CN104058998A - Alpha-amino and delta-hydroxyl adipic acid derivatives and preparation method and application thereof - Google Patents
Alpha-amino and delta-hydroxyl adipic acid derivatives and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses alpha-amino and delta-hydroxyl adipic acid derivatives and a preparation method and application thereof, and the products are synthesized by reaction of aryl acetate diazonium, alcohol and alpha, beta unsaturated imido ester under catalysis of rhodium acetate. The raw materials are cheap and easily obtained, two chiral carbons can be simultaneously constructed by one pot method, the preparation route is short, the operation is simple, the reaction condition is mild, the atom economy is high, the yield is high, and the alpha-amino and delta-hydroxyl adipic acid derivatives can be simultaneously obtained, diverse compound skeletons can be provided for use in screening of new drugs and pharmaceutical fields.
Description
Technical field
The invention belongs to medicine synthesising chemical technology field, relate to a kind of α-amido, δ-hydroxyl hexanodioic acid derivative and its preparation method and application.
Background technology
α-amido, δ-hydroxyl hexanodioic acid derivative is the important skeleton structure that a class has special medicinal compound, the important skeleton structure (Matrix.Biol.2002 of collagen protein, 21,559-566.), or as glycosylation reagent (J.Clin.Invest.1977,59,819.).Traditional preparation α-amido, the method of δ-hydroxyl hexanodioic acid derivative is that multi-step synthesis method is (taking Alpha-hydroxy prussiate as starting raw material, or 1,3-diolefine and nitrone are starting raw material etc.) (Eur.J.Org.Chem.2000,3683-3691; TetrahedronLett.2010,51,2160-2163), the shortcoming such as these prepare α-amido, and the method cost of δ-hydroxyl hexanodioic acid derivative is high, and productive rate is low, complex operation.
Summary of the invention
The present invention proposes a kind of α-amido, δ-hydroxyl hexanodioic acid derivative, and its structure is suc as formula shown in (I),
In formula (I),
Ar
1for phenyl, with the phenyl of substituted radical;
R is benzyl, with substituent benzyl, methyl, ethyl, sec.-propyl;
Ar
3for phenyl, with the phenyl of substituted radical;
Ts is p-toluenesulfonyl.
α-amido, δ-hydroxyl hexanodioic acid derivative is the important skeleton structure that a class has special medicinal compound, the important skeleton structure (Matrix.Biol.2002 of collagen protein, 21,559-566.), or as glycosylation reagent (J.Clin.Invest.1977,59,819.).Traditional preparation α-amido, the method of δ-hydroxyl hexanodioic acid derivative is that multi-step synthesis method is (taking Alpha-hydroxy prussiate as starting raw material, or 1,3-diolefine and nitrone are starting raw material etc.) (Eur.J.Org.Chem.2000,3683-3691; TetrahedronLett.2010,51,2160-2163), the shortcoming such as these prepare α-amido, and the method cost of δ-hydroxyl hexanodioic acid derivative is high, and productive rate is low, complex operation.Advantage of the present invention is that a step prepares polysubstituted α-amido, and δ-hydroxyl hexanodioic acid derivative, obtains very good cis-selectivity and yield.
The invention allows for a kind of α-amido, the preparation method of δ-hydroxyl hexanodioic acid derivative, diazonium compound, alcohol and α, it is synthetic suc as formula the described α-amido shown in (I) that β-unsaturated imines ester reacts under the catalysis of acetic acid rhodium, δ-hydroxyl hexanodioic acid derivative.
Preparation method's of the present invention reaction formula is:
Wherein, Ar
1for phenyl, with the phenyl of substituted radical; R is benzyl, with substituent benzyl, methyl, ethyl, sec.-propyl; Ar
3for phenyl, with the phenyl of substituted radical; Ts is p-toluenesulfonyl.
Wherein, described aryl acetate diazonium: alcohol: α, β-unsaturated imines: the mol ratio of acetic acid rhodium is (1.0-2.0): (1.0-2.0): 1.0: (0.01-0.02).
Preferably, described aryl acetate diazonium: alcohol: α, β-unsaturated imines: mol ratio=1.5 of acetic acid rhodium: 1.5: 1.0: 0.01.
Wherein, described alcohol is phenylcarbinol, p-nitrophenyl methyl alcohol, ortho-nitrophenyl methyl alcohol, methyl alcohol, ethanol, Virahol.
Wherein, described α, β-unsaturated imines ester is 4-rubigan α, β-unsaturated imines ester, 4-is to bromophenyl α, β-unsaturated imines ester, bromophenyl α between 4-, β-unsaturated imines ester, 4-is to fluorophenyl α, β-unsaturated imines ester, 4-p-nitrophenyl α, β-unsaturated imines ester, 4-p-methylphenyl α, β-unsaturated imines ester, 4-phenyl α, β-unsaturated imines ester.In the present invention, described α, β-unsaturated imines ester can prepare (referring to J.Org.Chem.2005,70,7451-7454) by beta, gamma-unsaturated-alpha-keto ester and para toluene sulfonamide.
Wherein, described aryl acetate diazonium: be benzene diazonium methyl acetate, a bromophenyl diazoacetic acid methyl esters, to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.In the present invention, aryl acetate diazonium can add alkali by corresponding ester and triazo-compound and prepare (referring to J.Org.Chem., 1968,33,3610-3618).
Preparation method of the present invention comprises: by alcohol, and α, β-unsaturated imines ester, acetic acid rhodium and organic solvent add in reaction flask, add water-retaining agent
molecular sieve 500-1000mg/mmol; Wherein, the add-on of organic solvent is 10-30ml/mmol α, β-unsaturated imines ester; Then, nitranilide ester being dissolved in organic solvent and obtaining diazonium solution, wherein, is 10-30ml/mmol group with imine moiety for the amount of the organic solvent that dissolves diazonium compound; Then at room temperature, by peristaltic pump, diazonium solution is added drop-wise in reaction flask, stirs, revolve to boil off to desolventize and obtain thick product, through column chromatography, obtain described α-amido, δ-hydroxyl hexanodioic acid derivative.
Wherein, described organic solvent is chloroparaffin, toluene or dimethylbenzene
The object of the present invention is to provide a kind of raw material cheap and easy to get, syntheti c route is short, α-amido simple to operate, the preparation synthetic method of δ-hydroxyl hexanodioic acid derivative.In order to achieve the above object, the inventive method is with diazonium compound, alcohol and α, and β-unsaturated imines ester, under the catalysis of acetic acid rhodium, is realized the synthetic α-amido of three component reaction, δ-hydroxyl hexanodioic acid derivative.The present invention adopts three component reaction one steps to obtain target product α-amido that alkylsulfonyl is protected, δ-hydroxyl hexanodioic acid derivative.The present invention first forms oxygen ylide with alcohol effect by nitranilide ester under the catalysis of Rh (II), pass through again α, β-unsaturated imines ester catches this active intermediate, thereby construct suc as formula (I) target product α-amido δ-hydroxyl hexanodioic acid derivative compound.Preparation method's one step of the present invention has built the synthetic preparation of two chiral carbon α-amido, δ-hydroxyl hexanodioic acid derivative simultaneously.
The organic solvent that the present invention is used and preparation α, the raw material aromatic aldehyde of β-unsaturated imines ester, pyruvic acid and para toluene sulfonamide, diazonium raw material Arylacetic acids methyl esters, triazo-compound, ethyl acetate, ethanol, titanium tetrachloride, triethylamine all can be buied in market.Toluene is before use through hydrolith processed, and other organic solvents all make in advance purifying before reaction and when column chromatography or distillation is processed.
The invention allows for suc as formula the α-amido shown in (I) application of δ-hydroxyl hexanodioic acid derivative in arrestin tyrosine phosphatase PTP1B activity.Example shows, α-amido of the present invention, and the inhibitor that δ-hydroxyl hexanodioic acid derivative can be used as effective arrestin tyrosine phosphatase enzymic activity is applied in field of medicaments.
The present invention has advantage and beneficial effect comprises: raw material diazonium compound, alcohol, α that the present invention is used, β-unsaturated imines ester and organic solvent are cheap and easy to get, synthetic with low cost.The present invention adopts one kettle way to build two chiral carbon simultaneously, and synthetic route 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 α-amido quickly and easily, δ-hydroxyl hexanodioic 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 taking 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.
Preparation method's of the present invention concrete steps comprise: first take alcohol: α, β-unsaturated imines ester: acetic acid rhodium=1.5: 1.0: 0.01 mol ratios, and by alcohol, α, β-unsaturated imines, acetic acid rhodium and organic solvent, add in reaction flask, adds water-retaining agent
molecular sieve 500-1000mg/mmol, the add-on of organic solvent is 10-30ml/mmol α, β-unsaturated imines ester; Then, nitranilide ester is dissolved in organic solvent, diazonium compound add-on is 1.5mmol/mmol α, and β-unsaturated imines ester, obtains diazonium solution, is 10-30ml/mmol for the amount of the organic solvent that dissolves diazonium; Then at room temperature, by peristaltic pump, diazonium solution is added drop-wise in reaction flask, within 1 hour, dropwises, continue to stir after 2 hours, 40-50 DEG C revolves to boil off and desolventizes, and obtains thick product.Be ethyl acetate by thick product by volume ratio: sherwood oil=1: 20～1: column chromatography in 5 solution, obtains α-amido, δ-hydroxyl hexanodioic acid derivative sterling.
Embodiment 1
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative A, yield 65%, dr is greater than 95: 5.
4H)，7.26(m，6H)，7.30(m，3H)，7.34(m，2H)，7.47(d，J(H，H)＝6.8Hz，2H)；
13C NMR(100MHz，CDCl
3)：δ＝21.47，52.26，52.51，52.77，63.19，88.34，125.77，126.99，127.41，127.59，127.80，127.86，128.31，128.35，129.24，131.72，133.10，135.19，135.49，136.08，138.24，138.92，143.72，164.51，171.39；
HRMS: calculated value: C
34h
32clNNaO
7s, [M+Na]
+656.1480; Observed value: 656.1470
Embodiment 2
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then p-methoxyphenyl diazotate (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative B, yield 90%, dr is greater than 95: 5.
13C NMR(100MHz，CDCl
3)：δ＝21.51，52.21，52.90，52.24，55.24，68.06，88.21，113.24，125.95，127.09，127.42，127.47，127.67，128.35，129.30，129.34，131.82，133.16，135.39，136.26，138.41，138.90，143.75，159.49，164.60，171.63；
HRMS: calculated value: C
35h
34clNNaO
8s, [M+Na]
+686.1586; Observed value: 686.1582
Embodiment 3
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then p-methylphenyl diazotate (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative C, yield 85%, dr is greater than 95: 5.
7.35(m，2H)，7.46(d，J(H，H)＝6.4Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ＝21.05，21.49，52.20，52.52，52.71，68.08，88.33，125.84，127.03，127.37，127.43，127.61，127.82，128.30，128.58，129.25，131.78，132.32，133.09，135.28，138.21，138.35，138.89，143.69，164.58，171.54；
HRMS: calculated value: C
35h
34clNNaO
7s, [M+Na]
+670.1637; Observed value: 670.1609
Embodiment 4
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then will be dissolved in methylene dichloride 1ml bromophenyl diazotate (0.3mmol), obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative D, yield 85%, dr is greater than 95: 5.
(H，H)＝8.4Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ＝21.50，52.40，52.59，52.70，68.34，87.99，122.68，125.95，127.04，127.49，127.60，127.81，128.42，129.30，129.75，131.02，131.75，133.40，134.73，134.90，136.05，137.91，138.54，143.84，164.39，170.95；
HRMS: calculated value: C
34h
31brClNNaO
7s, [M+Na]
+734.0585; Observed value: 734.0576
Embodiment 5
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then between inciting somebody to action, bromophenyl diazotate (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative E, yield 83%, dr is greater than 95: 5.
13CNMR(100MHz，CDCl
3)：δ＝21.49，52.46，52.62，52.77，68.46，87.88，122.06，125.93，126.54，127.12，127.47，127.60，127.74，128.40，129.29，131.06，131.47，131.68，133.40，134.80，137.83， 137.98，138.38，143.84，164.39，170.85；
HRMS: calculated value: C
34h
31brClNNaO
7s, [M+Na]
+734.0585; Observed value: 734.0610
Embodiment 6
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then rubigan diazotate (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative F, yield 84%, dr is greater than 95: 5.
(H，H)＝8.4Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ＝21.50，52.42，52.59，52.76，53.47，68.34，87.95，126.01，127.06，127.48，127.60，127.79，128.06，128.43，129.32，129.47，131.77，133.35，134.26，134.39，135.01，136.10，137.97，138.58，143.87，164.42，171.02；
HRMS: calculated value: C
34h
31cl
2nNaO
7s, [M+Na]
+690.1090; Observed value: 690.1056
Embodiment 7
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), ortho-nitrophenyl methyl alcohol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, then by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain
6.09(s，1H)，7.40-6.99(m，15H)，7.57(t，J＝7.6Hz，1H)，7.74(d，J＝7.8Hz，1H)，7.92(d，J＝8.2Hz，1H)；
13CNMR(100MHz，CDCl
3)：δ＝21.50，52.38，52.62，53.10，65.39，88.91，124.55，125.85，126.40，127.49，127.65，127.79，127.86，128.22，128.78，129.32，129.64，131.70，133.28，133.64，135.00，135.38，135.41，135.83，138.97，143.93，147.04，164.46，171.13；
HRMS: calculated value: C
34h
31clN
2naO
9s, [M+Na]
+701.1331; Observed value: 701.1331
Embodiment 8
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), p-nitrophenyl methyl alcohol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative H, yield 64%, dr is greater than 95: 5.
7.9Hz，1H)；
13CNMR(100MHz，CDCl
3)：δ＝21.50，52.39，52.62，52.82，67.32，88.74，123.55，125.89，126.41，127.32，127.48，127.78，128.24，128.82，129.31，129.66，131.73，133.36，135.32，135.34，135.74，138.87，143.99，146.13，147.18，164.37，171.16；
HRMS: calculated value: C
34h
31clN
2naO
9s, [M+Na]
+701.1331; Observed value: 701.1351
Embodiment 9
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), Virahol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative 1, yield 95%, dr is greater than 95: 5.
(d，J＝8.4Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ＝21.53，23.43，23.91，51.87，51.99，52.51，69.54，88.06，126.15，127.48，127.51，128.25，128.38，129.38，131.71，133.03，135.67，136.51，136.83，139.39，143.73，164.75，171.68；
HRMS: calculated value: C
30h
32clNNaO
7s, [M+Na]
+608.1480; Observed value: 608.1455
Embodiment 10
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), ethanol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative J, yield 82%, dr is greater than 95: 5.
13CNMR(100MHz，CDCl
3)：δ＝15.45，21.51，52.23，52.53，52.62，62.01，88.11，125.96，127.46，127.60，127.68，127.69，128.13，129.36，131.66，133.04，135.27，135.85，136.38，138.95，143.75，164.73，171.66；
HRMS: calculated value: C
29h
30clNNaO
7s, [M+Na]
+594.1324; Observed value: 594.1315
Embodiment 11
Take 4-rubigan α, β-unsaturated imines ester (0.20mmol), methyl alcohol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative K, yield 75%, dr is greater than 95: 5.
Hz，2H)；
13CNMR(100MHz，CDCl
3)：δ＝21.51，52.29，52.56，52.58，54.67，88.56，125.83，127.47，127.68，127.78，127.92，128.23，129.35，131.62，133.09，135.25，135.33，136.18，139.07，143.80，164.66，171.57；
HRMS: calculated value: C
28h
28clNNaO
7s, [M+Na]
+580.1167; Observed value: 580.1142
Embodiment 12
Take 4-p-methylphenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative L, yield 56%, dr is greater than 95: 5.
(H，H)＝8.4Hz，2H)；
13C NMR(100MHz，CDCl
3)：δ＝21.11，21.50，52.18，52.43，52.99，68.15，88.68，125.90，127.06，127.38，127.44，127.68，128.17，128.20，128.34，129.27，130.24，133.22，135.49，136.70，136.94，138.36，139.14，143.51，164.77，171.46；
HRMS: calculated value: C
35h
35nNaO
78, [M+Na]
+636.2026; Observed value: 636.2031
Embodiment 13
Take 4-to bromophenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative M, yield 68%, dr is greater than 95: 5.
(H，H)＝8.0Hz，2H)，7.06-7.14(m，10H)，7.17-7.28(m，5H)，7.39(d，J(H，H)＝8.0Hz，2H)；
13C NMR(100MHz，CDCl
3)：δ＝21.51，52.29，52.55，52.92，68.26，88.34，121.42，125.85，127.05，127.48，127.85，127.92，128.36，128.41，129.30，130.60，132.14，135.56，135.79，136.17，138.29，138.92，143.76，164.55，171.43；
HRMS: calculated value: C
34h
32brNNaO
7s, [M+Na]
+700.0975; Observed value: 700.1010
Embodiment 14
Take bromophenyl α between 4-, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative N, yield 63%, dr is greater than 95: 5.
(H，H)＝10.8，8.0Hz，1H)，7.05-7.15(m，9H)，7.16-7.27(m，5H)，7.39(d，J(H，H)＝8.0Hz，2H)；
13C NMR(100MHz，CDCl
3)：δ＝21.58，52.32，52.62，53.21，68.25，88.44，121.49，126.21，126.97， 127.43，127.47，127.84，127.94，128.43，128.49，128.97，129.37，130.34，133.22，135.47，136.26，138.32，138.48，139.02，143.82，164.61，171.35；
HRMS: calculated value: C
34h
32brNNaO
7s, [M+Na]
+700.0975; Observed value: 700.0995
Embodiment 15
Take 4-to fluorophenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative 0, yield 78%, dr is greater than 95: 5.
J(H，H)＝25.6Hz，1H)，6.74(m，1H)，6.86(m，2H)，7.13-7.19(m，11H)，7.24-7.28(m，5H)，7.41(dd，J(H，H)＝8.0，8.8Hz，2H)，；
13CNMR(100MHz，CDCl
3)：δ＝21.50，52.21，52.47，53.40，68.25，88.64，114.45，121.49，125.93，127.04，127.38，127.49，127.72，127.89，128.24，128.33，129.28，130.46，132.04，135.54，136.27136.43，138.35，138.38，139.07，143.70，164.75，171.50；
HRMS: calculated value: C
34h
32nFNaO
7s, [M+Na]
+640.1776; Observed value: 640.1750
Embodiment 16
Take 4-phenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, then by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amine
(d，J(H，H)＝12.0Hz，1H)，4.52(d，J(H，H)＝11.6Hz，1H)，4.71(d，J(H，H)＝10.4Hz，1H)，6.29(s，1H)，6.85(d，J(H，H)＝7.6Hz，2H)，7.04-7.10(m，10H)，7.12-7.27(m，8H)，7.41(d，J(H，H)＝8.0Hz，2H)；
13C NMR(100MHz，CDCl
3)∶δ＝21.52，52.24，52.50，53.40，68.21，88.65，125.96，127.05，127.33，127.40，127.46，127.55，127.74，128.06，128.26，128.35，129.30，130.47，135.55，136.46，136.54，138.39，139.06，143.59，164.77，171.51；
HRMS: calculated value: C
34h
33nNaO
7s, [M+Na]
+622.1870; Observed value: 622.1837
Embodiment 17
Take 4-p-nitrophenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), acetic acid rhodium (1.00mg, 0.002mmol), puts into small test tube reactor by them, adds water-retaining agent
molecular sieve 100mg, organic solvent add 2ml; Then nitranilide ester (0.3mmol) is dissolved in methylene dichloride 1ml, obtain diazonium solution, under room temperature, 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 DEG C and is desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative Q, yield 57%, dr is greater than 95: 5.
7.34-7.44(m，6H)，7.99(d，J＝8.4Hz，2H)；
13C NMR(100MHz，CDCl
3)：δ＝171.23，164.23，146.98，144.83，144.03，138.65，138.13，135.81，135.58，131.41，129.80，129.54，129.36，128.67，128.50，128.42，128.16，127.59，127.47，127.22，127.09，126.18，122.48，88.26，68.45，53.45，52.67，52.42，21.52.
HRMS: calculated value: C
34h
32n
2naO
9s, [M+Na]
+667.1721; Observed value: 667.1744
Embodiment 18 α-amido of the present invention, the inhibition biological activity test used screening model of δ-hydroxyl hexanodioic 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 adjusting 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.Substrate pNPP is hydrolyzed through PTP1B the free product obtaining 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 Na3VO4.
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, represents with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE).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
α-amido of the present invention, the inhibition of δ-hydroxyl hexanodioic acid derivative to Protein-tyrosine-phosphatase activity, sees the following form 2.
Table 2
Experimental result shows: with reference compound contrast, α-amido of the present invention, δ-hydroxyl hexanodioic acid derivative A～Q all shows the significantly good inhibition to PTP1B.α-amido of the present invention, δ-hydroxyl hexanodioic acid derivative can be used as effective histone tyrosine-phosphatase inhibitor and is applied to field of medicaments.
Claims (10)
1. α-the amido shown in formula (I), δ-hydroxyl hexanodioic acid derivative, is characterized in that, its structure is suc as formula shown in (I),
Wherein,
Ar
1for phenyl or with the phenyl of substituted radical;
R is benzyl, with substituent benzyl, methyl, ethyl or sec.-propyl;
Ar
3for phenyl or with the phenyl of substituted radical;
Ts is p-toluenesulfonyl.
2. α-the amido shown in formula (I), the preparation method of δ-hydroxyl hexanodioic acid derivative, is characterized in that aryl acetate diazonium, alcohol and α, β-unsaturated imines ester reacts synthetic described α-amido, δ-hydroxyl hexanodioic acid derivative under the catalysis of acetic acid rhodium; Described preparation method's reaction formula is:
Wherein, Ar
1for phenyl or with the phenyl of substituted radical; R is benzyl, with substituent benzyl, methyl, ethyl or sec.-propyl; Ar
3for phenyl or with the phenyl of substituted radical; Ts is p-toluenesulfonyl.
3. preparation method as claimed in claim 2, it is characterized in that, described aryl acetate diazonium: alcohol: α, β-unsaturated imines: the mol ratio of acetic acid rhodium is (1.0-2.0): (1.0-2.0): 1.0: (0.01-0.02).
4. preparation method as claimed in claim 2, is characterized in that, described alcohol is phenylcarbinol, p-nitrophenyl methyl alcohol, ortho-nitrophenyl methyl alcohol, methyl alcohol, ethanol, Virahol.
5. preparation method as claimed in claim 2, is characterized in that, described α, β-unsaturated imines ester is 4-rubigan α, β-unsaturated imines ester, and 4-is to bromophenyl α, β-unsaturated imines ester, bromophenyl α between 4-, β-unsaturated imines ester, 4-is to fluorophenyl α, β-unsaturated imines ester, 4-p-nitrophenyl α, β-unsaturated imines ester, 4-p-methylphenyl α, β-unsaturated imines ester, 4-phenyl α, β-unsaturated imines ester.
6. preparation method as claimed in claim 2, it is characterized in that, described aryl acetate diazonium is benzene diazonium methyl acetate, between bromophenyl diazoacetic acid methyl esters, to bromophenyl diazoacetic acid methyl esters, rubigan diazoacetic acid methyl esters, p-methoxyphenyl diazoacetic acid methyl esters, p-methylphenyl diazoacetic acid methyl esters.
7. preparation method as claimed in claim 2, is characterized in that, described water-retaining agent
molecular sieve 500-1000mg/mmol; The add-on of organic solvent is 10-30ml/mmol α, β-unsaturated imines ester.
8. preparation method as claimed in claim 2, is characterized in that, described preparation method comprises: by alcohol, and α, β-unsaturated imines ester, acetic acid rhodium and organic solvent add in reaction flask, add water-retaining agent
molecular sieve 500-1000mg/mmol; Wherein, the add-on of organic solvent is 10-30ml/mmol α, β-unsaturated imines ester; Then, nitranilide ester being dissolved in organic solvent and obtaining diazonium solution, wherein, is 10-30ml/mmol for the amount of the organic solvent that dissolves diazonium; Then at room temperature, by peristaltic pump, diazonium solution is added drop-wise in reaction flask, stirs, revolve to boil off to desolventize and obtain thick product, through column chromatography, obtain described α-amido, δ-hydroxyl hexanodioic acid derivative.
9. preparation method as claimed in claim 8, is characterized in that, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
10. suc as formula the α-amido shown in (I), the application of δ-hydroxyl hexanodioic acid derivative in arrestin tyrosine phosphatase enzymic activity.
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| US20010034369A1 (en) * | 1996-12-09 | 2001-10-25 | Scarborough Robert M. | Integrin antagonists |
| US20100061936A1 (en) * | 2008-09-05 | 2010-03-11 | Kui Shen | Unnatural amino acids capable of covalently modifying protein phosphatases and their use as general and specific inhibitors and probes |
| CN102234231A (en) * | 2010-04-26 | 2011-11-09 | 中国科学院上海药物研究所 | 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application |
| CN102491931A (en) * | 2011-11-11 | 2012-06-13 | 华东师范大学 | 3-substituted indolone derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20010034369A1 (en) * | 1996-12-09 | 2001-10-25 | Scarborough Robert M. | Integrin antagonists |
| US20100061936A1 (en) * | 2008-09-05 | 2010-03-11 | Kui Shen | Unnatural amino acids capable of covalently modifying protein phosphatases and their use as general and specific inhibitors and probes |
| CN102234231A (en) * | 2010-04-26 | 2011-11-09 | 中国科学院上海药物研究所 | 1-substituted-2-substituted-4- aryl substituted-butyl-2-alkene 1, 4-diketone compound, its preparation method and application |
| CN102491931A (en) * | 2011-11-11 | 2012-06-13 | 华东师范大学 | 3-substituted indolone derivative and preparation method and application thereof |
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| Title |
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| HIROMASA KIYOTA等: "Facile synthesis of (-)-tabtoxinine-β-lactam and its (3’R)-isomer", 《TETRAHEDRON LETTERS》, vol. 45, 31 December 2004 (2004-12-31), pages 8191 - 8194, XP004591079, DOI: doi:10.1016/j.tetlet.2004.09.033 * |
| 倪晓东，张惠斌，周金培: "蛋白质酪氨酸磷酸酯酶1B(PTP1B)抑制剂研究进展", 《药学与临床研究》, vol. 15, no. 4, 31 December 2007 (2007-12-31), pages 259 - 263 * |
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