CN112174853B - Method for preparing (Z) -N-hydroxy phenylamidine by ammonolysis - Google Patents
Method for preparing (Z) -N-hydroxy phenylamidine by ammonolysis Download PDFInfo
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- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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Abstract
The invention discloses a method for preparing (Z) -N-hydroxy benzamidine by an ammonolysis method, which comprises the following steps: step 1, completely or partially dissolving an alpha-halogenated benzaldoxime compound simultaneously containing E, Z configurations by adopting a first solvent to obtain a solution A; step 2, adding anhydrous sodium salt or potassium salt of a benzoate hydroxamic acid compound, and stirring to fully convert the (E) -alpha-halogenated benzoate aldoxime compound into (Z) to obtain a solution B; step 3, adding an anhydrous ammonia source, and performing ammonolysis reaction to generate (Z) -N-hydroxy phenylamidine to obtain a solution C; step 4, concentrating the solution C, and then adding water and a second solvent to dissolve most of the solids; filtering and separating liquid; post-treatment to obtain high-purity (Z) -N-hydroxy phenylamidine. The method can fully convert the E configuration in the raw materials into the Z configuration, and also avoids the problem that more alkaline hydrolysis side reactions occur during the E, Z configuration conversion reaction and ammonolysis reaction, so that the yield of the purified target product is improved to more than 95%.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a method for preparing (Z) -N-hydroxy phenylamidine by an ammonolysis method.
Background
The N-hydroxy benzamidine compound is an intermediate widely applied to the industries of medicines, pesticides, organic materials and organic fine chemical industry; the compound has E, Z two configurational isomers, and the general formula of the molecular structure is shown as follows:
r in the above formula is a substituent commonly found on benzene rings, such as aliphatic, aromatic, halogen, ester, amino, nitro, cyano, or a combination thereof, and the like (hereinafter).
N-hydroxy benzamidine compounds are most commonly used and one of the preparation methods with the lowest cost is to use alpha-halogenated benzaldoxime compounds for ammonolysis reaction; the ammonolysis reaction is applicable to the preparation of N-hydroxy benzamidine compounds in Z type and E type (or E, Z mixed type), and the reaction equation is as follows:
r in the above general formula is various substituents commonly used on benzene rings, such as aliphatic groups, aromatic groups, halogens, ester groups, amino groups, nitro groups, cyano groups, or a combination thereof, and the like. X in the above formula may be any one of three halogens (hereinafter, referred to as chlorine, bromine and iodine).
In different fields of application, it is often also necessary to obtain isomers of N-hydroxyphenylamidines of single configuration (Z or E). Because the raw material alpha-halogenated benzaldoxime compound before ammonolysis reaction often contains E, Z two configurations at the same time, and is extremely easy to mutually convert under different pH values, most E configurations can be converted into Z configurations under alkaline conditions; and the E-type and Z-type N-hydroxy benzamidine compounds are difficult to mutually convert. Therefore, when it is desired to obtain the Z-type N-hydroxy benzamidine compound, the following two methods are generally adopted:
the first method is to treat the alpha-halogenated benzaldoxime compound containing E, Z two configurations with alkali to convert E configuration into Z configuration as much as possible; and the ammonolysis reaction is performed simultaneously with (or after) the alkali treatment. Common bases include hydroxides of alkali metals such as lithium hydroxide (sodium hydroxide and potassium hydroxide), ammonia water, and the like; when ammonia is used, ammonia is both a catalyst for the E, Z configuration conversion reaction and a raw material for participating in the ammonolysis reaction.
However, in the method, as the halogen atom of the alpha-halogenated benzaldoxime compound is very active, the halogen atom can also generate alkaline hydrolysis reaction with most alkaline reagents while E, Z configuration conversion reaction is carried out, so as to generate a byproduct benzaldoxime acid compound and salt thereof; and the side reaction can continuously consume alkaline reagent, so that more than 20% of equivalent alkaline catalyst is needed to obtain better configuration conversion rate, and more alkaline hydrolysis byproducts are generated.
Taking ammonia as an example, the reaction equation is as follows:
in the method, even though ammonia water with weaker alkalinity is used as a configuration conversion catalyst (raw material of ammonolysis reaction at the same time), E, Z configuration conversion and ammonolysis reaction are carried out simultaneously and continuously, by-product benzoate hydroxamate with the content of up to 10-20% is also generated in the product, and the highest yield of the target product (Z-type N-hydroxy phenylamidine compound) after purification treatment is not more than 85%.
The second method is to carry out ammonolysis reaction with ammonia gas under anhydrous condition by using E, Z mixed alpha-halogenated benzaldoxime compound to obtain E, Z mixed N-hydroxy benzamidine compound. The method does not generate alkaline hydrolysis side reaction of alpha-halogenated benzaldoxime compounds; however, the E-isomer is not converted into Z-isomer, so that the E-isomer content in the product is high, the product needs to be removed by later purification, and the yield loss of the Z-isomer in the purification process is large. The yield of the target product ((Z) -N-hydroxyphenylamidine) of the process is even lower than in the first process described above. The reaction equation is as follows:
disclosure of Invention
The invention aims to solve the problems of more byproducts, difficult separation, low yield and the like in the preparation method of (Z) -N-hydroxy phenylamidine compounds, and provides an improved ammonolysis method for preparing (Z) -N-hydroxy phenylamidine, which has fewer byproducts, simple and convenient separation, high purity and high yield.
In order to achieve the above object, the present invention provides a process for preparing (Z) -N-hydroxyphenylamidine by ammonolysis, comprising:
step 1, fully or partially dissolving an alpha-halogenated benzaldoxime compound containing E, Z configurations by adopting a first solvent to obtain a solution A, wherein the first solvent is an alcohol solvent or a mixed organic solvent containing the alcohol solvent;
step 2, adding anhydrous sodium salt or potassium salt of the benzoate hydroxamic acid compound into the solution A, and stirring for a certain time at 0-60 ℃ to fully convert the (E) -alpha-halogenated benzoate aldoxime compound into the (Z) -alpha-halogenated benzoate aldoxime compound to obtain a solution B; wherein, the dosage of anhydrous sodium salt or potassium salt of the benzoate hydroxamic acid compound is 1-10 percent of the alpha-halogenated benzaldehyde oxime, and the molar ratio is calculated;
step 3, adding anhydrous ammonia source into the solution B, and reacting for a sufficient time at 20-100 ℃ to enable (Z) -alpha-halogenated benzaldehyde oxime to undergo ammonolysis reaction to generate (Z) -N-hydroxy phenylamidine, so as to obtain solution C; wherein the dosage of the anhydrous ammonia source is 1-2 times equivalent of the dosage of the alpha-halogenated benzaldoxime;
step 4, concentrating the solution C, adding water and a second solvent, and fully heating and stirring to dissolve most of the solids; filtering and separating liquid; the filtered filter cake is anhydrous sodium salt or potassium salt of the benzoate hydroxamic acid compound; the separated organic layer is a solution containing a target product (Z) -N-hydroxy phenylamidine, and the (Z) -N-hydroxy phenylamidine with high purity is obtained by recrystallization after concentration; the second solvent is selected from aromatic hydrocarbon, ether or halohydrocarbon solvents.
Preferably, the alcohol solvent is selected from any one or more than two of methanol, ethanol, isopropanol, ethylene glycol and ethylene glycol monomethyl ether.
Preferably, the mixed organic solvent containing an alcohol solvent further comprises: a non-alcoholic organic solvent which can improve the solubility of the alpha-halogenated benzaldoxime compound and can not react with the alpha-halogenated benzaldoxime compound.
Preferably, the non-alcohol organic solvent is selected from any one or more than two of benzene, toluene, tetrahydrofuran and methyl tertiary butyl ether.
Preferably, in the step 1, the amount of the first solvent is limited to at least 50% of the α -halobenzaldehyde oxime compound.
Preferably, in the step 2, the anhydrous sodium salt (or potassium salt) of the benzoate hydroxamic acid compound is used in an amount of 3-6% of the alpha-halogenated benzaldoxime in terms of mole ratio.
Preferably, in the step 2, the stirring temperature is 20-40 ℃; the reaction time is controlled between 1 and 24 hours.
Preferably, the anhydrous ammonia source is selected from any one or more than two of ammonia gas, or an anhydrous alcohol solution of ammonia gas, or ammonium bicarbonate.
Preferably, in the step 3, the anhydrous ammonia source is used in an amount of 1.05 to 1.2 times equivalent or 1.2 to 1.5 times equivalent or 1.5 to 2 times equivalent of the alpha-halogenated benzaldoxime in terms of mole number.
Preferably, in the step 3, the reaction temperature is controlled to be 30-60 ℃ and the reaction time is controlled to be 1-24 hours.
Preferably, in the step 4, the aromatic hydrocarbon solvent comprises any one or more than two of benzene, toluene and chlorobenzene; the ether solvent comprises any one or more than two of diethyl ether, methyl tetrahydrofuran, methyl tertiary butyl ether and methyl cyclopentyl ether; the halogenated hydrocarbon solvent comprises any one or more than two of 1, 2-dichloroethane, chloroform, carbon tetrachloride and trichloroethylene.
The invention has the technical effects that:
according to the invention, anhydrous sodium salt (or potassium salt) of the benzoic hydroxamic acid is used as a catalyst, so that the E and Z mixed alpha-halogenated benzaldoxime compounds undergo E, Z configuration conversion reaction, and alkaline hydrolysis side reaction of the alpha-halogenated benzaldoxime compounds does not occur, and the (Z) -alpha-halogenated benzaldoxime compounds with high content are obtained.
Compared with the invention, if sodium hydroxide (or potassium hydroxide) is directly added into the alpha-halogenated benzaldoxime compound to be used as a catalyst for E, Z configuration conversion reaction; or the added sodium salt (or potassium salt) of the benzohydroxamic acid contains water, so that sodium hydroxide (or potassium hydroxide) and water can lead to alkaline hydrolysis of the alpha-halogenated benzaldoxime compounds, thereby generating byproducts; furthermore, only acidic benzoic hydroxamic acid is produced before the alpha-haloaldoxime compound is consumed, and the sodium (or potassium) salt of basic benzoic hydroxamic acid cannot be obtained (or maintained). The corresponding reaction equation is as follows:
after the high-content (Z) -alpha-halogenated benzaldoxime compound is obtained, anhydrous ammonia gas, or an absolute alcohol solution of the ammonia gas, or nearly neutral ammonium bicarbonate is used as an ammonolysis raw material to carry out ammonolysis reaction of the alpha-halogenated benzaldoxime compound. Under anhydrous reaction conditions or reaction conditions close to neutrality (ammonium bicarbonate), the (Z) -alpha-halogenated benzaldoxime compound rarely undergoes alkaline hydrolysis side reaction, the conversion rate of the target product (Z) -N-hydroxy benzamidine compound is obviously improved, and the yield after purification can reach more than 95%.
Detailed Description
The structural general formula of the 'E, Z alpha-halogenated benzaldoxime compounds' with two configurations is as follows:
wherein R is various substituents commonly found on benzene rings, such as aliphatic, aromatic, halogen, ester, amino, nitro, cyano, or combinations thereof. The halogenation refers to any one or more than two substitutions of F, cl, br or I.
The term "anhydrous ammonia source" as used herein means that there is no direct introduction of water, such as no water impurities, no aqueous solution or no crystallization water. Ammonium bicarbonate, after ammonolysis, produces carbon dioxide and water, which cannot be strictly said to be an anhydrous or neutral ammonia source. However, the pH value of ammonium bicarbonate is close to neutral, so that even if a small amount of water is generated in the reaction, the alkaline hydrolysis side reaction is not caused substantially at the same time of the ammonolysis reaction.
The technical conception of the invention is as follows:
1. the alpha-halogenated benzaldoxime compound containing both configurations of E, Z is completely or partially dissolved in an alcohol solvent or a mixed organic solvent containing alcohols to obtain a solution A (which may be a solution or a suspension).
2. Adding anhydrous sodium (or potassium) salt of a benzoic hydroxamic acid compound to solution a; then stirring for a certain time at 0-60 ℃ to convert most of (E) -alpha-halogenated benzaldoxime compounds into (Z) -alpha-halogenated benzaldoxime compounds.
The anhydrous sodium (or potassium) salt of the benzoic hydroxamic acid compound can be purchased commercially or prepared using the following reaction equation:
the reaction equation for the configuration conversion is as follows:
3. introducing ammonia gas (or an absolute alcohol solution added with the ammonia gas or ammonium bicarbonate); then reacting for a time between 20 and 100 ℃ to enable the (Z) -alpha-halogenated benzaldehyde oxime to generate ammonolysis reaction to generate the (Z) -N-hydroxy benzamidine.
Based on the technical conception, the invention provides a method for preparing (Z) -N-hydroxy phenylamidine by an ammonolysis method, which comprises the following steps:
step 1, fully or partially dissolving an alpha-halogenated benzaldoxime compound containing E, Z configurations by adopting a first solvent to obtain a solution A, wherein the first solvent is an alcohol solvent or a mixed organic solvent containing the alcohol solvent;
step 2, adding anhydrous sodium salt or potassium salt of a benzoate hydroxamic acid compound as a catalyst into the solution A, and stirring for a certain time at 0-60 ℃ to fully convert the (E) -alpha-halogenated benzoate aldoxime compound into the (Z) -alpha-halogenated benzoate aldoxime compound to obtain a solution B; wherein, the dosage of anhydrous sodium salt or potassium salt of the benzoate hydroxamic acid compound is 1 to 10 percent of the equivalent of the alpha-halogenated benzaldehyde oxime;
step 3, adding anhydrous ammonia source into the solution B, and reacting for a sufficient time at 20-100 ℃ to enable (Z) -alpha-halogenated benzaldehyde oxime to undergo ammonolysis reaction to generate (Z) -N-hydroxy phenylamidine, so as to obtain solution C; wherein the dosage of the anhydrous ammonia source is 1-2 times equivalent of the dosage of the alpha-halogenated benzaldoxime;
step 4, concentrating the solution C to remove most of the alcohol solvents, adding water and a second solvent, and fully heating and stirring to dissolve most of the solids; filtering and separating liquid; the filtered filter cake is anhydrous sodium salt or potassium salt of the benzohydroxamic acid compound, and can be recycled and reused, for example, the filter cake can be used as the catalyst in the step 2; the separated organic layer is a solution containing a target product (Z) -N-hydroxy phenylamidine, and the (Z) -N-hydroxy phenylamidine with high purity is obtained by recrystallization after concentration; the second solvent is selected from aromatic hydrocarbon, ether or halohydrocarbon solvents.
The alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol and ethylene glycol monomethyl ether.
The mixed organic solvent containing the alcohol solvent further comprises: a non-alcoholic organic solvent which can improve the solubility of the alpha-halogenated benzaldoxime compound and can not react with the alpha-halogenated benzaldoxime compound. The non-alcohol organic solvent is selected from any one or more than two of benzene, toluene, tetrahydrofuran and methyl tertiary butyl ether.
The amount of the first solvent is preferably such that 50% or more of the α -halobenzaldoxime compound can be dissolved; preferably, it is completely soluble.
In the step 2, the anhydrous sodium salt (or potassium salt) of the catalyst of the benzoic hydroxamic acid compound is used in an amount which is 1 to 10 times equivalent, preferably 3 to 6 times equivalent, of the alpha-halogenated benzoic aldehyde oxime; the reaction temperature is controlled between 0 and 60 ℃, preferably between 20 and 40 ℃; the reaction time is controlled to be 1 to 24 hours, preferably 5 to 10 hours. The anhydrous sodium (or potassium) salt of the catalyst benzohydroxamic acid compound is commercially available; or the alpha-halogenated benzaldehyde oxime compound is subjected to alkaline hydrolysis and acid-base neutralization reaction with sodium hydroxide (or potassium hydroxide) with the equivalent weight of 2 times that of the alpha-halogenated benzaldehyde oxime compound; can also be recovered from step 4 of the present invention; finally, drying and dewatering to obtain the product.
In the step 3, the anhydrous ammonia source is selected from any one or more than two of ammonia gas, anhydrous alcohol solution of ammonia gas, or ammonium bicarbonate. The anhydrous ammonia source is used in an amount of 1 to 2 equivalents, preferably 1.05 to 1.2 equivalents, of the alpha-halobenzaldoxime. The reaction temperature is controlled between 20 and 100 ℃, preferably between 30 and 60 ℃; the reaction time is controlled to be 1 to 24 hours, preferably 3 to 10 hours.
In the step 4, the solvent may be a substituted benzene solvent such as benzene, toluene, chlorobenzene, etc., an ether solvent such as diethyl ether, methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, etc., a halogenated hydrocarbon solvent such as 1, 2-dichloroethane, chloroform, carbon tetrachloride, trichloroethylene, etc., or a mixture of the above solvents; the solvent is added in an amount sufficient to dissolve the desired product (Z) -N-hydroxyphenylamidine. The temperature at which the stirring, filtration and liquid separation are carried out may be between 0 and 130℃and preferably between 20 and 60 ℃.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethyl phenyl amidine is prepared by adopting an ammonolysis method, and the reaction equation is as follows:
51.9g (0.2 mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethylbenzaldoxime (E, Z configuration mixture) was dissolved in 250ml of absolute ethanol, 1.66g (0.006 mol) of anhydrous potassium salt of 2, 3-difluoro-5-trifluoromethylbenzoic acid was added thereto, and after stirring at 0 to 5℃for 24 hours, the temperature was raised to 20 to 30℃and ammonium bicarbonate was added in portions with stirring for 15.8g (0.2 mol) in total; stirring and reacting for 24 hours at 20-30 ℃ after the addition is completed. The mixture was concentrated under reduced pressure using a rotary evaporator to remove most of the ethanol, 200g of water and 200g of chloroform were added to the concentrated residue, and the mixture was stirred at 30 to 40℃until most of the solids were dissolved. Filtering while the mixture is hot, and recovering the obtained filter cake which is the potassium salt of 2, 3-difluoro-5-trifluoromethyl benzohydroxamic acid; separating the filtrate to obtain chloroform layer (lower layer), and water washing at 30-40deg.C for 2 times. The washed chloroform layer was concentrated again to remove chloroform, and after the concentrated residue was crystallized 2 times with methyl tert-butyl ether, the filter cake was filtered and dried to obtain 45.7g of (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenyl amidine, the purity of which was not less than 99.5% by liquid chromatography, and the yield was 95.3%.
Comparative example 1
Because the chemical stability of the raw material alpha-chloro-2, 3-difluoro-5-trifluoromethyl benzaldehyde oxime is poor, chromatographic analysis cannot be performed; however, the raw material α -chloro-2, 3-difluoro-5-trifluoromethylbenzaldehyde oxime used in comparative example 1 was prepared in the same batch as that of example 1, and its purity and E, Z configuration ratio were the same.
51.9g (0.2 mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethylbenzaldehyde oxime (E, Z configuration mixture) was dissolved in 250ml of absolute ethanol, heated to 20-30℃and added with stirring in portions with a total of 32.4g of 21% aqueous ammonia (0.4 mol); stirring and reacting for 24 hours at 20-30 ℃ after the addition is completed. The mixture was concentrated under reduced pressure using a rotary evaporator to remove most of the ethanol, 200g of water and 200g of chloroform were added to the concentrated residue, and the mixture was stirred at 30 to 40℃until most of the solids were dissolved. Filtering while the mixture is hot, separating the filtrate, and then preserving the temperature of the obtained chloroform layer (lower layer) for 2 times by water washing at the temperature of between 30 and 40 ℃. The washed chloroform layer was concentrated again to remove chloroform, and after the concentrated residue was crystallized 2 times with methyl tert-butyl ether, the filter cake was filtered and dried to obtain 39.8g of (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenyl amidine, the purity of which was not less than 99.5% by liquid chromatography and the yield was 83.1%.
It can be seen that if the aqueous ammonia source (ammonia water) is directly added into the alpha-halogenated benzaldoxime compound with two configurations of E, Z, more byproducts are produced, and the target product obtained by recrystallization has lower yield.
Comparative example 2
Because the chemical stability of the raw material alpha-chloro-2, 3-difluoro-5-trifluoromethyl benzaldehyde oxime is poor, chromatographic analysis cannot be performed; however, the raw material α -chloro-2, 3-difluoro-5-trifluoromethyl-benzaldehyde oxime used in comparative examples 1-2 was prepared in the same batch as that in example 1, and its purity and E, Z configuration ratio were the same.
51.9g (0.2 mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethylbenzaldehyde oxime (E, Z configuration mixture) was dissolved in 250ml of absolute ethanol, heated to 20-30℃and added in portions with stirring to an ammonia ethanol solution containing a total of 8.5g of ammonia (0.5 mol); stirring and reacting for 24 hours at 20-30 ℃ after the addition is completed. The mixture was concentrated under reduced pressure using a rotary evaporator to remove most of the ethanol, 200g of water and 200g of chloroform were added to the concentrated residue, and the mixture was stirred at 30 to 40℃until most of the solids were dissolved. Filtering while the mixture is hot, separating the filtrate, and then preserving the temperature of the obtained chloroform layer (lower layer) for 2 times by water washing at the temperature of between 30 and 40 ℃. The washed chloroform layer is concentrated again to remove chloroform, the concentrated residue is crystallized by methyl tertiary butyl ether for 2 times, and then filtered and dried to obtain 34.1g of (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethyl phenylamidine, the purity of the liquid chromatography is more than or equal to 98 percent, and the yield is 68.5 percent.
It can be seen that, if an anhydrous ammonia source (ammonia ethanol solution) is directly added into the alpha-halogenated benzaldoxime compound with two configurations of E, Z, the configuration conversion is not performed, and the target product obtained through recrystallization has low yield.
Example 2
The (Z) -N-hydroxy-4-trans- (4-ethyl) cyclohexylphenylamidine was prepared by ammonolysis, and the reaction equation was as follows:
62.0g (0.2 mol) of alpha-bromo-4-trans- (4-ethyl) cyclohexylbenzaldoxime (E, Z configuration mixture) was mixed with 200ml of anhydrous isopropanol and 100ml of toluene in a 1000ml autoclave, and then 3.18g (0.02 mol) of anhydrous sodium salt of benzoic hydroxamic acid was added thereto, and the mixture was stirred at 55 to 60℃for 1 hour. Then, an ammonia ethanol solution containing 6.8g ammonia (0.4 mol) in total was added, the autoclave was sealed, and the temperature was raised to 90 to 100℃with stirring for further reaction for 1 hour. Then cooling to below 40 ℃, taking out the reaction mixture, concentrating under reduced pressure by a rotary evaporator to remove most of isopropanol, adding 200g of water and 200ml of toluene into the concentrated residue, and stirring at 30-40 ℃ until most of the solid is dissolved. Filtering to obtain a filter cake which is sodium salt of the benzohydroxamic acid, and recovering; separating the filtrate to obtain toluene layer (upper layer), and washing with water at 30-40deg.C for 2 times. The toluene layer after washing is concentrated again to remove toluene, the concentrated residue is crystallized by ethanol for 2 times, and then the filter cake is filtered and dried to obtain 47.8g of (Z) -N-hydroxy-4-trans- (4-ethyl) cyclohexylphenylamidine, the purity of liquid chromatography is more than or equal to 99.6 percent, and the yield is 97.1 percent.
The invention provides a method for preparing (Z) -N-hydroxy benzamidine compounds by taking E, Z mixed alpha-halogenated benzaldoxime compounds as raw materials through E, Z configuration conversion reaction and ammonolysis reaction. The method takes anhydrous sodium salt (or potassium salt) of a benzoate hydroxamic acid compound as a catalyst for E, Z configuration conversion reaction, and takes anhydrous ammonia gas or nearly neutral ammonium bicarbonate as a raw material for ammonolysis reaction; not only can fully convert E configuration in raw materials into Z configuration, but also can avoid the problem that more alkaline hydrolysis side reactions occur when the alpha-halogenated benzaldehyde oxime compound performs E and Z configuration conversion reaction and ammonolysis reaction; the yield of the target product after purification is improved to more than 95 percent.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing. Accordingly, the scope of the invention should be limited only by the attached claims.
Claims (7)
1. A process for the ammonolysis of (Z) -N-hydroxyphenylamidine compounds, comprising:
the reaction equation is as follows:
；
；
wherein R is any one of halogen, amino, nitro, cyano, trifluoromethyl and (4-ethyl) cyclohexyl;
step 1, fully or partially dissolving an alpha-halogenated benzaldoxime compound containing E, Z two configurations by adopting a first solvent to obtain a solution A; wherein the first solvent is an alcohol solvent or a mixed organic solvent containing an alcohol solvent; the alcohol solvent is selected from any one or more than two of methanol, ethanol, isopropanol, ethylene glycol and ethylene glycol monomethyl ether; the mixed organic solvent containing the alcohol solvent is a non-alcohol organic solvent which can improve the solubility of the alpha-halogenated benzaldehyde oxime compound and can not react with the alpha-halogenated benzaldehyde oxime compound;
step 2, adding anhydrous sodium salt or potassium salt of a benzoate hydroxamic acid compound as a catalyst into the solution A, and stirring for 1-24h to fully convert the (E) -alpha-halogenated benzaldoxime compound into the (Z) -alpha-halogenated benzaldoxime compound to obtain a solution B; wherein the dosage of anhydrous sodium salt or potassium salt of the benzoate hydroxamic acid compound is 1% -10% of that of the alpha-halogenated benzoate oxime compound, and the molar ratio is calculated;
step 3, adding an anhydrous ammonia source into the solution B under stirring, and reacting for 1-24 hours to enable the (Z) -alpha-halogenated benzaldoxime compound to undergo ammonolysis reaction to generate a (Z) -N-hydroxy benzamidine compound, thereby obtaining a solution C; wherein the dosage of the anhydrous ammonia source is 1-2 times of equivalent of the alpha-halogenated benzaldehyde oxime compound, and the dosage is calculated by mole; wherein the anhydrous ammonia source is selected from any one or more than two of ammonia gas, or an anhydrous alcohol solution of ammonia gas, or ammonium bicarbonate;
step 4, concentrating the solution C, adding water and a second solvent, and fully heating and stirring to dissolve the (Z) -N-hydroxy benzamidine compound; filtering and separating liquid; the separated organic layer is a solution containing a target product (Z) -N-hydroxy benzamidine compound, and the (Z) -N-hydroxy benzamidine compound with high purity is obtained by concentrating and then recrystallizing; the second solvent is easy to dissolve the (Z) -N-hydroxy benzamidine compound and is insoluble in water; the second solvent is selected from aromatic hydrocarbon, ether or halohydrocarbon solvents; the aromatic hydrocarbon solvent comprises any one or more than two of benzene, toluene and chlorobenzene; the ether solvent comprises any one or more than two of diethyl ether, methyl tetrahydrofuran, methyl tertiary butyl ether and methyl cyclopentyl ether; the halogenated hydrocarbon solvent comprises any one or more than two of 1, 2-dichloroethane, chloroform, carbon tetrachloride and trichloroethylene.
2. The method for preparing (Z) -N-hydroxy benzamidine compound according to claim 1, wherein the non-alcoholic organic solvent is one or more selected from benzene, toluene, tetrahydrofuran and methyl tert-butyl ether.
3. The method for preparing (Z) -N-hydroxyphenylamidine compound by ammonolysis according to claim 1, wherein the amount of the first solvent used in the step 1 is limited by at least 50% of the α -halobenzaldoxime compound.
4. The method for preparing (Z) -N-hydroxy benzamidine compounds according to claim 1, wherein in the step 2, the anhydrous sodium salt or potassium salt of the benzoic hydroxamic acid compound is used in an amount of 3% -6% of the α -halogenated benzaldoxime compound in terms of molar ratio.
5. The method for preparing (Z) -N-hydroxyphenylamidine compound according to claim 1, wherein the stirring temperature in the step 2 is 0 to 60 ℃.
6. The method for preparing (Z) -N-hydroxy benzamidine compounds according to claim 1, wherein in the step 3, the anhydrous ammonia source is used in an amount of 1.05 to 1.2 equivalents or 1.2 to 1.5 equivalents or 1.5 to 2 equivalents of the α -halogenobenzaldehyde oxime compounds in terms of mole number.
7. The method for preparing (Z) -N-hydroxyphenylamidine compound according to claim 1, wherein the reaction temperature is controlled to be 20-100 ℃ in the step 3.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147879A (en) * | 1988-10-20 | 1992-09-15 | Biorex Kutato-Fejleszto Kft | O-(3-amino-2-hydroxypropyl)-hydroximic acid halides and process for preparing the same |
| CN109879769A (en) * | 2019-03-22 | 2019-06-14 | 邯郸市赵都精细化工有限公司 | A kind of bromo element recycles the method for preparing aminomethylbenzoic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5147879A (en) * | 1988-10-20 | 1992-09-15 | Biorex Kutato-Fejleszto Kft | O-(3-amino-2-hydroxypropyl)-hydroximic acid halides and process for preparing the same |
| CN109879769A (en) * | 2019-03-22 | 2019-06-14 | 邯郸市赵都精细化工有限公司 | A kind of bromo element recycles the method for preparing aminomethylbenzoic acid |
Non-Patent Citations (2)
| Title |
|---|
| (S)-N-叔丁氧羰基-3-羟基-1-金刚烷甘氨酸的合成;王建塔等;《广州化工》;20170608(第11期);全文 * |
| 取代苯甲脒盐酸盐类化合物的合成方法研究;郑玉安等;《染料与染色》;20160428(第02期);全文 * |
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