CN112174853A - Method for preparing (Z) -N-hydroxybenzamidine by ammonolysis - Google Patents
Method for preparing (Z) -N-hydroxybenzamidine by ammonolysis Download PDFInfo
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- CN112174853A CN112174853A CN202011207539.6A CN202011207539A CN112174853A CN 112174853 A CN112174853 A CN 112174853A CN 202011207539 A CN202011207539 A CN 202011207539A CN 112174853 A CN112174853 A CN 112174853A
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- C07C259/00—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
- 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-hydroxybenzamidine by an ammonolysis method, which comprises the following steps: step 1, dissolving alpha-halogenated benzaldehyde oxime compound containing E, Z two configurations simultaneously completely or partially by adopting a first solvent to obtain a solution A; step 2, adding anhydrous sodium salt or potassium salt of the benzohydroxamic acid compound, and stirring to fully convert the (E) -alpha-halogenated benzaldehyde oxime compound into a (Z) form to obtain a solution B; step 3, adding an anhydrous ammonia source, and carrying out ammonolysis reaction to generate (Z) -N-hydroxybenzamidine to obtain a solution C; step 4, concentrating the solution C, and adding water and a second solvent to dissolve most of the solid; then filtering and separating liquid; and (Z) -N-hydroxybenzamidine with high purity is obtained after post-treatment. The method can fully convert the E configuration in the raw material into the Z configuration, also avoids the problem of more side reactions of alkaline hydrolysis in the conversion reaction and the ammonolysis reaction of the E and Z configurations, and improves the yield of the purified target product to more than 95 percent.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a method for preparing (Z) -N-hydroxybenzamidine by an ammonolysis method.
Background
The N-hydroxybenzamidine compounds are intermediates widely applied to the industries of medicines, pesticides, organic materials and organic fine chemicals; the compound has E, Z isomers with two configurations, and the general formula of the molecular structure is shown as follows:
r in the general formula is various substituents commonly found on benzene ring, such as aliphatic group, aromatic group, halogen, ester group, amino group, nitro group, cyano group, or their combination group, and the like (the same below).
The N-hydroxybenzamidine compounds are the most common and one of the preparation methods with the lowest cost, namely, alpha-halogenated benzaldehyde oxime compounds are used for aminolysis reaction; the ammonolysis reaction is suitable for preparing Z type and E type (or E, Z mixed type) N-hydroxybenzamidine compounds, and the general formula of the reaction equation is as follows:
r in the general formula is various substituent groups commonly found on a benzene ring, such as aliphatic group, aromatic group, halogen, ester group, amino group, nitro group, cyano group, or a combination group thereof, and the like. X in the above general formula may be any one of three halogens, i.e., chlorine, bromine and iodine (the same applies hereinafter).
In different fields of application, it is often necessary to obtain isomers of N-hydroxybenzamidines in a single configuration (Z or E). Because the raw material alpha-halogenated benzaldehyde oxime compound before ammonolysis reaction usually contains E, Z two configurations at the same time, and is easy to be converted mutually under the condition of different pH values, most of E configurations can be converted into Z configurations under the alkaline condition; the E type and Z type N-hydroxy benzene amidine compounds are difficult to be transformed mutually. Therefore, when it is desired to obtain the Z-form N-hydroxybenzamidines, the following two methods are generally adopted:
the first method is to treat alpha-halogenated benzaldehyde oxime compound containing E, Z two configurations simultaneously with alkali to convert E configuration into Z configuration as much as possible; and the ammonolysis reaction is carried out simultaneously with (or after) the alkali treatment. The commonly used alkali includes alkali metal hydroxides such as lithium hydroxide (sodium hydroxide, potassium hydroxide) and the like, ammonia water and the like; when ammonia is used, it is both a catalyst for the E, Z configuration conversion reaction and a starting material for the aminolysis reaction.
However, in the method, because the halogen atom of the alpha-halogenated benzaldehyde oxime compound is very active, the halogen atom can also have alkaline hydrolysis reaction with most alkaline reagents while the E, Z configuration conversion reaction is carried out, and a by-product of the benzaldehyde hydroxamic acid compound and the salt thereof are generated; moreover, the side reaction continuously consumes alkaline reagent, which results in the need to add more than 20% of equivalent of alkaline catalyst to obtain better configuration conversion ratio and generate more alkaline hydrolysis by-products.
For example, ammonia is used, and the reaction equation is as follows:
in the method, even if ammonia water with weak alkalinity is used as a configuration conversion catalyst (and is also used as a raw material for ammonolysis reaction), E, Z configuration conversion and ammonolysis reaction are simultaneously and continuously carried out, the by-product of benzohydroxamate can be up to 10-20% in the product, and the maximum yield of the target product (Z-type N-hydroxybenzamidine compound) after purification treatment is not more than 85%.
In the second method, E, Z mixed alpha-halogenated benzaldehyde oxime compound and ammonia gas are subjected to ammonolysis reaction under anhydrous condition to obtain E, Z mixed N-hydroxybenzamidine compound. Although the method does not generate the side reaction of alkaline hydrolysis of the alpha-halogenated benzaldehyde oxime compound; however, since the E-isomer is not converted into the Z-isomer, the E-isomer content in the product is high, and the product needs to be purified and removed at a later stage, and the yield loss of the Z-isomer is large in the purification process. Therefore, the yield of the target product ((Z) -N-hydroxybenzamidines) in the method is even lower than that in the first method. 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 of a preparation method of (Z) -N-hydroxybenzamidine compounds, and provides an improved ammonolysis method for preparing (Z) -N-hydroxybenzamidine, which has few byproducts, simple and convenient separation, high purity and high yield.
In order to achieve the above object, the present invention provides a method for preparing (Z) -N-hydroxybenzamidine by an ammonolysis method, comprising:
step 1, dissolving alpha-halogenated benzaldehyde oxime compound containing E, Z two configurations completely or partially 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 benzohydroxamic acid compound into the solution A, and then stirring for a certain time at 0-60 ℃ to fully convert the (E) -alpha-halogenated benzaldehyde oxime compound into a (Z) -alpha-halogenated benzaldehyde oxime compound to obtain a solution B; wherein, the dosage of the anhydrous sodium salt or the potassium salt of the benzohydroxamic acid compound is 1 to 10 percent of the alpha-halogenated benzaldoxime, and the dosage is calculated by the mol ratio;
step 3, adding an anhydrous ammonia source into the solution B, and reacting at 20-100 ℃ for enough time to allow the (Z) -alpha-halogenated benzaldehyde oxime to perform ammonolysis reaction to generate (Z) -N-hydroxybenzamidine to obtain a solution C; wherein the amount of the anhydrous ammonia source is 1-2 times equivalent of the alpha-halogenated benzaldehyde oxime;
step 4, concentrating the solution C, adding water and a second solvent, and fully heating and stirring to dissolve most of the solid; then filtering and separating liquid; the filtered filter cake is anhydrous sodium salt or potassium salt of the benzohydroxamic acid compound; the organic layer of the liquid separation is a solution containing the target product (Z) -N-hydroxybenzamidine, and the high-purity (Z) -N-hydroxybenzamidine is obtained by recrystallization after concentration; the second solvent is selected from aromatic hydrocarbon, ether or halogenated hydrocarbon solvent.
Preferably, the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol and ethylene glycol monomethyl ether.
Preferably, the mixed organic solvent containing an alcohol solvent further comprises: non-alcoholic organic solvents that improve the solubility of alpha-halobenzaldehyde oximes without reacting with them.
Preferably, the non-alcoholic organic solvent is selected from any one or a mixture of more than two of benzene, toluene, tetrahydrofuran and methyl tert-butyl ether.
Preferably, in 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 amount of the anhydrous sodium salt (or potassium salt) of the benzohydroxamic acid compound is 3 to 6 percent of the alpha-halogenated benzaldoxime, calculated by mole ratio.
Preferably, in the step 2, the stirring temperature is 20-40 ℃; the reaction time is controlled to be 1-24 hours.
Preferably, the anhydrous ammonia source is selected from one or a mixture of more than two of ammonia gas, anhydrous alcohol solution of ammonia gas or ammonium bicarbonate.
Preferably, in step 3, the amount of the anhydrous ammonia source is 1.05 to 1.2 times equivalent, or 1.2 to 1.5 times equivalent, or 1.5 to 2 times equivalent of the α -halobenzaldehyde oxime, calculated by mole.
Preferably, in step 3, the reaction temperature is controlled to be 30-60 ℃ and the reaction time is controlled to be 1-24 hours.
Preferably, in step 4, the aromatic hydrocarbon solvent comprises any one or a mixture of two or more of benzene, toluene and chlorobenzene; the ether solvent comprises one or more of diethyl ether, methyl tetrahydrofuran, methyl tert-butyl ether and methyl cyclopentyl ether; the halogenated hydrocarbon solvent contains any one or more than two of 1, 2-dichloroethane, chloroform, carbon tetrachloride and trichloroethylene.
The invention has the technical effects that:
the invention takes anhydrous sodium salt (or potassium salt) of benzohydroxamic acid as a catalyst, so that the E and Z mixed alpha-halogenated benzaldehyde oxime compound has E, Z configuration conversion reaction, and the alkaline hydrolysis side reaction of the alpha-halogenated benzaldehyde oxime compound can not occur, thereby obtaining the high-content (Z) -alpha-halogenated benzaldehyde oxime compound.
Compared with the invention, if sodium hydroxide (or potassium hydroxide) is directly added into the alpha-halogenated benzaldehyde oxime 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, the sodium hydroxide (or potassium hydroxide) and the water can cause alkaline hydrolysis of the alpha-halogenated benzaldoxime compound, and a byproduct is generated; and only acidic benzohydroxamic acid can be generated before the alpha-halogenated benzaldehyde oxime compound is completely consumed, and alkaline sodium salt (or potassium salt) of the benzohydroxamic acid cannot be obtained (or maintained). The corresponding reaction equation is as follows:
after the (Z) -alpha-halogenated benzaldehyde oxime compound with high content is obtained, anhydrous ammonia gas, an anhydrous alcohol solution of the ammonia gas or nearly neutral ammonium bicarbonate is used as an ammonolysis raw material to carry out ammonolysis reaction on the alpha-halogenated benzaldehyde oxime compound. Under the anhydrous reaction condition or the reaction condition close to neutrality (ammonium bicarbonate), the (Z) -alpha-halogenated benzaldehyde oxime compound rarely undergoes alkaline hydrolysis side reaction, the conversion rate of the generated target product (Z) -N-hydroxybenzamidine compound is obviously improved, and the yield after purification can reach more than 95%.
Detailed Description
The structural general formula of the 'E, Z two-configuration alpha-halogenated benzaldehyde oxime compound' is as follows:
By "anhydrous source of ammonia" in the context of the present invention is meant that no water is introduced directly, e.g., no water impurities, no aqueous solution or no water of crystallization. Ammonium bicarbonate produces carbon dioxide and water after the ammonolysis reaction and cannot be strictly said to be an anhydrous or neutral source of ammonia. However, since the pH of ammonium bicarbonate is close to neutral, even if a small amount of water is generated during the reaction, the side reaction of alkaline hydrolysis occurs substantially without causing the aminolysis reaction.
The technical concept of the invention is as follows:
1. the alpha-halogenated benzaldehyde oxime compound containing E, Z two configurations is dissolved in alcohol solvent or mixed organic solvent containing alcohol to obtain solution A, which may be solution or suspension.
2. Adding anhydrous sodium salt (or potassium salt) of benzohydroxamic acid compounds into the solution A; and then stirring for a certain time at the temperature of 0-60 ℃ to convert most of (E) -alpha-halogenated benzaldehyde oximes into (Z) -alpha-halogenated benzaldehyde oximes.
The anhydrous sodium (or potassium) salt of the benzohydroxamic acid compound can be purchased commercially or prepared using the following reaction equation:
the reaction equation for the configurational transformation is as follows:
3. introducing ammonia (or adding anhydrous alcohol solution of ammonia or adding ammonium bicarbonate); and then reacting at 20-100 ℃ for enough time to carry out ammonolysis reaction on the (Z) -alpha-halogenated benzaldehyde oxime to generate (Z) -N-hydroxybenzamidine.
Based on the technical concept, the invention provides a method for preparing (Z) -N-hydroxybenzamidine by an ammonolysis method, which comprises the following steps:
step 1, dissolving alpha-halogenated benzaldehyde oxime compound containing E, Z two configurations completely or partially 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 benzohydroxamic acid compound into the solution A as a catalyst, and then stirring for a certain time at 0-60 ℃ to fully convert the (E) -alpha-halogenated benzaldehyde oxime compound into a (Z) -alpha-halogenated benzaldehyde oxime compound to obtain a solution B; wherein the dosage of the anhydrous sodium salt or the potassium salt of the benzohydroxamic acid compound is 1 to 10 percent of equivalent weight of the alpha-halogenated benzaldoxime;
step 3, adding an anhydrous ammonia source into the solution B, and reacting at 20-100 ℃ for enough time to allow the (Z) -alpha-halogenated benzaldehyde oxime to perform ammonolysis reaction to generate (Z) -N-hydroxybenzamidine to obtain a solution C; wherein the amount of the anhydrous ammonia source is 1-2 times equivalent of the alpha-halogenated benzaldehyde oxime;
step 4, concentrating the solution C to remove most of the alcohol solvent, adding water and a second solvent, and fully heating and stirring to dissolve most of the solid; then filtering and separating liquid; the filtered filter cake is anhydrous sodium salt or potassium salt of the benzohydroxamic acid compound, and can be recycled, for example, the filter cake is used as the catalyst in the step 2; the organic layer of the liquid separation is a solution containing the target product (Z) -N-hydroxybenzamidine, and the high-purity (Z) -N-hydroxybenzamidine is obtained by recrystallization after concentration; the second solvent is selected from aromatic hydrocarbon, ether or halogenated hydrocarbon solvent.
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: non-alcoholic organic solvents that improve the solubility of alpha-halobenzaldehyde oximes without reacting with them. The non-alcoholic organic solvent is selected from any one or a mixture of more than two of benzene, toluene, tetrahydrofuran and methyl tert-butyl ether.
The dosage of the first solvent is preferably that more than 50% of alpha-halogenated benzaldehyde oxime compounds can be dissolved; preferably, it is completely soluble.
In the step 2, the dosage of the anhydrous sodium salt (or potassium salt) of the catalyst benzohydroxamic acid compound is 1-10% of the equivalent of the alpha-halogenated benzaldehyde oxime, and preferably 3-6% of the equivalent of the alpha-halogenated benzaldehyde oxime; the reaction temperature is controlled between 0 and 60 ℃, preferably between 20 and 40 ℃; the reaction time is controlled to be 1-24 hours, preferably 5-10 hours. The anhydrous sodium salt (or potassium salt) of the catalyst benzohydroxamic acid compound can be purchased from the market; or the alpha-halogenated benzaldehyde oxime compound and 2 times of sodium hydroxide (or potassium hydroxide) are subjected to alkaline hydrolysis and acid-base neutralization reaction to obtain the compound; can also be recovered from the step 4 of the invention; finally, the product is dried and dewatered for use.
In step 3, the anhydrous ammonia source is selected from one or more of ammonia gas, anhydrous alcohol solution of ammonia gas, and ammonium bicarbonate. The amount of the anhydrous ammonia source is 1-2 times equivalent of the alpha-halogenated benzaldehyde oxime, and preferably 1.05-1.2 times equivalent. The reaction temperature is controlled to be between 20 and 100 ℃, and preferably between 30 and 60 ℃; the reaction time is controlled to be 1-24 hours, preferably 3-10 hours.
In step 4, the solvent added may be substituted benzene solvents such as benzene, toluene, chlorobenzene, etc., ether solvents such as diethyl ether, methyl tetrahydrofuran, methyl tert-butyl ether, methyl cyclopentyl ether, etc., halogenated hydrocarbon solvents such as 1, 2-dichloroethane, chloroform, carbon tetrachloride, trichloroethylene, etc., or a mixture of the foregoing solvents; the amount of the solvent is added according to the proportion that the target product (Z) -N-hydroxybenzamidine can be fully dissolved. The temperature for heating, stirring, filtering and separating may be 0 to 130 ℃, preferably 20 to 60 ℃.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
(Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenylamidine is prepared by an ammonolysis method, the reaction equation is as follows:
dissolving 51.9g (0.2mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethyl benzaldehyde oxime (E, Z configuration mixture) in 250ml of absolute ethanol, adding 1.66g (0.006mol) of anhydrous potassium salt of 2, 3-difluoro-5-trifluoromethyl benzaldehyde hydroxamic acid, keeping the temperature at 0-5 ℃, stirring for 24 hours, heating to 20-30 ℃, and adding 15.8g (0.2mol) of ammonium bicarbonate in batches under stirring; and stirring and reacting for 24 hours at the temperature of 20-30 ℃ after the addition. And concentrating under reduced pressure by using a rotary evaporator to remove most of ethanol, adding 200g of water and 200g of chloroform into the concentrated residue, and stirring at 30-40 ℃ until most of solid is dissolved. Filtering while the solution is hot to obtain a filter cake which is the sylvite of the 2, 3-difluoro-5-trifluoromethyl benzohydroxamic acid and recycling; separating the filtrate to obtain a chloroform layer (lower layer), and then washing the chloroform layer (lower layer) for 2 times at the temperature of 30-40 ℃. The chloroform layer after washing is concentrated again to remove the chloroform, the concentrated residue is crystallized for 2 times by methyl tert-butyl ether, and then the (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenyl amidine of 45.7g is obtained after filtration and drying of the filter cake, the purity of the liquid chromatography is more than or equal to 99.5 percent, and the yield is 95.3 percent.
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 carried out; however, the starting material α -chloro-2, 3-difluoro-5-trifluoromethylbenzaldoxime used in comparative example 1 was the same as that used in example 1 in the same batch, and the purity and E, Z configuration ratio were completely the same.
Dissolving 51.9g (0.2mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethyl benzaldehyde oxime (E, Z configuration mixture) in 250ml of absolute ethanol, heating to 20-30 ℃, and adding 32.4g of 21% ammonia water (0.4mol) in batches under stirring; and stirring and reacting for 24 hours at the temperature of 20-30 ℃ after the addition. And concentrating under reduced pressure by using a rotary evaporator to remove most of ethanol, adding 200g of water and 200g of chloroform into the concentrated residue, and stirring at 30-40 ℃ until most of solid is dissolved. Filtering while hot, separating the filtrate, and washing the obtained chloroform layer (lower layer) with water at 30-40 ℃ for 2 times. The chloroform layer after washing was concentrated again to remove chloroform, and the concentrated residue was crystallized 2 times with methyl tert-butyl ether, filtered and the filter cake was dried to obtain 39.8g of (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenylamidine with a liquid chromatography purity of 99.5% or more and a yield of 83.1%.
Therefore, if an aqueous ammonia source (ammonia water) is directly added into the E, Z alpha-halogenated benzaldehyde oxime compound with two configurations, more byproducts are generated, 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 carried out; however, the starting material α -chloro-2, 3-difluoro-5-trifluoromethylbenzaldehyde oxime used in comparative examples 1 to 2 was the same as that used in example 1 in the same lot, and the purity and E, Z configuration ratio were completely the same.
Dissolving 51.9g (0.2mol) of alpha-chloro-2, 3-difluoro-5-trifluoromethyl benzaldehyde oxime (E, Z configuration mixture) in 250ml of absolute ethanol, heating to 20-30 ℃, and adding ammonia ethanol solution containing 8.5g ammonia (0.5mol) in total in batches under stirring; and stirring and reacting for 24 hours at the temperature of 20-30 ℃ after the addition. And concentrating under reduced pressure by using a rotary evaporator to remove most of ethanol, adding 200g of water and 200g of chloroform into the concentrated residue, and stirring at 30-40 ℃ until most of solid is dissolved. Filtering while hot, separating the filtrate, and washing the obtained chloroform layer (lower layer) with water at 30-40 ℃ for 2 times. The chloroform layer after washing was concentrated again to remove chloroform, and the concentrated residue was crystallized 2 times with methyl tert-butyl ether, filtered and dried to give 34.1g of (Z) -N-hydroxy-2, 3-difluoro-5-trifluoromethylphenylamidine with a liquid chromatography purity of 98% or more and a yield of 68.5%.
Therefore, if an anhydrous ammonia source (ammonia ethanol solution) is directly added into the E, Z two-configuration alpha-halogenated benzaldehyde oxime compound, configuration conversion is not carried out, and the target product is obtained through recrystallization, so that the yield is low.
Example 2
(Z) -N-hydroxy-4-trans- (4-ethyl) cyclohexyl phenyl amidine is prepared by an ammonolysis method, and the reaction equation is as follows:
62.0g (0.2mol) of α -bromo-4-trans- (4-ethyl) cyclohexyl benzaldehyde oxime (E, Z configuration mixture) was mixed with 200ml of anhydrous isopropanol and 100ml of toluene in a 1000ml autoclave, and then 3.18g (0.02mol) of anhydrous sodium salt of benzohydroxamic acid was added thereto, followed by stirring at 55 to 60 ℃ for 1 hour. Then, an ammonia ethanol solution containing 6.8g of ammonia (0.4mol) in total is added, the autoclave is sealed, and the temperature is raised to 90-100 ℃ under stirring for further reaction for 1 hour. And then cooling to below 40 ℃, taking out the reaction mixture, carrying out reduced pressure concentration by using 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 solids are dissolved. Filtering to obtain a filter cake which is the sodium salt of the benzohydroxamic acid and recycling; separating the filtrate to obtain a toluene layer (upper layer), and washing the toluene layer (upper layer) with water at 30-40 ℃ for 2 times. The toluene layer after washing was concentrated again to remove toluene, and the concentrated residue was crystallized with ethanol 2 times, filtered and dried to obtain 47.8g of (Z) -N-hydroxy-4-trans- (4-ethyl) cyclohexylphenylamidine with a liquid chromatography purity of 99.6% or more and a yield of 97.1%.
The invention provides a method for preparing (Z) -N-hydroxybenzamidine compounds by taking E, Z mixed alpha-halogenated benzaldehyde oximes as raw materials through E, Z configuration conversion reaction and ammonolysis reaction. The method takes anhydrous sodium salt (or potassium salt) of a benzohydroxamic acid compound as a catalyst for conversion reaction of the E and Z configuration, and takes anhydrous ammonia gas or nearly neutral ammonium bicarbonate as a raw material for ammonolysis reaction; not only can fully convert the E configuration in the raw materials into the Z configuration, but also avoids the problem that more alkaline hydrolysis side reactions occur when the alpha-halogenated benzaldehyde oxime compound is subjected to E and Z configuration conversion reaction and ammonolysis reaction; the yield of the purified target product is improved to over 95 percent.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.
Claims (10)
1. A process for preparing (Z) -N-hydroxybenzamidines by an ammonolysis process, comprising:
step 1, completely or partially dissolving alpha-halogenated benzaldehyde oxime compounds containing E, Z two configurations by adopting a first solvent to obtain a solution A;
step 2, adding anhydrous sodium salt or potassium salt of a benzohydroxamic acid compound into the solution A as a catalyst, and stirring for a certain time to fully convert the (E) -alpha-halogenated benzaldehyde oxime compound into a (Z) -alpha-halogenated benzaldehyde oxime compound to obtain a solution B; wherein, the dosage of the anhydrous sodium salt or the potassium salt of the benzohydroxamic acid compound is 1 to 10 percent of the alpha-halogenated benzaldoxime, and the dosage is calculated by the mol ratio;
step 3, adding an anhydrous ammonia source into the solution B under stirring, and reacting for enough time to allow the (Z) -alpha-halogenated benzaldehyde oxime to carry out ammonolysis reaction to generate (Z) -N-hydroxybenzamidine to obtain a solution C; wherein the amount of the anhydrous ammonia source is 1-2 times equivalent of the alpha-halogenated benzaldehyde oxime in terms of mole number;
step 4, concentrating the solution C, adding water and a second solvent, and fully heating and stirring to dissolve the (Z) -N-hydroxybenzamidine; then filtering and separating liquid; the organic layer of the liquid separation is a solution containing the target product (Z) -N-hydroxybenzamidine, and the high-purity (Z) -N-hydroxybenzamidine is obtained by recrystallization after concentration; the second solvent is readily soluble in (Z) -N-hydroxybenzamidine and insoluble in water.
2. The process for producing (Z) -N-hydroxybenzamidine by an ammonolysis method according to claim 1, wherein the first solvent is an alcohol solvent or a mixed organic solvent containing an alcohol solvent; the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, ethylene glycol and ethylene glycol monomethyl ether.
3. The process for preparing (Z) -N-hydroxybenzamidines by ammonolysis according to claim 2, characterized in that said mixed organic solvent containing alcoholic solvents further comprises: non-alcoholic organic solvents that improve the solubility of alpha-halobenzaldehyde oximes without reacting with them.
4. The process for preparing (Z) -N-hydroxybenzamidine by ammonolysis according to claim 3, wherein said non-alcoholic organic solvent is selected from any one or a mixture of two or more of benzene, toluene, tetrahydrofuran and methyl tert-butyl ether.
5. The process for preparing (Z) -N-hydroxybenzamidines by ammonolysis according to claim 1, wherein in step 1, the first solvent is used in an amount such that at least 50% or more of the α -halobenzaldehyde oxime compound is dissolved.
6. The process for preparing (Z) -N-hydroxybenzamidine by ammonolysis according to claim 1, wherein in step 2, the anhydrous sodium or potassium salt of benzohydroxamic acid is used in an amount of 3 to 6% by mole of the α -halobenzaldoxime.
7. The method for preparing (Z) -N-hydroxybenzamidine by an ammonolysis process according to claim 1, wherein in step 2, the stirring temperature is 0 to 60 ℃; the reaction time is controlled to be 1-24 hours.
8. The process for preparing (Z) -N-hydroxybenzamidine by ammonolysis according to claim 1, wherein in step 3, the anhydrous source of ammonia is selected from ammonia gas, an anhydrous alcoholic solution of ammonia gas, or a mixture of two or more of ammonium bicarbonate; the amount of the anhydrous ammonia source is 1.05-1.2 times equivalent or 1.2-1.5 times equivalent or 1.5-2 times equivalent of the alpha-halogenated benzaldehyde oxime, and the amount is calculated by mole.
9. The method for preparing (Z) -N-hydroxybenzamidine by an ammonolysis process according to claim 1, wherein in step 3, the reaction temperature is controlled to be 20 to 100 ℃ and the reaction time is controlled to be 1 to 24 hours.
10. The process for preparing (Z) -N-hydroxybenzamidines by ammonolysis according to claim 1, wherein in step 4, said second solvent is selected from aromatic hydrocarbons, ethers, or halogenated hydrocarbon solvents; the aromatic hydrocarbon solvent contains any one or mixture of more than two of benzene, toluene and chlorobenzene; the ether solvent comprises one or more of diethyl ether, methyl tetrahydrofuran, methyl tert-butyl ether and methyl cyclopentyl ether; the halogenated hydrocarbon solvent contains any one or more than two of 1, 2-dichloroethane, chloroform, carbon tetrachloride and trichloroethylene.
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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 |
|---|
| 王建塔等: "(S)-N-叔丁氧羰基-3-羟基-1-金刚烷甘氨酸的合成", 《广州化工》 * |
| 郑玉安等: "取代苯甲脒盐酸盐类化合物的合成方法研究", 《染料与染色》 * |
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