Preparation method of N-benzyl hydroxylamine hydrochloride
By using sodium bisulfite as a catalyst during the N-benzylhydroxylamine hydrochloride synthesis and synthesizing under mild reaction conditions, the problems of low yield, high cost, poor safety and high environmental pressure in the existing methods are solved, and efficient, safe, environmentally friendly and economical production results are achieved.
Patent Information
- Application Number
- CN202510133962.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-06
- Publication Date
- 2025-05-09
AI Technical Summary
The existing N-benzylhydroxylamine hydrochloride synthesis methods have problems such as low yield, high cost, poor safety or high environmental pressure, which limits the prospects of its industrial production.
The synthesis was carried out under mild reaction conditions using sodium bisulfite as a hydrolysis catalyst. By mixing dibenzylamine and sodium tungstate in methanol, adding hydrogen peroxide dropwise and insulated, then transferring to another solvent to react with sodium bisulfite, finally adding hydrochloric acid at low temperature to form hydrochloride.
It significantly improves the safety of the production process, realizes the reuse of by-products, reduces production costs, improves the environmental protection and economicality of the process, and provides an efficient, safe, environmentally friendly and economical solution for the industrial production of N-benzylhydroxylamine hydrochloride.
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Figure BDA0005262542560000031
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing N-benzylhydroxylamine hydrochloride. Background Art
[0002] N-Benzylhydroxylamine hydrochloride is an important organic synthesis intermediate, widely used in the field of organic chemistry, especially in nitrone chemistry. It can be used to synthesize biologically active compounds, such as a key intermediate for the novel antiplatelet drug ticagrelor. However, existing synthesis methods have many problems in industrial production, which limits their wide application.
[0003] At present, the synthesis of N-benzylhydroxylamine hydrochloride is mainly achieved by the following methods. First, dibenzylamine is used as the starting material, and hydrogen peroxide is used to oxidize it under the catalysis of tungstate to generate C-phenyl-N-benzylnitrone, which is then reacted with hydroxylamine hydrochloride to obtain the target product. Although this method is simple to operate, it has the problem of incomplete oxidation of hydrogen peroxide, which makes it difficult to completely convert the intermediate product N,N-dibenzylhydroxylamine, and the yield is low, about 60% to 65%. In addition, there is a risk of flash explosion when hydrogen peroxide and dibenzylamine are mixed, which brings safety hazards to industrial production.
[0004] Another common synthesis method is the oximation reduction method. This method uses the oximation reaction of benzaldehyde and hydroxylamine hydrochloride, and then reduces it with sodium cyanoborohydride to obtain N-benzylhydroxylamine, and finally forms a hydrochloride. However, this method uses the expensive reducing agent sodium cyanoborohydride, which significantly increases the production cost. At the same time, the reduction reaction itself is a high-risk process and has certain safety risks, which limits its industrial prospects.
[0005] In addition, there are studies to improve the synthesis efficiency by optimizing the reaction conditions. For example, ethylene glycol is used as a solvent, sodium tungstate is added as a catalyst, hydrogen peroxide is added dropwise for oxidation reaction, and then the intermediate product is further converted with sodium hypochlorite aqueous solution, and finally N-benzylhydroxylamine hydrochloride with higher purity and yield (about 87.3%) is obtained. Although this method improves the yield to a certain extent, it still requires the use of a large amount of organic solvents, and the post-processing process is relatively complicated.
[0006] Finally, the continuous synthesis process has also been applied to the synthesis of N-benzylhydroxylamine hydrochloride. This process avoids the risk of high-temperature decomposition in the traditional method by reacting benzyl chloride with hydroxylamine hydrochloride at low temperature. However, this method still requires the use of a large amount of organic solvents and the post-processing process is complicated, which limits its large-scale application.
[0007] In summary, the existing N-benzylhydroxylamine hydrochloride synthesis methods generally have problems such as low yield, high cost, poor safety or high environmental pressure. Therefore, developing an efficient, safe, environmentally friendly and low-cost synthesis method is of great significance to meet the needs of industrial production. Summary of the invention
[0008] The object of the present invention is to provide a method for preparing N-benzylhydroxylamine hydrochloride in view of the deficiencies in the prior art.
[0009] To achieve the above object, the technical solution adopted by the present invention is:
[0010] Provided is a method for preparing N-benzylhydroxylamine hydrochloride, the steps comprising:
[0011] S1, dibenzylamine and sodium tungstate dihydrate are mixed in a first solvent; hydrogen peroxide is added dropwise at 5°C-10°C; the mixture is kept at 5°C-10°C for 4-6 hours, and then the mixture is heated to 20°C-25°C and kept for 9-11 hours; and C-phenyl-N-benzyl nitrone is obtained by a first post-treatment;
[0012] S2, transferring the C-phenyl-N-benzyl nitrone to a second solvent; under the protection of an inert gas, at a temperature below 10° C., dropwise adding a saturated aqueous solution of sodium bisulfite; keeping the temperature at 5° C.-10° C. for 4-6 hours; and performing a second post-treatment to obtain N-benzyl hydroxylamine;
[0013] S3. Under the protection of inert gas, add isopropanol solution of hydrochloric acid to the N-benzylhydroxylamine at 0°C-5°C until the pH is 2-3; stir at 0°C-5°C for 2-4 hours; and perform the third post-treatment to obtain N-benzylhydroxylamine hydrochloride.
[0014] Preferably, the first solvent is methanol.
[0015] Preferably, the first post-treatment comprises: transferring the reaction solution into pre-cooled water, stirring and cooling to 5°C-10°C for crystallization, and separating the solid from the liquid, and the obtained solid is the C-phenyl-N-benzyl nitrone.
[0016] Preferably, the second solvent is tert-butyl methyl ether and / or methanol.
[0017] Preferably, the second post-treatment comprises: under the protection of an inert gas, allowing the reactants to stand for stratification, adding sodium sulfate to the upper organic phase, drying, and filtering to obtain the N-benzylhydroxylamine.
[0018] Preferably, the second post-treatment further comprises: after the reactants are allowed to stand for stratification, the lower aqueous phase and the precipitated solid are separated by solid-liquid separation to obtain benzaldehyde sulfinic acid sodium salt.
[0019] Preferably, the third post-treatment is solid-liquid separation, and the obtained solid is N-benzylhydroxylamine hydrochloride.
[0020] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:
[0021] First, in the existing synthesis method, N-benzylhydroxylamine hydrochloride is easily decomposed or even exploded under high temperature conditions, especially in the concentration process in the later stage of the reaction, and this problem seriously affects the safety of industrial production; while the present invention completely avoids the risk of thermal decomposition of N-benzylhydroxylamine hydrochloride during the reaction and post-treatment process by controlling the reaction temperature at room temperature or low temperature, thereby significantly improving the safety of the production process and providing reliable guarantee for industrial production;
[0022] Secondly, the by-product generated during the reaction of the present invention is benzaldehyde sodium bisulfite, which can be reused through simple collection and purification steps; this design not only reduces the discharge of waste and reduces the pressure on the environment, but also improves the utilization rate of resources, making the entire process more green and environmentally friendly, and meeting the requirements of sustainable development;
[0023] In addition, compared with the existing methods, the present invention does not require the use of expensive reducing agents (such as sodium cyanoborohydride) and does not require complicated high-temperature concentration steps, thereby significantly reducing production costs; at the same time, due to mild reaction conditions and simple operation, the feasibility of the process and the prospect of industrial application are further improved;
[0024] In summary, the present invention adopts sodium bisulfite as a hydrolysis catalyst and performs synthesis under mild reaction conditions, which not only solves the safety problem existing in the existing method, but also realizes the recycling of by-products, reduces production costs, improves the environmental protection and economy of the process, and provides an efficient, safe, environmentally friendly and economical solution for the industrial production of N-benzylhydroxylamine hydrochloride. DETAILED DESCRIPTION
[0025] The specific embodiments of the present invention will be described in detail below.
[0026] Unless otherwise defined, technical or scientific terms used in the claims and the specification shall have the common meanings understood by persons having ordinary skills in the technical field to which the present invention belongs.
[0027] The words "include" or similar words used in the patent application specification and claims of the present invention mean that the items appearing before "include" include the items listed after "include" or their equivalents, and do not exclude other items.
[0028] The numerical values mentioned in the present invention include all numerical values that increase from low to high by one unit, assuming that there are at least two units between any lower value and the higher value. For example, if a component or a physical quantity is said to be from 1 to 100, 10 to 90 is more preferred, and 20 to 80 is the most preferred, it is intended to express that values such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, 41 to 49 are clearly listed in this specification; for values less than 1, 0.0001, 0.001, 0.01 or 0.1 are considered to be more suitable as a unit. The above examples are for illustrative purposes only. In fact, all numerical combinations between the lowest value and the highest value listed are deemed to be clearly listed in this specification in a similar manner.
[0029] Example 1
[0030] This embodiment provides a method for preparing N-benzylhydroxylamine hydrochloride, the steps comprising:
[0031]
[0032] S1. In a 2.0L four-necked reaction flask, 100g of dibenzylamine and 2.5g of sodium tungstate dihydrate were mixed in 400mL of methanol (first solvent); the temperature was cooled to 5°C-10°C in an ice-water bath, and 160mL of hydrogen peroxide was added dropwise to the four-necked reaction flask; the temperature was kept at 5°C-10°C for 5 hours, and then the temperature was raised to 20°C-25°C and kept for 10 hours; the reaction solution was transferred to 800mL of pre-cooled water, and the mixture was stirred and cooled. The mixture was cooled to 5°C-10°C for crystallization and filtered to obtain 120 g of a white solid (i.e., C-phenyl-N-benzyl nitrone), 97 g of which was dried and the yield was 90.6%. HNMR (300 MHz.DMSO) 8.38-8.28 (m, 2H), 8.21 (s, 1H), 7.50 (dd, 1.5 Hz, 2H), 7.46-7.25 (m, 6H), 2.67 (s, 2H);
[0033] S2, in a 1.0L four-necked reaction bottle, transfer 120g of the wet product of the C-phenyl-N-benzyl nitrone to a second solvent (300mL of tert-butyl methyl ether and 30g of methanol); under the protection of nitrogen (inert gas), at below 10°C, add dropwise a saturated aqueous solution of sodium bisulfite (composed of 52.6g of sodium bisulfite and 160g of water); keep warm at 5°C-10°C for 5 hours; under the protection of inert gas, let the reactants stand for stratification, add 10g of sodium sulfate to the upper organic phase, dry for 30 minutes and filter, the filtrate is N-benzylhydroxylamine; at the same time, the lower aqueous phase and the precipitated solid are filtered to recover benzaldehyde sulfinic acid sodium salt;
[0034] S3. Under the protection of inert gas, add 56 g of 30% hydrochloric acid in isopropanol solution to the N-benzylhydroxylamine at 0°C-5°C until the pH is 2-3; stir at 0°C-5°C for 3 hours; filter and dry in vacuo to obtain 55 g of N-benzylhydroxylamine hydrochloride with a yield of 74.9% and HPLC purity of 98.5%. HNMR (300MHz.DMSO) 10.5 (br, 2H), 9.97 (br, 1H), 7.60-7.46 (m, 2H), 7.46-7.35 (m, 3H), 3.91 (s, 2H).
[0035] Example 2
[0036] This embodiment provides a method for preparing N-benzylhydroxylamine hydrochloride, the steps comprising:
[0037] S1. In a 1000L reactor, 50kg of dibenzylamine and 1.25kg of sodium tungstate dihydrate were mixed in 200L of methanol (first solvent); the temperature was cooled to 5°C-10°C in an ice-water bath, and 80L of hydrogen peroxide was added dropwise to the reactor; the temperature was kept at 5°C-10°C for 5 hours, and then the temperature was raised to 20°C-25°C and kept for 10 hours; the reaction solution was transferred to 400L of pre-cooled water, stirred and cooled to 5°C-10°C for crystallization, centrifuged, and rinsed with water to obtain 57kg of white solid (i.e., C-phenyl-N-benzyl nitrone), 49kg on a dry basis, and the yield was 91.9%;
[0038] S2, in a 500L four-necked reaction flask, transfer 57kg of the wet product of the C-phenyl-N-benzyl nitrone to a second solvent (150L of tert-butyl methyl ether and 15kg of methanol); under the protection of nitrogen (inert gas), at a temperature below 10°C, add dropwise a saturated aqueous solution of sodium bisulfite (prepared from 27kg of sodium bisulfite and 80kg of water); keep warm at 5°C-10°C for 5 hours; under the protection of inert gas, allow the reactants to stand and stratify, add 5kg of sodium sulfate to the upper organic phase, dry for 30 minutes, and filter under nitrogen pressure to obtain N-benzylhydroxylamine; at the same time, the lower aqueous phase and the precipitated solid are centrifuged to recover benzaldehyde sulfinic acid sodium salt;
[0039] S3. Under the protection of inert gas, add 28 kg of 30% hydrochloric acid in isopropanol solution to the N-benzylhydroxylamine at 0°C-5°C until the pH is 2-3; stir at 0°C-5°C for 3 hours; centrifuge and vacuum dry to obtain 27.7 kg of N-benzylhydroxylamine hydrochloride with a yield of 75.6% and an HPLC purity of 98.5%.
[0040] In summary, the present invention adopts sodium bisulfite as a hydrolysis catalyst and performs synthesis under mild reaction conditions, which not only solves the safety problem existing in the existing method, but also realizes the recycling of by-products, reduces production costs, improves the environmental protection and economy of the process, and provides an efficient, safe, environmentally friendly and economical solution for the industrial production of N-benzylhydroxylamine hydrochloride.
[0041] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the specification of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing N-benzylhydroxylamine hydrochloride, characterized in that the steps include: S1, dibenzylamine and sodium tungstate dihydrate are mixed in a first solvent; hydrogen peroxide is added dropwise at 5°C-10°C; the mixture is kept at 5°C-10°C for 4-6 hours, and then the mixture is heated to 20°C-25°C and kept for 9-11 hours; and C-phenyl-N-benzyl nitrone is obtained by a first post-treatment; S2, transferring the C-phenyl-N-benzyl nitrone to a second solvent; under the protection of an inert gas, at a temperature below 10° C., dropwise adding a saturated aqueous solution of sodium bisulfite; keeping the temperature at 5° C.-10° C. for 4-6 hours; and performing a second post-treatment to obtain N-benzyl hydroxylamine; S3, under the protection of inert gas, at 0°C-5°C, add a solution of hydrochloric acid in isopropanol to the N-benzylhydroxylamine until the pH is 2-3; stir at 0°C-5°C for 2-4 hours; After the third post-treatment, N-benzylhydroxylamine hydrochloride is obtained.
2. The preparation method according to claim 1, characterized in that: The first solvent is methanol.
3. The preparation method according to claim 1, characterized in that: The first post-treatment comprises: transferring the reaction solution into pre-cooled water, stirring and cooling to 5°C-10°C for crystallization, and separating the solid from the liquid, and the obtained solid is the C-phenyl-N-benzyl nitrone.
4. The preparation method according to claim 1, characterized in that: The second solvent is tert-butyl methyl ether and / or methanol.
5. The preparation method according to claim 1, characterized in that: The second post-treatment comprises: under the protection of an inert gas, allowing the reactants to stand for stratification, adding sodium sulfate to the upper organic phase, drying, and filtering to obtain the N-benzylhydroxylamine.
6. The preparation method according to claim 5, characterized in that: The second post-treatment further comprises: after the reactants are allowed to stand for stratification, the lower aqueous phase and the precipitated solid are separated into solid and liquid to obtain benzaldehyde sulfinic acid sodium salt.
7. The preparation method according to claim 1, characterized in that: The third post-treatment is solid-liquid separation, and the obtained solid is N-benzylhydroxylamine hydrochloride.