CN102531950A - Method for preparing O-benzylhydroxylamine hydrochloride - Google Patents
Method for preparing O-benzylhydroxylamine hydrochloride Download PDFInfo
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- CN102531950A CN102531950A CN2012100136483A CN201210013648A CN102531950A CN 102531950 A CN102531950 A CN 102531950A CN 2012100136483 A CN2012100136483 A CN 2012100136483A CN 201210013648 A CN201210013648 A CN 201210013648A CN 102531950 A CN102531950 A CN 102531950A
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- benzyl
- hydrochloride
- phenylmethoxyamine hydrochloride
- phenylmethoxyamine
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Abstract
The invention discloses a method for preparing O-benzylhydroxylamine hydrochloride, which is characterized in that in the method for synthesizing the O-benzylhydroxylamine hydrochloride by using halogenated benzyl as alkylation, the O-benzylhydroxylamine hydrochloride is prepared by heating a mixed product obtained after the alkylation reaction is finished to 55 to 65 DEG C in the water environment, slowly and dropwise adding aqueous solution of NaOH with stirring, stopping dropwise adding the aqueous solution of NaOH when no halogenated benzyl component exists in a reaction system and then carrying out the process steps of hydrolyzing, separating, refining and drying; the product with purity of over 98 percent can be produced; the requirement on the quality can be met; and the method is simple, convenient and safe.
Description
Technical field
The present invention relates to technical field of organic synthesis, specifically is a kind of method for preparing Phenylmethoxyamine hydrochloride.
Background technology
Phenylmethoxyamine hydrochloride is the synthetic midbody of using of a kind of important medicine.Being applied to medicine when synthetic, is to reach (potentiometric determination) more than 98% to the basic demand of Phenylmethoxyamine hydrochloride purity.
At present, can realize that the Phenylmethoxyamine hydrochloride preparation method of suitability for industrialized production has three kinds, be respectively: 1. with the yellow ketoxime method of training the strong CN1488625A representative that waits of Xiamen University; 2. the azanol disulfonic acid method that is the CN1819991A representative of grade with the modern well of BASF AG; 3. with the N-acetylhydroxylamine method of beautiful " a series of O-substituted alkyl hydroxylamine compounds synthetic " (Zhejiang University's master thesis in the 2006) representative in road.
It is alkylating reagent that above-mentioned three kinds of methods all adopt halogenation benzyl (mainly referring to Benzyl Chloride or cylite); Treating processes after alkylated reaction finishes is also the same substantially, the hydrochloric acid hydrolysis alkylate with slough the separating of protection base, protection base and bullion Phenylmethoxyamine hydrochloride, to the several steps such as refining and oven dry of bullion Phenylmethoxyamine hydrochloride.But the purity of the Phenylmethoxyamine hydrochloride that three kinds of methods are produced is lower, does not far reach market more than 98% to the requirement of quality.
Summary of the invention
The objective of the invention is to overcome the deficiency of above-mentioned prior art, and a kind of method for preparing Phenylmethoxyamine hydrochloride is provided, mainly solve the low problems such as requirement of market that do not reach of Phenylmethoxyamine hydrochloride purity that existing method is produced quality.
For achieving the above object, technical scheme of the present invention is: a kind of method for preparing Phenylmethoxyamine hydrochloride, and its special character is: the employing halogenation benzyl in routine is in the method for the synthetic Phenylmethoxyamine hydrochloride of alkylating reagent; With the mix products after the alkylated reaction end; Having in the presence of the water, be warming up to 55-65 ℃, slowly dripping the NaOH aqueous solution while stirring; Behind non-halogen benzyl composition in the reaction system; Promptly stop to drip the NaOH aqueous solution, then by common process be hydrolyzed, separate, make with extra care, the stoving process step, make Phenylmethoxyamine hydrochloride.
Further, said halogenation benzyl is Benzyl Chloride or cylite.
Further, the method for said synthetic Phenylmethoxyamine hydrochloride is ketoxime method, azanol disulfonic acid method and N-acetylhydroxylamine method.
Further; Mix products after said alkylated reaction finishes; Be meant the reaction system itself that is generated; Or the enriched material that extracts in the reaction system, enriched material is meant the intermediate product that contains with compound method corresponding O-benzyl ketoxime or O-benzyl hydroxylamine disulfonic acid or O-benzyl N-acetylhydroxylamine, enriched material is added water carry out subsequent operations.
Further, said Phenylmethoxyamine hydrochloride purity is more than 98%.
Compared with present technology a kind of method for preparing Phenylmethoxyamine hydrochloride of the present invention has outstanding substantive distinguishing features and marked improvement; 1, the halogenation benzyl in the mix products after the employing NaOH aqueous solution finishes alkylated reaction decomposes; Make and do not contain the halogenation benzyl in the system; Surpass 98% product thereby make three kinds of methods that prepare Phenylmethoxyamine hydrochloride all can produce purity, to reach the requirement of market to quality; 2, easy, the safety of this method.
Embodiment
In order to understand better and to implement, the present invention is elaborated below in conjunction with embodiment.
Embodiment 1, is example with the synthetic Phenylmethoxyamine hydrochloride of ketoxime method, and the embodiment 1 that adopts CN1488625A is maternal, and the reagent and the consumption of same steps as are identical, to an identical step row title, specifies for improving step, and step is following:
Step 1 is synthesized the free azanol,
Step 2 synthesizing hydroxyamine acetoxime,
Step 3 is synthesized benzyloxy amine acetoxime,
Take by weighing NaH (2.95g, 73.8mmol), nitrogen protection adds DMF (90ml), the frozen water cooling, 0 ℃ drips acetoxime (3.6g, MDF 49.3mmol) (20ml) solution down; Dropwise at 0 ℃ and continue reaction 0.5h, (5.6ml 46.5mmol), continues reaction 0.5h after adding to begin to drip benzyl bromine BnBr; Add saturated NH
4CL cancellation reaction adds entry (500ml);
Be warmed up to 60 ℃ then, slowly drip the 30%NaOH aqueous solution, sampling at any time, GC stops to drip the 30%NaOH aqueous solution after detecting the disappearance of benzyl bromine peak;
After reducing to room temperature, (3 * 20ml) extract, and the organic phase of merging is used the saturated common salt water washing, uses anhydrous sodium sulfate drying, filter, and drain solvent and obtain benzyloxy amine acetoxime bullion with ether;
Step 4 is synthesized Phenylmethoxyamine hydrochloride
(oil bath is warming up to 60 ℃, filters to obtain micro mist look solid for 8g, the HCL (10mL) of adding 12M in single neck bottle 49mmol) to benzyloxy amine acetoxime bullion is housed; Solid is washed with sherwood oil, the Phenylmethoxyamine hydrochloride that obtains through ethanol/methylene recrystallization, oven for drying again.
The Phenylmethoxyamine hydrochloride that the foregoing description 1 makes records purity 98.8% through potentiometric titration.
Simultaneously, adopt the identical method of embodiment 1 of CN1488625A, promptly reproduce the method for the embodiment 1 of CN1488625A, the Phenylmethoxyamine hydrochloride that makes records purity through potentiometric titration and is merely 83%.
Embodiment 2, are example with the synthetic Phenylmethoxyamine hydrochloride of azanol disulfonic acid method, adopt the scheme of CN1819991A embodiment 2, and the alkylating reagent of this embodiment is changed to benzyl chloride to generate purpose product Phenylmethoxyamine hydrochloride by Mono Chloro Acetic Acid; Step is following:
The aqueous solution (2mol/L) of 500ml azanol sodium disulfonate and the aqueous sodium hydroxide solution of 80g 50% are dropped in the beaker, after adding the 126.6g benzyl chloride, stirred 24 hours at 50 ℃; When the PH of reaction solution drops to 9 or following and definite reaction terminating;
Reaction system is warming up to 55 ℃, and the aqueous sodium hydroxide solution of slow Dropwise 5 0% is taken a sample at any time while stirring, and GC stops Dropwise 5 0% aqueous sodium hydroxide solution after detecting the disappearance of benzyl chloride peak;
The 9.8g vitriol oil is added in the reaction solution, and this mixture is heated 24 hours down with hydrolysis reaction product (O-benzyl hydroxylamine disulfonic acid) and remove sulfonic acid group at about 90 ℃ with normal pressure; Reaction solution is reduced to room temperature, and using 50% aqueous sodium hydroxide solution to be neutralized to pH value is 7, uses 700ml ethyl acetate extraction organic phase then; ETHYLE ACETATE is removed in decompression, then 107g 36% hydrochloric acid is added in the residue, is heated to 70 ℃ residue is dissolved entirely, reduces to the room temperature recrystallization again, filters and obtains Phenylmethoxyamine hydrochloride, and it is 98.9% that oven for drying after potential volumetry records purity.
Simultaneously, adopt the scheme of CN1819991A embodiment 2, the alkylating reagent of this embodiment is changed to benzyl chloride by Mono Chloro Acetic Acid, the Phenylmethoxyamine hydrochloride that makes records purity through potentiometric titration and is merely 90%.
Embodiment 3; With the synthetic Phenylmethoxyamine hydrochloride of N-acetylhydroxylamine method is example, and it is maternal adopting " synthesizing of a series of O-substituted alkyl hydroxylamine compounds " (road is beautiful, Zhejiang University's master thesis in 2006) described " synthetic model experiment processes of 6.5 O-benzyl hydroxylamines "; The reagent and the consumption of same steps as are identical; To identical step summary, specify for improving step, step is following:
The preparation of O-benzyl acetyl hydroxyl (O-benzyl N-acetylhydroxylamine): in the 1000ml round-bottomed flask that has reflux exchanger, TM, whisking appliance, adding ETHYLE ACETATE (154g, 1.75mol), water (50g), oxammonium hydrochloride (69.5g, 1.0mol).The water-bath controlled temperature stirs down in 20 ℃, and use tap funnel dropping mass percent concentration is 28% NaOH aqueous solution 328g; Synthermal subsequently down stirring reaction 1h, reaction finish the back in 25～30 ℃ slowly drip down Benzyl Chlorides (177.1g, 1.4mol); After reacting about 24 hours; Fall by product with petroleum ether extraction, use chloroform extraction then 3 times, in extraction liquid, add anhydrous Na
2SO
4Drying, concentrate product;
The preparation of O-benzyl hydroxylamine: the product of gained is thrown in the round-bottomed flask of the 500ml that has reflux exchanger, TM, whisking appliance;
Add 100g water, warming while stirring to 65 ℃, synthermal subsequently 28% the NaOH aqueous solution of slowly dripping down, sampling at any time after GC detects the Benzyl Chloride peak and disappears, stops to drip the NaOH aqueous solution; Be cooled to room temperature,, in extraction liquid, add anhydrous Na with chloroform extraction 3 times
2SO
4Drying, concentrate product; The product of gained is thrown in the round-bottomed flask of the 500ml that has reflux exchanger, TM, whisking appliance;
Add 35% industrial concentrated hydrochloric acid 98.0g, in 80 ℃ of following vigorous stirring reactions, reaction finishes to drip 28% the NaOH aqueous solution, transfers pH value between 9-10, with chloroform extraction 3 times, and the adding anhydrous Na
2SO
4Drying feeds hydrogen chloride gas in extraction liquid, generate O-benzyl hydroxylamine hydrochloride deposition, filters, dries, and it is 98.3% that potentiometric titration records purity.
Simultaneously; (road is beautiful to adopt " synthesizing of a series of O-substituted alkyl hydroxylamine compounds "; Zhejiang University's master thesis in 2006) described " the synthetic model experiment processes of 6.5 O-benzyl hydroxylamines " are reproduced, and the O-benzyl hydroxylamine hydrochloride that makes is recorded purity through potentiometric titration be merely 94%.
Can find out that by above three embodiment when reappearing above-mentioned three kinds of synthetic Phenylmethoxyamine hydrochloride methods, the Phenylmethoxyamine hydrochloride finished product purity of preparation is the highest can only to be refined to 94%, far not reach market more than 98% requirement of quality; And adopt method of the present invention, promptly in the mix products after alkylated reaction finishes, before adding hydrochloric acid is hydrolyzed into Phenylmethoxyamine hydrochloride with it; Mix products with after the alkylated reaction end is having in the presence of the water, is warming up to 55-65 ℃; Slowly drip the NaOH aqueous solution while stirring; Behind non-halogen benzyl composition in the reaction system, promptly stop to drip the NaOH aqueous solution, the common process by three kinds of methods carries out afterwards; The Phenylmethoxyamine hydrochloride finished product purity that polishing goes out is easy to just can reach more than 98%, satisfies the requirement of market to quality fully.
In addition; Mix products after alkylated reaction finishes also can adopt the enriched material that extracts in the reaction system; Enriched material is meant the intermediate product that contains with compound method corresponding O-benzyl ketoxime or O-benzyl hydroxylamine disulfonic acid or O-benzyl N-acetylhydroxylamine, enriched material is added water carry out subsequent operations.
Claims (5)
1. method for preparing Phenylmethoxyamine hydrochloride is characterized in that: adopting the halogenation benzyl is in the method for the synthetic Phenylmethoxyamine hydrochloride of alkylating reagent, the mix products after alkylated reaction is finished; Having in the presence of the water, be warming up to 55-65 ℃, slowly dripping the NaOH aqueous solution while stirring; Behind non-halogen benzyl composition in the reaction system; Promptly stop to drip the NaOH aqueous solution, be hydrolyzed then, separate, make with extra care, the stoving process step, make Phenylmethoxyamine hydrochloride.
2. use according to right and require 1 described a kind of method for preparing Phenylmethoxyamine hydrochloride, it is characterized in that said halogenation benzyl is Benzyl Chloride or cylite.
3. use according to right and require 1 described a kind of method for preparing Phenylmethoxyamine hydrochloride, the method that it is characterized in that said synthetic Phenylmethoxyamine hydrochloride is ketoxime method, azanol disulfonic acid method and N-acetylhydroxylamine method.
4. use the 3 described a kind of methods that prepare Phenylmethoxyamine hydrochloride that require according to right; It is characterized in that the mix products after said alkylated reaction finishes; Be meant the reaction system itself that is generated; Or the enriched material that extracts in the reaction system, enriched material is meant the intermediate product that contains with compound method corresponding O-benzyl ketoxime or O-benzyl hydroxylamine disulfonic acid or O-benzyl N-acetylhydroxylamine.
5. use according to right and require 1 described a kind of method for preparing Phenylmethoxyamine hydrochloride, it is characterized in that said Phenylmethoxyamine hydrochloride purity is more than 98%.
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| CN2012100136483A CN102531950A (en) | 2012-01-17 | 2012-01-17 | Method for preparing O-benzylhydroxylamine hydrochloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926681A (en) * | 2015-07-14 | 2015-09-23 | 西安近代化学研究所 | Purification method of O-benzylhydroxylamine hydrochloride |
| CN105152975A (en) * | 2015-07-21 | 2015-12-16 | 北京桑普生物化学技术有限公司 | Synthetic method for acetohydroxamic acid |
| CN106905196A (en) * | 2017-02-27 | 2017-06-30 | 华东理工大学 | Benzene sulfonyl reagent and preparation method and application |
| CN109369449A (en) * | 2018-12-25 | 2019-02-22 | 浙江工业大学 | A kind of method of synthesizing oxime ether |
| CN114181107A (en) * | 2021-11-08 | 2022-03-15 | 宁波睿田科技有限公司 | Synthesis method of benzyloxy amine hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488625A (en) * | 2003-08-25 | 2004-04-14 | 厦门大学 | Method for synthesizing benzyloxy amine hydrochloride |
| CN1819991A (en) * | 2003-08-29 | 2006-08-16 | 巴斯福股份公司 | Preparation of O-substituted hydroxylamines |
| CN102282111A (en) * | 2008-12-16 | 2011-12-14 | 雪佛龙美国公司 | Reduction of organic halide contamination in hydrocarbon products |
-
2012
- 2012-01-17 CN CN2012100136483A patent/CN102531950A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1488625A (en) * | 2003-08-25 | 2004-04-14 | 厦门大学 | Method for synthesizing benzyloxy amine hydrochloride |
| CN1819991A (en) * | 2003-08-29 | 2006-08-16 | 巴斯福股份公司 | Preparation of O-substituted hydroxylamines |
| CN102282111A (en) * | 2008-12-16 | 2011-12-14 | 雪佛龙美国公司 | Reduction of organic halide contamination in hydrocarbon products |
Non-Patent Citations (1)
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| 路娟: "一系列O-取代烷基羟胺化合物的合成", 《中国优秀硕士论文全文数据库 工程科技I辑(月刊) 2009年》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926681A (en) * | 2015-07-14 | 2015-09-23 | 西安近代化学研究所 | Purification method of O-benzylhydroxylamine hydrochloride |
| CN105152975A (en) * | 2015-07-21 | 2015-12-16 | 北京桑普生物化学技术有限公司 | Synthetic method for acetohydroxamic acid |
| CN106905196A (en) * | 2017-02-27 | 2017-06-30 | 华东理工大学 | Benzene sulfonyl reagent and preparation method and application |
| CN109369449A (en) * | 2018-12-25 | 2019-02-22 | 浙江工业大学 | A kind of method of synthesizing oxime ether |
| CN114181107A (en) * | 2021-11-08 | 2022-03-15 | 宁波睿田科技有限公司 | Synthesis method of benzyloxy amine hydrochloride |
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Application publication date: 20120704 |