CN1223581C - Method for synthesizing benzyloxy amine hydrochloride - Google Patents
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- CN1223581C CN1223581C CN 03157827 CN03157827A CN1223581C CN 1223581 C CN1223581 C CN 1223581C CN 03157827 CN03157827 CN 03157827 CN 03157827 A CN03157827 A CN 03157827A CN 1223581 C CN1223581 C CN 1223581C
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Abstract
The present invention relates to a method for synthesizing important medicine and an intermediate body organically synthesized, namely benzyloxy amine hydrochloride. A quantitative reaction of hydroxylamine hydrochloride is carried out to obtain acetone oxime, and oxygen benzylation is carried out under the action of sodium hydrogen; lastly, temperature is controlled to protect nearly quantitative obtained benzyloxy amine hydrochloride under the action of concentrated hydrochloric acid. The molecular weight of a mesosome is slightly increased in the process of synthesization, and each step of reaction has high yield; reaction substrate substances and reagents are conventional reagents, and therefore, the present invention has the advantages of low price, easy acquirement, low cost, simple technological process and reaction operation, template condition, nearly no complicated by-products. The whole process can be carried out without the separation of column chromatography until products are obtained by recrystallization in the last step. The present invention can be used for synthesizing large amounts of benzyloxy hydroxylamine hydrochloride and has good application prospects.
Description
Technical Field
The invention relates to a method for synthesizing important drugs and an organic synthesis intermediate, namely benzyloxyamine hydrochloride.
Background
The reason why the benzyloxyamine is unstable but it can exist stably as a hydrochloride salt is of great interest in the early stage of the synthesis of the benzyloxyamine hydrochloride because it is effective in treating pulmonary tuberculosis, and 5% mg of benzyloxyamine or 10% of benzyloxyamine dissolved in bovine serum is effective in treating pulmonary tuberculosis, while it can reduce the cholesterol content in blood. Currently, the benzyloxyamine is used as an important drug intermediate and an organic synthesis intermediate, is commonly used in reactions such as the introduction of hydroxylamine and oxime, and has high commercial value, so the synthesis research of the benzyloxyamine still attracts much attention. Although it is a widely used synthetic intermediate, it is now produced by a few large reagent companies in the world, asia is only available from tokyo chemical synthesis and shicheng pharmaceuticals in japan, and it is relatively expensive due to limited methods for mass synthesis. The reported methods for synthesizing benzyloxyamine include a direct condensation method, a commonly used method for synthesizing benzylation on nitrogen protection oxygen, and the like. The direct condensation method is a method utilizing electrophilic amination of benzyl alcohol, which is an atom-efficient method, such as the method directly utilizing sodium alkoxide and ammonia chloride as reported by Truitt, P. et al (J.Am.chem.Soc.1948, 70: 2829.),
the disadvantage of this reaction is that the yield of the reaction is low, less than 5%. Subsequently Theilacker, W.et al (Angew. chem.1956, 68: 303) increased the yield to 30% -40%, but the alkoxide required a 40-fold excess, which was not an ideal route for large scale synthesis and was rarely used in subsequent syntheses. In addition to direct condensation, the method generally considered is to selectively alkylate on hydroxyl groups, first protecting the hydrogen on the nitrogen from alkylation on the oxygen on the nitrogen. The most widely reported and widely used in the literature is the oxyalkylation using N-hydroxyphthalimide as substrate. The most widely used route of this method is that from N-hydroxy-phthalimide, reported by Grochowski, E.et al (Grochowski, E.; Jurczak, J.Synth. Commun.1976: 682-.
This method is most commonly used because it has high yield and can synthesize a large amount of benzyloxyamine, and the later reported methods also commonly use similar substrates or similar steps with only slight modifications to the reaction conditions. Harned, a.m.; hanson, P.R, (Harned, A.M.; Hanson, P.R. org. Lett.2002, 6: 1007-one 1010) also reported that benzyloxyimides were obtained by Mitsunobu reaction followed by hydrazine to give the product, except that they developed a novel process in which the intermediate was not isolated by column chromatography, adsorbed onto a resin, easily separated by filtration from the Mitsunobu reaction mixture and then desorbed.
A＝(1MesH2)(PCy3)(Cl)-Ru＝CHPh
Wherein the reaction conditions and reagents are as follows:
(a)iBnOH，PPh3，DIAD，THF，rt；ii 5mol％ of A，CH2Cl2，reflux；ii EtOCH＝CH2；iv MeOH then filter，
(b)NH2NH2，THF，rt，72％from BnoH
this method can produce high-purity benzyloxyamine in high yield without substituted hydrazine (DEADH)2) Triphenylphosphine oxide, etc. have an influence on the purity of the product, but hydrazine is still used. In addition, protection of nitrogen using sterically bulky groups, in addition to N-hydroxyphthalimide as the hydroxylamine nitrogen protection form, the method of Maskill, H (Maskill, H.J.chem.Soc., Perkin Trans.2001, 2: 1742-1747.) is simpler and safer.
Tr＝trityl or substituted trityl
They use a group with larger steric hindrance to protect the hydrogen on nitrogen, so that the alkali can only act on the hydrogen on oxygen, the product obtained by alkylation on oxygen is unstable under acidic condition, and the product can be easily removed under the action of acid and alkali. The reaction is simple to operate, the use of hydrazine is avoided, but the removal of a protecting group formed by a huge aromatic group and the generation of a byproduct are also great hidden troubles. Truitt, P.et al (J.Am.chem.Soc.1952, 74: 3956-3957) attempted to obtain alkoxyamine hydrochloride by condensation of the sodium salt of hydroxylamine acetone oxime with a halogenated hydrocarbon starting from acetone oxime to form an oxo-substituted hydroxylamine acetone oxime.
However, this document does not indicate a specific method and yield for alkylation on oxygen, nor does it report the yield for removal of the protecting group on nitrogen, only the yield for the benzyloxyamine analog. This method was not used for large scale synthesis and the reported yield of the benzhydrylamine synthesis over the next decade was not high, suggesting that this route was not a convenient high yield route.
The conventional synthesis methods reported in the above documents have the following disadvantages:
a. from the atom economy perspective
The benzyloxyamine hydrochloride has a low molecular weight and is released when used. The conventional methods reported in the literature have too much amplification of the mass of reaction intermediates, and not only are the reaction treatment troublesome, but also the atomic efficiency is low.
b. From the viewpoint of safety and environmental friendliness
The polyaryl rings used in the bulky group protection strategy can cause environmental pollution. The Mitsunobu reaction still adopted in the mass synthesis at present has the disadvantages of more and more byproducts, triphenyl phosphine oxide and diethyl azine dicarboxylate which are at least equivalent to the products, difficult separation and purification and serious burden to the environment. In addition, the action of hydrazine is very dangerous and its requirements for operation and reaction systems are very strict.
c. From the cost and process requirements perspectives
No matter complex large protecting groups are selected or azodicarbonic Diethyl Ester (DEAD) or azodicarbonic diisopropyl ester (DIAD) used in Mitsunobu reaction is adopted, the cost of the reagent is high, low-temperature storage is needed, and the difficulty of large-scale synthesis is increased. However, oxygen-free conditions are required to be ensured in the reaction, otherwise, the yield of the reaction is reduced in the light case, explosion occurs in the heavy case, and the control is not easy in the industry.
Disclosure of Invention
The invention aims to develop a new method for conveniently and quickly synthesizing a large amount of important medical intermediate benzyloxyamine hydrochloride by taking hydroxylamine hydrochloride as a raw material.
The specific synthetic route of the invention is as follows:
in the following description and examples that follow, specific synthetic products are represented by Arabic numerals according to the numbering in the structural formulae. Where Me represents a methyl group, M represents a metal ion, Bn represents a benzyl group, and DMF represents dimethylformamide.
The invention takes hydroxylamine hydrochloride 1 as a raw material to synthesize the benzyloxyamine hydrochloride 4, which comprises the following specific steps:
step 1, dissolving hydroxylamine hydrochloride 1 in water at normal temperature, and reacting for 0.5-5h by using an alkali at the reaction temperature of 0-50 ℃ to obtain hydroxylamine. The base is an inorganic base, in particular sodium hydroxide, potassium hydroxide or potassium carbonate.
And 2, reacting the obtained hydroxylamine with acetone at 0-60 ℃ for 3-15 h, and extracting a product by using ether to obtain a compound 2. The ether is C2-C4Especially diethyl ether and tetrahydrofuran.
And 3, reacting the compound 2with alkali in an aprotic solvent to form negative ions, and reacting with benzyl halide at 0-40 ℃ for 0.5-5h to obtain a compound 3. The aprotic solvent is dimethyl sulfoxide (DMSO) or Dimethylformamide (DMF). The base is calcium hydrogen or sodium hydrogen, especially sodium hydrogen. The benzyl halide refers to benzyl chloride, benzyl bromide or benzyl iodide, especially benzyl chloride or benzyl bromide.
And (3) reacting the compound 3 and 6M-12M hydrochloric acid in the step (4) at 45-80 ℃ for 1-2 h, preferably reacting the compound with l 0-12M hydrochloric acid at 45-60 ℃, dissolving the mixture in alcohol after decompression concentration, concentrating the solution again, adding a small amount of water, and extracting the solution by using an organic solvent to obtain a compound 4 bright white solid. Or concentrated and recrystallized directly (in alcohol and an ether). The alcohol is C1-C4The monohydric alcohols are, in particular, methanol and ethanol, and the organic solvent is ethyl acetate, dichloromethane or petroleum ether. The ether is C2-C4Especially diethyl ether and tetrahydrofuran.
The invention selects acetone oxime as the protection form of hydroxylamine nitrogen, the molecular weight of the intermediate is not increased much, the reaction yield of each step is high, and the atom economy of the whole route is good. The reaction substrate and the reagent are conventional reagents, are cheap and easy to obtain, and have low cost. The method has the advantages of simple process flow, simple reaction operation, mild conditions and almost no complex by-products, and the whole process can be separated without column chromatography until the final step of recrystallization to obtain the product, thereby having good application prospect.
Detailed Description
The present invention will be described in detail with reference to examples.
Example 1
Step 1 Synthesis of free hydroxylamine
Hydroxylamine hydrochloride (403mg, 5.8mmol) was weighed, 1.3mL of ethanol was added and the solution was stirred at room temperature to completely dissolve hydroxylamine hydrochloride. Slowly adding an aqueous solution (0.3mL) of sodium hydroxide (725mg, 18.1mmol) in batches, controlling the reaction temperature at 25-40 ℃, and naturally stirring and cooling the reaction system to room temperature after the alkali is added for reaction for 0.5 h. The reaction was carried out without isolation.
Step 2 Synthesis of hydroxylamine acetone oxime 2
And (3) dropwise adding acetone (0.3mL) by using a dropping funnel, violently releasing heat when adding the acetone, cooling by using an ice bath, and simultaneously controlling the reaction temperature to be 0-60 ℃ by controlling the dropping speed of the acetone. After the reaction is stable, the reaction is carried out for 15h at room temperature. Extraction with ether, washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, draining the solvent on a water pump, and concentration on an oil pump to give 210mg of colorless solid hydroxylamine acetone oxime, with a yield of 98% in two steps, which was used directly in the next reaction without purification. The product mp 59-61 ℃, MS (ESI, m/z): 74(M + H)+，100)。
Step 3 Synthesis of benzyloxyamineacetonoxime 3
NaH (2.76g, 69mmol) was weighed, mineral oil on the sodium-hydrogen surface was washed off with dry tetrahydrofuran under nitrogen, DMF (90mL) was added after washing, cooled in an ice-water bath, a solution of hydroxylamine acetonoxime (3.6g, 49.3mmol) in DMF (20mL) was added dropwise at 0 ℃ and after addition reaction continued at 0 ℃ for 0.5h until no significant bubbling occurred. Benzyl bromide (BnBr) (5.4ml, 44.8mmol) was added dropwise, and after addition was complete the reaction was continued at room temperature for 0.5 h. Adding saturated NH4The reaction was quenched with Cl, water (500mL) was added, extracted with (3 × 20mL) ether, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, the solvent pumped off on a water pump, pumped off again on an oil pump, and the next reaction was carried out without separation or by column chromatography (EtOAc: PE ═ 1: 150) to give 7.65g of benzyloxyamidoacetone oxime (colorless liquid) in 86% yield. MS (ESI, m/z): 164(M + H)+，100)，IR(film)υmax：3032，2918，1454，1367，1070，1025，880，698 cm-1.1H-NMR(500MHz，CDCl3)δ：1.88(m，6H，(CH3)2C)，5.08(s，2H，CH2Ph)，7.30-7.40(m，5H，Ar)ppm。
Step 4 Synthesis of benzyloxyamine hydrochloride 4
Under the ice bath condition, 12M HCl (10mL) is directly dripped into a single-neck bottle filled with benzyloxyamidoacetone oxime (8g, 49mmol), after the addition is finished, the mixture is heated by an oil bath to 60 ℃ for reaction for 2h, a large amount of solid is generated in the bottle, and the solid is concentrated under reduced pressure to remove excessive acid,so that a slightly pink solid is obtained. Washing with petroleum ether gave 7.4g of crude white solid in 96% yield, which was recrystallized from methanol/dichloromethane to give 6.4g of bright white flaky solid in 80% yield. mp234-237 deg.C (methanol/dichloromethane). Nuclear magnetic resonance spectroscopy using a Varian unit +500 model nuclear magnetic resonance spectrometer,1H NMR(500MHz，DMSO-6d)δ：5.08(s，2H)，7.42(s，5H)，11.26(broad s，3H)ppm。
example 2
Step 1 liberation of free hydroxylamine
Hydroxylamine was prepared from compound 1 by the method of example 1.
Hydroxylamine hydrochloride (10.0g, 144mmol) was weighed in a two-necked flask equipped with a dropping funnel, and 15mL of water was added to the two-necked flask, and the solution was stirred at room temperature to completely dissolve the hydroxylamine hydrochloride. Firstly, slowly adding potassium hydroxide (8.9g, 158mmol) in batches in an ice bath, controlling the reaction temperature to be not more than 50 ℃ after finishing adding the alkali, cooling the reaction system to room temperature after 5 hours, and directly carrying out the next reaction.
Step 2 Synthesis of hydroxylamine acetone oxime 2
Hydroxylamine acetonoxime was prepared from hydroxylamine as in example 1.
Dropwise adding acetone (14mL) by using a dropping funnel, violently releasing heat when adding the acetone, and controlling the reaction temperature at 30-60 ℃ by controlling the dropping speed of the acetone. After the reaction is stable, the reaction is carried out for 13h at room temperature. Extraction with ether (3X 10mL) and combined organic phases washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, solvent pumped off on a water pump and concentrated on an oil pump to give 10.2g of colorless solid hydroxylamine acetone oxime in 95% yield over two steps, which was used directly in the next reaction without purification.
Step 3 Synthesis of benzyloxyamineacetonoxime 3
Benzyloxyamidoacetone oxime was prepared from compound 2 as in example 1.
NaH (139mg, 5.8mmol) was weighed, mineral oil on the sodium-hydrogen surface was washed off with dry tetrahydrofuran under nitrogen, DMF (29mL) was added after washing, cooled in an ice-water bath, a solution of hydroxylamine acetonoxime (346mg, 4.8mmol) in DMF (24mL) was added dropwise at 0 ℃ and the reaction continued at 0 ℃ for 0.5h after addition until no significant bubbling occurred. Benzyl bromide (BnBr) (0.87ml, 7.2mmol) was added dropwise and after addition the reaction was continued for 0.5h at 40 ℃ with heating in an oil bath. Adding saturated NH4The reaction was quenched with Cl, water (250mL) was added, extracted with (3 × 20mL) ether, and the combined organic phases were washed with 2mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, solvent pumped off on a water pump, concentrated on an oil pump, and column chromatographed (EtOAc: PE ═ 1: 150) to give 551mg of benzyloxyamidoacetone oxime (colorless liquid) in 72% yield.
Step 4 Synthesis of benzyloxyamine hydrochloride 4
Benzyloxyamine hydrochloride was prepared from compound 3 by the method of example 1.
Example 3
Step 1 Synthesis of free hydroxylamine
Hydroxylamine was prepared from compound 1 by the method of example 1.
Step 2 Synthesis of hydroxylamine acetone oxime 2
Hydroxylamine acetonoxime was prepared from hydroxylamine as in example 2.
Step 3 Synthesis of benzyloxyamineacetonoxime 3
Benzyloxyamidoacetone oxime was prepared from compound 2 as in example 1.
NaH (1.9g, 82mmol) is weighed, mineral oil on the sodium-hydrogen surface is washed off by dry tetrahydrofuran under nitrogen atmosphere, DMF (200mL) is added after washing, ice water bath cooling is carried out, a DMF (50mL) solution of hydroxylamine acetone oxime (5g, 68.5mmol) is added dropwise at 0 ℃, reaction is continued for 0.5h at 0 ℃ after dropwise addition is finished until no obvious bubbling occurs. Benzyl bromide (BnBr) (8.2ml, 68.5mmol) was added dropwise to the ice-water bath, and the reaction was continued for 5h after the addition was complete. Adding saturated NH4The reaction was quenched with Cl, water (1000mL) was added, extracted with (4X 20mL) ether, and the combined organic phases were washed with 4mL saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, the solvent pumped off on a water pump, and concentrated on an oil pump for the next reaction directlyOr column chromatography (EtOAc: PE ═ 1: 150) to give 7.4g of benzyloxyamidoacetone oxime (colorless liquid) in 70% yield.
Step 4 Synthesis of benzyloxyamine hydrochloride 4
Benzyloxyamine hydrochloride was prepared from compound 3 by the method of example 1.
Under the ice bath condition, 6M HCl (9mL) is directly dripped into a single-neck bottle filled with benzyloxyamidoacetone oxime (7.5g, 46mmol), after the addition is finished, the mixture is heated by an oil bath to be heated to 80 ℃ for reaction, the reaction lasts for 1.5h, a large amount of solid is generated in the bottle, the reaction is concentrated under reduced pressure, excessive acid is removed, a slightly pink solid is obtained, and the mixture is washed by petroleum ether, so that a crude product, namely a white solid, is obtained, wherein the yield is 63 percent and 4.95 g.
Claims (12)
1. The method for synthesizing the hydrochloride of the benzyloxy amine is characterized in that the synthetic route is as follows:
the specific synthesis steps are as follows:
step 1, dissolving hydroxylamine hydrochloride 1 in water at normal temperature, and reacting for 0.5-5h by using an alkali at the reaction temperature of 0-50 ℃ to obtain hydroxylamine;
step 2, reacting the obtained hydroxylamine with acetone at 0-60 ℃ for 3-15 h, and extracting a product with ether to obtain a compound 2;
step 3, reacting the compound 2 with alkali in an aprotic solvent to form negative ions, and then reacting with benzyl halide at 0-40 ℃ for 0.5-5h to obtain a compound 3;
reacting the compound 3 and 6M-12M hydrochloric acid in the step 4 at 45-80 ℃ for 1-2 h, concentrating under reduced pressure, dissolving with an alcohol, concentrating again, adding a small amount of water, and extracting with an organic solvent to obtain a compound 4 bright white solid; or concentrating and recrystallizing directly in alcohol and ether.
2. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein in step 1, the base is an inorganic base selected from sodium hydroxide, potassium hydroxide or potassium carbonate.
3. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, characterized in that in step 2 the ether is C2-C4Is selected fromdiethyl ether or tetrahydrofuran.
4. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein in step 3, the aprotic solvent is selected from dimethyl sulfoxide or dimethylformamide.
5. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein in step 3, the benzyl halide is selected from benzyl chloride, benzyl bromide or benzyl iodide.
6. The method for synthesizing benzyloxyamine hydrochloride according to claim 5, wherein in step 3, the benzyl halide is selected from the group consisting of benzyl chloride and benzyl bromide.
7. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, characterized in that in step 4, the alcohol isIs selected from C1-C4A monohydric alcohol of (a); the organic solvent is selected from ethyl acetate, dichloromethane or petroleum ether; said ether is selected from C2-C4The fatty ether of (a).
8. The method for synthesizing benzyloxyamine hydrochloride according to claim 7, wherein in step 4, the ether is selected from diethyl ether or tetrahydrofuran.
9. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, characterized in that the base in step 3 is selected from sodium hydrogen.
10. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein the hydrochloric acid in step 4 is 10 to 12M.
11. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein the reaction temperature in step 4 is 45 to 60 ℃.
12. The method for synthesizing benzyloxyamine hydrochloride according to claim 1, wherein the alcohol in step 4 is methanol or ethanol.
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Families Citing this family (9)
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| CN102093253A (en) * | 2010-11-29 | 2011-06-15 | 浙江大学宁波理工学院 | Preparation method of benzoxylamine hydrochloride compounds |
| CN102531950A (en) * | 2012-01-17 | 2012-07-04 | 烟台奥东化学材料有限公司 | Method for preparing O-benzylhydroxylamine hydrochloride |
| CN102718810B (en) * | 2012-06-27 | 2015-03-11 | 山东圣泉新材料股份有限公司 | After-treatment method of benzylation reaction product |
| CN104926681A (en) * | 2015-07-14 | 2015-09-23 | 西安近代化学研究所 | Purification method of O-benzylhydroxylamine hydrochloride |
| CN109134331B (en) * | 2018-07-24 | 2019-12-24 | 宜昌东阳光药业股份有限公司 | Synthesis method of azithromycin genotoxic impurity |
| CN109369449A (en) * | 2018-12-25 | 2019-02-22 | 浙江工业大学 | A kind of method of synthesizing oxime ether |
| CN109956884B (en) * | 2019-04-28 | 2022-03-08 | 浙江圣安化工股份有限公司 | Preparation method of benzyloxyamine hydrochloride |
| CN112645835A (en) * | 2020-12-19 | 2021-04-13 | 宁波四明化工有限公司 | Preparation method of benzyloxyamine hydrochloride |
| 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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