CN101531606A - Method for synthesizing alpha-alkoxyl-beta-amino ester derivative - Google Patents
Method for synthesizing alpha-alkoxyl-beta-amino ester derivative Download PDFInfo
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Abstract
The invention provides a method for synthesizing an alpha-alkoxyl-beta-amino ester derivative, and relates to a process for synthesizing an intermediate compound of an anticancer medicament. The method comprises the following steps: weighing rhodium acetate, o-aminophenol, aldehyde, alkoxytitanium and a diazo compound according to molar ratio of 0.01:1.0:1.0:1.1:2.0; dissolving the aldehyde, the o-aminophenol, the alkoxytitanium, the rhodium acetate and a dehydrating agent in an organic solvent; stirring the mixture for 2 to 3 hours at room temperature to prepare a reaction system; dissolving the diazo compound into the solvent consisting of the organic solvent by a sampling pump to be injected into the reaction system; dripping saturated NaHCO3 aqueous solution to perform a quenching reaction after 2 to 3 hours of reaction; removing the solvent by reduced pressure distillation to prepare a crude product of the alpha-alkoxyl-beta-amino ester derivative with two chiral centers; and carrying out column chromatography on the crude product by ethyl acetate and sherwood oil according to the ratio of 1:50-1:20 to obtain a pure product. The method has convenient and safe operation, short reaction time and high efficiency; the reaction condition at room temperature is mild; raw materials have wide resources; and the product can be widely applied to synthesis of intermediate compound of the anticancer medicament.
Description
Technical field
The synthetic method of a kind of alpha-alkoxy base-beta-amino ester derivative relates to a kind of technology of synthetic cancer therapy drug intermediate, belongs to the medicine chemical technology field.
Background technology
Alpha-alkoxy base-beta-amino ester derivative is the important skeleton structure that a class makes up natural product, in peptidase inhibitors amastatin (he decides Ah) and bestatin (ubenimex) structure, this similar skeleton structure is arranged all, similar structural framework is also arranged in anti-cancer medicine paclitaxel in addition.Taxol is a kind of material with highly effective antineoplastic activity that extracts from Chinese yew genus plants, and mammary cancer, ovarian cancer, nonsmall-cell lung cancer etc. are all had good curative effect, is one of main medicine for the treatment of at present the type disease.The method of producing taxol has natural extract, culture plant cell and chemosynthesis etc.Wherein, extract female loop section---the baccatin III and the 10-deacetylate baccatin III (10-DAB) of taxol from the needle of Chinese yew genus plants, the semisynthesis that links with the C-13 side chain of chemosynthesis is the method for the production taxol of current extensive employing again.In semi-synthesizing technology, the C-13 side chain of synthesis of optically active---(2R, 3S)-N-benzoyl-3-phenylisoserine is a vital step.And alpha-alkoxy base-beta-amino ester derivative can be by taking off alkoxyl group, and step conversion such as hydrolysis become to have the material of similar skeleton.In recent years, discover that some paclitaxel analogs have better antitumour activity.Therefore the analogue of synthetic a series of C-13 side chains docks with 10-DAB, and the means by combinatorial chemistry might filter out more effective, targetedly cancer therapy drug.
The chemical synthesis process of prior art alpha-alkoxy base-beta-amino ester derivative is the rapid synthesis method of multistep, people such as Yu Wenao are raw material with phenyl aldehyde and ethyl chloroacetate, through the Derzen condensation, azide, the catalytic hydrogenation multistep realizes that synthetic (Xiamen University's journal (natural science edition) 1999.38.20) this method shortcoming of its diastereomer is that step is many, productive rate is low, complex operation.
Because multi-component reaction has high flexibility, highly selective, atom economy, the high characteristics such as energy and ease for operation of exploring, growing along with the Atom economy notion in recent years, multi-component reaction more and more becomes the focus of research.Multi-component reaction is applied to the synthetic field of medicine has very wide prospect.(Chem.Commun.2008 6564-6566) has reported with diazonium compound, alcohol, aldehyde and amine at chirality protonic acid and Rh Xu Xinfang etc.
2(OAc)
4Common catalytic four component reaction, single stage method is prepared the alpha-hydroxyl-beta-aminophenol derivative of a series of high enantioselectivity.Its weak point is that at first amine, aldehyde and chirality protonic acid will be in sal epsom and 4
Stirred 12 hours under the condition of dewatering agents such as molecular sieve, so that aldehyde and amine reaction generate imines, the activation capacity of this explanation chirality protonic acid is strong not enough, and its secondary response will react under-20 ℃ cold condition, the 3rd, the aldehyde in the employed substrate is aromatic aldehyde.
Summary of the invention
The object of the present invention is to provide a kind of simple to operate, reaction conditions gentleness, alpha-alkoxy base-beta-amino ester derivative synthetic method that raw material sources are wide.Specifically be that single stage method is prepared a series of alpha-alkoxy base-beta-amino ester derivatives with two chiral centres with diazonium compound, titan-alkoxide, o-aminophenol and four component reaction of aldehyde under the catalysis of acetic acid rhodium.
In order to achieve the above object, we use the surrogate of titan-alkoxide as alcohol.Because titan-alkoxide can be used as a kind of Lewis acid this reaction system is played the activatory effect, add a small amount of sal epsom and 4 in the reaction process
Molecular sieve only at room temperature stirs and can form the original position imines in 2～3 hours as dewatering agent.Amine is not to use common aromatic amine in addition, but adopts the aromatic amine that hydroxyl activated on the ortho position, and its purpose remains the activity of intensified response substrate, and can slough the amido that aryl gains freedom through deriving.Diazonium is decomposed into metal carbene under the catalysis of acetic acid rhodium, at first generate oxygen ylide intermediate with titan-alkoxide, the generated in-situ imines of aldehyde and o-aminophenol and then catch this active intermediate and obtain reaction product, in reaction process, titan-alkoxide activates reaction system as Lewis acid simultaneously.What participate in the seizure of oxygen ylide in the reaction mechanism is the generated in-situ imines of aldehyde and o-aminophenol.Reaction only needs at room temperature can carry out, and condition is more gentle, and the scope of aldehyde can expand to alkanoic.
The general formula that the present invention designs synthetic alpha-alkoxy base-beta-amino ester derivative is:
Wherein: Ar
1Be phenyl, or all kinds of substituted-phenyl
Ar
2Be o-hydroxy-phenyl
R
1Be alkoxyl group
R
2Be phenyl, or all kinds of substituted-phenyl.
The reaction equation of synthetic alpha-alkoxy base of the present invention-beta-amino ester derivative:
Wherein: Ar
1Be phenyl, or all kinds of substituted-phenyl
Ar
2Be adjacent hydroxyl amino
R
1Be alkoxyl group
R
2Be phenyl, or all kinds of substituted-phenyl.
The synthetic method of alpha-alkoxy base of the present invention-beta-amino ester derivative is as follows:
Measure the acetic acid rhodium earlier: o-aminophenol: aldehyde: titan-alkoxide: diazonium compound=0.01:1.0:1.0:1.1:2.0 mol ratio, then aldehyde, o-aminophenol, titan-alkoxide, acetic acid rhodium and dewatering agent are dissolved in the organic solvent, stir under the room temperature and made reaction system in 2～3 hours, with sampling pump the solution that diazonium compound is dissolved in the organic solvent composition is slowly injected above-mentioned reaction system, time control 1～3 hour, after sample introduction finishes, continue reaction 2～3 hours, drip saturated NaHCO then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes to desolvate and makes the alpha-alkoxy base-beta-amino ester derivative crude product with two chiral centres, and crude product ethyl acetate: sherwood oil=1:50～1:20 is carried out column chromatography, obtains straight product;
Above-mentioned diazonium compound is the phenyl diazonium acetate, or the substituted-phenyl diazonium acetate;
Above-mentioned titan-alkoxide is a purity titanium tetraethoxide, or the four different third oxygen titaniums;
Above-mentioned aldehyde is phenyl aldehyde, o-chlorobenzaldehyde, m chlorobenzaldehyde, 4-chloro-benzaldehyde, aubepine, to cyanobenzaldehyde, paranitrobenzaldehyde, piperonylaldehyde, 1-naphthaldehyde or furfural;
Above-mentioned dewatering agent is 4
Molecular sieve, add-on adds 500mg 4 for the 1mmol o-aminophenol
Molecular sieve;
Above-mentioned organic solvent is methylene dichloride, trichloromethane, toluene, 1,2-ethylene dichloride, tetrahydrofuran (THF), acetonitrile or dimethylbenzene.
The effect that the present invention is useful is: can make up alpha-alkoxy base-beta-amino ester derivative by single step reaction, easy to operate and safe, the reaction times is short, the efficient height; Reaction conditions gentleness under the room temperature; Raw material sources are wide.
Embodiment
Embodiment 1
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), phenyl aldehyde (0.5mmol), the four different third oxygen titaniums (0.55mmol) and 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stir under the room temperature and made reaction system in 2～3 hours, phenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes to desolvate and obtains crude product, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 75%, and the dr value is 79:21.Yellow?oil；
1H?NMR(500MHz，CDCl
3)δ(ppm)7.25-7.35(m，5H)，7.10-7.13(m，3H)，6.97-6.99(m，2H)，6.51-6.71(m，4H)，5.80(br，1H)，5.10(s，1H)，4.67(br，1H)，3.91(m，1H)，3.70(s，3H)，1.18(d，3H，J＝6.1Hz)，0.97(d，3H，J＝6.1Hz)；
13C?NMR(125MHz，CDCl
3)δ(ppm)172.6，145.8，138.1，136.5，134.5，129.2，129.0，128.2，127.4，127.3，127.1，120.9，119.5，116.6，114.7，86.9，68.8，64.5，51.9，23.8，23.2.
Embodiment 2
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), 4-chloro-benzaldehyde (0.5mmol), the four different third oxygen titaniums with (0.55mmol) with 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stirring under the room temperature and made reaction system in 2～3 hours, phenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2In, with sampling pump this solution is slowly injected above-mentioned reaction system, time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 68%, and the dr value is 74:26.Yellow?oil；
1H?NMR(300MHz，CDCl
3)δ(ppm)7.25-7.34(m，4H)，7.08(d，2H，J＝8.5Hz)，6.91(d，2H，J＝8.5Hz)，6.48-6.71(m，4H)，5.65(br，1H)，5.11(br，1H)，4.59(br，1H)，3.92(m，1H)，3.73(s，3H)，1.17(d，3H，J＝5.9Hz)，0.97(d，3H，J＝5.9Hz)；
13C?NMR(75MHz，CDCl
3)δ(ppm)172.4，145.5，136.6，136.0，134.2，133.1，130.5，129.0，128.4，127.5，127.3，121.0，119.5，116.3，114.7，86.7，68.9，63.8，52.1，23.9，23.1.
Embodiment 3
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), aubepine (0.5mmol) and purity titanium tetraethoxide (0.55mmol) 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stirring under the room temperature and made reaction system in 2～3 hours, phenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 53%, and the dr value is 67:33.Yellow?oil；
1H?NMR(300MHz，CDCl
3)δ(ppm)7.26-7.38(m，5H)，6.89-6.92(d，2H)，6.51-6.69(m，6H)，5.95(br，1H)，5.06(s，1H)，4.45(br，1H)，3.92(m，1H)，3.72(s，6H)，1.18(d，3H，J＝6.1Hz)，0.97(d，3H，J＝6.1Hz)；
13C?NMR(75MHz，CDCl
3)δ(ppm)172.7，158.6，145.7136.5，134.5，130.2，130.1，129.0，128.2，127.4，120.8，119.4，116.5，114.6，112.5，86.9，68.7，63.8，55.0，52.0，23.8，23.1.
Embodiment 4
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), 2 furan carboxyaldehyde (0.5mmol) and the four different third oxygen titaniums (0.55mmol) 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stirring under the room temperature and made reaction system in 2～3 hours, phenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 69%, and the dr value is 76:24.Yellow?oil；
1H?NMR(300MHz，CDCl
3)δ(ppm)7.17-7.32(m，6H)，6.83-6.84(m，2H)，6.57-6.63(m，2H)，6.19(br，1H)，5.58(br，1H)，4.93(br，1H)，4.04(m，1H)，3.85(s，3H)，1.17(d，3H，J＝5.9Hz)，1.10(d，3H，J＝5.9Hz)；
13C?NMR(75MHz，CDCl
3)δ(ppm)172.7，151.5，149.2，141.1，136.6，133.5，128.3，128.2，127.5，123.3，121.2，120.0，115.3，110.1，109.2，86.3，69.1，61.5，52.4，23.7，23.4.
Embodiment 5
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), phenyl aldehyde (0.5mmol) and the four different third oxygen titaniums (0.55mmol) 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stir under the room temperature and made reaction system in 2～3 hours, bromophenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 67%, and the dr value is 77:23.Yellow?oil；
1H?NMR(500MHz，CDCl
3)δ(ppm)7.28-7.49(m，5H)，7.10-7.14(m，4H)，6.94-6.95(m，2H)，4.94(s，1H)，3.75(s，3H)，3.54(m，1H)，3.42(q，2H)，1.25(t，3H)；
13C?NMR(125MHz，CDCl
3)δ(ppm)171.8，146.6，137.9，135.5，134.3，129.5，129.0，128.4，128.2，127.6，127.4，127.3，127.2，127.1，120.7，120.4，117.8，114.7，87.5，65.6，61.6，52.2，29.7，15.3.
Embodiment 6
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), paranitrobenzaldehyde (0.5mmol) and the four different third oxygen titaniums (0.55mmol) 4
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stirring under the room temperature and made reaction system in 2～3 hours, p-methoxyphenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3mlCH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 55%, and the dr value is 53:47.Yellowoil；
1HNMR(300MHz，CDCl
3)δ(ppm)7.96(d，2H，J＝8.8Hz)，7.26.-7.34(m，7H)，7.15(d，2H，J＝8.8Hz)，6.60-6.69(m，3H)，6.47-6.50(m，2H)，5.43(br，1H)，5.32(d，1H，J＝10.7Hz)，4.78(d，1H，J＝10.7Hz)，3.90(m，1H)，3.75(s，3H)，1.66(br，1H)，1.22(d，3H，J＝5.9Hz)，0.99(d，3H，J＝5.9Hz)；
13C?NMR(75MHz，CDCl
3)δ(ppm)171.9，147.2，146.0，144.9，135.3，133.845，130.1，128.8，128.7，127.7，127.0，122.2，121.2，119.5，115.3，114.7，86.49，69.112，63.6，52.3，23.9，23.0.
Embodiment 7
With acetic acid rhodium (0.005mmol), o-aminophenol (0.5mmol), 4-chloro-benzaldehyde (0.5mmol) and the four different third oxygen titaniums (0.55mmol)
Molecular sieve (250mg) is dissolved in 6ml CH
2Cl
2In, stir under the room temperature and made reaction system in 2～3 hours, bromophenyl diazoacetic acid methyl esters (1.0mmol) is dissolved in 3ml CH
2Cl
2The middle solution of forming slowly injects above-mentioned reaction system with sampling pump with this solution, and time control 1～3 hour after sample introduction finishes, continues reaction 2～3 hours, drips saturated NaHCO to reaction system then
3The aqueous solution reacts in order to cancellation, and vacuum rotary steam removes and to desolvate, and crude product is carried out column chromatography, and (ethyl acetate: sherwood oil=1:50～1:20) obtains straight product.Productive rate is 65%, and the dr value is 74:26.Yellow?oil；
1H?NMR(300MHz，CDCl
3)δ(ppm)7.39(d，2H，J＝7.9Hz)，7.20-7.26(m，2H)，7.21(d，2H，J＝8.0Hz)，6.53-6.70(m，6H)，5.85(br，1H)，5.09(br，1H)，4.50(br，1H)，3.83(m，1H)，3.73(s，3H)，1.16(d，3H，J＝6.1Hz)，0.97(d，3H，J＝6.1Hz)；
13C?NMR(75MHz，CDCl
3)δ(ppm)172.2，158.8，145.3，135.4，134.4，130.9，130.4，130.1，129.6，122.5，121.0，119.3，116.1，114.5，112.6，86.5，68.9，63.6，55.0，52.1，23.8，23.0。
Claims (1)
1. the synthetic method of alpha-alkoxy base-beta-amino ester derivative, it is characterized in that: measure the acetic acid rhodium earlier: o-aminophenol: aldehyde: titan-alkoxide: diazonium compound=0.01:1.0:1.0:1.1:2.0 mol ratio, then with aldehyde, o-aminophenol, titan-alkoxide, acetic acid rhodium and dewatering agent are dissolved in the organic solvent, stir under the room temperature and made reaction system in 2～3 hours, with sampling pump the solution that diazonium compound is dissolved in the organic solvent composition is slowly injected above-mentioned reaction system, time control 1～3 hour, after sample introduction finishes, continue reaction 2～3 hours, dripping the saturated NaHCO3 aqueous solution then reacts in order to cancellation, vacuum rotary steam removes to desolvate and makes the alpha-alkoxy base-beta-amino ester derivative crude product with two chiral centres, crude product ethyl acetate: sherwood oil=1:50～1:20 is carried out column chromatography, obtain straight product;
Above-mentioned diazonium compound is the phenyl diazonium acetate, or the substituted-phenyl diazonium acetate;
Above-mentioned titan-alkoxide is a purity titanium tetraethoxide, or the four different third oxygen titaniums;
Above-mentioned aldehyde is phenyl aldehyde, o-chlorobenzaldehyde, m chlorobenzaldehyde, 4-chloro-benzaldehyde, aubepine, to cyanobenzaldehyde, paranitrobenzaldehyde, piperonylaldehyde, 1-naphthaldehyde or furfural;
Above-mentioned dewatering agent is
Molecular sieve, add-on adds 500mg for the 1mmol o-aminophenol
Molecular sieve;
Above-mentioned organic solvent is methylene dichloride, trichloromethane, toluene, 1,2-ethylene dichloride or dimethylbenzene.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906445A (en) * | 2010-06-18 | 2010-12-08 | 西南大学 | Synthesis method of 2H-1-benzopyran-2-ketone derivatives |
| CN103193662A (en) * | 2013-04-18 | 2013-07-10 | 北京科技大学 | Method for preparing Beta-amino ester through copper-catalyzed three-component coupling reaction |
| CN104803864A (en) * | 2014-01-29 | 2015-07-29 | 华东师范大学 | Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof |
| CN109896969A (en) * | 2019-02-11 | 2019-06-18 | 华东师范大学 | A kind of chiral alpha-quaternary carbon-alpha-hydroxyl-beta-aminoketone derivativess and its synthetic method |
-
2009
- 2009-04-13 CN CN200910049179A patent/CN101531606A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906445A (en) * | 2010-06-18 | 2010-12-08 | 西南大学 | Synthesis method of 2H-1-benzopyran-2-ketone derivatives |
| CN101906445B (en) * | 2010-06-18 | 2013-01-23 | 西南大学 | Synthesis method of 2H-1-benzopyran-2-ketone derivatives |
| CN103193662A (en) * | 2013-04-18 | 2013-07-10 | 北京科技大学 | Method for preparing Beta-amino ester through copper-catalyzed three-component coupling reaction |
| CN104803864A (en) * | 2014-01-29 | 2015-07-29 | 华东师范大学 | Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof |
| CN104803864B (en) * | 2014-01-29 | 2017-01-11 | 华东师范大学 | Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof |
| CN109896969A (en) * | 2019-02-11 | 2019-06-18 | 华东师范大学 | A kind of chiral alpha-quaternary carbon-alpha-hydroxyl-beta-aminoketone derivativess and its synthetic method |
| CN109896969B (en) * | 2019-02-11 | 2021-12-07 | 华东师范大学 | Chiral alpha-quaternary carbon-alpha-hydroxy-beta-aminoketone derivative and synthesis method thereof |
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