CN104109108A - Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof - Google Patents

Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof Download PDF

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CN104109108A
CN104109108A CN201310571906.4A CN201310571906A CN104109108A CN 104109108 A CN104109108 A CN 104109108A CN 201310571906 A CN201310571906 A CN 201310571906A CN 104109108 A CN104109108 A CN 104109108A
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alpha
quaternary carbon
imines
phenyl
diamines
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胡文浩
邱林
郭鑫
吕峰平
刘顺英
杨琍苹
吴翔
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East China Normal University
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East China Normal University
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Abstract

The invention discloses alpha-quaternary carbon contained alpha,beta-diamino acid derivatives and a cocatalytic preparation method and application thereof. The alpha-quaternary carbon contained alpha,beta-diamino acid derivatives comprise a threo-form alpha-quaternary carbon contained alpha,beta-diamino acid derivative as shown in a formula (I) and an erythro-form alpha-quaternary carbon contained alpha,beta-diamino acid derivative as shown in a formula (II). The alpha-quaternary carbon contained alpha,beta-diamino acid derivatives are synthesized by a reaction of three components consisting of aryl acetate diazonium, arylamine, and sulfamide imine under co-catalysis of rhodium acetate and squaric acid amide or metal magnesium salt. The raw materials used in the invention are low in cost and easily available, and two chiral carbons are constructed at the same time by using a one-pot method. The method is short in preparation route, simple to operate and mild in reaction condition; the catalysts are easy to synthesize; the method has high atomic economy and high yield, poses no environmental pollution and can conveniently prepare the threo-form or/and the erythro-form alpha-quaternary carbon contained alpha,beta-diamino acid derivative at the same time. Diversified compound frameworks are provided and can be used for novel medicine screening and pharmaceutical preparation technology.

Description

The α of alpha-position quaternary carbon, β-diamines acid derivative and altogether catalysis preparation method and application
Technical field
The invention belongs to medicine synthesising chemical technology field, relate to a kind of α of alpha-position quaternary carbon, β-diamines acid derivative and its preparation method and application.
Background technology
α, β-diamines acid derivative is the important skeleton structure that a class has special medicinal compound, at lymphoma medicine bleomycin (bleomycin), antitubercular agent capromycin (capreomycins), all has this type of skeleton structure in the structures such as Viothenate (viomycin).The α of alpha-position quaternary carbon, β-diamines acid derivative can be as the synthetic precursor (US2009156830A1) with the imidazoline heterocycle compound of anticancer and Anti-arthritic activity, for the synthesis of series of new Effective Anti cancer drug.
Disclosed α in recent years, the synthetic method of β-diamines acid derivative, for example, Chem.Rev.2005,105,3167., Org.Biomol.Chem., 2005,3,1362., J.Am.Chem.Soc., 2008,130,2170..Existing α, β-diamines acid derivative synthetic method is mostly by synthetic the obtaining of mannich reaction of glycinate and imines.But the greatest drawback of these class methods is the α that can only selectivity obtain cis-configuration, β-diamines acid derivative.In addition, cis-selectivity with the mannich reaction of glycinate and N-para toluene sulfonamide imines by efficient chiral catalyst regulates and controls, cis and trans optically active α have been obtained high enantioselectivity, β-diamines acid derivative (J.Am.Chem.Soc., 2008,130,14362).In existing synthetic method, the reaction suitability of substrate is very narrow, and being only confined to part material substrate can react, and catalyst levels is large, severe reaction conditions.Have document open take that diazonium compound, alcoxyl acid amides and imines be raw material three component reaction can a step build the α of the alpha-position quaternary carbon with two chiral centres, β-diamines acid derivative (J.Am.Chem.Soc., 2011,133,8428).But weak point is, in the three component products that build by this reaction, the aryl protection on nitrogen-atoms cannot effective elimination and further derive.
In sum, existing α, β-diamines acid derivative synthetic method exists the reaction suitability of substrate very narrow mostly, and being only confined to part material substrate can react, and catalyst levels is large, severe reaction conditions or be unfavorable for further derivative shortcoming.The invention provides the α of the alpha-position quaternary carbon of easy synthetic suitable, anti-configuration, the method for β-diamines acid derivative diastereomeric compound, blocking group is convenient to remove, and the bioactivity screening of compound and research are had very important significance.
Summary of the invention
The present invention proposes a kind of α of alpha-position quaternary carbon, β-diamines acid derivative, it comprises the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative, formula (II), β-diamines acid derivative;
Wherein,
Ar 1for phenyl, with the phenyl of substituted radical;
Ar 2for phenyl, with the phenyl of substituted radical;
Ar 3for phenyl, with the phenyl of substituted radical;
R is Ts or Ns, and wherein, Ts is p-toluenesulfonyl, and Ns is p-nitrophenyl alkylsulfonyl.
The present invention proposes a kind of α of alpha-position quaternary carbon, β-diamines acid derivative is the novel α containing sulfoamido, β-bis-amido acid compound, sulfoamido is extensively present in (Chem.Rev.2011,111, PR1 in a lot of bioactive molecule structures, J.Med.Chem.2007,50,5457), may there is positive meaning to the activity of compound.
Compared with prior art, the present invention adopts metal rhodium and the cheap sour acid amides in side or metal magnesium salts to be total to the α that catalytic one-stage is prepared alpha-position quaternary carbon, β-diamines acid derivative, reaction is efficient cheap, simple to operate, reaction conditions is gentle, has obtained good yield, and provide structure various α, β-diamines acid derivative.
The present invention also proposes that a kind of raw material is cheap and easy to get, syntheti c route is short, the α of simple to operate, free of contamination alpha-position quaternary carbon, the synthesis preparation method of β-diamines acid ester derivant.The present invention adopts sulphonamide imines as the 3rd component substrate, strengthens imines active, thereby effectively catch ammonium ylide by the sour acid amides in side or metal magnesium salts as co-catalyst, obtains α, β-diamines acid derivative.Thereby the alkylsulfonyl protecting group in the product that the present invention prepares is convenient to remove and is convenient to further derive, and bioactivity screening and research are had to extremely important meaning.To achieve these goals, method of the present invention is with diazonium compound, and arylamine and sulphonamide imines, under the common catalysis of acetic acid rhodium and the sour acid amides in side or metal magnesium salts, are realized the α of the synthetic alpha-position quaternary carbon of three component reaction, β-diamines acid derivative.The present invention adopts the α of the target product alpha-position quaternary carbon of three component reaction one steps acquisition alkylsulfonyl protections, β-diamines acid derivative.
The invention provides a kind of α of alpha-position quaternary carbon, the common catalysis preparation method of β-diamines acid derivative, diazonium compound, arylamine and sulphonamide imines, under the common catalysis of acetic acid rhodium, the sour acid amides in side or metal magnesium salts, are realized the α of the synthetic alpha-position quaternary carbon of three component reaction, β-diamines acid derivative; Wherein, the α of described alpha-position quaternary carbon, β-diamines acid derivative comprises the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative, formula (II), β-diamines acid derivative;
Wherein, Ar 1for phenyl, with the phenyl of substituted radical; Ar 2for phenyl, with the phenyl of substituted radical; Ar 3for phenyl, with the phenyl of substituted radical; R is p-toluenesulfonyl or p-nitrophenyl alkylsulfonyl.
Wherein, Ar 1for phenyl, with the phenyl of substituted radical; Ar 2for phenyl, with the phenyl of substituted radical; Ar 3for phenyl, with the phenyl of substituted radical; R is p-toluenesulfonyl or p-nitrophenyl alkylsulfonyl.
Described catalysis preparation method's reaction formula is altogether:
Wherein, Ar 1for phenyl, with the phenyl of substituted radical; Ar 2for phenyl, with the phenyl of substituted radical; Ar 3for phenyl, with the phenyl of substituted radical; Ts is p-toluenesulfonyl; Ns is p-nitrophenyl alkylsulfonyl.
Wherein, described sulphonamide imines is N-p-toluenesulfonyl phenyl imine; N-p-toluenesulfonyl rubigan imines; N-p-toluenesulfonyl is to bromophenyl imines; N-p-toluenesulfonyl p-nitrophenyl imines; N-p-toluenesulfonyl m-nitro base imines; N-p-toluenesulfonyl p-trifluoromethyl phenyl imines; N-p-toluenesulfonyl is to cyano-phenyl imines; N-p-toluenesulfonyl p-methylphenyl imines; N-p-nitrophenyl alkylsulfonyl is to bromophenyl imines, N-p-toluenesulfonyl m-nitro base imines.Described sulphonamide imines be by aromatic aldehyde and sulphonamide through dehydrating condensation prepare (refer to Synlett., 1994,493-494).
Wherein, described arylamine is aniline, Ortho-Chloro aniline, m-chloro aniline, p-Chlorobenzoic acid amide, o-bromoaniline, para-bromoaniline, adjacent Iodoaniline, ORTHO ANISIDINE.
Wherein, described diazonium compound is benzene diazonium methyl acetate, a bromophenyl diazoacetic acid methyl esters, and to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.Described diazonium compound be by corresponding ester and triazo-compound add alkali prepare (refer to J.Org.Chem., 1968,33, aryl ethyl diazoacetate 3610-3618).
Wherein, described side acid acid amides by the acid of raw material side is synthetic, obtain (consult J.Am.Chem.Soc., 2008,130,14416-14417).Described side acid acid amides is suc as formula shown in (III),
Wherein, R 1for p-trifluoromethyl phenyl, 3,5-bis-trifluoromethyls;
R 2for phenmethyl, cyclohexyl, the tertiary butyl.
Wherein, described metal magnesium salts is magnesium fluoride, trifluoromethanesulfonic acid magnesium.
Wherein, described sulphonamide imines: arylamines: the sour acid amides in side or metal magnesium salts: the mol ratio of acetic acid rhodium is 1.0:(1.5-2.5): (1.0-2.5): (0.05-0.2): (0.01-0.02).
Preferably, described sulphonamide imines: arylamines: the sour acid amides in side or metal magnesium salts: the mol ratio of acetic acid rhodium is 1.0:1.3:0.1:0.01.
Preparation method of the present invention comprises step: described sulphonamide imines, arylamines, the sour acid amides in side or metal magnesium salts, acetic acid rhodium and organic solvent are added in reaction flask, and wherein, the add-on of described organic solvent is 10-30ml/mmol sulphonamide imines; Then, described diazonium compound being dissolved in organic solvent and obtaining diazonium solution, wherein, is 10-30ml/mmol sulphonamide imines for dissolving the amount of the organic solvent of diazonium compound; Then at room temperature by peristaltic pump, diazonium solution is added drop-wise in reaction flask, stirring reaction, revolves to boil off to desolventize and obtains thick product; Through column chromatography, the α of alpha-position quaternary carbon shown in obtaining, β-diamines acid ester derivant.
Wherein, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
Wherein, for dissolving the organic solvent amount of aryl acetate diazonium, be 10-30ml/mmol.
Organic solvent and raw material aromatic aldehyde and the aromatic amine of preparing imines that the present invention is used, diazonium raw material Arylacetic acids methyl esters, triazo-compound, ethyl acetate, ethanol, all can buy in market.Toluene is before use through hydrolith processed, and other organic solvents all make in advance purifying before reaction and during column chromatography or distillation is processed.
The present invention first forms ammonium ylide with arylamine effect by nitranilide ester under the catalysis of Rh (II), sulphonamide imines by the sour acid amides in side or metal Louis catalytic activation catches this active intermediate again, thereby construct suc as formula (I) and target product α (II), β-bis-amido carboxylic acid ester derivative compound.
The invention allows for the α of alpha-position quaternary carbon, the application of β-diamines acid derivative in arrestin tyrosine phosphatase enzymic activity.The α of this alpha-position quaternary carbon, acid derivative comprises β-diamines: the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative and formula (II), β-diamines acid derivative.Experiment shows, the present invention includes the α of the alpha-position quaternary carbon of formula (I), formula (II), and the inhibitor that β-diamines acid derivative can be used as Protein-tyrosine-phosphatase activity is applied in field of medicaments.
Advantage of the present invention and beneficial effect comprise: raw material diazonium compound, imines, arylamine that the present invention is used, the sour acid amides in side or metal magnesium salts and organic solvent are cheap and easy to get, synthetic with low cost.Synthetic route of the present invention is simple, by the co-catalyst being easy to get, and a step establishing target product.The present invention has Atom economy, highly selective, and high yields etc., meet the requirement of Green Chemistry.The present invention can synthesize the α of alpha-position quaternary carbon quickly and easily, β-diamines acid derivative, and blocking group is convenient to remove, and is conducive to further derive, thereby multifarious compound skeleton is provided, and new medicament screen and pharmaceutical technology are had very important significance.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Do not deviating under the spirit and scope of inventive concept, variation and advantage that those skilled in the art can expect are all included in the present invention, and take appending claims as protection domain.Implement process of the present invention, condition, reagent, experimental technique etc., except the content of mentioning specially below, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention's one step has built two chiral carbon simultaneously and has prepared α, and the synthetic route of β-diamines acid derivative comprises:
First take arylamine: sulphonamide imines: the sour acid amides in side or metal magnesium salts: acetic acid rhodium=1.3:1.0:0.1:0.01 mol ratio, by arylamine, sulphonamide imines, the sour acid amides in side or metal magnesium salts, acetic acid rhodium and organic solvent, add in reaction flask, the add-on of organic solvent is 10-30ml/mmol group with imine moiety.
Then, aryl acetate diazonium being dissolved in organic solvent and obtaining diazonium solution, is 10-30ml/mmol for dissolving the amount of the organic solvent of diazonium.
Aryl acetate diazonium add-on is 1.5mmol/mmol group with imine moiety.
Then, under room temperature reaction condition, by peristaltic pump, diazonium solution is added drop-wise to reaction system, after within 4 hours, dropwising, continue stirs after 4 hours, 40-50 ℃ revolves to boil off and desolventizes, and obtains thick product.By thick product, by volume ratio, be column chromatography in the solution of ethyl acetate: sherwood oil=1:20～1:5, obtain the α of alpha-position quaternary carbon, β-diamines acid derivative sterling.
The α of synthetic product alpha-position quaternary carbon, β-diamines acid derivative is the α that comprises the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative and formula (II), the mixture of β-diamines acid derivative.
The α of the alpha-position quaternary carbon that preparation method of the present invention obtains, β-diamines acid derivative is a mixture, comprises formula (I) and formula (II), wherein, formula (I) is (15-50) with the proportional range of formula (II): (50-85).
Embodiment 1
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol), acetic acid rhodium (1.00mg, 0.002mmol); side sour acid amides IIIA (0.02mmmol); aniline (0.30mmol), puts into small test tube reactor by them, adds the 5.6ml methylene dichloride heavily steaming under room temperature.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product A.Yield 53%, dr is 50::50.
The sign of A:
1h NMR (400MHz, CDCl 3) δ 7.35-7.26 (m, 4H), 7.26-7.13 (m, 3H), 7.07 (m, 2H), 7.00-6.84 (m, 4H), 6.60 (m, 1H), 6.44 (d, J=8.5Hz, 2H), 6.20 (d, J=7.8Hz, 2H), 5.36 (d, J=9.1Hz, 1H), 5.15 (d, J=9.2Hz, 1H), 4.83 (s, 1H), 3.56 (s, 3H), 2.26 (s, 3H). 13c NMR (101MHz, CDCl 3) δ 170.47,143.21,142.52,135.81,133.21,132.76,129.87,129.20,128.38,128.32,127.70,127.47,127.02,125.91,121.41,117.71,114.55,69.38,61.96,51.74,20.40; ESCI-HRMS calculated value: C 29h 27brN 2naO 4s, [M+Na] +601.0767; Observed value: 601.0787.
Embodiment 2
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol), acetic acid rhodium (1.00mg, 0.002mmol); side sour acid amides IIIB (0.02mmmol); aniline (0.30mmol), puts into small test tube reactor by them, adds the 5.6ml methylene dichloride heavily steaming under room temperature.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product A.Yield 52%, dr is 50::50.
Embodiment 3
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol), acetic acid rhodium (1.00mg, 0.002mmol); side sour acid amides IIIC (0.02mmmol); aniline (0.30mmol), puts into small test tube reactor by them, adds the 5.6ml methylene dichloride heavily steaming under room temperature.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product A.Yield 50%, dr is 50::50.
Embodiment 4
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol), acetic acid rhodium (1.00mg, 0.002mmol); magnesium fluoride (0.02mmmol); aniline (0.30mmol), puts into small test tube reactor by them, adds the 5.6ml methylene dichloride heavily steaming under room temperature.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product A.Yield 55%, dr is 50::50.
Embodiment 5
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol), acetic acid rhodium (1.00mg, 0.002mmol); trifluoromethanesulfonic acid magnesium (0.02mmmol); aniline (0.30mmol), puts into small test tube reactor by them, adds the 5.6ml methylene dichloride heavily steaming under room temperature.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product A.Yield 50%, dr is 50::50.
Embodiment 6
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); Ortho-Chloro aniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product B.Yield 50%, dr is 69:31.
The sign of B:
1h NMR (400MHz, CDCl 3) δ 7.41 (d, J=7.2Hz, 2H), 7.36-7.19 (m, 6H), 7.16 (d, J=8.4Hz, 1H), 7.01-6.93 (m, 2H), 6.70 (d, J=7.3Hz, 2H), 6.63 (d, J=8.4Hz, 1H), 6.56 (dd, J=11.9, 4.4Hz, 2H), 5.92 (d, J=8.2Hz, 1H), 5.84 (d, J=9.3Hz, 1H), 5.52 (s, 1H), 5.18 (d, J=9.4Hz, 1H), 3.65 (s, 3H), 2.31 (s, 3H), (another isomer) 7.41 (d, J=7.2Hz, 2H), 7.36-7.19 (m, 6H), 7.16 (d, J=8.4Hz, 1H), 7.01-6.93 (m, 2H), 6.70 (d, J=7.3Hz, 2H), 6.63 (d, J=8.4Hz, 1H), 6.45 (d, J=8.3Hz, 1H), 6.18 (d, J=8.2Hz, 1H), 6.02 (s, 1H), 5.03 (d, J=10.9Hz, 1H), 3.54 (s, 3H), 2.30 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 171.46,143.34,140.49,136.93,134.12,131.15,130.05,129.25,129.13,128.72,128.54,128.35,127.07,126.90,126.72,122.59,120.73,118.66,115.18,70.17,63.83,53.00,21.41, ESCI-HRMS calculated value: C 29h 26brClN 2naO 4s[M+Na] +635.0377, observed value: 635.0358
Embodiment 7
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); m-chloro aniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product C.Yield 64%, dr is 64:36.
The sign of C: 1h NMR (400MHz, CDCl 3) δ 7.40-7.23 (m, 2H), 7.18 (d, J=3.1Hz, 2H), 7.07 (d, J=8.3Hz, 2H), 6.92 (dd, J=21.7, 8.1Hz, 3H), 6.77 (d, J=7.7Hz, 1H), 6.53 (d, J=7.9Hz, 1H), 6.43 (d, J=8.3Hz, 2H), 6.34 (d, J=8.3Hz, 2H), 6.21 (s, 1H), 5.98 (d, J=8.2Hz, 1H), 5.48 (d, J=9.8Hz, 1H), 5.10 (d, J=9.8Hz, 1H), 4.99 (s, 1H), 3.58 (s, 3H), 2.26 (s, 3H), (another isomer) 7.40-7.23 (m, 2H), 7.18 (d, J=3.1Hz, 2H), 7.07 (d, J=8.3Hz, 2H), 6.92 (dd, J=21.7, 8.1Hz, 3H), 6.77 (d, J=7.7Hz, 1H), 6.53 (d, J=7.9Hz, 1H), 6.43 (d, J=8.3Hz, 2H), 6.34 (d, J=8.3Hz, 2H), 6.21 (s, 1H), 5.98 (d, J=8.2Hz, 1H), 5.33 (s, 1H), 4.74 (d, J=11.0Hz, 1H), 3.49 (s, 3H), 2.24 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 171.14,145.52,145.34,143.72,136.70,136.55,134.92,134.31,134.27,133.98,133.63,133.08,131.01,130.80,130.29,130.13,129.65,129.42,129.35,129.31,128.65,128.40,128.24,128.12,127.03,126.94,122.58,122.16,118.86,118.55,116.39,115.58,114.19,113.26,70.34,70.12,65.22,63.08,52.91,52.71,21.43, ESCI-HRMS calculated value: C 29h 26brClN 2naO 4s, [M+Na] +635.0377, observed value: 635.0383
Embodiment 8
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); p-Chlorobenzoic acid amide (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product D.Yield 64%, dr is 51:49.
The sign of D: 1h NMR (400MHz, CDCl 3) δ 7.41-7.28 (m, 3H), 7.28-7.17 (m, 3H), 7.14 (d, J=8.4Hz, 2H), 7.01 (m, 3H), 6.93 (dd, J=13.4, 8.8Hz, 2H), 6.48 (d, J=8.4Hz, 2H), 6.19 (d, J=8.9Hz, 2H), 5.46 (d, J=9.6Hz, 1H), 5.18 (d, J=9.7Hz, 1H), 5.03 (s, 1H), 3.65 (s, 3H), 2.32 (s, 3H), (another isomer) δ 7.41-7.28 (m, 3H), 7.28-7.17 (m, 3H), 7.14 (d, J=8.4Hz, 2H), 7.01 (m, 3H), 6.93 (dd, J=13.4, 8.8Hz, 2H), 6.39 (dd, J=11.3, 8.7Hz, 4H), 6.05 (d, J=11.0Hz, 1H), 5.38 (s, 1H), 4.84 (d, J=11.0Hz, 1H), 3.55 (s, 1H), 2.31 (s, 1H), 13c NMR (101MHz, CDCl 3) δ 171.61,171.21,143.67,143.38,143.19,136.67,136.48,134.95,133.94,133.58,133.15,131.46,131.43,130.97,130.78,130.29,130.14,129.39,129.36,129.25,128.66,128.38,128.25,128.10,127.03,126.92,122.52,122.13,117.94,117.05,110.93,110.56,70.36,70.20,65.11,63.02,52.89,52.70,21.41, ESCI-HRMS calculated value: C 29h 26brClN 2naO 4s, [M+Na] +635.0377, observed value: 635.0376
Embodiment 9
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); o-bromoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product E.Yield 47%, dr is 71:29.
The sign of E: 1h NMR (400MHz, CDCl 3) δ 7.33 (d, J=8.0Hz, 3H), 7.24 (d, J=8.0Hz, 2H), 7.16 (d, J=7.6Hz, 3H), 7.08 (d, J=8.2Hz, 2H), 6.88 (d, J=8.0Hz, 2H), 6.66 (d, J=7.8Hz, 1H), 6.56 (d, J=8.2Hz, 2H), 6.42 (t, J=7.6Hz, 1H), 5.85-5.81 (m, 2H), 5.43 (s, 1H), 5.11 (d, J=9.3Hz, 1H), 3.58 (s, 3H), 2.23 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 171.47,143.32,141.49,136.96,134.34,134.04,132.47,131.14,130.13,129.23,128.69,128.52,128.37,127.37,126.92,122.57,119.18,115.33,111.41,70.38,63.88,53.02,21.41; ESCI-HRMS calculated value: C 29h 26br 2clN 2naO 4s, [M+Na] +678.9872; Observed value: 678.9850
Embodiment 10
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); para-bromoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product F.Yield 53%, dr is 51:49.
The sign of E: 1h NMR (400MHz, CDCl 3) δ 7.28 (dd, J=15.1, 7.9Hz, 2H), 7.15 (dd, J=20.1, 5.2Hz, 5H), 7.03 (d, J=8.2Hz, 1H), 6.97-6.77 (m, 5H), 6.32 (d, J=8.2Hz, 2H), 6.14 (d, J=8.4Hz, 2H), 5.35 (s, 1H), 5.11 (d, J=9.9Hz, 1H), 4.73 (d, J=11.1Hz, 1H), 3.46 (s, 3H), 2.22 (s, 3H) (another isomer) δ 7.28 (dd, J=15.1, 7.9Hz, 3H), 7.15 (dd, J=20.1, 5.2Hz, 6H), 6.96-6.78 (m, 4H), 6.39 (d, J=8.2Hz, 2H), 5.97 (d, J=8.6Hz, 2H), 5.68 (d, J=9.9Hz, 1H), 5.06 (s, 1H), 3.56 (s, 3H), 2.22 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 171.47,171.20,144.07,143.90,143.69,137.30,136.61,136.41,134.95,133.89,133.55,133.15,130.95,130.78,130.32,130.19,129.40,129.37,129.27,128.68,128.58,128.38,128.24,128.07,127.08,126.95,122.48,122.13,118.46,117.62,80.39,79.93,70.29,70.03,65.19,63.01,52.94,52.74,21.45.ESCI-HRMS calculated value: C 29h 26br 2clN 2o 4s, [M+Na] +678.9872, observed value: 678.9856
Embodiment 11
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product G.Yield 54%, dr is 82:18.
The sign of G:
1h NMR (400MHz, CDCl 3) δ 7.56 (d, J=7.8Hz), 7.35 (d, J=7.6Hz), 7.22 (t, J=7.8Hz), 7.20-7.11 (m), 7.06 (d, J=8.1Hz), 6.88 (d, J=8.0Hz), 6.71 (s), 6.57 (d, J=8.2Hz), 6.30 (s), 5.81 (d, J=8.5Hz), 5.22 (d, J=2.5Hz), 5.14 (d, J=9.1Hz), 3.59 (s), 2.23 (s); 13c NMR (101 MHz, CDCl 3) δ 171.52,143.82,143.30,139.23,137.02,134.50,133.93,131.13,130.28,129.21,128.65,128.49,128.39,128.28,126.92,122.54,120.04,114.81,87.30,70.77,63.79,53.06,21.41; ESCI-HRMS calculated value: C 29h 26brIN 2naO 4s, [M+Na] +726.9734; Observed value: 726.9707
Embodiment 12
Take N-p-toluenesulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); ORTHO ANISIDINE (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product H.Yield 43%, dr is 57:43.
The sign of H: 1h NMR (400MHz, CDCl 3) δ 7.38-7.20 (m, 3H), 7.20-7.08 (m, 2H), 7.04-6.97 (m, 2H), 6.87 (dd, J=14.1, 8.0Hz, 2H), 6.67 (dd, J=20.3, 8.0Hz, 1H), 6.53 (d, J=8.1Hz, 2H), 6.42 (d, J=7.9Hz, 2H), 5.97-5.85 (m, 1H), 5.78 (d, J=7.9Hz, 2H), 5.47 (s, 1H), 5.13 (d, J=8.8Hz, 1H), 3.74 (s, 3H), 3.53 (s, 3H), 2.23 (s, 3H), (another isomer) 7.38-7.20 (m, 3H), 7.20-7.08 (m, 2H), 7.04-6.97 (m, 2H), 6.87 (dd, J=14.1, 8.0Hz, 2H), 6.67 (dd, J=20.3, 8.0Hz, 1H), 6.53 (d, J=8.1Hz, 2H), 6.42 (d, J=7.9Hz, 2H), 5.97-5.85 (m, 1H), 5.78 (d, J=7.9Hz, 2H), 5.19 (s, 1H), 4.98 (d, J=10.5Hz, 1H), 3.81 (s, 3H), 3.42 (s, 3H), 2.22 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 171.88,171.84,147.93,147.49,143.33,143.24,136.99,136.88,135.36,134.93,134.56,134.22,134.15,134.01,130.80,130.73,130.37,130.33,129.21,129.15,128.88,128.80,128.32,128.14,127.03,126.98,122.24,122.06,120.41,120.36,118.21,117.88,114.94,113.78,109.86,109.67,70.18,64.44,63.41,55.86,55.76,52.79,52.64,21.42, ESCI-HRMS calculated value: C 30h 29brN 2naO 5s, [M+Na] +631.0873, observed value: 631.0878
Embodiment 13
Take N-p-nitrophenyl alkylsulfonyl to bromophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product I.Yield 48%, dr is 70:30.
The sign of I: 1h NMR (400MHz, CDCl 3) δ 7.97-7.89 (m, 2H), 7.55 (dd, J=7.8,1.4Hz, 1H), 7.51-7.43 (m, 2H), 7.38 (dd, J=7.8,1.6Hz, 2H), 7.16-7.23 (m, 5H), 6.84 (d, J=8.4Hz, 2H), 6.72-6.61 (m, 1H), 6.37 (s, 1H), 6.34-6.25 (m, 1H), 5.74 (dd, J=8.3,1.1Hz, 1H), 5.03 (d, J=4.5Hz, 1H), 4.91 (s, 1H), 3.61 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.89,148.50,144.79,142.59,138.19,134.14,133.12,130.73,129.21,127.77,127.72,127.15,126.93,126.85,122.82,122.36,119.42,114.31,86.75,69.55,63.95,52.17; ESCI-HRMS calculated value: C 28h 24brIN 3o 6s, [M+H] +735.9536; Observed value: 735.8245
Embodiment 14
Take N-p-toluenesulfonyl p-nitrophenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product J.Yield 70%, dr is 68:32.
The sign of J: 1h NMR (400MHz, CDCl 3) δ 7.79 (d, J=8.8Hz, 2H), 7.58 (dd, J=7.9, 1.4Hz, 1H), 7.36-7.29 (m, 2H), 7.29-7.22 (m, 3H), 7.22-7.14 (m, 3H), 6.92 (dd, J=8.2, 6.7Hz, 2H), 6.86 (d, J=8.1Hz, 1H), 6.73 (d, J=8.7Hz, 2H), 6.36 (d, J=7.7Hz, 1H), 5.97 (d, J=7.9Hz, 1H), 5.89-5.84 (m, 1H), 5.31 (d, J=7.8Hz, 1H), 5.19 (s, 1H), 3.62 (s, 3H), 2.21 (s, 3H), (another isomer) δ 7.79 (d, J=8.8Hz, 2H), 7.58 (dd, J=7.9, 1.4Hz, 1H), 7.36-7.29 (m, 2H), 7.29-7.22 (m, 3H), 7.22-7.14 (m, 3H), 6.92 (dd, J=8.2, 6.7Hz, 2H), 6.86 (d, J=8.1Hz, 1H), 6.73 (d, J=8.7Hz, 2H), 6.36 (d, J=7.7Hz, 1H), 6.06 (dd, J=8.3, 1.2Hz, 1H), 5.76 (s, 1H), 5.14 (d, J=10.6Hz, 1H), 3.50 (s, 3H), 2.16 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 170.37,146.50,142.66,142.39,141.61,138.34,135.79,133.56,128.70,128.31,127.79,127.55,127.25,126.03,125.93,121.87,119.53,113.68,86.68,69.78,62.04,52.30,20.34, ESCI-HRMS calculated value: C 29h 26iN 3naO 6s, [M+Na] +694.0479, observed value: 694.0474
Embodiment 15
Take N-p-toluenesulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product K.Yield 52%, dr is 76:24.
The sign of K: 1h NMR (400MHz, CDCl 3) δ 7.88 (dd, J=8.1,1.0Hz, 1H), 7.60-7.43 (m, 2H), 7.32 (d, J=7.2Hz, 2H), 7.29-7.19 (m, 3H), 7.13 (m, 4H), 6.91-6.69 (m, 3H), 6.38-6.29 (m, 1H), 6.13 (d, J=8.1Hz, 1H), 5.91 (dd, J=8.2,1.0Hz, 1H), 5.34 (d, J=8.1Hz, 1H), 5.25 (s, 1H), 3.64 (s, 3H), 2.16 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.32,146.51,142.48,142.38,138.33,136.18,135.78,133.91,133.47,128.31,127.85,127.74,127.56,127.49,127.37,125.89,122.54,121.96,119.40,113.53,86.58,69.70,61.76,52.38,20.25; ESCI-HRMS Calcd.for C 29h 26iN 3naO 6s, [M+Na] +694.0466; Observed value: 694.0463
Embodiment 16
Take N-p-toluenesulfonyl to cyano-phenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product L.Yield 52%, dr is 73:27.
The sign of L: 1h NMR (400MHz, CDCl 3) δ 7.57 (dd, J=7.9,1.3Hz, 1H), 7.35-7.29 (m, 2H), 7.22 (m, 9H), 6.91 (d, J=8.1Hz, 2H), 6.86 (d, J=8.3Hz, 2H), 6.73 (s, 1H), 6.33 (d, J=0.9Hz, 1H), 5.95 (t, J=8.6Hz, 1H), 5.84 (dd, J=8.3,1.1Hz, 1H), 5.26 (d, J=8.0Hz, 1H), 5.19 (s, 1H), 3.61 (s, 3H), 2.25 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.37,142.56,142.45,139.62,138.31,135.83,133.55,130.54,128.45,128.29,127.71,127.56,127.41,127.32,125.92,119.41,117.16,113.70,111.03,86.56,69.78,62.29,52.26,20.39; ESCI-HRMS calculated value: C 30h 26iN 3naO 4s, [M+Na] +674.0581; Observed value: 674.0563
Embodiment 17
Take N-p-toluenesulfonyl p-trifluoromethyl phenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product M.Yield 40%, dr is 71:29.
The sign of M: 1h NMR (400MHz, CDCl 3) δ 7.57 (dd, J=7.9,1.4Hz, 1H), 7.42-7.31 (m, 2H), 7.25-7.10 (m, 7H), 6.80 (dd, J=15.7,8.1Hz, 4H), 6.75-6.67 (m, 1H), 6.31 (td, J=7.8,1.3Hz, 1H), 5.90 (d, J=9.0Hz, 1H), 5.84 (dd, J=8.3,1.2Hz, 1H), 5.29 (d, J=9.0Hz, 1H), 5.27 (s, 1H), 3.62 (s, 3H), 2.17 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.44,142.61,142.31,138.26,137.91,135.87,133.50,128.13,128.07,127.59,127.56,127.46,127.35,125.88,123.78,123.75,119.13,113.66,86.38,69.72,62.34,52.18,20.14; ESCI-HRMS calculated value: C 30h 26f 3iN 2naO 4s, [M+Na] +717.0502; Observed value: 717.0472
Embodiment 18
Take N-p-toluenesulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking p-methylphenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product N.Yield 57%, dr is 80:20.
The sign of N: 1h NMR (400MHz, CDCl 3) δ 7.94-7.87 (m, 1H), 7.57 (dd, J=7.9, 1.4Hz, 1H), 7.49 (s, 1H), 7.26 (dd, J=8.2, 5.2Hz, 2H), 7.23-7.05 (m, 4H), 6.97 (d, J=8.2Hz, 2H), 6.87 (d, J=8.1Hz, 2H), 6.76 (dd, J=11.3, 4.1Hz, 1H), 6.33 (dd, J=11.9, 4.5Hz, 1H), 5.99 (d, J=7.7Hz, 1H), 5.93 (dd, J=8.3, 1.1Hz, 1H), 5.30 (d, J=7.7Hz, 1H), 5.19 (s, 1H), 3.63 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), (another isomer) 7.94-7.87 (m, 1H), 7.57 (dd, J=7.9, 1.4Hz, 1H), 7.49 (s, 1H), 7.26 (dd, J=8.2, 5.2Hz, 2H), 7.23-7.05 (m, 4H), 6.97 (d, J=8.2Hz, 2H), 6.87 (d, J=8.1Hz, 2H), 6.76 (dd, J=11.3, 4.1Hz, 1H), 6.33 (dd, J=11.9, 4.5Hz, 1H), 6.08 (dt, J=8.3, 4.1Hz, 1H), 5.83 (dd, J=18.3, 8.6Hz, 1H), 5.67 (s, 1H), 5.14 (t, J=8.6Hz, 1H), 3.50 (s, 3H), 2.26 (s, 3H), 2.14 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 170.45,146.55,142.47,142.40,138.31,137.73,136.40,135.88,133.98,130.44,128.31,128.26,127.82,127.50,127.14,126.00,125.87,122.56,121.97,119.38,113.55,86.62,69.55,61.77,52.31,20.27,20.02, ESCI-HRMS calculated value: C 30h 28iN 3naO 6s, [M+Na] +708.0636, observed value: 708.0627
Embodiment 19
Take N-p-toluenesulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking p-methoxyphenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product O.Yield 36%, dr is 77:23.
The sign of O: 1h NMR (400MHz, CDCl 3) δ 7.94-7.88 (m, 1H), 7.52 (m, 2H), 7.32-7.22 (m, 2H), 7.22-7.05 (m, 4H), 6.85 (t, J=19.6Hz, 3H), 6.74 (dd, J=33.1,8.7Hz, 3H), 6.38-6.31 (m, 1H), 5.93 (dd, J=8.3,1.2Hz, 1H), 5.26 (d, J=7.4Hz, 1H), 5.16 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 2.19 (s, 3H); (another isomer) 7.94-7.88 (m, 1H), 7.52 (m, 2H), 7.32-7.22 (m, 2H), 7.22-7.05 (m, 4H), 6.85 (t, J=19.6Hz, 3H), 6.74 (dd, J=33.1,8.7Hz, 3H), 6.38-6.31 (m, 1H), 6.10 (dd, J=8.3,1.3Hz, 1H), 5.90-5.86 (m, 1H), 5.64 (s, 1H), 3.73 (s, 3H), 3.52 (s, 3H), 2.15 (s, 3H);
13c NMR (101MHz, CDCl 3) δ 170.53,158.70,146.60,142.44,138.31,136.39,135.90,133.93,128.61,128.28,127.86,127.53,125.85,122.48,122.02,119.40,113.58,112.93,86.61,69.26,62.02,54.23,52.30,28.68,20.26; ESCI-HRMS calculated value: C 30h 28iN 3naO 7s, [M+Na] +724.0585; Observed value: 724.0562
Embodiment 20
Take N-p-toluenesulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Take bromophenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product P.Yield 55%, dr is 79:21.
The sign of P: 1h NMR (400MHz, CDCl 3) δ 7.96 (dd, J=8.1,1.1Hz, 1H), 7.66 (s, 1H), 7.57 (dd, J=7.9,1.3Hz, 1H), 7.35-7.22 (m, 6H), 7.22-7.09 (m, 2H), 6.91 (d, J=8.1Hz, 2H), 6.76 (dd, J=11.3,4.2Hz, 1H), 6.35 (td, J=7.8,1.2Hz, 1H), 6.08 (d, J=8.3Hz, 1H), 5.80 (dd, J=8.3,1.1Hz, 1H), 5.17 (d, J=8.3Hz, 1H), 5.12 (s, 1H), 3.64 (s, 3H), 2.21 (s, 3H); (another isomer) 7.96 (dd, J=8.1,1.1Hz, 1H), 7.66 (s, 1H), 7.57 (dd, J=7.9,1.3Hz, 1H), 7.35-7.22 (m, 6H), 7.22-7.09 (m, 2H), 6.91 (d, J=8.1Hz, 2H), 6.76 (dd, J=11.3,4.2Hz, 1H), 6.39 (t, J=5.7Hz, 1H), 5.98 (dt, J=14.9,7.5Hz, 1H), 5.85 (t, J=10.9Hz, 1H), 5.68 (s, 1H), 5.08 (d, J=10.5Hz, 1H), 3.50 (s, 3H), 2.15 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.10,146.77,142.65,142.13,138.42,136.21,135.59,133.70,132.81,130.70,130.62,129.00,128.39,128.22,127.51,125.98,125.82,122.38,122.34,122.19,119.66,113.60,86.60,69.18,62.39,52.50,20.34; ESCI-HRMS calculated value: C 29h 25brIN 3naO 6s, [M+Na] +771.9584; Observed value: 771.9581
Embodiment 21
Take N-p-nitrophenyl alkylsulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product Q.Yield 58%, dr is 80:20.
The sign of Q: 1h NMR (400MHz, CDCl 3) δ 8.04 (d, J=7.5Hz, 1H), 8.00-7.89 (m, 2H), 7.86 (s, 1H), 7.62-7.50 (m, 3H), 7.34 (t, J=7.4Hz, 2H), 7.21 (s, 2H), 7.18 (d, J=10.1Hz, 3H), 6.75-6.65 (m, 1H), 6.53 (s, 1H), 6.34 (td, J=7.8,1.3Hz, 1H), 5.81 (dd, J=8.3,1.1Hz, 1H), 5.18 (s, 1H), 4.87 (s, 1H), 3.64 (s, 3H); (another isomer) 8.04 (d, J=7.5Hz, 1H), 8.00-7.89 (m, 2H), 7.86 (s, 1H), 7.62-7.50 (m, 3H), 7.34 (t, J=7.4Hz, 2H), 7.21 (s, 2H), 7.18 (d, J=10.1Hz, 3H), 6.79 (s, 1H), 6.40 (s, 1H), 6.23 (s, 1H), 6.04 (dd, J=8.3,1.2Hz, 1H), 5.63 (s, 1H), 5.25-5.19 (m, 1H), 3.52 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.77,148.69,146.99,144.46,142.21,138.32,136.82,134.05,133.67,128.54,128.02,127.96,127.73,127.37,127.21,126.94,126.61,122.95,122.84,122.63,119.88,114.03,87.03,69.56,63.22,52.44; ESCI-HRMS calculated value: C 28h 23iN 4naO 8s, [M+Na] +725.0173; Observed value: 725.0152
Embodiment 22
Take N-p-nitrophenyl alkylsulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking p-methylphenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product R.Yield 52%, dr is 76:24.
The sign of R: 1h NMR (400MHz, CDCl 3) δ 7.96 (m, 1H), 7.66-7.47 (m, 4H), 7.44-7.29 (m, 2H), 7.20-7.08 (m, 4H), 6.94 (d, J=8.1Hz, 2H), 6.72 (dd, J=11.4,4.1Hz, 1H), 6.54 (s, 1H), 6.33 (td, J=7.8,1.3Hz, 1H), 5.80 (dd, J=8.3,1.1Hz, 1H), 5.13 (s, 1H), 4.83 (s, 1H), 3.62 (s, 3H), 2.21 (s, 3H); (another isomer) 7.96 (m, 1H), 7.66-7.47 (m, 4H), 7.44-7.29 (m, 2H), 7.20-7.08 (m, 4H), 6.94 (d, J=8.1Hz, 2H), 6.78 (dd, J=12.1,4.9Hz, 1H), 6.43-6.36 (m, 1H), 6.19 (s, 1H), 6.04 (dd, J=8.3,1.2Hz, 1H), 5.53 (s, 1H), 3.50 (s, 1H), 2.26 (s, 1H); 13c NMR (101MHz, CDCl 3) δ 170.86,148.60,146.99,144.44,142.32,138.26,138.11,137.03,135.87,133.69,130.95,128.59,128.55,127.95,127.34,127.22,127.09,126.99,126.40,122.85,122.81,119.76,114.05,86.99,69.37,63.30,52.35,19.93; ESCI-HRMS calculated value: C 29h 26iN 4o 8s, [M+H] +717.0438; Observed value: 717.0324
Embodiment 23
Take N-p-nitrophenyl alkylsulfonyl m-nitro base imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); adjacent Iodoaniline (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking a bromophenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product S.Yield 54%, dr is 85:15.
The sign of S: 1h NMR (400MHz, CDCl 3) δ 8.17-8.03 (m, 1H), 8.03-7.87 (m, 3H), 7.68-7.48 (m, 4H), 7.45-7.31 (m, 3H), 7.31-7.24 (m, 1H), 7.19 (s, 1H), 7.01 (t, J=8.0Hz, 1H), 6.72 (d, J=7.1Hz, 1H), 6.59 (s, 1H) 6.35 (td, J=7.7,1.3Hz, 1H), 5.70 (dd, J=8.3,1.2Hz, 1H), 5.06 (s, 1H), 4.80 (s, 1H), 3.63 (s, 3H); 13c NMR (101MHz, CDCl 3) δ 170.36,148.80,147.15,144.22,141.96,138.38,136.59,136.53,133.43,131.08,129.83,129.40,128.90,127.41,126.82,125.18,123.17,123.08,122.48,122.17,120.08,114.12,86.92,68.98,63.93,52.61,52.36; ESCI-HRMS calculated value: C 28h 23iN 4o 8s, [M+H] +780.9386; Observed value: 780.8243
Embodiment 24
Take N-p-toluenesulfonyl p-methylphenyl imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); p-Chlorobenzoic acid amide (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product T.Yield 15%, dr is 69:31.
The sign of T: 1h NMR (400MHz, CDCl 3) δ 7.26 (dd, J=17.0, 8.2Hz, 4H), 7.20-7.10 (m, 3H), 6.93-6.87 (m, 2H), 6.87-6.80 (m, 4H), 6.65 (d, J=7.9Hz, 1H), 6.36 (d, J=8.0Hz, 2H), 6.29 (d, J=8.9Hz, 2H), 5.76 (d, J=10.9Hz, 1H), 5.28 (s, 1H), 4.80 (d, J=10.9Hz, 1H), 3.48 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H), (another isomer) 7.26 (dd, J=17.0, 8.2Hz, 3H), 7.20-7.10 (m, 3H), 6.93-6.87 (m, 2H), 6.87-6.80 (m, 3H), 6.78 (d, J=7.9Hz, 2H), 6.44 (d, J=8.1Hz, 2H), 6.11 (d, J=8.9Hz, 2H), 5.25 (s, 1H), 5.05 (s, 1H), 5.04 (d, J=8.3Hz, 1H), 3.57 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 170.75,142.24,141.99,136.77,135.96,135.72,134.26,130.55,128.59,128.18,128.02,127.85,127.52,127.41,127.36,127.31,127.03,126.88,126.04,125.86,122.43,116.28,115.40,69.31,64.02,51.58,20.31,19.93, ESCI-HRMS calculated value: C 30h 32clN 2naO 7s, [M+Na] +571.1552, observed value: 571.1423
Embodiment 25
Take N-p-toluenesulfonyl rubigan imines (0.20mmol); acetic acid rhodium (1.00mg; 0.002mmol); side sour acid amides IIIA (0.02mmmol); p-Chlorobenzoic acid amide (0.30mmol); they are put into small test tube reactor, under room temperature, add the 5.6ml methylene dichloride heavily steaming.Taking phenyl diazoacetic acid methyl esters (0.26mmol) is dissolved in the methylene dichloride that 2.8ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, after injection, continue stirring at normal temperature after 2 hours, filter, filtrate is revolved to boil off in 40 ℃ and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1:20～1:5) isolate the α that obtains alpha-position quaternary carbon, β-diamines acid derivative straight product U.Yield 40%, dr is 55:45.
The sign of U: 1h NMR (400MHz, CDCl 3) δ 7.25 (t, J=7.1Hz, 4H), 7.22-7.10 (m, 3H), 6.92 (dd, J=8.2, 6.2Hz, 2H), 6.89-6.81 (m, 4H), 6.79 (d, J=8.5Hz, 1H), 6.40 (d, J=8.5Hz, 2H), 6.34-6.26 (m, 2H), 5.42 (d, J=9.7Hz, 1H), 5.31 (s, 1H), 5.12 (d, J=9.7Hz, 1H), 4.77 (d, J=11.0Hz, 1H), 3.48 (s, 3H), 2.22 (s, 3H), (another isomer) 7.25 (t, J=7.1Hz, 3H), 7.22-7.10 (m, 3H), 6.92 (dd, J=8.2, 6.2Hz, 2H), 6.89-6.81 (m, 4H), 6.79 (d, J=8.5Hz, 1H), 6.48 (d, J=8.5Hz, 2H), 6.16-6.08 (m, 2H), 5.42 (d, J=9.7Hz, 1H), 5.12 (d, J=9.7Hz, 1H), 4.98 (s, 1H), 3.57 (s, 3H), 2.24 (s, 3H), 13c NMR (101MHz, CDCl 3) δ 170.65,142.59,141.90,135.69,135.52,134.03,133.33,132.95,132.47,132.12,128.93,128.79,128.38,128.32,128.20,127.65,127.59,127.55,127.51,127.33,127.20,127.06,126.99,126.79,126.01,125.89,116.48,115.58,69.32,61.95,51.64,20.32, ESCI-HRMS calculated value: C 29h 26c12N 2naO 4s, [M+Na] +591.0883, observed value: 591.0885
The α of embodiment 25 alpha-position quaternary carbon of the present invention, the inhibition biological activity test used screening model of β-diamines acid derivative to Protein-tyrosine-phosphatase activity:
Title: PTP1B
Another name: PTPN1
English full name: protein tyrosine phosphatase1B
Chinese full name: Protein-tyrosine-phosphatase PTP1B
Brief introduction: PTP1B is first certified protein-tyrosine-phosphatase (protein tyrosine phosphatase); the experiment on mice of rejecting by PTP1B shows; PTP1B passes through the dephosphorization acidylate to insulin receptor, and then plays very important effect in regulating insulin sensitivity and metabolism of fat process.Thereby, optionally, highly active PTP1B inhibitor has important value in the treatment of diabetes and obesity.
Screening method:
Protocol?id：25
Protocol?name：PTP1B?activity?assay，absorbance
Instrument:
VERSAmax(Molecular?Devices，USA).
Material: PTP1B, this laboratory applications escherichia expression system obtains gst fusion protein
Substrate, pnPP.
Process: adopt photoabsorption detection method, detect enzymic activity in the flat transparent microwell plate in 96 holes or 384 holes.The free product that substrate pNPP obtains through PTP1B hydrolysis has very strong photoabsorption at 405nm place.The variation of monitoring 405nm place optical absorption intensity by microplate reader, calculates initial velocity of reaction.The control compound adopting in experiment is Na3V04.
Sample preparation: sample dissolves with DMSO, cryopreservation, within the concentration of DMSO in final system is controlled at the scope that does not affect detection of active.
Data processing and presentation of results:
Primary dcreening operation is selected under single concentration conditions, and for example 20 μ g/ml, test the activity of sample.For showing active sample under certain condition, for example inhibiting rate %Inhibition is greater than 50, test agents amount dependence, it is IC50/EC50 value, by sample activity, sample concentration is carried out Nonlinear Quasi and obtained, calculating software used is Graphpad Prism4, and the model that matching is used is sigmoidaldose-response (varible slope), for most of inhibitor screening models, matched curve bottom and top are set as to 0 and 100.Generally, each sample all arranges multiple hole (n >=2) in test, in result, with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE), represents.Activated result is all listed as with * and is marked in activity.Each test all has the compound of having reported as reference.
The inhibition of reference compound to Protein-tyrosine-phosphatase activity, sees the following form 1.
Table 1
The α of alpha-position quaternary carbon of the present invention, the inhibition of β-diamines acid derivative to Protein-tyrosine-phosphatase activity, sees the following form 2.
Table 2
ID Sample number into spectrum Protocolid Concentration Type Unit Result Error Remarks
1 A 25 20μg/mL IC50 μg/mL 1.31 0.62 ?
2 B 25 20μg/mL IC50 μg/mL 0.89 0.51 ?
3 C 25 20μg/mL IC50 μg/mL 1.42 0.88 ?
4 D 25 20μg/mL IC50 μg/mL 5.89 0.65 ?
5 E 25 20μg/mL IC50 μg/mL 6.56 0.51 ?
6 F 25 20μg/mL IC50 μg/mL 9.31 0.84 ?
7 G 25 20μg/mL IC50 μg/mL 1.54 0.49 ?
[0171]?
8 H 25 20μg/mL IC50 μg/mL 8.56 1.12 ?
9 I 25 20μg/mL IC50 μg/mL 10.04 7.01 ?
10 J 25 20μg/mL IC50 μg/mL 0.92 0.18 ?
11 K 25 20μg/mL IC50 μg/mL 2.76 0.93 ?
12 L 25 20μg/mL IC50 μg/mL 2.20 0.21 ?
13 M 25 20μg/mL IC50 μg/mL 9.01 2.31 ?
14 N 25 20μg/mL IC50 μg/mL 8.18 1.21 ?
15 O 25 20μg/mL IC50 μg/mL 3.26 1.81 ?
16 P 25 20μg/mL IC50 μg/mL 11.91 2.31 ?
17 Q 25 20μg/mL IC50 μg/mL 3.41 0.51 ?
18 R 25 20μg/mL IC50 μg/mL 3.62 0.91 ?
19 S 25 20μg/mL IC50 μg/mL 10.01 2.01 ?
20 T 25 20μg/mL IC50 μg/mL 10.72 2.75 ?
21 U 25 20μg/mL IC50 μg/mL 1.70 0.51 ?
Above-mentioned showing, with reference compound contrast, the α of alpha-position quaternary carbon of the present invention, β-diamines acid derivative A～U all shows the significantly good inhibition to PTP1B, can be used as effective histone tyrosine-phosphatase inhibitor and is applied to field of medicaments.

Claims (10)

1. a α for alpha-position quaternary carbon, β-diamines acid derivative, is characterized in that, it comprises the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative, formula (II), β-diamines acid derivative;
Wherein,
Ar 1for phenyl, with the phenyl of substituted radical;
Ar 2for phenyl, with the phenyl of substituted radical;
Ar 3for phenyl, with the phenyl of substituted radical;
R is Ts or Ns, and wherein, Ts is p-toluenesulfonyl, and Ns is p-nitrophenyl alkylsulfonyl.
2. the α of alpha-position quaternary carbon, the common catalysis preparation method of β-diamines acid derivative, the α of described alpha-position quaternary carbon, β-diamines acid derivative comprises the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative and formula (II), β-diamines acid derivative, it is characterized in that, aryl acetate diazonium, arylamine and sulphonamide imines are under the common catalysis of acetic acid rhodium, the sour acid amides in side or metal magnesium salts, realize the α of the synthetic alpha-position quaternary carbon of three component reaction, β-diamines acid derivative; Described catalysis preparation method's reaction formula is altogether:
Wherein,
Ar 1for phenyl, with the phenyl of substituted radical;
Ar 2for phenyl, with the phenyl of substituted radical;
Ar 3for phenyl, with the phenyl of substituted radical;
R is Ts or Ns, and wherein, Ts is p-toluenesulfonyl, and Ns is p-nitrophenyl alkylsulfonyl.
3. the common catalysis preparation method as shown in claim 2, is characterized in that,
Described sulphonamide imines is N-p-toluenesulfonyl phenyl imine, N-p-toluenesulfonyl rubigan imines, N-p-toluenesulfonyl is to bromophenyl imines, N-p-toluenesulfonyl p-nitrophenyl imines, N-p-toluenesulfonyl m-nitro base imines, N-p-toluenesulfonyl p-trifluoromethyl phenyl imines, N-p-toluenesulfonyl is to cyano-phenyl imines, N-p-toluenesulfonyl p-methylphenyl imines, N-p-nitrophenyl alkylsulfonyl is to bromophenyl imines, N-p-toluenesulfonyl m-nitro base imines;
Described arylamine is aniline, Ortho-Chloro aniline, m-chloro aniline, p-Chlorobenzoic acid amide, o-bromoaniline, para-bromoaniline, adjacent Iodoaniline, ORTHO ANISIDINE;
Described aryl acetate diazonium is benzene diazonium methyl acetate, a bromophenyl diazoacetic acid methyl esters, and to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.
4. the common catalysis preparation method as shown in claim 2, is characterized in that, described side acid acid amides is suc as formula shown in (III),
Wherein, R 1for p-trifluoromethyl phenyl, 3,5-bis-trifluoromethyls; R 2for phenmethyl, cyclohexyl, the tertiary butyl.
5. the common catalysis preparation method as shown in claim 2, is characterized in that, described metal magnesium salts is magnesium fluoride, trifluoromethanesulfonic acid magnesium.
6. the common catalysis preparation method as shown in claim 2, it is characterized in that described sulphonamide imines: arylamine: aryl acetate diazonium: the sour acid amides in side or metal magnesium salts: the mol ratio of acetic acid rhodium is 1.0:(1.5-2.5): (1.0-2.5): (0.05-0.2): (0.01-0.02).
7. the common catalysis preparation method as shown in claim 2, is characterized in that, described sulphonamide imines: arylamines: the sour acid amides in side or metal magnesium salts: the mol ratio of acetic acid rhodium is 1.0:1.3:0.1:0.01.
8. the common catalysis preparation method as shown in claim 2, it is characterized in that, comprise step: described sulphonamide imines, arylamines, the sour acid amides in side or metal magnesium salts, acetic acid rhodium and organic solvent are added in reaction flask, and wherein, the add-on of described organic solvent is 10-30ml/mmol; Then, described diazonium compound being dissolved in organic solvent and obtaining diazonium solution, wherein, is 10-30ml/mmol sulphonamide imines for dissolving the amount of the organic solvent of diazonium compound; Then at room temperature by peristaltic pump, diazonium solution is added drop-wise in reaction flask, stirring reaction, revolves to boil off to desolventize and obtains thick product; Through column chromatography, obtain the α of institute's moat alpha-position quaternary carbon, β-diamines acid ester derivant.
9. the common catalysis preparation method as shown in claim 8, is characterized in that, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
10. the α of alpha-position quaternary carbon as claimed in claim 1, the application of β-diamines acid derivative in arrestin tyrosine phosphatase enzymic activity, wherein, the α of described alpha-position quaternary carbon, β-diamines acid derivative comprises the α of the Soviet Union's formula alpha-position quaternary carbon shown in formula (I), the α of the erythro form alpha-position quaternary carbon shown in β-diamines acid derivative and formula (II), β-diamines acid derivative.
CN201310571906.4A 2013-04-17 2013-11-15 Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof Pending CN104109108A (en)

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