阅读说明：本技术 一种o-/n-烷基取代羟胺盐的制备方法 (Preparation method of O-/N-alkyl substituted hydroxylamine salt ) 是由 刘现可 魏斌 隋福明 李锡才 初笑霖 柳鹏 马运旺 于 2021-08-16 设计创作，主要内容包括：本发明涉及一种N-/O-烷基取代羟胺盐的制备方法,属于精细化工、农药或原料药化工技术领域。本发明以肟的N-/O-烷基化物与羟胺无机盐反应,生成N-/O-烷基取代羟胺无机盐和肟。本发明通过前所未有的羟胺交换发明,提供一种高效、环保制备N-/O-烷基取代羟胺盐的方法,制备N-/O-烷基取代羟胺无机盐的同时,肟可经重新制备生成肟的N-/O-烷基化物,实现物料循环；反应过程无需使用当量的酸、碱中和,避免了现行方法使用大量酸、碱和产生无机盐固废缺点,更加绿色环保。而且所述的制备方法反应条件温和,避免了传统工艺高污染、高耗能的缺点。其中,R-(1)、R-(2)、R如权利要求和说明书所述。(The invention relates to a preparation method of N-/O-alkyl substituted hydroxylamine salt, belonging to the technical field of fine chemical industry, pesticide or bulk drug chemical industry. The invention uses N-/O-alkylate of oxime to react with hydroxylamine inorganic salt to generate N-/O-alkyl substituted hydroxylamine inorganic salt and oxime. The invention provides a method for efficiently and environmentally preparing N-/O-alkyl substituted hydroxylamine salt through unprecedented hydroxylamine exchange, and the method can be used for preparing N-/O-alkyl substituted hydroxylamine inorganic salt and simultaneously preparing oxime into N-/O-alkylate of the oxime through re-preparation, thereby realizing material circulation; the reaction process does not need to use equivalent acid and alkali for neutralization, thereby avoiding the defects of using a large amount of acid and alkali and generating inorganic salt solid waste in the existing method and being more environment-friendly. And the preparation method has mild reaction conditions, and avoids the defects of high pollution and high energy consumption of the traditional process. Wherein R is 1 、R 2 R is as described in the claims and specification.)

1. A process for the preparation of an O-/N-alkyl-substituted hydroxylamine salt, characterized in that an N-/O-alkylate of an oxime is reacted with a hydroxylamine salt in a solvent to form the oxime and an inorganic N-/O-alkylhydroxylamine salt:

wherein the content of the first and second substances,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-a 10-membered aryl or heteroaryl group, said heteroaryl group containing at least one heteroatom of N, O or S;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy;

r is C1-C6 alkyl;

HA＝HCl,H₂SO₄,H₃PO₄,HBr,HI。

2. the method according to claim 1, wherein the reaction mixture,

wherein the content of the first and second substances,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, said heteroaryl containing at least one heteroatom of N, O or S;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy.

3. The method according to claim 1, wherein the reaction mixture,

wherein the content of the first and second substances,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, said heteroaryl containing one O atom;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy.

4. The method according to claim 1, wherein the reaction mixture,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C4 alkyl, substituted or unsubstituted phenyl,The substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl,A benzyloxy group;

r is C1-C4 alkyl;

HA＝HCl,H₂SO₄,H₃PO₄,HBr,HI。

5. the process according to any one of claims 1 to 4, wherein the solvent is methanol, ethanol, acetonitrile or a mixed solvent of water and an organic solvent as described above.

6. The process according to any one of claims 1 to 4, wherein the reaction temperature is from 0 ℃ to 100 ℃, preferably from 0 ℃ to 70 ℃.

7. The process according to any one of claims 1 to 4, wherein the molar ratio of the N-/O-alkylate of the oxime to the hydroxylamine salt is: 1: 0.1-1: 10, preferably 1: 0.5-1: 2.

8. the method according to any one of claims 1 to 4, wherein the oxime product is obtained by precipitation, extraction, recrystallization or column chromatography.

9. A process according to any one of claims 1 to 8, wherein the oxime product is reacted with an alkylating agent to produce an oxime N-/O-alkylate, preferably dimethyl sulfate, diethyl sulfate, dimethyl carbonate, a halogenated hydrocarbon.

Technical Field

The invention relates to a preparation method of N-/O-alkyl substituted hydroxylamine salt, belonging to the technical field of fine chemical industry, pesticide or bulk drug chemical industry.

Background

N-/O-alkyl substituted hydroxylamine salts (formula I) are important pharmaceutical and chemical intermediates, and represent compounds: o-methylhydroxylamine hydrochloride (methoxyamine hydrochloride), N-methylhydroxylamine hydrochloride, O-ethylhydroxylamine hydrochloride (ethoxyamine hydrochloride), O-benzylhydroxylamine hydrochloride and the like. Wherein, N-alkyl substituted hydroxylamine salt is used for preparing nitrone 1, 3-dipole body, various isoxazoline compounds are conveniently constructed through cycloaddition reaction, and the isoxazoline compounds are widely applied in agriculture; the O-alkyl substituted hydroxylamine salt, typical compounds of methoxylamine hydrochloride and benzyloxylamine hydrochloride are important medical intermediates and are used for producing crude drugs such as antibiotic cefuroxime and the like.

In the formula, R₁、R₂Independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl; HA ═ HCl, H₂SO₄,H₃PO₄,HBr,HI。

The synthesis method of N-/O-alkyl substituted hydroxylamine salt has different structures and different methods, takes a typical compound methoxylamine hydrochloride as an example, and the preparation method mainly comprises the following material classification: sulfur dioxide process (hydroxylamine disulfonate process), ethyl acetate protection process, acetoxime/butanone oxime process, benzaldehyde process, etc. The reaction process of the methods needs acid and alkali catalysis, and inorganic salt solid waste is generated; in the purification process, a method of neutralizing by strong base and re-salifying after methoxyamine distillation is adopted, and repeated acid-base neutralization not only generates a large amount of solid wastes, but also has potential safety hazards, the nature of free alkali is unstable, high-temperature distillation has explosion risks, and serious safety accident cases are listed at home and abroad. The production process is complicated, and belongs to a typical backward process with high pollution and high energy consumption.

TABLE 1 preparation of methoxyamine hydrochloride

The existing process has the defects of high pollution and high energy consumption and increasingly strict environmental protection requirements, and the industry needs a safe, environment-friendly and green method urgently.

Disclosure of Invention

The technical problem solved by the invention is to provide the preparation method of the N-/O-alkyl substituted hydroxylamine salt, which is more environment-friendly, simple, free from acid and base catalysis, free from using strong acid and strong base in the conventional method, free from generating solid wastes from the source and capable of recycling materials, aiming at the defects of large dosage of strong acid and strong base and outstanding environmental protection problems of three wastes in the preparation method of the N-/O-alkyl substituted hydroxylamine salt.

The invention is realized by the following technical scheme:

a preparation method of N-/O-alkyl substituted hydroxylamine salt specifically comprises the following steps:

reacting the N-/O-alkylate of the oxime with a hydroxylamine salt in a solvent to form the oxime and an inorganic N-/O-alkylhydroxylamine salt:

wherein the solvent includes, but is not limited to: an organic solvent such as methanol, ethanol, acetonitrile, etc., or a mixed solvent of water and the above organic solvent.

Preferably, the solvent is water, a mixed solvent of methanol-water or ethanol-water.

Wherein:

R₁、R₂independently hydrogen, unsubstituted orPhenyl substituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl or heteroaryl, said heteroaryl containing at least one heteroatom of N, O or S;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy;

r is C1-C6 alkyl;

HA＝HCl,H₂SO₄,H₃PO₄,HBr,HI。

further, the air conditioner is provided with a fan,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-6 membered aryl or heteroaryl, said heteroaryl containing one O atom;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy;

further, the air conditioner is provided with a fan,

R₁、R₂independently hydrogen, unsubstituted or phenyl-substituted C1-C4 alkyl, substituted or unsubstituted phenyl, furyl;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy;

r is C1-C4 alkyl;

HA＝HCl,H₂SO₄,H₃PO₄,HBr,HI。

taking methoxylamine hydrochloride as an example, the reaction formula is as follows:

taking N-methyl substituted hydroxylamine as an example, the reaction formula is:

further, the oxime prepared by the method of the present invention may be precipitated and separated from the reaction solution, or separated by extraction, recrystallization, column chromatography, etc.

The hydroxylamine is in the form of salt, such as hydroxylamine hydrochloride, sulfate, phosphate, hydrobromic acid, hydroiodic acid, etc., preferably hydrochloride.

The reaction temperature is 0 to 100 ℃, preferably 0 to 70 ℃.

The molar ratio of the N-/O-alkylate of the oxime to the hydroxylamine salt is: 1: 0.1-1: 10, preferably 1: 0.5-1: 2.

the experimental result shows that the aminolysis reaction process of the N-methylate of the furfural oxime and the hydroxylamine hydrochloride is complete under the mild reaction condition; in the aminolysis reaction of oxime methyl ether and hydroxylamine hydrochloride, although the substrate structure has good applicability and functional groups are well tolerated, the reaction has a reversible equilibrium phenomenon. The product methoxyamine and the raw material hydroxylamine have similar nucleophilicity, and in order to make the equilibrium reaction have application value, the good crystallization performance and the easy separation and purification characteristics of oxime can be utilized to precipitate the product oxime from the reaction liquid and promote the equilibrium to be carried out rightwards; in addition, the method can be used repeatedly to make up for the defect of incomplete reaction.

Taking methoxylamine hydrochloride as an example, the invention adopts oxime methyl ether and NH₂Performing aminolysis exchange reaction on OH & HCl to generate methoxylamine hydrochloride and oxime, wherein oxime can be used for preparing oxime methyl ether by a methylation method, so that material circulation is realized; acid and alkali catalysis is not needed in the reaction process, so that the use of strong acid and strong alkali in the conventional method is avoided, and the generation of solid waste is avoided from the source.

R' is hydrogen, unsubstituted or phenyl-substituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl or heteroaryl, said heteroaryl containing at least one heteroatom of N, O or S;

the substituent is halogen, halogenated C1-C4 alkyl, C1-C6 alkoxy, nitro, hydroxyl, tert-butyloxycarbonyl and benzyloxy.

Oxime methylation using conventional methylating agents such as dimethyl sulfate produces a certain amount of N-methide in addition to O-methide oxime methyl ether. N-methylates can also undergo hydroxylamine aminolysis exchange reactions to produce N-methyl hydroxylamine salts and oximes. The selectivity of the O-and N-methylation reactions is closely related to the cis/reaction configuration of the starting oxime, with the cis configuration mainly producing N-methylated products and the trans configuration mainly producing O-methylated products. Therefore, by controlling the configuration of the raw materials, O-and N-methylated products of oxime can be selectively generated, and O-and N-methylated hydroxylamine salts can be selectively obtained by exchanging hydroxylamine salts. Taking cheap furfural as an example, controlling cis/trans configuration of an oximation product by changing acid-base conditions of a reaction solution, wherein when the reaction is carried out under the alkaline condition, the product oxime mainly takes trans form; when reacted under acidic conditions, the product oxime predominates in cis. And further influences the O-and N-reaction selectivity of oxime methylation products, and the reaction process for selectively generating O-and N-methylated hydroxylamine hydrochloride is as follows:

has the advantages that: compared with the prior art, the invention has the advantages that:

the invention takes oxime N-/O-alkylate as a raw material to react with hydroxylamine salt to generate N-/O-alkylated substituted hydroxylamine salt and oxime. Oxime can be prepared into starting material oxime N-/O-alkylate by a literature method, so that material circulation is realized; the reaction does not need acid and alkali catalysis, does not produce inorganic salt solid waste, and is more green and environment-friendly.

(1) According to the preparation method of the N-/O-alkyl substituted hydroxylamine salt, oxime is generated while the N-/O-alkylated hydroxylamine salt is generated, and the oxime can be prepared by a literature methylation method to obtain a raw material oxime N-/O-alkylate, so that material circulation is realized;

(2) according to the preparation method of the N-/O-alkyl substituted hydroxylamine salt, acid and alkali catalysts are not needed in the reaction process, the defects that a large amount of acid and alkali is used in the traditional route and solid waste is generated are overcome, and the environmental protection advantage is obvious;

(3) the preparation method of the N-/O-alkyl substituted hydroxylamine salt has mild reaction conditions, and avoids the defects of high pollution and high energy consumption of the traditional process.

Detailed Description

The present invention will be described in further detail with reference to examples, but the present invention is not limited to the examples.

The raw materials used in the embodiment of the invention are all commercial products without special description, and the used test devices or test instruments are all conventional instruments and devices in the industry.

Example 1:

equation (b)

Adding 3.90g (17.32mmol,1.00eq) of 2,4, 6-trimethoxybenzaldehyde oxime methyl ether, 1.41g (20.33mmol,1.17eq) of hydroxylamine hydrochloride, 45.04g of ethanol and 7.50g of water into a 50ml reaction bottle, stirring and dissolving at 15 ℃, generating white precipitate when heating to 20 ℃, and stirring and reacting for 0.5h at the temperature of 60-70 ℃. TLC was used to monitor the progress of the reaction (EA: PE: 1, UV254, R)_f(-C＝NOH):0.2/R_f(-C＝NOMe):0.5). Cooling to 10-15 ℃, stirring for crystal precipitation, suction filtering, collecting solids and drying to obtain 1.68g (theory 3.66g, yield 45.90%, HPLC purity 96.545%, mp: 203-204 ℃,¹H NMR(300MHz,DMSO-d₆)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).¹³C NMR(125MHz,DMSO-d₆) δ 55.4,55.8,91.0,102.4,142.4,159.2,161.6.); evaporating the filtrate to dryness, washing with water, filtering, collecting the solid, recovering 2.29g of unreacted raw material 2,4, 6-trimethoxy benzaldehyde oxime methyl ether (purity of HPLC 90.577%, mp: 79-81 ℃,¹H NMR(400MHz,DMSO-d₆)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s,3H). The filtrate was evaporated to dryness to give 0.37g of solids containing methoxyamine hydrochloride (theory 1.45g, yield 25.52%, mp:149 ℃ -150 ℃).

Preparing raw materials:

in a 100ml reaction vessel were charged 4.02g (20.49mmol,1.00eq) of 2,4, 6-trimethoxybenzaldehyde, 2.56g (36.92mmol,1.80eq) of methoxyamine hydrochloride, and 30.0ml of methanol, and the mixture was dissolved at 15 ℃ with stirring. TLC monitoring (EA: PE ═ 1:1, UV254,R_f(-CHO):0.3/R_f(-C＝NOMe)0.5) the reaction progresses until the reaction of the raw materials is complete. Dropwise adding sodium carbonate/water solution (3.20g/30.00g) to generate white precipitate, vacuum filtering, washing with water, drying to obtain 3.90g of 2,4, 6-trimethoxybenzaldehyde methyl ether (theory 4.48g, yield 87.05%, mp: 79-81 deg.C, HPLC purity: 100%,¹H NMR(400MHz,DMSO-d₆)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s,3H).)。

preparation of a reference solution:

adding 0.0790g (0.4027mmol,1.00eq) of 2,4, 6-trimethoxybenzaldehyde, 0.0345g (0.4965mmol,1.23eq) of hydroxylamine hydrochloride and 1.0ml of methanol into a 4ml sample bottle, ultrasonically shaking at 35-40 ℃ for 30min (10 x 3), and detecting by HPLC that the conversion of the raw materials is complete and the main peak purity of the product 2,4, 6-trimethoxybenzaldehyde oxime is as follows: 99.435%, (¹HNMR(300MHz,DMSO-d₆)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).¹³C NMR(125MHz,DMSO-d₆)δ:55.4,55.8,91.0,102.4,142.4,159.2,161.6.)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 2:

equation (b)

Adding 0.5780g (2.5661mmol,1.00eq) of 2,4, 6-trimethoxybenzaldehyde oxime methyl ether, 0.2101g (3.0234mmol,1.18eq) of hydroxylamine hydrochloride, 4ml of methanol and 5ml of water into a 50ml reaction bottle, stirring and dissolving at 15-20 ℃, and generating white precipitate. TLC was used to monitor the progress of the reaction (EA: PE: 1, UV254, R)_f(-NOH):0.2/R_f(-C＝NOMe):0.5). Filtering the reaction liquid at 15-20 ℃ for 3h, washing with water, collecting the solid, recovering 0.3313g of the raw material 2,4, 6-trimethoxy benzaldehyde oxime methyl ether (the HPLC purity is 92.312%, mp: 79-81 ℃,¹HNMR(400MHz,DMSO-d₆)8.18(s,1H),6.26(s,1H),3.81(s,3H),3.79(s,3H),3.77(s,3H),3.37(s, 3H); steaming the filtrateDrying to obtain solid, washing with water, filtering, collecting solid to obtain 0.1960g (theory 0.4878g, yield 40.1804%, HPLC purity 88.899, mp: 203-204 deg.C,¹H NMR(300MHz,DMSO-d₆)δ:3.77(6H,s),3.80(3H,s),6.26(2H,s),8.13(OH,s),10.8(1H,s).¹³C NMR(125MHz,DMSO-d₆) δ 55.4,55.8,91.0,102.4,142.4,159.2,161.6.); the filtrate was evaporated to dryness and washed with dichloromethane to obtain 0.1648g of methoxyamine hydrochloride-containing solid (theory 0.2143g, yield 76.9015%, mp: 145-150 ℃).

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 3:

equation (b)

Adding 0.9769g (4.3371mmol,1.00eq) of 2,4, 5-trimethoxybenzaldehyde oxime methyl ether, 0.1503g (2.1628mmol,0.50eq) of hydroxylamine hydrochloride, 20.0ml of methanol and 2.5ml of water into a 100ml reaction bottle, stirring and dissolving at 16 ℃, controlling the temperature to be 38-40 ℃, stirring and reacting, and monitoring the reaction process by TLC (EA: PE is 1:1, UV254, R is 254: 1)_f(-C＝NOH):0.5/R_f(-C＝NOMe):0.6). Cooling to 6 ℃, stirring, crystallizing, filtering, recovering 0.3700g (97.347% of HPLC purity) of unreacted raw material 2,4, 5-trimethoxy benzaldehyde oxime methyl ether,¹H NMR(400MHz,DMSO-d₆)8.25(s,1H),7.14(s,1H),6.72(s,1H),3.85(s,3H),3.83(s,3H),3.81(s,3H),3.36(s, 3H); concentrating the filtrate to dryness, adding 15.0ml of water, and performing suction filtration to obtain 0.4170g of a mixture of 2,4, 5-trimethoxybenzaldehyde oxime and oxime methyl ether (the purity of HPLC is: -C-NOH 8.012%, -C-NOMe 88.038%); the filtrate was concentrated to dryness to give 0.0881g of methoxyamine hydrochloride-containing solid (theory 0.1806g, yield 48.78%, mp:145 ℃ -150 ℃ C.).

Preparing raw materials:

a50 ml reaction flask was charged with 2.1248g (10.8298mmol,1.00eq) of 2,4, 5-trimethoxybenzaldehyde and 1.3576g (16.2553mmol, 1.00eq) of methoxylamine hydrochloride50eq), methanol 30.0ml, stirred at 15 ℃ and monitored by TLC (EA: PE ═ 1:1, UV254, R)_f(-CHO):0.4/R_f(-C＝NOMe)0.6) the reaction progresses until the reaction of the raw materials is complete. Adding 35.0ml of water to generate white precipitate, performing suction filtration, washing with water, and drying to obtain 1.9700g of 2,4, 5-trimethoxybenzaldehyde oxime methyl ether (theory 2.4393g, yield 80.7609%, HPLC purity 99.509%,¹H NMR(400MHz,DMSO-d₆)8.25(s,1H),7.14(s,1H),6.72(s,1H),3.85(s,3H),3.83(s,3H),3.81(s,3H),3.36(s,3H).)。

preparation of a reference solution:

adding 0.0890g (0.4536mmol,1.00eq) of 2,4, 5-trimethoxybenzaldehyde, 0.0363g (0.5181mmol,1.14eq) of hydroxylamine hydrochloride, 1.0ml of methanol and ultrasonic oscillation at 35-40 ℃ for 30min (10 x 3) into a 4ml sample bottle, and detecting by HPLC that the raw material is completely converted and the HPLC purity of the product 2,4, 5-trimethoxybenzaldehyde oxime is main peak, namely, Trans or Cis, is 67.268%/19.665% (the product is 2,4, 5-trimethoxybenzaldehyde oxime¹H NMR(400MHz,DMSO-d₆)δ＝10.94(s,1H),8.20(s,1H),7.17(s,1H),6.71(s,1H),3.82(s,3H),3.80(s,3H),3.37(s,3H).)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 4:

equation (b)

A50 ml reaction flask was charged with 0.7671g (4.2579mmol,1.00eq) of 2-nitrobenzaldehyde oxime methyl ether, 0.1483g (2.1341mmol,0.50eq) of hydroxylamine hydrochloride, 20.0ml of methanol, and 1.0ml of water, and the mixture was stirred at 40 ℃ for reaction for 3 hours and monitored by TLC (EA: PE: 1:3, UV254, R)_f(-NOH):0.2/R_f(-C＝NOMe):0.5). Cooling to 5-10 ℃, stirring, crystallizing, filtering, washing with water, recovering solids, and obtaining 0.537g of the raw material 2-nitrobenzaldehyde oxime methyl ether (HPLC purity: -C ═ NOMe 99.404%); the filtrate was concentrated to dryness, washed with water and filtered to obtain 0.3830g of a solid (HPLC purity: -C-NOH 13.214%; C-NOMe 50.459%); concentrating the filtrate to dryness to obtain a filtrate containing0.1069g of methoxyamine hydrochloride solid (theoretical 0.1782g, yield 59.99%, mp: 145-150 ℃ C.).

Preparing raw materials:

in a 50ml reaction flask were added 1.9974g (13.2174mmol,1.00eq), 1.6624g (19.9048mmol,1.51eq) of 2-nitrobenzaldehyde, 15.0ml of methanol, and the mixture was stirred at 15 ℃ for 1 hour. TLC monitoring (EA: PE ═ 1:3, UV254, R_f(-CHO):0.4/R_f(-C＝NOMe)0.5) the reaction progresses until the reaction of the raw materials is complete. Adding 20.0ml of water into the reaction solution, stirring for crystallization, filtering, washing and drying to obtain 2.2866g of 2-nitrobenzaldehyde oxime methyl ether (the theoretical amount is 2.3812g, the yield is 96.03 percent, the HPLC purity is Trans or Cis: 96.624%/3.064%, mp: 98-100 ℃,¹H NMR(500MHz,CDCl₃):δ＝8.62(s,1H),8.06(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,1H),7.65(t,J＝7.5Hz,1H),7.55(dt,J＝8.5,1.5Hz,1H),4.04(s,3H)ppm.¹³C NMR(125MHz,CDCl₃):δ＝147.9,144.9,133.4,130.1,128.7,127.3,124.8,62.5ppm.)。

preparation of a reference solution:

adding 0.0720g (0.4764mmol,1.00eq) of 2-nitrobenzaldehyde, 0.0388g (0.5583mmol,1.17eq) of hydroxylamine hydrochloride, 1.0ml of methanol, 0.0500g (0.4941mmol,1.04eq) of triethylamine, performing ultrasonic treatment at 15-20 ℃ for 20min (10 x 2) into a 4ml sample bottle, and detecting complete conversion of raw materials by HPLC (high performance liquid chromatography), wherein the main peak purity of the product 2-nitrobenzaldehyde oxime is Trans or Cis: 70.010%/24.701%. (¹H NMR(300MHz,DMSO-d₆):δ＝11.78(s,1H,OH),8.40(s,1H,N＝CH),8.04(d,J＝7.8Hz,1H,Ar-H),7.88(d,J＝7.8Hz,1H,Ar-H),7.76(d,J＝7.8Hz,1H,Ar-H),7.67–7.62(m,1H,Ar-H))

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 5:

equation (b)

In a 50ml reaction flaskAdding 0.3731g (2.0710mmol,1.00eq) of 4-nitrobenzaldehyde oxime methyl ether, 0.0748g (1.0764mmol,0.52eq) of hydroxylamine hydrochloride, 15.0ml of methanol and 1.0ml of water, stirring at 40 ℃ for reaction for 3h, and monitoring by TLC (EA: PE: 1:3, UV254, R)_f(-NOH):0.5/R_f(-C＝NOMe):0.6). Cooling to 5-10 ℃, stirring, crystallizing, filtering, washing with water to obtain 0.2305g of solid (HPLC purity: -C-NOMe 99.628%); concentrating the filtrate to dryness, washing with water, performing suction filtration, and washing to obtain 0.1520g of solid (HPLC purity: -C-NOH 8.609%, -C-NOMe 89.859%); the filtrate was concentrated to dryness to give 0.0502g of methoxyamine hydrochloride-containing solid (theory 0.0899g, yield 55.84%, mp:145 ℃ -150 ℃ C.).

Preparing raw materials:

in a 50ml reaction flask were added 1.9360g (12.8111mmol,1.00eq), 1.4160g (16.9546mmol,1.32eq) of 4-nitrobenzaldehyde, and 15.0ml of methanol, and the mixture was dissolved at 15 ℃ with stirring. TLC monitoring (EA: PE ═ 1:3, UV254, R_f(-CHO):0.4/R_f(-C＝NOMe)0.6) the reaction progresses until the reaction of the raw materials is complete. Adding 20.0ml of water into the reaction solution, stirring for crystallization, filtering, washing with water, drying to obtain 2.6843g of 4-nitrobenzaldehyde oxime methyl ether (theory 2.8856g, yield 93.0240%, HPLC purity Trans or Cis: 73.780%/25.818%, mp: 101-103 ℃,¹H NMR(300MHz,CDCl₃),δ8.24(d,2H,J_HH＝8.9Hz),8.11(s,2H),7.75(d,2H,J_HH＝8.9Hz),4.04(s,3H).)。

preparation of a reference solution:

adding 0.0600g (0.3970mmol,1.0eq) of 4-nitrobenzaldehyde, 0.0367g (0.5281mmol,1.33eq) of hydroxylamine hydrochloride and 1.0ml of methanol into a 4ml sample bottle, ultrasonically oscillating for 30min (10 x 3) at 35-40 ℃, completely converting the raw materials by HPLC detection, and obtaining the product of 4-nitrobenzaldehyde oxime with main peak purity of Trans or Cis: 72.909%/25.016% (10 x 3)¹H NMR(300MHz,DMSO-d₆):δ＝11.85(s,1H,OH),8.31(s,1H,N＝CH),8.26(d,J_HH＝9.0Hz,2H,Ar-H),7.85(d,J_HH＝9.0Hz,2H,Ar-H).)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 6:

equation (b)

2.38g (15.74mmol,1.0eq), hydroxylamine hydrochloride 0.55(7.91mmol,0.5eq), methanol 10.0ml, and water 5.0ml were added to a 50ml reaction flask, and the reaction was stirred at 40 ℃ and monitored by TLC (EA: PE: 1:3, UV254, R)_f(-NOH):0.4/R_f(-C＝NOMe):0.7). Cooling to 5-10 ℃, adding 10.0ml of chloroform for extraction, washing with water, and concentrating an organic phase to dryness to obtain 2.13g of 2-hydroxybenzaldehyde oxime/2-hydroxybenzaldehyde oxime methyl ether concentrated solution (the HPLC purity is-C-NOH 15.446%, and-C-NOMe 83.861%); the aqueous phase is concentrated to dryness to give 0.64g of solids containing methoxyamine hydrochloride (theory 0.66g, yield 96.96%, mp: 145-150 ℃ C.).

Preparing raw materials:

2.00g (16.38mmol,1.00eq) of 2-hydroxybenzaldehyde, 2.10g (25.14mmol,1.53eq) of methoxyamine hydrochloride and 10.0ml of methanol were put in a 50ml reaction flask and dissolved at 15 ℃ with stirring. TLC monitoring (EA: PE ═ 1:3, UV254, R_f(-CHO):0.6/R_f(-C＝NOMe)0.7) the reaction progresses until the reaction of the raw materials is completed. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to dryness to obtain 2.38g of liquid 2-hydroxybenzaldehyde oxime methyl ether (theory 2.48g, yield 95.97%, HPLC purity 99.205%,¹H NMR(500MHz,DMSO-d₆)δ＝9.91(s,1H),8.34(s,1H),7.52–7.47(d,J＝7.7Hz,1H),7.24–7.19(t,J_HH＝8.0Hz,1H),6.88–6.84(d,J_HH＝8.2Hz,1H),6.83–6.78(t,J_HH＝7.6Hz,1H),3.85(s,3H).¹³C NMR(126MHz,DMSO-d₆)δ156.57,146.84,131.82,127.65,119.95,118.12,116.71,62.16.)。

preparation of a reference solution:

adding 0.0530g (0.4340mmol,1.00eq) of 2-hydroxybenzaldehyde, 0.0331g (0.4763mmol,1.10eq) of hydroxylamine hydrochloride, 0.0499g of triethylamine and 1.0ml of methanol into a 4ml sample bottle, ultrasonically shaking at 35-40 ℃ for 30min (10 x 3), and detecting complete conversion of raw materials by HPLC (high performance liquid chromatography), wherein the product is 2-hydroxybenzaldehyde oximePurity of main peak: 97.265%, (¹H NMR(400MHz,DMSO-d6):δ＝8.33(s,1H),7.49–7.47(dd,1H),7.25–7.21(dd,1H),6.90–6.86(m,2H)；¹³C NMR(100MHz,DMSO-d₆):δ＝156.42,147.96,130.93,128.30,119.80,118.72,116.46.)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 7:

equation (b)

A50 ml reaction flask was charged with 2.27g (12.53mmol,1.00eq) of 3-methoxy-4-hydroxybenzaldehyde oxime methyl ether, 0.44g (6.33mmol,0.50eq) of hydroxylamine hydrochloride, 5.0ml of methanol, and 5.0ml of water, and the reaction was stirred at 40 ℃ and monitored by TLC (EA: PE ═ 1:3, UV254, R_f(-NOH):0.1/R_f(-C＝NOMe):0.4). Cooling to 10-15 ℃, adding 10.0ml of dichloromethane for extraction, washing with water, and concentrating an organic phase to dryness to obtain 1.86g of a 3-methoxy-4-hydroxybenzaldehyde oxime/3-methoxy-4-hydroxybenzaldehyde oxime methyl ether concentrated solution (the HPLC purity is-C-NOH 9.315%, and-C-NOMe 79.046%); the aqueous phase is concentrated to dryness to obtain 0.51g of solids containing methoxyamine hydrochloride (theory 0.53g, yield 96.22%, mp: 145-150 ℃).

Preparing raw materials:

in a 50ml reaction vessel were charged 2.0g (13.15mmol,1.00eq) of 3-methoxy-4-hydroxybenzaldehyde, 1.60g (19.16mmol,1.45eq) of methoxyamine hydrochloride, and 10.0ml of methanol, and the mixture was dissolved at 15 ℃ with stirring. TLC monitoring (EA: PE ═ 1:3, UV254, R_f(-CHO):0.2/Rf_(-C＝NOMe)0.4) the reaction progresses until the reaction of the raw materials is complete. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to dryness to obtain 2.27g of liquid 3-methoxy-4-hydroxybenzaldehyde oxime methyl ether (theory 2.38g, yield 95.38%, HPLC purity Trans or Cis: 84.232%/12.361%,¹H NMR(400MHz,DMSO-d₆)δ＝9.50(s,1H),8.07(s,1H),7.17(d,J_HH＝2.0Hz,1H),7.00(dd,J₁＝2.0Hz,J₂＝8.0Hz,1H),6.80(d,J_HH＝8.0Hz,1H),3.84(s,3H),3.78(s,3H).)。

preparation of a reference solution:

adding 0.0652g (0.4285mmol,1.00eq) of 3-methoxy-4-hydroxybenzaldehyde, 0.0363g (0.5224mmol,1.22eq) of hydroxylamine hydrochloride, 1.0ml of methanol and ultrasonic oscillation at 35-40 ℃ for 30min (10 x 3) into a 4ml sample bottle, detecting that the raw material is completely converted by HPLC, and detecting that the product 3-methoxy-4-hydroxybenzaldehyde oxime has main peak HPLC purity Trans or Cis of 59.805%/36.046% (10 x 3)¹H NMR(400MHz,DMSO-d₆)δ＝10.85(s,1H),9.36(s,1H),7.99(s,1H),7.16(d,J_HH＝1.8Hz,1H),6.97(dd,J_HH＝8.1,1.8Hz,1H),6.77(d,J_HH＝8.1Hz,1H),3.77(s,3H).¹³C NMR(101MHz,DMSO-d6)δ＝148.1,148.0,147.8,124.4,120.5,115.4,109.1,55.4.)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 8:

equation (b)

A50 ml reaction flask was charged with 2.51g (11.73mmol,1.0eq) of 4-bromobenzaldoxime methyl ether, 0.49g (7.05mmol,0.60eq) of hydroxylamine hydrochloride, 5.0ml of methanol, and 5.0ml of water, and the mixture was stirred at 45 ℃ for 3 hours and monitored by TLC (EA: PE: 1:3, UV254, R)_f(-NOH):0.5/R_f(-C＝NOMe):0.7). Cooling to 10-15 ℃, extracting with dichloromethane, washing with water, and concentrating an organic phase to dryness to obtain 2.18g of 4-bromobenzaldehyde oxime/4-bromobenzaldehyde oxime methyl ether concentrated solution (the HPLC purity is: -C ═ NOH 18.782%, -C ═ NOMe: 75.119%); the aqueous phase is concentrated to dryness to obtain 0.48g of solids containing methoxyamine hydrochloride (theory 0.59g, yield 81.36%, mp: 145-150 ℃).

Preparing raw materials:

a50 ml reaction flask was charged with 2.13g (11.51mmol,1.00eq) of 4-bromobenzaldehyde and 1.40g (16.00 eq) of methoxylamine hydrochloride76mmol,1.46eq) and 10.0ml of methanol were dissolved at 25 ℃ with stirring. TLC monitoring (EA: PE ═ 1:3, UV254, R_f(-CHO):0.5/R_f(-C＝NOMe)0.7) the reaction progresses until the reaction of the raw materials is completed. Dropwise adding sodium carbonate/water solution, extracting with dichloromethane, washing with water, concentrating the organic phase to dryness to obtain 2.51g of liquid 4-bromobenzaldehyde oxime methyl ether (theory 2.46g, yield 100%, HPLC purity Trans or Cis: 92.734%/6.145%,¹H NMR(CDC1₃)δ＝3.88(s,3H,CH3),7.33(s,1H,CH＝N-),7.43-8.20(m,4H,ArH).)。

preparation of a reference solution:

adding 0.0809g (0.4373mmol,1.0eq) of 4-bromobenzaldehyde, 0.0345g (0.4965mmol,1.14eq) of hydroxylamine hydrochloride, 1.0ml of methanol and 30min (10 x 3) of 35-40 ℃ ultrasonic oscillation into a 4ml sample bottle, completely converting the HPLC detection raw materials, and obtaining the product of 4-bromobenzaldehyde oxime with main peak HPLC purity Trans or Cis of 89.688%/8.167% ((10 x 3))¹H NMR(300MHz,DMSO-d₆):δ＝11.38(s,1H,OH),8.13(s,1H,N＝CH),7.63–7.55(m,4H,Ar-H).)。

[ -CHO/-C ═ NOH/-C ═ NOMe purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

Example 9:

equation (b)

Adding 1.20g (9.50mmol,1.00eq) of furfuryl oxime N-methide, 0.66g (9.50mmol,1.00eq) of hydroxylamine hydrochloride and 10.0ml of water into a 50ml reaction bottle, stirring at 0-4 ℃ for reaction to generate white needle-shaped precipitates, and monitoring the reaction progress by TLC. Filtering, collecting solid, washing with water to obtain furfuryl aldoxime¹H NMR(400MHz,CD₃OD): δ — 7.56(dd,1H),7.40(s,1H),7.27(d,1H),6.56(m, 1H)). The filtrate is concentrated to be dry and washed by methanol to obtain white solid containing N-methylhydroxylamine hydrochloride.

Preparing raw materials:

in a 50ml reaction flask were added 4.85g (50.40mmol,1.00eq) of furfural and 4.63g of N-methylhydroxylamine hydrochloride(55.45mmol,1.10eq), sodium bicarbonate 4.66g (55.45mmol,1.10eq), water 10.0ml, stirring the reaction at 0 ℃, and monitoring the reaction progress by TLC until the raw materials react completely, generating white precipitate. Filtering, collecting solid, drying to obtain 6.32g of furfuryl aldoxime N-methylate (A)¹H NMR(300MHz,CDC1₃)δ＝3.8(s,3H,CH₃),6.5,7.4–7.7(m,3H,furan),7.8(m,1H CH).)。

Preparation of a reference substance:

adding 39.78g (0.57mmol,1.10eq) of hydroxylamine hydrochloride and 240ml of water into a 250ml bottle, stirring at 0-5 ℃, dropwise adding 50.00g (0.50mmol,1.00eq) of furfural, controlling the temperature to be 0-5 ℃, stirring and reacting for 2 hours after the dropwise adding is finished, and monitoring the reaction process by TLC until the raw materials are completely reacted to generate white precipitates. Filtering, collecting solid, washing with water and drying to obtain the product of furfural oxime 56.10g (yield 97.06%, HPLC purity 99.346%,¹H NMR(400MHz,CD₃OD):δ＝7.56(dd,1H),7.40(s,1H),7.27(d,1H),6.56(m,1H).)。

[ -CHO/-C ═ NOH/-C ═ NMe ═ O purity analysis method ]

HPLC conditions: water/acetonitrile, C₁₈(250×4.6mm，5μm)、254nm、1.0ml/min、30℃、20μl。

As shown in the above experimental results, the oxime N-/O-alkylate is used as a raw material and reacts with the hydroxylamine salt to generate N-/O-alkylated substituted hydroxylamine salt and oxime. Preparing an initial raw material oxime N-/O-alkylate from oxime, and realizing material circulation; the reaction does not need acid and alkali catalysis, does not produce inorganic salt solid waste, and is more green and environment-friendly.