In some embodiments of the present invention, in the step (2), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.3.
In some embodiments of the invention, in the step (2), the mass ratio of the reaction solvent to the compound of formula III is 2-20: 1.
In some embodiments of the present invention, in the step (2), the mass ratio of the reaction solvent to the compound of formula III is 5 to 15: 1.
in some embodiments of the invention, in step (2), the nitroso compound is selected from nitrite and/or nitrite ester.
In some embodiments of the invention, in step (2), the nitroso compound is selected from the group consisting of sodium nitrite, potassium nitrite, isopropyl nitrite, and a combination of one or more of tert-butyl nitrite.
In some embodiments of the invention, in step (2), the molar ratio of nitroso compound to compound of formula III is 1-2: 1.
In some embodiments of the invention, in step (2), the catalyst comprises an acid catalyst and/or a transition metal salt catalyst.
In some embodiments of the present invention, in the step (2), the acid catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid.
In some embodiments of the invention, in the step (2), the molar ratio of the acid catalyst to the compound of formula III is 1-2: 1.
In some embodiments of the invention, in step (2), the transition metal salt catalyst is selected from the group consisting of CuCl, CuBr, CuI, CuOAc, CuCl2、CuBr2、CuI2、Cu(OAc)2、CuSO4、CoCl2、CoBr2、CoSO4、Co(acac)2、CoCl3、CoBr3、CoI3、Co(acac)3、FeCl2、FeBr2、FeSO4、Fe(acac)2、FeCl3、FeBr3、Fe(acac)3And the like.
In some embodiments of the invention, in step (2), the transition metal salt catalyst is selected from the group consisting of CuCl, CuBr, CuI, CuOAc, CuCl2、CuBr2、CuSO4、Cu(OAc)2One or more of the above.
In some embodiments of the present invention, in the step (2), the molar ratio of the transition metal salt catalyst to the compound of formula III is 0.01 to 2.0: 1.
in some embodiments of the present invention, in the step (2), the molar ratio of the transition metal salt catalyst to the compound of formula III is 0.1 to 0.8: 1.
in some embodiments of the present invention, in the step (2), the reaction temperature is-5 to 50 ℃.
In some embodiments of the present invention, in the step (2), the reaction temperature is-5 to 30 ℃.
In some embodiments of the present invention, in the step (2), the post-treatment method of the reaction is: extracting, and desolventizing the organic phase to obtain the compound shown in the formula I.
Detailed Description
The inventors of the present invention have found a novel process for producing pentafluorophenol by intensive studies. The preparation method of pentafluorophenol provided by the invention has low cost, the reaction conditions of the whole reaction route are mild, and the prepared target product has the characteristics of high yield, high purity and the like, thereby completing the invention.
The invention provides a preparation method of pentafluorophenol, wherein the structure of the pentafluorophenol is shown as a formula I:
the preparation method of pentafluorophenol provided by the invention can comprise a Hofmann rearrangement reaction, wherein the Hofmann rearrangement reaction specifically comprises the following steps: carrying out Hofmann rearrangement reaction on the compound of the formula II in the presence of alkali and a halogenated reagent to prepare a compound of a formula III, wherein the reaction equation is as follows:
in the preparation method of pentafluorophenol provided by the present invention, the hofmann rearrangement reaction can be performed in a reaction solvent, and a person skilled in the art can select a suitable solvent type and a suitable solvent usage amount according to a reaction raw material (for example, a compound of formula II, a base, a halogenated reagent, etc.), so that a solvent system can have good solubility to the reaction raw material. In a specific embodiment of the present invention, the mass ratio of the reaction solvent used in the hofmann rearrangement reaction to the compound of formula II may be 2 to 20:1, can also be 5-15: 1. in another embodiment of the present invention, the reaction solvent used in the hofmann rearrangement reaction may be water and/or an organic solvent, more specifically, water and an organic solvent, and the mass ratio of the organic solvent to the water may be not more than 0.5, and may also be not more than 0.3, and the organic solvent may be a combination including, but not limited to, one or more of acetonitrile, methanol, ethanol, isopropanol, propanol, and the like.
In the preparation method of pentafluorophenol provided by the present invention, a person skilled in the art can select an appropriate base and adjust the amount of the base used according to a reaction system. In one embodiment of the present invention, the base used in the hofmann rearrangement reaction may be selected from one or a combination of more of lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and the molar ratio of the base to the compound of formula II may be 2 to 5: 1, can also be 3 ~ 4.5: 1.
in the preparation method of pentafluorophenol provided by the invention, a person skilled in the art can select a proper halogenating reagent according to a reaction system and adjust the using amount of the halogenating reagent. In one embodiment of the present invention, the halogenating agent used in the hofmann rearrangement reaction may be one or more selected from chlorine, bromine, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), Dibromohydantoin (DBH), and the like, and preferably may be chlorine and/or bromine, and the molar ratio of the halogenating agent to the compound II may be 0.5 to 2:1, may be 1.0 to 1.5: 1.
in the preparation method of pentafluorophenol provided by the invention, the reaction temperature in the Hofmann rearrangement reaction can be-10-100 ℃, and can also be 0-80 ℃, and in some specific embodiments, the reaction temperature can be 70-80 ℃. The reaction time can be adjusted by those skilled in the art according to the reaction progress, for example, the reaction progress of the rearrangement reaction can be judged by liquid chromatography, and for example, the reaction time can be 8 to 24 hours.
In the preparation method of pentafluorophenol provided by the invention, the post-treatment method of the Hofmann rearrangement reaction can be as follows: extracting, and desolventizing the organic phase to obtain the compound shown in the formula III. One skilled in the art can select a suitable extraction solvent depending on the desired product, for example, the extraction solvent used can be a combination including, but not limited to, one or more of methyl tert-butyl ether, toluene, methylene chloride, ethylene dichloride, and the like.
The preparation method of pentafluorophenol provided by the invention can also comprise a diazo hydrolysis reaction, wherein the diazo hydrolysis reaction specifically comprises the following steps: the compound of formula I is prepared by diazotizing a compound of formula III with a nitroso compound and hydrolyzing in the presence of a catalyst, wherein the diazotization hydrolysis reaction is a reaction in which diazotization of aromatic primary amine occurs to generate diazo compound and further hydrolysis, and the reaction equation is as follows:
in the preparation method of pentafluorophenol provided by the present invention, the diazo hydrolysis reaction can be performed in a reaction solvent, and one skilled in the art can select a proper kind of solvent and a proper amount of solvent to be used according to the reaction raw material (e.g., the compound of formula III, the nitroso compound, the catalyst, etc.), so that the solvent system can have good solubility for the compound of formula II and/or the base and/or the halogenated reagent. In a specific embodiment of the invention, the mass ratio of the reaction solvent used in the diazo hydrolysis reaction to the compound of formula III is 2-20: 1, can also be 5 ~ 15: 1. in another embodiment of the present invention, the reaction solvent used in the diazo hydrolysis reaction may be water and/or an organic solvent, more specifically, water and an organic solvent, the mass ratio of the organic solvent to water may be not more than 0.5, and may also be not more than 0.3, and the organic solvent may be a combination including, but not limited to, one or more of methanol, ethanol, isopropanol, propanol, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran, dioxane, methyl tert-butyl ether, methyl isoamyl ether, and the like.
In the preparation method of pentafluorophenol provided by the present invention, a person skilled in the art can select an appropriate nitroso compound according to a reaction system and adjust the amount of the nitroso compound used. In one embodiment of the present invention, the nitroso compound used in the diazo hydrolysis reaction may be a nitrite and/or nitrite ester, and may specifically include, but is not limited to, sodium nitrite (NaNO)2) Potassium nitrite (KNO)2) One or more of isopropyl nitrite (i-PrONO), tert-butyl nitrite (t-BuONO) and the like, wherein the molar ratio of the nitroso compound to the compound in the formula III can be 1-2: 1.
In the preparation method of pentafluorophenol provided by the present invention, a person skilled in the art can select an appropriate catalyst for the diazo hydrolysis reaction according to the reaction system and adjust the amount of the catalyst used, for example, the catalyst can be an acid catalyst and/or a transition metal salt catalyst. In one embodiment of the present invention, the acid catalyst used in the diazo hydrolysis reaction may be a combination including, but not limited to, one or more of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, and the like, with an acid catalystThe molar ratio of the compound of formula III may be 1-2: 1. In another embodiment of the present invention, the transition metal salt catalyst used in the diazo hydrolysis reaction may be one including, but not limited to, CuCl, CuBr, CuI, CuOAc, CuCl2、CuBr2、CuI2、Cu(OAc)2、CuSO4、CoCl2、CoBr2、CoSO4、Co(acac)2、CoCl3、CoBr3、CoI3、Co(acac)3、FeCl2、FeBr2、FeSO4、Fe(acac)2、FeCl3、FeBr3、Fe(acac)3Etc., more specifically including but not limited to CuCl, CuBr, CuI, CuOAc, CuCl2、CuBr2、CuSO4、Cu(OAc)2And the like, and the molar ratio of the transition metal salt catalyst to the compound of formula III may be 0.01 to 2.0:1, and may be 0.1 to 0.8: 1.
in the preparation method of pentafluorophenol provided by the invention, the reaction temperature in the diazo hydrolysis reaction can be-5-50 ℃, and can also be-5-30 ℃. The reaction time can be adjusted by one skilled in the art according to the reaction progress, for example, the reaction progress of the diazo hydrolysis reaction can be judged by liquid chromatography, and for example, the reaction time can be 1 to 24 hours.
In the preparation method of pentafluorophenol provided by the invention, the post-treatment method of the diazo hydrolysis reaction can be as follows: extracting, and desolventizing the organic phase to obtain the compound shown in the formula I. One skilled in the art can select a suitable extraction solvent depending on the desired product, for example, the extraction solvent used can be a combination including, but not limited to, one or more of methyl tert-butyl ether, toluene, methylene chloride, ethylene dichloride, and the like.
The preparation method of pentafluorophenol provided by the invention has the advantages of easily available raw materials, short whole reaction synthesis route, mild reaction conditions, simple and convenient product purification operation, high product purity, stable quality, low cost of the whole reaction route, and suitability for industrial large-scale popularization and use.
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It is to be understood that the processing equipment or apparatus not specifically identified in the following examples is conventional in the art.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
Example 1
68g of sodium hydroxide are added to 1200g of water at 0 to 10 ℃. 75g of bromine is dripped into a sodium hydroxide aqueous solution and stirred for 1h at the temperature of 0-10 ℃. 90g of a pentafluorobenzamide solid was added in portions to the above reaction solution, and the reaction was carried out while controlling the inner temperature at 80 ℃. After the reaction is finished, the temperature is reduced to 20 ℃, 200g of methyl tert-butyl ether is added into the reaction solution, the mixture is stirred, kept stand, layered and the organic phase is concentrated at 30 ℃ to obtain 69g of pentafluoroaniline, the yield is 89.5%, and the content is more than 95% by HPLC analysis.
Examples 2 to 6
The results obtained in the same manner as in example 1 except that the kind of the organic solvent was changed are shown in Table 1:
TABLE 1
Examples 7 to 8
The results obtained in the same manner as in example 1 except that the kind of the base was changed are shown in Table 2:
TABLE 2
| Examples | Alkali | Use amount (molar ratio) | Yield (%) |
| 7 | Lithium hydroxide | 4:1 (vs. pentafluorobenzamide) | 83％ |
| 8 | Potassium hydroxide | 3.5:1 | 86％ |
Examples 9 to 14
The procedure of example 1 was otherwise the same as in example 1 except that the amounts of the base (sodium hydroxide, for example) and the compound II were changed, and the results are shown in Table 3:
TABLE 3
| Examples | Molar ratio of base to Compound II | Yield (%) |
| 9 | 2.3:1 | 40％ |
| 10 | 3.5:1 | About 70 percent |
| 11 | 3.6:1 | 75％ |
| 12 | 3.8:1 | 83％ |
| 13 | 4.0:1 | 89％ |
| 14 | 4.5:1 | 83％ |
Examples 15 to 19
The results obtained in the same manner as in example 1 except that the kind of the halogenating agent was changed are shown in Table 4:
TABLE 4
| Examples | Halogenated agents | Use amount (molar ratio) | Yield (%) |
| 15 | Chlorine gas | 1.1:1 (vs. pentafluorobenzamide) | 86％ |
| 16 | Bromine compound | 1.1:1 | 89.5％ |
| 17 | N-chlorosuccinimide (NCS) | 1.1:1 | 83％ |
| 18 | N-bromosuccinimide (NBS) | 1.1:1 | 85％ |
| 19 | Dibromo hydantoin (DBH) | 0.55:1 | 82％ |
Examples 20 to 24
The reaction temperature was changed, and the results are shown in Table 5, which are otherwise the same as in example 1
TABLE 5
Example 25
Adding 50g of pentafluoroaniline and 100g of water into the system, dropwise adding 50g of 30% HCl, stirring and dissolving, cooling to 0-5 ℃, dropwise adding a sodium nitrite aqueous solution (21g of sodium nitrite is dissolved in 50g of water), and keeping the temperature at 0-5 ℃ for 1 h. And (3) dropwise adding the prepared diazonium salt to a system (11 g of cuprous chloride, 50g of water and 100g of acetonitrile), controlling the internal temperature to be 20-30 ℃, and preserving the temperature after dropwise adding. After the reaction is finished, concentrating the reaction solution at 30-40 ℃ under reduced pressure, adding 200g of dichloromethane, stirring, standing, separating, and concentrating the obtained lower organic phase at 20-30 ℃ to obtain 41g of pentafluorophenol, wherein the yield is 82%, and the content is over 95% by HPLC analysis.
Examples 26 to 32
The solvent was changed, and the results are shown in Table 6, which is otherwise the same as in example 25:
TABLE 6
| Examples | Reaction solvent | Amount of solvent (weight ratio) | Yield (%) |
| 26 | Water and methanol | 4:2:1 | 75％ |
| 27 | Water (W) | 4:1 | 72％ |
| 28 | Water and isopropyl alcohol | 4:2:1 | 76％ |
| 29 | Water and tetrahydrofuran | 4:2:1 | 79％ |
| 30 | Water and methyl tetrahydrofuran | 3:2:1 | 80％ |
| 31 | Water and dioxane | 7:2:1 | 77％ |
| 32 | Water and methyl isoamyl ether | 3:2:1 | 75％ |
Examples 33 to 34
The diazotization reagent species were changed, and the results are shown in Table 7, which are otherwise the same as in example 25:
TABLE 7
| Examples | Diazotising reagents | Use amount (molar ratio) | Yield (%) |
| 33 | Nitrous acid isopropyl ester | 1.1:1 (relative to pentafluoroaniline) | 79％ |
| 34 | Nitrous acid tert-butyl ester | 1.1:1 | 85％ |
Examples 35 to 37
The results obtained in example 25 were shown in Table 8, except that the kind of acid was changed:
TABLE 8
Examples 38 to 48
The results obtained in example 25 were shown in Table 9, except that the kind of the transition metal salt was changed:
TABLE 9
| Examples | Transition metal salt | Use amount (molar ratio) | Yield (%) |
| 38 | CuBr | 0.4:1 (relative to pentafluoroaniline) | 80％ |
| 40 | CuCl2 | 0.4:1 | 79％ |
| 42 | CuSO4 | 0.4:1 | 83％ |
| 43 | CoCl2 | 0.8:1 | 74％ |
| 50 | FeCl3 | 1.4:1 | 76％ |
| 51 | Fe(acac)3 | 0.4:1 | 70％ |
Examples 52 to 58
The results obtained in example 25 were obtained by varying the amount of the transition metal salt (cuprous chloride, for example), and are shown in Table 10:
watch 10
| Examples | Molar ratio of transition metal salt catalyst to Compound III | Yield (%) |
| 52 | 0.01:1 | ～30％ |
| 53 | 0.05:1 | ～45％ |
| 54 | 0.1:1 | ～62％ |
| 55 | 0.3:1 | 75％ |
| 56 | 0.5:1 | 85％ |
| 57 | 0.8:1 | 79％ |
| 58 | 1.5:1 | 75％ |
Examples 59 to 62
The reaction temperature was changed, and the results are shown in Table 11, which is otherwise the same as in example 25:
TABLE 11
| Examples | Reaction temperature (. degree.C.) | Yield (%) |
| 59 | -5～0 | 60％ |
| 60 | -5～10 | 74％ |
| 61 | -5～20 | 82％ |
| 62 | -5～30 | 80％ |
In conclusion, the present invention effectively overcomes various disadvantages of the prior art and has high industrial utilization value.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (7)
1. A preparation method of pentafluorophenol comprises the following steps:
(1) hofmann rearrangement reaction: carrying out rearrangement reaction on the compound of the formula II in the presence of alkali and a halogenating reagent to prepare the compound of the formula III, wherein the reaction equation is as follows:
(2) diazo hydrolysis reaction: diazotizing a compound shown in the formula III and a nitroso compound, and hydrolyzing in the presence of a catalyst to obtain a compound shown in the formula I, wherein the reaction equation is as follows:
in the step (2), the reaction is carried out in a reaction solvent, the reaction solvent is water and an organic solvent, the organic solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, acetonitrile, tetrahydrofuran, methyl tetrahydrofuran, dioxane, methyl tert-butyl ether, butyl ether and methyl isoamyl ether, and the mass ratio of the organic solvent to the water is not more than 0.5;
in the step (1), the molar ratio of the alkali to the compound of the formula II is 3-4.5: 1;
in the step (1), the halogenating reagent is one or more of chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide and dibromohydantoin.
2. The process for producing pentafluorophenol according to claim 1, wherein in the step (1), the reaction is carried out in a reaction solvent which is water and/or an organic solvent;
and/or in the step (1), the mass ratio of the reaction solvent to the compound of the formula II is 2-20: 1;
and/or, in the step (1), the alkali is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide;
and/or, in the step (1), the molar ratio of the base to the compound of the formula II is 2-5: 1;
and/or in the step (1), the molar ratio of the halogenated reagent to the compound II is 0.5-2: 1;
and/or in the step (1), the reaction temperature is-10-100 ℃;
and/or in the step (1), the post-treatment method of the reaction is as follows: extracting, and desolventizing the organic phase to obtain the compound shown in the formula III.
3. The method for preparing pentafluorophenol according to claim 2, wherein in the step (1), the organic solvent is selected from one or more of acetonitrile, methanol, ethanol, isopropanol, and propanol;
and/or in the step (1), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.5;
and/or in the step (1), the mass ratio of the reaction solvent to the compound of the formula II is 5-15: 1;
and/or, in the step (1), the halogenating agent is selected from chlorine and/or bromine;
and/or in the step (1), the molar ratio of the halogenated reagent to the compound II is 1.0-1.5: 1;
and/or in the step (1), the reaction temperature is 0-80 ℃.
4. The process for preparing pentafluorophenol according to claim 3, wherein in the step (1), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.3;
and/or in the step (1), the reaction temperature is 70-80 ℃.
5. The process for producing pentafluorophenol according to claim 1,
and/or in the step (2), the mass ratio of the reaction solvent to the compound of the formula III is 2-20: 1;
and/or, in said step (2), the nitroso compound is selected from nitrite and/or nitrite ester;
and/or in the step (2), the molar ratio of the nitroso compound to the compound shown in the formula III is 1-2: 1;
and/or, in the step (2), the catalyst comprises an acid catalyst and/or a transition metal salt catalyst;
and/or in the step (2), the reaction temperature is-5-50 ℃;
and/or in the step (2), the post-treatment method of the reaction is as follows: extracting, and desolventizing the organic phase to obtain the compound shown in the formula I.
6. The process for producing pentafluorophenol according to claim 5,
and/or in the step (2), the mass ratio of the reaction solvent to the compound of the formula III is 5-15: 1;
and/or, in the step (2), the nitroso compound is selected from one or more of sodium nitrite, potassium nitrite, isopropyl nitrite and tert-butyl nitrite;
and/or, in the step (2), the acid catalyst is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid;
and/or in the step (2), the molar ratio of the acid catalyst to the compound of the formula III is 1-2: 1;
and/or, in the step (2), the transition metal salt catalyst is selected from CuCl, CuBr, CuI, CuOAc and CuCl2、CuBr2、CuI2、Cu(OAc)2、CuSO4、CoCl2、CoBr2、CoSO4、Co(acac)2、CoCl3、CoBr3、CoI3、Co(acac)3、FeCl2、FeBr2、FeSO4、Fe(acac)2、FeCl3、FeBr3、Fe(acac)3One or more combinations of;
and/or in the step (2), the molar ratio of the transition metal salt catalyst to the compound of the formula III is 0.01-2.0: 1;
and/or in the step (2), the reaction temperature is-5-30 ℃.
7. The process for preparing pentafluorophenol according to claim 6, wherein in the step (2), the reaction solvent is water and an organic solvent, and the mass ratio of the organic solvent to the water is not more than 0.3;
and/or, in the step (2), the transition metal salt catalyst is selected from CuCl, CuBr, CuI, CuOAc and CuCl2、CuBr2、CuSO4、Cu(OAc)2One or more combinations of;
and/or in the step (2), the molar ratio of the transition metal salt catalyst to the compound shown in the formula III is 0.1-0.8: 1.
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