Preparation method of hydroxylamine derivative

Abstract

The invention discloses a preparation method of a hydroxylamine derivative, under the action of a catalyst, a hydroxylamine aqueous solution and a functional group-containing compound react to obtain the hydroxylamine derivative, the catalyst is a basic catalyst, and the molar ratio of the functional group-containing compound to hydroxylamine in the hydroxylamine aqueous solution is 1: (1-2); the molar ratio of the functional group-containing compound to the basic catalyst is 1: (0.001-0.5). The method has the advantages of good catalytic activity, high reaction efficiency, easiness in separation of the catalyst, and greenness and environmental protection.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a method for preparing hydroxylamine derivatives. Background Art

[0002] The downstream derivatives of hydroxylamine mainly include compounds such as oximes, hydroxamic acids / isohydroxamic acids, and amidoximes. These compounds are widely used in the fields of materials, medicine, pesticides, flotation, etc. Currently, the processes for preparing these compounds mainly include the hydroxylamine salt neutralization method, that is, using hydroxylamine sulfate or hydroxylamine hydrochloride as raw materials, and using no catalyst, phase transfer catalyst, or organic base as a catalyst. In a solution, sodium hydroxide and other bases are used for neutralization to obtain free hydroxylamine, and then the target product is obtained by reacting with the substrate. This technology has the following problems:

[0003] (1) A large amount of waste salts are easily generated during the process of preparing free hydroxylamine by alkali neutralization, and other metal ions in the alkali often catalyze the decomposition of hydroxylamine and contaminate the product.

[0004] For example, CN112851544A discloses a method for synthesizing O-(3-chloro-2-propenyl)hydroxylamine, which includes the following steps: heating a hydroxylamine solution and methyl isobutyl ketone to react to obtain methyl isobutyl ketoxime, and then reacting methyl isobutyl ketoxime with 1,3-dichloropropene and an alkali solution. After the reaction is completed, the product O-(3-chloro-2-propenyl)hydroxylamine is obtained through post-treatment. The disadvantage is that hydroxylamine solution is prepared by using hydroxylamine salt through an alkaline ion exchange resin, and then reacting with methyl isobutyl ketone to obtain methyl isobutyl ketoxime. However, a large amount of waste brine will still be generated during the replacement of the alkaline ion exchange resin.

[0005] Another example is CN114394916A, which discloses a method for preparing O-3-chloro-2-propenylhydroxylamine, including the following steps: S1 adding an aqueous hydroxylamine solution and methyl acetate to a flask and mixing them completely, then adding 4-dimethylaminopyridine catalyst, and then dropping liquid alkali into the flask for reaction; S2 adding trans-1,3-dichloropropene to the flask again, heating up and maintaining the temperature for reaction; S3 adding hydrochloric acid and stirring, and then carrying out a reflux reaction; S4 separating the organic matter by vacuum distillation, and then adding liquid alkali to adjust the pH; S5 carrying out extraction at room temperature, and then vacuum distilling to remove the solvent to obtain O-3-chloro-2-propenylhydroxylamine. The disadvantage is that free hydroxylamine is prepared by neutralizing hydroxylamine sulfate with an alkali, and then reacting with methyl acetate under alkaline and DMAP catalysis to obtain acetohydroxamic acid. Although the reaction rate and yield are improved, a large amount of waste brine will still be generated, and other metal ions in the alkali will catalyze the decomposition of hydroxylamine and contaminate the product.

[0006] (2) When preparing relatively complex hydroxylamine derivatives or hydroxylamine derivatives for special purposes (such as cyclododecanone oxime, mibefradil oxime, erythromycin A oxime, etc.), generally a phase transfer catalyst or an organic base is used as a catalyst, and hydroxylamine salt or aqueous solution is used as a raw material. During the reaction, it is basically an oil-water two-phase system, and the residual catalyst is difficult to separate, the reaction rate is slow, and the yield is low.

[0007] For example, CN117105859A discloses a method for synthesizing 1-hydroxy-2-pyridone compounds, which is prepared by reacting a substituted 2-pyrone with an aqueous hydroxylamine solution under the catalysis of a phase transfer catalyst (such as polyethylene glycol, quaternary ammonium salt, crown ether, etc.) to obtain hydroxypyridone. The disadvantage is that the aqueous hydroxylamine solution is prepared by reacting hydroxylamine hydrochloride or sulfate with an equimolar amount of sodium hydroxide or potassium hydroxide aqueous solution, and a large amount of waste brine will still be generated. The residual catalyst is difficult to separate, the reaction rate is slow, and the yield is low.

[0008] Another example is that CN114106071A discloses a method for synthesizing selamectin, specifically: Doramectin is oxidized by manganese dioxide, oximated and de-sugared in one step with an aqueous solution of hydroxylamine hydrochloride, and finally selectively reduced under the action of Wilkinson catalyst and hydrogen to obtain selamectin. The disadvantage is that the oximation process takes up to 35-48 hours, and the crude product purity is 75-80%.

[0009] Another example is that CN102617675A discloses a method for preparing high-purity erythromycin A oxime. This method is to design a pre-prepared hydroxylamine methanol solution with high purity and relatively good stability as an oximation reagent, use a mild organic acid as a catalyst for the oximation reaction, and carry out the oximation reaction with erythromycin thiocyanate or erythromycin A base as a raw material in a suitable polar solvent. The disadvantage is that the oximation process takes up to 7-8 hours and the yield is low.

[0010] In summary, during the preparation of hydroxylamine derivatives, the existing technologies have problems such as low reaction efficiency, long reaction time without a catalyst; low catalyst activity and difficult separation of the residual catalyst when there is a catalyst; or a large amount of waste salt is easily generated during the preparation of hydroxylamine aqueous solution by alkali neutralization. Summary of the Invention

[0011] The present invention overcomes the defects of the prior art and provides a method for preparing hydroxylamine derivatives with good catalytic activity, high reaction efficiency, easy separation of the catalyst, and environmental friendliness.

[0012] To solve the above technical problems, the present invention is achieved through the following technical solutions: A preparation method of a hydroxylamine derivative, in which an aqueous hydroxylamine solution and a compound containing a functional group react under the action of a catalyst to obtain a hydroxylamine derivative. The catalyst is a basic catalyst, and the molar ratio of the compound containing a functional group to hydroxylamine in the aqueous hydroxylamine solution is 1:1 to 2; the molar ratio of the compound containing a functional group to the basic catalyst is 1:0.001 to 0.5.

[0013] As a preferred embodiment of the present invention, the reaction is carried out in a solvent.

[0014] As a preferred embodiment of the present invention, the solvent can be alcohols, hydrocarbons, halogenated hydrocarbons; the solvent is more preferably one of methanol, toluene, and dichloromethane.

[0015] As a preferred embodiment of the present invention, the basic catalyst is one of basic oxides, alkali metal hydroxides, ammonia water, and strongly basic ion exchange resins.

[0016] As a preferred embodiment of the present invention, the basic oxide is magnesium oxide; the alkali metal hydroxide is one of sodium hydroxide, calcium hydroxide, and potassium hydroxide.

[0017] As a preferred embodiment of the present invention, the compound containing a functional group is a C=O-containing compound and a C≡N-containing compound. The C=O-containing compound is preferably one of 2-pentanone, cyclododecanone, methyl acetate, 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyranone, 3-methylbutyraldehyde, and methyl octanoate; the C≡N-containing compound is preferably one of erythromycin thiocyanate and 4-cyano-N-(2-fluorophenyl)benzamide.

[0018] As a preferred embodiment of the present invention, the aqueous hydroxylamine solution is a free aqueous hydroxylamine solution, and its free hydroxylamine concentration is 10 wt% to 60 wt% (wt%, mass percentage).

[0019] As a preferred embodiment of the present invention, the reaction temperature is 0 to 100 °C, and the time is 0.5 to 2.5 hours.

[0020] The compound containing a functional group in the present invention contains a carbonyl group (C=O) or a cyano group (C≡N). Among them, O and N have relatively large electronegativity, so the connected C has a partial positive charge. Its reaction with hydroxylamine (NH2OH) is a nucleophilic substitution or nucleophilic addition reaction. During the reaction process, the N in NH2OH attacks the carbon in the carbonyl group or cyano group to form an addition intermediate, and then hydrogen is removed or obtained to form the final product.

[0021] Hydroxylamine itself has a certain nucleophilicity. For example, hydroxylamine and acetone can quickly form acetone oxime. However, for compounds with poor water solubility, large molecular weight or large steric hindrance, the nucleophilicity of hydroxylamine itself is not sufficient to drive the reaction, resulting in a long reaction time and low yield. And the general technology is to use the hydroxylamine salt neutralization method to obtain free hydroxylamine first, but other metal ions in the base often catalyze the decomposition of hydroxylamine and contaminate the product. The basic catalyst in the present invention can significantly enhance the nucleophilic activity of free hydroxylamine, enhance the attack on the C atom in the compounds containing C=O and C≡N, so as to quickly form the target product, and the amount of the basic catalyst used is small, and a pure product free of metal ion contamination can be obtained through simple separation. The strength and amount of the basic catalyst are very crucial. If the amount used is too small, the catalytic effect is not obvious; if the amount used is too large, it will lead to the decomposition of hydroxylamine. Therefore, in the present invention, the molar ratio of the compound containing a functional group to the basic catalyst is preferably 1:0.001 - 0.5.

[0022] The basic catalyst in the present invention is easy to separate, such as magnesium oxide, etc., and it can be separated through conventional filtration operations due to its poor solubility. When the hydroxylamine aqueous solution reacts with the compound containing a functional group, it is basically an oil-water two-phase system, and inorganic catalysts such as alkali metal hydroxides and ammonia can be separated through conventional oil-water separation. In continuous production, strongly basic ion exchange resins can be filled in the reactor in the form of solid fillers for long-term operation.

[0023] Compared with the prior art, the present invention has the following advantages:

[0024] 1. The catalyst has good activity and high reaction efficiency. The existing processes basically use no catalyst, phase transfer catalyst or organic base as the catalyst. The present invention uses a basic catalyst, which can significantly enhance the nucleophilic activity of free hydroxylamine, enhance the attack on the C atom in the compounds containing C=O and C≡N, so as to quickly form the target product, significantly shortening the reaction time and fundamentally solving the problems of long reaction time and low reaction efficiency existing in the prior art.

[0025] 2. It is green and environmentally friendly and produces no waste salt. Compared with the process route generally using hydroxylamine salt as the raw material, the present invention uses hydroxylamine aqueous solution as the raw material and adopts a suitable basic catalyst and optimizes the reaction parameters, and the amount of the basic catalyst used is small, avoiding the generation of waste salt or metal ion contamination during the alkali neutralization process, and a pure product can be quickly separated.

[0026] 3. The catalyst is easy to separate and the process is simple. The basic catalyst in the present invention is easy to separate, such as magnesium oxide, etc., and it can be separated through conventional filtration operations due to its poor solubility. When the hydroxylamine aqueous solution reacts with the compound containing a functional group, it is basically an oil-water two-phase system, and inorganic catalysts such as alkali metal hydroxides and ammonia can be separated through conventional oil-water separation. In continuous production, strongly basic ion exchange resins can be filled in the reactor in the form of solid fillers for long-term operation.

[0027] 4. Wide application range and easy industrialization. The method of the present invention can be widely applied to the preparation of hydroxylamine downstream derivatives such as oximes, hydroxamic acids / isohydroxamic acids, and amidoximes, especially for the preparation of relatively complex hydroxylamine derivatives or hydroxylamine derivatives for special purposes (such as cyclododecanone oxime, mibefradil oxime, erythromycin A oxime, etc.). Specific embodiments

[0028] The present invention will be described in more detail below through examples, but the present invention is not limited to the described examples.

[0029] The raw materials and equipment in the examples of the present invention can be obtained commercially, among which:

[0030] Hydroxylamine aqueous solution: Zhejiang Jinhua New Materials Co., Ltd., with a specification of 50 ± 2 wt%, and different concentrations of hydroxylamine aqueous solution can be obtained by dilution.

[0031] Example 1

[0032] Add 86.1 g (1 mol) of 2-pentanone into a 1000 ml four-necked flask equipped with a mechanical stirrer, a water-cooled reflux pipe, and a dropping funnel. Slowly add 308.8 g of 10.9 wt% hydroxylamine aqueous solution (containing 1.02 mol of hydroxylamine) dropwise under stirring conditions, and then add 1 g of 40 wt% sodium hydroxide aqueous solution (containing 0.01 mol of sodium hydroxide). Keep the temperature at 40 °C and react for 1 hour. After the reaction is completed, the oil and water are separated, and 101 g of the oil layer is obtained. The content of 2-pentanone oxime is 99.6%, and the yield is 99.5%.

[0033] Example 2

[0034] Add 200 g of toluene solution containing cyclododecanone (the content of cyclododecanone is 50.1 wt%, 0.5 mol) into a 500 ml four-necked flask equipped with a mechanical stirrer, a water-cooled reflux pipe, and a dropping funnel. Slowly add 70.9 g of 25.6 wt% hydroxylamine aqueous solution (0.55 mol) dropwise under stirring conditions, and then add 1.4 g of 25 wt% ammonia water (0.05 mol). Keep the reaction temperature at 60 °C and react for 0.5 hour. After the reaction is completed, the oil and water are separated, and 207 g of the oil layer is obtained. The content of cyclododecanone oxime is 99.2%, and the yield is 99.0%.

[0035] Example 3

[0036] In a tubular reactor filled with 150 ml of strongly basic ion exchange resin packing (model IRA910), methanol, methyl acetate, and an aqueous hydroxylamine solution were simultaneously added using a peristaltic pump. The concentration of the aqueous hydroxylamine solution was 50.8 wt%, and the molar ratio of methanol, methyl acetate, and hydroxylamine was 1:1:1. The total feed flow rate was 15 ml / min, and the reactor temperature was controlled at 5°C. The reaction solution was collected at the outlet end, with the content of acetohydroxamic acid being 37.0% and the yield being 98.1%.

[0037] Example 4

[0038] In a 250 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux tube, and a dropping funnel, 22.3 g (0.1 mol) of 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyranone and 60 g of dichloromethane were added. Under stirring, 35.6 g (0.11 mol) of a 10.2% wt aqueous hydroxylamine solution was slowly added dropwise, and then 0.8 g (0.02 mol) of magnesium oxide was added. The reaction was carried out at 80°C for 0.5 hours. After the reaction, the catalyst magnesium oxide was separated by filtration, the oil and water were separated, and the solvent of the oil layer was removed by rotary evaporation. 23.8 g of the crude product was obtained, in which the content of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone was 96.3% and the yield was 96.7%.

[0039] Example 5

[0040] In a 250 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux tube, and a dropping funnel, 22.3 g (0.1 mol) of 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyranone and 60 g of dichloromethane were added. Under stirring, 45.3 g (0.14 mol) of a 10.2 wt% aqueous hydroxylamine solution was slowly added dropwise, and then 0.2 g (0.005 mol) of sodium hydroxide was added. The reaction was carried out at 30°C for 0.5 hours. After the reaction, the catalyst sodium hydroxide was separated by filtration, the oil and water were separated, and the solvent of the oil layer was removed by rotary evaporation. 23.6 g of the crude product was obtained, in which the content of 1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2(1H)-pyridone was 96.7% and the yield was 96.3%.

[0041] Example 6

[0042] In a 1000 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux tube, and a dropping funnel, 86.1 g (1 mol) of 3-methylbutyraldehyde and 1.5 g (0.02 mol) of calcium hydroxide were added. Under stirring, 133.8 g (1.05 mol) of a 25.9 wt% aqueous hydroxylamine solution was slowly added dropwise. The reaction was carried out at 55°C for 1 hour. After the reaction, the catalyst calcium hydroxide and the water layer were separated, and 100.9 g was obtained, in which the content of 3-methylbutyraldoxime was 98.5% and the yield was 98.3%.

[0043] Example 7

[0044] 15.8 g (0.1 mol) of methyl octanoate, 50 g of methanol, and 0.02 g (0.0005 mol) of sodium hydroxide were added to a 250 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux condenser, and a dropping funnel. 38 g (0.12 mol) of a 10.4 wt% hydroxylamine aqueous solution was slowly added dropwise under stirring conditions, and the reaction was carried out at a reaction temperature of 40 °C for 1 hour. After the reaction was completed, it was neutralized with a small amount of hydrochloric acid, and methanol was removed under reduced pressure from the reaction solution to precipitate a solid. After washing with water, 15.6 g of a solid was obtained, in which the content of octanohydroxamic acid was 95.2% and the yield was 93.4%.

[0045] Example 8

[0046] 40 g (0.05 mol) of erythromycin thiocyanate, 100 g of methanol, and 0.6 g (0.01 mol) of potassium hydroxide were added to a 100 ml three-necked flask equipped with mechanical stirring, a water-cooled reflux condenser, and a dropping funnel. 4.9 g (0.075 mol) of a 50.3 wt% hydroxylamine aqueous solution was slowly added dropwise under stirring conditions, and the reaction was carried out at a reaction temperature of 20 °C for 2 hours. After the reaction was completed, 200 ml of water was added to precipitate a solid. After filtration and washing with water, 38 g of a solid was obtained, in which the content of erythromycin A oxime was 96.3% and the yield was 94.1%.

[0047] Example 9

[0048] 60 g (0.25 mol) of 4-cyano-N-(2-fluorophenyl)benzamide, 120 g of methanol, and 2 g (0.05 mol) of sodium hydroxide were added to a 250 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux condenser, and a dropping funnel. 18.3 g (0.275 mol) of a 49.5 wt% hydroxylamine aqueous solution was slowly added dropwise under stirring conditions, and the reaction was carried out at a reaction temperature of 40 °C for 1.5 hours. After the reaction was completed, 120 g of water was added to precipitate a precipitate. After filtration and washing with water, 67.5 g of a solid was obtained, in which the content of N-(2-fluorophenyl)-4-(N'-hydroxyformamidinyl)benzamide was 98.5% and the yield was 97.4%.

[0049] Comparative Example 1

[0050] The implementation method was the same as that of Example 1, except that the 40 wt% sodium hydroxide aqueous solution was replaced with 4-dimethylaminopyridine disclosed in CN114394916A, and the dosage was 0.1 mol. Finally, 105.9 g of an oil layer was separated, the content of 2-pentanone oxime was 79.3%, and the yield was 83.0%.

[0051] Comparative Example 2

[0052] 86.1 g (1 mol) of 2-pentanone was added to a 1000 ml four-necked flask equipped with mechanical stirring, a water-cooled reflux condenser, and a dropping funnel. 308.8 g (1.02 mol) of a 10.9 wt% aqueous hydroxylamine solution was slowly added dropwise under stirring, and the reaction was carried out at 40 °C for 6 hours. After the reaction was completed, the oil and water were separated by layering, and 95.1 g of the oil layer was obtained, with a 2-pentanone oxime content of 68.2% and a yield of 65.0%.

Claims

1. A method for preparing a hydroxylamine derivative, in which an aqueous hydroxylamine solution and a compound containing a functional group react under the action of a catalyst to obtain a hydroxylamine derivative, characterized in that, The catalyst described is a basic catalyst. The molar ratio of the functional group-containing compound to hydroxylamine in the hydroxylamine aqueous solution is 1:1 to 2; the molar ratio of the functional group-containing compound to the basic catalyst is 1:0.001 to 0.

5.

2. The method for preparing a hydroxylamine derivative according to claim 1, characterized in that, The reaction described is carried out in a solvent.

3. The method for preparing a hydroxylamine derivative according to claim 2, characterized in that, The solvent is one of methanol, toluene, and dichloromethane.

4. The method for preparing a hydroxylamine derivative according to claim 1, characterized in that, The basic catalyst is one of basic oxides, alkali metal hydroxides, ammonia water, and strongly basic ion exchange resins.

5. The method for preparing a hydroxylamine derivative according to claim 4, wherein, The basic oxide is magnesium oxide; the alkali metal hydroxide is one of sodium hydroxide, calcium hydroxide, and potassium hydroxide.

6. The method for preparing the hydroxylamine derivative according to claim 1, characterized in that, The functional group-containing compound is a C=O-containing compound and a C≡N-containing compound.

7. The method for preparing the hydroxylamine derivative according to claim 6, wherein, The C=O-containing compound is one of 2-pentanone, cyclododecanone, methyl acetate, 4-methyl-6-(2,4,4-trimethylpentyl)-2-pyranone, 3-methylbutyraldehyde, and methyl octanoate; the C=O-containing compound is one of erythromycin thiocyanate and 4-cyano-N-(2-fluorophenyl)benzamide.

8. The method for preparing a hydroxylamine derivative according to claim 1, characterized in that, The hydroxylamine aqueous solution is a free hydroxylamine aqueous solution, and its free hydroxylamine concentration is 10 wt% to 60 wt%.

9. The method for preparing a hydroxylamine derivative according to claim 1, characterized in that, The temperature of the reaction is 0 to 100 °C, and the time is 0.5 to 2.5 hours.