CN104910034A - Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof - Google Patents

Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof Download PDF

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CN104910034A
CN104910034A CN201410091014.9A CN201410091014A CN104910034A CN 104910034 A CN104910034 A CN 104910034A CN 201410091014 A CN201410091014 A CN 201410091014A CN 104910034 A CN104910034 A CN 104910034A
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phenyl
preparation
alpha
organic solvent
acid derivative
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胡文浩
郑庆
江俊
刘顺英
马晓初
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East China Normal University
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East China Normal University
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Abstract

The invention discloses a preparation method of an alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon. The preparation method comprises the following steps: dissolving aromatic aldehyde, arylamine, chiral phosphoric acid, p-cymene ruthenium dichloride dimer and a 4A molecular sieve in an organic solvent, adding an organic solvent of a diazo-compound, reacting at the temperature of minus 10 DEG C- minus 20 DEG C, and carrying out rotary evaporateion to obtain the alpha, beta-diamino acid derivative of alpha-quaternary carbon. Raw materials of the derivative are simple and easily available. The preparation method is simple and safe to operate, has advantages of high atom economy, high yield and high selectivity, and is of great significance for the screening and pharmaceutical preparation technology of a new drug.

Description

There is the α of optically active alpha-position quaternary carbon, β-diamines acid derivative and its preparation method and application
Technical field
The invention belongs to synthesis chemical technology field, be specifically related to a kind of α of alpha-position quaternary carbon, β-diamines acid derivative and its preparation method and application.
Background technology
There is optically active 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 synthetic method of a series of α, the β of development in recent years-diamines acid derivative is mutually supplemented and improves (Chem.Rev.2005,105,3167., Org.Biom0l.Chem., 2005,3,1362., J.Am.Chem.Soc., 2008,130,2170.).Existing α, β-diamines acid derivative synthetic method is obtained by the mannich Reactive Synthesis of glycinate and imines mostly.
Recently, synthesizing this class formation is regulated and controled by the cis-selectivity of efficient chiral catalyst with the mannich reaction of glycinate and N-para toluene sulfonamide imines, obtain cis and trans optically active α high enantioselectivity, β-diamines acid derivative (J.Am.Chem.Soc., 2008,130,14362).But at present for the α of optical activity alpha-position quaternary carbon, the synthesis pertinent literature report of β-diamines acid derivative seldom (Chem.Soc.Rev., 2009,38,1940.).
US2009156830A1 discloses a kind of with diazonium compound, phosphoramidate and keto ester imines be raw material three components reaction, a step builds optically active α, β-two method of amido diacid derivative with two chiral centres.But the substrate amine of above-mentioned patent is phosphoramidate, for the result that arylamine does not obtain.The substrate of imines mainly keto ester and P-nethoxyaniline is prepared and obtains, and the scope of substrate compares limitation, and imines is prior preparative separation and obtains, and the efficiency of reaction is low, less economical.Final product in patent is the dicarboxylic acid derivatives of α, β-diamino.
The invention provides a kind of α of new optical purity alpha-position quaternary carbon, β-diamines monocarboxylic acid derivative compound and simple synthesis thereof, prepare the final product different from US2009156830A1, the bioactivity screening of each enantiomeric compounds and research have been had very important significance.Raw material in the present invention adopts commercially available arylamine and aromatic aldehyde product, and without the need to carrying out the operation of synthesizing imine product, the step of synthesis is easier, and efficiency is higher, and economy is better.
Summary of the invention
The object of the invention is to propose a kind of raw material cheap and easy to get, simple to operate, the α of the optical activity alpha-position quaternary carbon of high yield, the synthesis technique of β-diamines acid derivative.
To achieve these goals, method of the present invention is with diazonium compound, arylamine and aromatic aldehyde, under the common catalysis of Paracymene ruthenous chloride dimer and chiral phosphoric acid, realize the α of the optically active alpha-position quaternary carbon of high enantioselective synthesis, β-diamines acid derivative.The present invention adopts three components to react a step and obtains the α with optically active alpha-position quaternary carbon, and β-diamines acid derivative, as shown in following structural formula (I I).
R in formula 1for aryl (to bromophenyl, o-bromophenyl, asks bromophenyl, rubigan, asks chloro-phenyl-or Chloro-O-Phenyl for phenyl, p-nitrophenyl), methyl etc.;
R 2for methyl, ethyl etc.;
R 3for phenyl, 2,5-Dimethoxyphenyl etc.;
R 4for to bromophenyl, p-trifluoromethyl phenyl, rubigan, phenyl, 2-furyl etc.
The α of the alpha-position quaternary carbon that the present invention proposes, the preparation method of β-diamines acid derivative, with diazonium, arylamine, aromatic aldehyde is raw material, Paracymene ruthenous chloride dimer, and chiral phosphoric acid is catalyzer, molecular sieve is that water-retaining agent carries out a step asymmetry catalysis, obtains the α of single alpha-position quaternary carbon, β-diamines acid derivative with the chiral phosphoric acid energy catalyzed reaction highly selective that triphen is silica-based.Its process is, described aromatic aldehyde, arylamine, chiral phosphoric acid, Paracymene ruthenous chloride dimer, 4A molecular sieve are dissolved in described organic solvent, add the organic solvent solution of described diazonium compound, reaction at-10 DEG C ~-20 DEG C also obtains the α of described alpha-position quaternary carbon through revolving to steam, β-diamines acid derivative, shown in following reaction formula (1):
The reaction scheme of preparation method of the present invention, as follows:
Above-mentioned diazonium adds alkali by corresponding ester and triazo-compound and prepares the diazonium compounds such as (referring to J.Org.Chem., 1968,33,3610-3618) aryldiazonium ethyl acetate, benzyl ethyl diazoacetate, methyl ethyl diazoacetate.
The above-mentioned organic solvent amount for dissolving diazonium compound is 20 ~ 30ml/mmol aromatic aldehyde compound.
Above-mentioned chiral phosphoric acid structure chiral phosphoric acid structure is such as formula shown in (I), and the Ar in formula is that triphenyl is silica-based, phenyl, p-methylphenyl, p-methoxyphenyl, to fluorophenyl, and 3,5-difluorophenyl, to fluoroform phenyl, 3,5-bis-trifluorophenyl or 9-phenanthryl etc.
Chiral phosphoric acid is obtained (referring to J.Am.Chem.Soc., 2006,128,84-86) by the synthesis of raw material (S)-1,1 '-binaphthol.
In preparation method of the present invention, described arylamine: aromatic aldehyde: chiral phosphoric acid: Paracymene ruthenous chloride dimer mol ratio=1.0:1.0:0.05:0.01; The add-on of water-retaining agent 4A molecular sieve is 1 ~ 2g/mmol aromatic aldehyde, and the add-on of organic solvent is 20 ~ 30ml/mmol aromatic aldehyde.
In preparation method of the present invention, the preparation method of the organic solvent solution of described diazonium compound is: take diazonium in molar ratio=1.1:1.0: arylamine, is dissolved in described organic solvent, obtains the organic solvent solution of diazoamino solution and described diazonium compound.The consumption of described organic solvent is 20 ~ 30ml/mmol aromatic aldehyde.
In preparation method of the present invention, be obtained by reacting the α of described alpha-position quaternary carbon, β-diamines acid derivative is through ethyl acetate: sherwood oil is with volume ratio=1:50 ~ 1:20 column chromatography.
In preparation method of the present invention, described organic solvent comprises chloroparaffin, toluene or dimethylbenzene.
The organic solvent that the present invention is used, aromatic aldehyde and aromatic amine, diazonium starting aryl methyl acetate, 2-methyl-acetoacetic ester and triazo-compound, chiral phosphoric acid raw material (S)-1,1 '-binaphthol, ethyl acetate all can be buied in market.
In the present invention, toluene is before use through hydrolith processed, and other organic solvents process with making purifying during column chromatography all in advance or distilling before the reaction.
The invention allows for the α with optically active alpha-position quaternary carbon, the β-application of diamines acid derivative in the medicine preparing Tumor suppression.Particularly, described medicine is used as XBP1 and shears inhibitor.
The present invention has the following advantages:
Raw material diazonium compound, aromatic aldehyde, arylamine and organic solvent used of the present invention are cheap and easy to get, and therefore the present invention synthesizes α, β-diamines acid ester derivant with low cost.
Prioritizing selection Paracymene ruthenous chloride dimer of the present invention, as metal catalyst, can obtain higher yield, ee value relative to rhodium acetate, allyl palladium chloride.
Synthetic route of the present invention is simple, a step establishing target product.
The present invention has Atom economy, highly selective, high yield etc., meets the requirement of Green Chemistry.
The present invention can the α of the alpha-position quaternary carbon of synthesis of optically active quickly and easily, and β-diamines acid derivative, provides multifarious compound scaffold, has very important significance to new medicament screen and pharmaceutical technology.
Embodiment
In conjunction with following specific embodiment, the present invention is described in further detail.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention's synthesis has the α of optically active alpha-position quaternary carbon, and the reaction equation of β-diamines acid derivative is:
Preparation method of the present invention is as follows:
First take amine in molar ratio: aldehyde: chiral phosphoric acid: Paracymene ruthenous chloride dimer=1.0:1.0:0.05:0.01, the amine adding successively and weigh up in advance is added in the round-bottomed flask of drying in advance, aldehyde, chiral phosphoric acid catalyzer, Paracymene ruthenous chloride dimer and water-retaining agent molecular sieve, water-retaining agent the add-on of molecular sieve is 1-2g/mmol aldehyde, at room temperature in round-bottomed flask, adds organic solvent, and the amount of organic solvent is 20-30ml/mmol aldehyde, round-bottomed flask is at room temperature stirred 1h, low-temp reaction bath at putting into-10 DEG C again stirs 1h. then, take diazonium in molar ratio: amine=1.1:1.0, by diazonium, amine puts into a bottle, with in organic solvent dissolution, be 20-30ml/mmol aldehyde for dissolving the amount of the organic solvent of diazoamino, stir and obtain diazoamino solution, by in diazoamino solution inhalation syringe, then by peristaltic pump, diazoamino solution is slowly added drop-wise in reaction flask, within 2 hours, dropwise, continue at-10 DEG C, stir TLC after 1 hour to monitor to reacting end, solids removed by filtration impurity, revolve to boil off in 40 DEG C of-50 DEG C of vacuum and desolventize, obtain thick product, be ethyl acetate by thick product volume ratio: the developping agent of sherwood oil=1:50 ~ 1:20 carries out column chromatography, obtains the α with optically active alpha-position quaternary carbon, β-diamines acid derivative sterling.
Embodiment 1
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0.00lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmo1) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mmo1) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take phenyldiazonium methyl acetate (19.4mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product A again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 82%, d.r. value >20: 1, ee value 96%.
1H NMR(400MHz，CDC13)δ7.47(d，J=3.8Hz，2H)，7.33-7.26(6H)，6.96(d，J=8.1Hz，2H)，6.710(d，J=8.6Hz，1H)，6.58(d，J=8.1Hz，1H)，6.14-6.08(3H)，5.95(s，1H)，5.80(s，1H)，5.70(d，J=10.1Hz，1H)，5.32(d，J=10.1Hz，1H)，3.84(s，3H)，3.76-3.54(m，9H)，3.33(s，3H).
13C NMR(101MHz，CDC1 3)δ172.12，154.50，153.70，142.22，141.99，137.21，136.95，136.52，135.61，131.08，130.39，128.65，128.29，127.93，122.04，110.90，110.29，101.62，101.43，99.38，99.21，70.41，63.46，56.53，56.12，55.38，54.95，52.70.
Embodiment 2
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, 4-chloro-benzaldehyde (14.1mg, 0.1mmol) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take phenyldiazonium methyl acetate (19.4mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product B again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 85%, d.r. value >20: 1, ee value 96%.
1H NMR(400MHz，CDC1 3)δ7.47(d，J=3.8Hz，2H)，7.40-7.23(m，4H)，7.17(d，J=8.0Hz，2H)，7.02(d，J=8.0Hz，2H)，6.70(d，J=8.6Hz，1H)，6.58(d，J=8.2Hz，1H)，6.15-6.08(t，J=13.2Hz，3H)，5.95(s，1H)，5.80(s，1H)，5.70(d，J=10.0Hz，1H)，5.33(d，J=10.1Hz，1H)，3.84(s，3H)，3.77-3.54(m，9H)，3.34(s，3H).
13C NMR(101MHz，CDC1 3)δ172.14，154.50，153.71，142.22，141.99，137.23，136.54，136.40，135.63，133.78，130.04，128.66，128.28，128.15，127.93，110.91，110.29，101.61，101.42，99.38，99.21，70.47，63.42，56.53，56.13，55.38，54.95，52.69.
Embodiment 3
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () 1mmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, p-trifluoromethyl benzaldehyde (17.4mg, 0.1mmol) molecular sieve (1 () () mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take phenyldiazonium methyl acetate (19.4mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product C again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 91%, d.r. value >20: 1, ee value 95%.
1H NMR(400MHz，CDC1 3)δ7.46(d，J=7.2Hz，4H)，7.29(s，3H)，7.21(d，J=7.9Hz，2H)，6.70(d，J=8.7Hz，1H)，6.59(d，J=8.3Hz，1H)，6.16-6.09(m，3H)，5.95(s，1H)，5.82(s，1H)，5.76(d，J=10.1Hz，1H)，5.43(d，J=10.1Hz，1H)，3.84(s，3H)，3.70-3.56(m，9H)，3.34(s，3H).
13C NMR(101MHz，CDC13)δ172.03，154.47，153.67，142.20，142.00，137.07，136.42，135.47，129.10，128.57，128.37，128.04，124.87，124.84，110.85，110.24，101.71，101.51，99.39，99.11，70.47，63.58，56.48，56.09，55.39，54.95，52.77.
Embodiment 4
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmo1) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mm01) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take fluorophenyl diazoacetic acid methyl esters (21.4mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product D again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 63%, d.r. value > 20:1, ee value 90%.
1H NMR(400MHz，CDC1 3)δ7.47-7.45(dd，J=8.7，5.4Hz，2H)，7.33(d，J=8.3Hz，2H)，6.99-6.95(t，J=8.7Hz，2H)，6.90(d，J=8.3Hz，2H)，6.70(d，J=8.7Hz，1H)，6.59(d，J=8.2Hz，1H)，6.16-6.15(dd，J=8.7，2.8Hz，1H)，6.12-6.06(m，2H)，5.93(s，1H)，5.76(d，J=2.7Hz，1H)，5.66(d，J=10.2Hz，1H)，5.20(d，J=10.2Hz，1H)，3.83(s，3H)，3.69(s，3H)，3.65(s，3H)，3.61(s，3H)，3.40(s，3H)，1.54(s，2H).
13C NMR(101MHz，CDC1 3)δ171.96，163.62，161.16，154.47，153.74，142.23，142.08，137.05，136.59，135.43，132.17，132.14，131.17，130.78，130.70，130.30，122.18，115.17，114.96，110.82，110.33，101.58，101.44，99.59，99.39，69.93，64.01，56.50，56.17，55.38，55.03，52.76.
Embodiment 5
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mmo1) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take bromophenyl diazoacetic acid methyl esters (28.1mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product E again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 71%, d.r. value >20:1, ee value 95%.
1H NMR(400MHz，CDC1 3)δ7.41(d，J=8.6Hz，2H)，7.39-7.31(m，4H)，6.91(d，J=8.3Hz，2H)，6.70(d，J=8.7Hz，1H)，6.59(d，J=8.4Hz，1H)，6.17-6.08(ddd，J=14.3，10.2，2.9Hz，3H)，5.92(s，1H)，5.75(d，J=2.7Hz，1H)，5.64(d，J=10.3Hz，1H)，5.19(d，J=10.2Hz，1H)，3.83(s，3H)，3.69(s，3H)，3.65(s，3H)，3.61(s，3H)，3.42(s，3H).
13C NMR(101MHz，CDC1 3)δ170.69，153.43，152.70，141.20，141.05，135.94，135.43，134.55，134.29，130.27，130.19，129.69，129.25，121.26，121.23，109.77，109.29，100.59，100.39，98.64，98.36，69.03，62.84，55.45，55.14，54.36，54.03，51.79.
Embodiment 6
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mmol) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take and ask bromophenyl diazoacetic acid methyl esters (28.1mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product F again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 51%, d.r. value >20: 1, ee value 92%.
1H NMR(400MHz，CDC1 3)δ7.69(s，1H)，7.44(d，J=7.9Hz，1H)，7.39(d，J=8.1Hz，1H)，7.33(d，J=8.3Hz，2H)，7.16-7.12(t，J=7.9Hz，1H)，6.86(d，J=8.4Hz，2H)，6.70(d，J=8.7Hz，1H)，6.60(d，J=8.6Hz，1H)，6.16(dd，J=8.7，2.8Hz，1H)，6.10(dd，J=8.6，2.8Hz，1H)，6.07(d，J=2.7Hz，1H)，5.90(s，1H)，5.76(d，J=2.8Hz，1H)，5.67(d，J=10.3Hz，1H)，5.14(d，J=10.2Hz，1H)，3.84(s，3H)，3.72(s，3H)，3.64(s，3H)，3.61(s，3H)，3.42(s，3H).
13C NMR(101MHz，CDC1 3)δ171.57，154.45，153.76，142.26，142.12，138.82，136.96， 136.27，135.28，132.12，131.17，130.24，129.60，127.62，122.29，122.27，110.84，110.40，101.66，101.62，99.78，99.53，70.08，64.26，56.50，56.26，55.40，55.13，52.81.
Embodiment 7
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0. () () lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmo1) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mmo1) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take and ask p-methoxy-phenyl diazoacetic acid methyl esters (22.7mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product G again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 58%, d.r. value >20: 1, ee value 91%.
1H NMR(400MHz，CDC1 3)δ7.33(2H)，7.30-7.24(m，3H)，7.24-7.16(m，1H)，7.15-7.02(m，2H)，6.97(2H)，6.84(1H)，6.69(1H)，6.58(1H)，6.12(3H)，5.88(2H)，5.71(s，1H)，5.28(1H)，3.90-3.81(m，3H)，3.72-3.54(m，12H)，3.42-3.33(m，3H).
13C NMR(101MHz，CDC1 3)δ172.00，159.50，154.48，153.72，142.16，142.00，138.06，137.18，136.96，135.63，131.06，130.37，129.19，122.03，121.05，114.15，113.98，110.84，110.26，101.56，101.50，99.36，99.17，70.40，63.65，56.53，56.11，55.37，55.16，55.01，52.71.
Embodiment 8
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0.001mmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, furtural (9.6mg, 0.1mmol) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take phenyldiazonium methyl acetate (19.4mg, 0.11 mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product H again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 78%, d.r. value >20: 1, ee value 93%.
1H NMR(400MHz，CDC1 3)δ7.50-7.43(m，2H)，7.27(d，J=3.7Hz，2H)，6.69-6.61(dd，J=22.6，8.6Hz，2H)，6.26(d，J=2.2Hz，1H)，6.21(s，1H)，6.18-6.06(m，3H)，6.01(d，J=3.0Hz，1H)，5.79(d，J=2.4Hz，1H)，5.43-5.33(dd，J=29.4，10.7Hz，2H)，3.83(s，3H)，3.68(d，J=6.8Hz，9H)，3.35(s，3H)，1.57(s，3H).
13C NMR(101MHz，CDC1 3)δ172.09，154.61，153.72，151.73，142.37，142.11，142.05，137.52，136.21，135.93，128.55，127.95，127.76，111.01，110.78，110.34，109.15，101.72，101.40，100.18，99.31，69.95，59.34，56.70，56.35，55.50，55.04，52.68.
Embodiment 9
Take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0.00lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, furtural (9.6mg, 0.1mmol) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take and ask p-methoxy-phenyl diazoacetic acid methyl esters (22.7mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product I again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 67%, d.r. value >20: 1, ee value 85%.
1H NMR(400MHz，CDC1 3)δ7.28(s，1H)，7.19-7.15(t，J=7.9Hz，1H)，7.09(d，J=7.8Hz，1H)，7.05(s，1H)，6.81(d，J=7.9Hz，1H)，6.68(d，J=8.6Hz，1H)，6.62(d，J=8.5Hz，1H)，6.23(d，J=14.6Hz，2H)，6.15-6.11(t，J=8.8Hz，2H)，6.06(s，1H)，6.01(d，J=1.7Hz，1H)，5.84(s，1H)，5.43-5.40(d，J=10.6Hz，1H)，5.32(d，J=10.6Hz，1H)，3.82(s，3H)，3.72-3.64(m，12H)，3.39(s，3H).
13C NMR(101MHz，CDC1 3)δ171.96，159.24，154.61，153.77，151.74，142.32，142.15，142.06，137.84，137.47，135.98，128.83，120.96，114.04，113.88，111.00，110.76，110.37，109.13， 101.81，101.36，100.18，99.26，69.98，59.43，56.72，56.33，55.50，55.16，55.10，52.68.
Embodiment 10
Take aniline (9.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0.001mmo1), the BINOL phosphoric acid (4.3mg of the silica-based replacement of (S)-3,3 '-triphenyl, 0.005mmmo1), phenyl aldehyde (10.6mg, 0.1mmo1) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take phenyldiazonium methyl acetate (19.4mg, 0.11mmo1), aniline (9.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continuing-10 DEG C after injection stirs after 1 hour, filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, the α obtaining optical activity alpha-position quaternary carbon is isolated, β-diamines acid derivative straight product J again by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 43%, d.r. value >20: 1, ee value 89%.
1H NMR(400MHz，CDC1 3)δ7.33(d，J=6.4Hz，2H)，7.20-7.12(7H)，7.00-6.97(2H)，6.96-6.86(m，4H)，6.59(d，J=6.9Hz，2H)，6.42(d，J=7.4Hz，2H)，6.26(d，J=7.6Hz，2H)，5.24(s，1H)，4.93(s，1H)，4.70(s，1H)，3.65(s，3H).
13C NMR(101MHz，CDC1 3)δ171.23，145.08，143.83，136.13，134.16，128.47，128.14，127.73，127.38，127.14，127.08，127.00，126.75，117.16，116.95，114.20，112.73，69.86，63.11，51.71，28.67.
Embodiment 11
take 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), Paracymene ruthenous chloride dimer (1.2mg, 0.00lmmo1), (S)-3, the BINOL phosphoric acid (4.3mg, 0.005mmmol) of the silica-based replacement of 3 '-triphenyl, p-bromobenzaldehyde (18.5mg, 0.1mmol) molecular sieve (100mg), adds the toluene 2ml heavily steamed, they is put into small test tube reactor, at room temperature react 1h, then put into low-temp reaction bath be cooled to-10 DEG C.Take methyl ethyl diazoacetate (14.1mg, 0.11mmo1), 2,5-dimethoxyaniline (15.3mg, 0.1mmo1), two compound are dissolved in the toluene that 2ml heavily steams, and within 1 hour, inject reaction system by peristaltic pump, continue-10 DEG C after injection and stir after 1 hour, slowly return to stirring at room temperature 1h (make diazo decomposition complete) again, TLC detects.Filter, filtrate is revolved to boil off in 40 DEG C and is desolventized, then isolates the α obtaining optical activity alpha-position quaternary carbon, β-diamines acid derivative straight product K by column chromatography (sherwood oil: ethyl acetate=1:30 ~ 1:10).Yield 50%, d.r. value >20: 1, ee value 87%.
1H NMR(400MHz，CDC1 3)δ7.42(d，J=8.4Hz，2H)，7.20(d，J=8.4Hz，2H)，6.68-6.63(dd，J=10.0，8.7Hz，2H)，6.23-6.19(m，2H)，6.10(dd，J=8.6，2.8Hz，1H)，5.93(d，J=2.8Hz，1H)，5.85(d，J=8.5Hz，1H)，5.37(s，1H)，4.68(d，J=8.5Hz，1H)，4.25-4.17(m，J=10.7，7.1Hz，1H)，4.11-4.03(m，J=10.8，7.1Hz，1H)，3.82(s，3H)，3.74(s，3H)，3.69(s，3H)，3.62(s，3H)，1.59(s，3H)，1.20-1.16(t，J=7.1Hz，3H).
13C NMR(101MHz，CDC1 3)δ173.48，154.40，154.15，142.96，142.10，137.37，137.02，136.12，131.47，129.95，122.06，110.68，110.25，101.38，100.88，99.41，99.36，77.34，77.02，76.71，64.32，63.57，61.69，56.31，56.25，55.47，55.35，20.15，13.98.
Compound prepared by above embodiment 1 ~ 11, as shown in following list:
Embodiment 12
To the cell model determination of activity that the α of alpha-position quaternary carbon of the present invention, β-diamines acid derivative is sheared XBP1mRNA in the present embodiment.
XBP1 gene is in high expression level state, among researching and developing at present, and achieves certain clinical therapeutic efficacy about the micromolecular inhibitor of x B P1.X B P1 inhibitor self just can the growth of Tumor suppression, if the chemicotherapy method in conjunction with other can more effective killing off tumor cells, therefore, carries out neoplasm targeted therapy will become study hotspot for x B P1.The expression of XBP1 activated protein needs to shear through reticulon IRE1, and this model has the function judging XBP1 level of shear, thus screens the compound suppressing XBP1 to shear on the mold, as antineoplastic candidate compound.
Experimental technique:
Instrument:
Envision2101 multi-functional microwell plate enzyme mark
Material:
384Flat White culture plate
Luciferase detection substrate
Process:
1, seed cell 8000/50ul/ hole, with DMEM10%FBS one-tenth 96 look culture plate for no reason.
2, at 37 DEG C, 24 hours of 5%C02.
3, tunicamycin (tunicamycin, final concentration is 1 μ g/mi) liquid 50 μ 1 is added.
4, the compound (step 3) adding 1 μ 1 inserts described plate (the 1st step).
5, at 37 DEG C, 8 hours of 5%C02.
6, add 20 μ 1, at room temperature hatch 20 minutes.
7, reading.
Sample preparation:
Sample DMSO dissolves, cryopreservation, and the concentration of DMSO in final system controls within the scope not affecting detection of active.
Data processing and result illustrate:
Under primary dcreening operation selects single concentration conditions, such as 20 μ g/mi, test the activity of sample.For showing active sample under certain condition, such as inhibiting rate %Inhibition is greater than 50, test agents amount dependence, i.e. ICso/ECs0 value, by sample activity, sample concentration is carried out to Nonlinear Quasi and obtains, calculating software used is Graphpad Prism4, and the model that matching uses is sigmoidal dose-response(varible slope), for most of inhibitor screening model, bottom matched curve and top is set as 0 and 100.In one situation, each sample all arranges multiple hole (n >=2) in testing, represents in the result with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE).
The detected result that the activity that the compounds of this invention A ~ K prepared in embodiment 1 ~ 11 shears XBP1 suppresses, as shown in the table:
ID Sample number into spectrum Protocol id Concentration Type Unit Result Error
1 A 92 10ug／mL ％Inhibition percent 95.3 5.3
[0120]
2 B 92 10ug／mL ％Inhibition percent 129.3 2.7
3 C 92 10ug／mL ％Inhibition percent 99.7 1.2
4 D 92 10ug／mL ％Inhibition percent 97.0 2.4
5 E 92 10ug／mL ％Inhibition percent 101.9 1.0
6 F 92 10ug／mL ％Inhibition percent 107.7 2.3
7 G 92 10ug／mL ％Inhibition percent 107.6 1.8
8 H 92 10ug／mL ％Inhibition percent 109.1 2.9
9 I 92 10ug／mL ％Inhibition percent 89.7 2.6
10 K 92 10ug／mL ％Inhibition percent 114.3 2.9
Above experimental result shows: the α of alpha-position quaternary carbon of the present invention, β-diamines acid derivative compd A ~ I, K all shows the remarkable inhibition sheared XBP1, and compound of the present invention is sheared inhibitor as effective XBP1 and be can be used for Tumor suppression and be applied to field of medicaments.
Protection content of the present invention is not limited to above embodiment.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.

Claims (10)

1. have a α for optically active alpha-position quaternary carbon, β-diamines acid derivative, is characterized in that, as following structural formula (") shown in:
Wherein,
R 1for phenyl, p-nitrophenyl, to bromophenyl, o-bromophenyl, asks bromophenyl, rubigan, asks chloro-phenyl-or Chloro-O-Phenyl, or methyl;
R 2for methyl, or ethyl;
R 3for phenyl, or 2,5 one Dimethoxyphenyls;
R 4for to bromophenyl, p-trifluoromethyl phenyl, rubigan, phenyl, or 2 one furyls.
2. have a α for optically active alpha-position quaternary carbon, the preparation method of β-diamines acid derivative, is characterized in that, by aromatic aldehyde, arylamine, chiral phosphoric acid, Paracymene ruthenous chloride dimer, molecular sieve is dissolved in organic solvent, adds the organic solvent solution of diazonium compound, and reaction at one 10 DEG C ~ mono-20 DEG C also obtains the α of a described α quaternary carbon, β mono-diamines acid derivative, shown in following reaction formula (1) through revolving to steam:
Wherein,
R 1for phenyl, p-nitrophenyl, to bromophenyl, o-bromophenyl, asks bromophenyl, rubigan, asks chloro-phenyl-or Chloro-O-Phenyl, or methyl;
R 2for methyl, or ethyl;
R 3for phenyl, or 2,5 one Dimethoxyphenyls;
R 4for to bromophenyl, p-trifluoromethyl phenyl, rubigan, phenyl, or 2 one furyls.
3. preparation method as claimed in claim 2, is characterized in that, described chiral phosphoric acid structure such as formula shown in (I),
Wherein, Ar is that triphenyl is silica-based, phenyl, p-methylphenyl, p-methoxyphenyl, to fluorophenyl, and 3,5-difluorophenyl, to fluoroform phenyl, 3,5-bis-trifluorophenyl or 9-phenanthryl.
4. preparation method as claimed in claim 2, is characterized in that, described arylamine: aromatic aldehyde: chiral phosphoric acid: Paracymene ruthenous chloride dimer mol ratio=1.0:1.0:0.05:0.01; The add-on of water-retaining agent 4A molecular sieve is 1 ~ 2g/mmol aromatic aldehyde, and the add-on of organic solvent is 20 ~ 30ml/mmol aromatic aldehyde.
5. preparation method as claimed in claim 2, it is characterized in that, the preparation method of the organic solvent solution of described diazonium compound is: take diazonium in molar ratio=1.1:1.0: arylamine, be dissolved in described organic solvent, obtain the organic solvent solution of diazoamino solution and described diazonium compound.
6. preparation method as claimed in claim 5, it is characterized in that, the consumption of described organic solvent is 20 ~ 30ml/mmol aromatic aldehyde.
7. preparation method as claimed in claim 2, it is characterized in that, be obtained by reacting the α of described alpha-position quaternary carbon, β-diamines acid derivative is through ethyl acetate: sherwood oil is with volume ratio=1:50 ~ 1:20 column chromatography.
8. preparation method as claimed in claim 2, it is characterized in that, described organic solvent comprises chloroparaffin, toluene or dimethylbenzene.
9. there is the α of optically active alpha-position quaternary carbon, the β-application of diamines acid derivative in the medicine preparing Tumor suppression shown in formula (I I).
10. apply as claimed in claim 9, it is characterized in that, described medicine is used as XBP1 and shears inhibitor.
CN201410091014.9A 2014-03-13 2014-03-13 Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof Pending CN104910034A (en)

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* Cited by examiner, † Cited by third party
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CN105130834A (en) * 2015-09-30 2015-12-09 中国科学院兰州化学物理研究所 Preparation method of beta-amido-alpha-amino-acid ester derivative
CN110218214A (en) * 2018-03-02 2019-09-10 华东师范大学 A kind of benzo [3,3,1] oxa- bridged ring ketal derivatives and its synthetic method and application

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CN102295582A (en) * 2011-05-13 2011-12-28 华东师范大学 Preparation method of alpha, beta-diamino acid derivatives with alpha-quaternary carbon

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CN102295582A (en) * 2011-05-13 2011-12-28 华东师范大学 Preparation method of alpha, beta-diamino acid derivatives with alpha-quaternary carbon

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105130834A (en) * 2015-09-30 2015-12-09 中国科学院兰州化学物理研究所 Preparation method of beta-amido-alpha-amino-acid ester derivative
CN110218214A (en) * 2018-03-02 2019-09-10 华东师范大学 A kind of benzo [3,3,1] oxa- bridged ring ketal derivatives and its synthetic method and application
CN110218214B (en) * 2018-03-02 2021-12-24 华东师范大学 Benzo [3,3,1] oxabridged cyclic ketal derivative and synthetic method and application thereof

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