CN103242209A - Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives - Google Patents
Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives Download PDFInfo
- Publication number
- CN103242209A CN103242209A CN 201310090604 CN201310090604A CN103242209A CN 103242209 A CN103242209 A CN 103242209A CN 201310090604 CN201310090604 CN 201310090604 CN 201310090604 A CN201310090604 A CN 201310090604A CN 103242209 A CN103242209 A CN 103242209A
- Authority
- CN
- China
- Prior art keywords
- preparation
- amido
- unsaturated imines
- phenyl
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *C=CC(*)=N* Chemical compound *C=CC(*)=N* 0.000 description 3
- OAQNSVCIRDZOTC-UHFFFAOYSA-N CC(C)C(C(OC)=O)=N Chemical compound CC(C)C(C(OC)=O)=N OAQNSVCIRDZOTC-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives. The preparation method comprises the step of reacting aryl diazo acetate, alcohol and alpha, beta-unsaturated imidate under the catalysis of rhodium acetate to synthesize the alpha-amido, delta-hydroxyl adipic acid derivatives. The preparation method provided by the invention is low in price of raw materials and easy in acquisition of raw materials, can be used for simultaneously constructing two chiral carbon atoms by adopting a one-kettle way, has the advantages of short preparation route, simplicity in operation, mild reaction conditions, high atom economy and high yield, can be used for conveniently and simultaneously obtaining alpha-amido, delta-hydroxyl adipic acid derivatives, provides diverse compound skeletons, and has very important significance for new drug screening and pharmaceutical process.
Description
Technical field
The invention belongs to medicine synthesising chemical technology field, relate to a kind of α-amido, δ-hydroxyl hexanodioic acid derivative preparation method.
Background technology
α-amido, δ-hydroxyl hexanodioic acid derivative is the important skeleton structure that a class has special medicinal compound, is 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 for δ-hydroxyl hexanodioic acid derivative are the rapid synthesis method of multistep (be starting raw material with the Alpha-hydroxy prussiate, or 1,3-diolefine and nitrone being starting raw material etc.) (Eur.J.Org.Chem.2000,3683-3691; Tetrahedron Lett.2010,51,2160-2163), these prepare α-amido, the method cost height of δ-hydroxyl hexanodioic acid derivative, productive rate is low, shortcomings such as complex operation.
Summary of the invention
The present invention overcomes the above-mentioned deficiency of prior art, a kind of α-amido is proposed, the preparation method of δ-hydroxyl hexanodioic acid derivative, diazonium compound, pure and mild α, β-unsaturated imines ester reacts synthetic described α-amido, δ-hydroxyl hexanodioic acid derivative under the catalysis of acetic acid rhodium;
In the formula (I), Ar
1For phenyl, have the phenyl of substituted radical; R is benzyl, have substituent benzyl, methyl, ethyl, sec.-propyl; Ar
3For phenyl, have the phenyl of substituted radical; Ts is p-toluenesulfonyl;
Described preparation method's reaction formula is:
Wherein, Ar
1For phenyl, have the phenyl of substituted radical; R is benzyl, have substituent benzyl, methyl, ethyl, sec.-propyl; Ar
3For phenyl, have 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: the mol ratio of acetic acid rhodium=1.5: 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, the bromophenyl α of 4-, β-unsaturated imines ester, bromophenyl α between 4-, β-unsaturated imines ester, the fluorophenyl α of 4-, 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.Among the present invention, described α, β-unsaturated imines ester can be prepared by beta, gamma-unsaturated-alpha-ketoacid ester and para toluene sulfonamide (see also J.Org.Chem.2005,70,7451-7454).
Wherein, described aryl acetate diazonium: be the 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.Among the present invention, aryl acetate diazonium can by corresponding ester and triazo-compound add alkali prepare (see also J.Org.Chem., 1968,33,3610-3618).
Preparation method of the present invention comprises: with alcohol, and α, β-unsaturated imines ester, acetic acid rhodium and organic solvent add in the 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, the nitranilide ester is dissolved in obtains diazonium solution in the organic solvent, wherein, the amount that is used for the organic solvent of dissolving diazonium compound is the 10-30ml/mmol group with imine moiety; Then at room temperature, by peristaltic pump the diazonium drips of solution is added in the 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, the preparation 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 to use diazonium compound, and pure and mild α, β-unsaturated imines ester realize that three component reaction synthesize α-amido, δ-hydroxyl hexanodioic acid derivative under the catalysis of acetic acid rhodium.The present invention adopts one step of three component reaction to obtain target product α-amido that alkylsulfonyl is protected, δ-hydroxyl hexanodioic acid derivative.The present invention forms oxygen ylide with the alcohol effect by the nitranilide ester earlier under the catalysis of Rh (II), pass through α again, β-unsaturated imines ester catches this active intermediate, thereby constructs suc as formula (I) target product α-amido δ-hydroxyl hexanodioic acid derivative compound.Preparation method of the present invention makes up the synthetic preparation of two chiral carbon α-amido, δ-hydroxyl hexanodioic acid derivative one step 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, but triethylamine is all buied in market.Toluene is before use through the hydrolith processed, and other organic solvents all make purifying in advance before reaction and during column chromatography or distillation is handled.
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, and be synthetic with low cost.The present invention adopts one kettle way to make up two chiral carbon simultaneously, and synthetic route is simple, by the co-catalyst that is 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.Under the spirit and scope that do not deviate from inventive concept, variation and advantage that those skilled in the art can expect all are included in the present invention, and are protection domain with the appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content of mentioning specially, 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: take by weighing alcohol: α earlier, β-unsaturated imines ester: acetic acid rhodium=1.5: 1.0: 0.01 mol ratios, and with alcohol, α, β-unsaturated imines, acetic acid rhodium and organic solvent add in the reaction flask, add water-retaining agent
Molecular sieve 500-1000mg/mmol, the add-on of organic solvent is 10-30ml/mmol α, β-unsaturated imines ester; Then, the nitranilide ester is dissolved in the organic solvent, the diazonium compound add-on is 1.5mmol/mmol α, and β-unsaturated imines ester obtains diazonium solution, and the amount that is used for the organic solvent of dissolving diazonium is 10-30ml/mmol; Then at room temperature, by peristaltic pump the diazonium drips of solution is added in the reaction flask, dropwised in 1 hour, continue to stir after 2 hours, 40-50 ℃ revolves to boil off and desolventizes, and obtains thick product.Be ethyl acetate with thick product volume ratio: column chromatography in the solution of sherwood oil=1: 20～1: 5 obtains α-amido, the δ-pure product of hydroxyl hexanodioic acid derivative.
Embodiment 1
Take by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of A:
1HNMR(400MHz，CDCl
3)：δ＝2.36(s，3H)，3.49(s，3H)，3.76(s，3H)，4.34(d，J(H，H)＝9.2Hz，1H)，4.64(d，J(H，H)＝9.6Hz，1H)，4.87(d，J(H，H)＝8.4Hz，1H)，6.26(s，1H)，6.93(d，J(H，H)＝6.8Hz，2H)，7.13(m，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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then p-methoxyphenyl diazotate (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of B:
1HNMR(400MHz，CDCl
3)：δ＝2.35(s，3H)，3.49(s，3H)，3.74(s，3H)，3.78(s，3H)，4.28(d，J＝11.7Hz，1H)，4.59(d，J＝11.7Hz，1H)，4.83(d，J＝10.6Hz，1H)，6.31(s，1H)，6.77(d，J＝8.6Hz，2H)，6.94(d，J＝8.2Hz，2H)，7.13(m，6H)，7.27(m，7H)，7.45(d，J(H，H)＝11.9Hz，2H)；
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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then p-methylphenyl diazotate (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of C:
1HNMR(400MHz，CDCl
3)：δ＝2.32(s，3H)，2.36(s，3H)，3.50(s，3H)，3.75(s，3H)，4.34(d，J(H，H)＝9.2Hz，1H)，4.60(d，J(H，H)＝9.2Hz，1H)，4.83(d，J(H，H)＝8.4Hz，1H)，6.29(s，1H)，6.93(d，J(H，H)＝6.4Hz，2H)，7.06(m，4H)，7.13(m，4H)，7.25(m，1H)，7.30(m，3H)，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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then will be dissolved among the methylene dichloride 1ml bromophenyl diazotate (0.3mmol), obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of D:
1HNMR(400MHz，CDCl
3)：δ＝2.39(s，3H)，3.51(s，3H)，3.78(s，3H)，4.29(d，J(H，H)＝11.6Hz，1H)，4.63(d，J(H，H)＝11.6Hz，1H)，4.91(d，J(H，H)＝10.8Hz，1H)，6.24(s，1H)，6.96(d，J(H，H)＝8.8Hz，2H)，7.15(m，6H)，7.28(m，2H)，7.33(m，3H)，7.39(m，4H)，7.47(d，J(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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Bromophenyl diazotate (0.3mmol) is dissolved among the methylene dichloride 1ml between then inciting somebody to action, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of E:
1HNMR(400MHz，CDCl
3)：δ＝2.37(s，3H)，3.50(s，3H)，3.77(s，3H)，4.29(d，J(H，H)＝9.6Hz，1H)，4.63(d，J(H，H)＝9.2Hz，1H)，4.86(d，J(H，H)＝8.4Hz，1H)，6.22(s，1H)，6.93(d，J(H，H)＝6.8Hz，2H)，7.15(m，6H)，7.28(m，2H)，7.33(m，3H)，7.39(m，4H)，7.47(d，J(H，H)＝8.4Hz，2H)；
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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then rubigan diazotate (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of F:
1HNMR(400MHz，CDCl
3)：δ＝2.39(s，3H)，3.51(s，3H)，3.78(s，3H)，4.31(d，J(H，H)＝11.6Hz，1H)，4.63(d，J(H，H)＝11.6Hz，1H)，4.91(d，J(H，H)＝10.8Hz，1H)，6.25(s，1H)，6.96(d，J(H，H)＝8.4Hz，2H)，7.15(m，6H)，7.28(m，2H)，7.33(m，3H)，7.39(m，4H)，7.48(d，J(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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), ortho-nitrophenyl methyl alcohol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative G, yield 56%, dr was greater than 95: 5.
The sign of G:
1HNMR(400MHz，CDCl
3)：δ＝2.25(s，3H)，3.37(s，3H)，3.62(s，3H)，4.60(d，J＝15.1Hz，1H)，4.90(dd，J＝12.8，7.6Hz，2H)，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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), p-nitrophenyl methyl alcohol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of H:
1HNMR(400MHz，CDCl
3)：δ＝2.35(s，3H)，3.46(s，3H)，3.76(s，3H)，4.36(d，J＝13.3Hz，1H)，?4.73(d，J＝13.3Hz，1H)，5.02(d，J＝10.7Hz，1H)，6.17(s，1H)，7.04(d，J＝7.8Hz，1H)，7.13(d，J＝7.8Hz，1H)，7.18(d，J＝7.7Hz，1H)，7.48-7.21(m，4H)，8.18(d，J＝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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), Virahol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative I, yield 95%, dr was greater than 95: 5.
The sign of I:
1HNMR(400MHz，CDCl
3)：δ＝0.97(d，J＝6Hz，3H)，1.17(d，J＝6Hz，3H)，2.42(s，3H)，3.54(s，3H)，3.72(s，3H)，3.86(m，1H)，4.76(d，J＝10Hz，1H)，6.82(d，J＝8.8Hz，2H)，7.10(m，4H)，7.24(m，5H)，7.59(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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), ethanol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of J:
1HNMR(400MHz，CDCl
3)：δ＝1.24(dd，J＝12.8，5.9Hz，3H)，2.37(s，3H)，3.40-3.21(m，1H)，3.52(s，3H)，3.57(m，1H)，3.75(s，3H)，4.65(d，J＝10.6Hz，1H)，6.49(s，1H)，6.83(d，J＝7.7Hz，2H)，7.13-7.02(m，4H)，7.23-7.13(m，6H)，7.54(d，J＝7.6Hz，2H)；
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 by weighing 4-rubigan α, β-unsaturated imines ester (0.20mmol), methyl alcohol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of K:
1HNMR(400MHz，CDCl
3)：δ＝2.36(s，3H)，3.28(s，3H)，3.51(s，3H)，3.77(s，3H)，4.71(d，J＝10.6Hz，1H)，6.33(s，1H)，6.85(d，J＝7.7Hz，2H)，7.13-7.02(m，6H)，7.26-7.12(m，4H)，?7.50(d，J＝7.6Hz，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 by weighing 4-p-methylphenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of L:
1HNMR(400MHz，CDCl
3)：δ＝2.31(s，3H)，2.39(s，3H)，3.54(s，3H)，3.78(s，3H)，4.36(d，J(H，H)＝11.6Hz，1H)，4.60(d，J(H，H)＝12.0Hz，1H)，4.75(d，J(H，H)＝10.4Hz，1H)，6.83(d，J(H，H)＝8.4Hz，1H)，6.97(d，J(H，H)＝8.0Hz，1H)，7.20(m，6H)，7.32(m，4H)，7.54(d，J(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
7S, [M+Na]
+636.2026; Observed value: 636.2031
Embodiment 13
Take by weighing the bromophenyl α of 4-, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of M:
1HNMR(400MHz，CDCl
3)：δ＝2.23(s，3H)，3.42(s，3H)，3.69(s，3H)，4.26(d，J(H，H)＝12.0Hz，1H)，4.56(d，J(H，H)＝12.4Hz，1H)，4.78(d，J(H，H)＝10.8Hz，1H)，6.16(s，1H)，6.79(d，J(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 by weighing bromophenyl α between 4-, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of N:
1HNMR(400MHz，CDCl
3)：δ＝2.27(s，3H)，3.42(s，3H)，3.66(s，3H)，4.25(d，J(H，H)＝12.0Hz，1H)，4.56(d，J(H，H)＝11.6Hz，1H)，4.72(d，J(H，H)＝10.8Hz，1H)，6.26(s，1H)，6.79(d，J?(H，H)＝8.0Hz，1H)，6.90(t，J(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 by weighing the fluorophenyl α of 4-, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative O, yield 78%, dr was greater than 95: 5.
1HNMR(400MHz，CDCl
3)：δ＝2.28(s，3H)，3.43(d，J(H，H)＝5.2Hz，3H)，3.67(s，3H)，4.27(d，J(H，H)＝12.0Hz，1H)，4.54(dd，J(H，H)＝11.6，11.2Hz，1H)，4.75(dd，J(H，H)＝10.8，10.8Hz，1H)，6.22(d，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＝21.50，52.21，52.47，53.40，68.25，88.64，114.45，121.49，125.93，127.04，127.38，127.49，127.72，127.89，128.24，128.33，129.28，130.46，132.04，135.54，136.27?136.43，138.35，138.38，139.07，143.70，164.75，171.50；
HRMS: calculated value: C
34H
32NFNaO
7S, [M+Na]
+640.1776; Observed value: 640.1750
Embodiment 16
Take by weighing 4-phenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and desolventized, again by column chromatography (eluent: sherwood oil: ethyl acetate=1: 20～1: 5) isolate and obtain α-amido, δ-hydroxyl hexanodioic acid derivative P, yield 64%, dr was greater than 95: 5.
The sign of P:
1HNMR(400MHz，CDCl
3)：δ＝2.27(s，3H)，3.43(s，3H)，3.67(s，3H)，4.26(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 by weighing 4-p-nitrophenyl α, β-unsaturated imines ester (0.20mmol), phenylcarbinol (0.30mmol), (1.00mg 0.002mmol), puts into the small test tube reactor with them to the acetic acid rhodium, adds water-retaining agent
Molecular sieve 100mg, the adding 2ml of organic solvent; Then nitranilide ester (0.3mmol) is dissolved among the methylene dichloride 1ml, obtain diazonium solution, injected reaction system in 1 hour by peristaltic pump under the room temperature, injection finished back continuation stirring at normal temperature after 2 hours, filtered, and filtrate is revolved to boil off in 40 ℃ and 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 was greater than 95: 5.
The sign of Q:
1HNMR(400MHz，CDCl
3)：δ＝2.35(s，3H)，3.46(s，3H)，3.77(s，3H)，4.35(d，J＝12.4Hz，2H)，4.68?(d，J＝11.6Hz，2H)，5.13(d，J＝10.8Hz，2H)，6.16(s，1H)，7.15(d，J＝7.5Hz，2H)，7.23-7.32(m，13H)，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.
Claims (8)
1. α-the amido shown in the formula (I), the preparation method of δ-hydroxyl hexanodioic acid derivative is characterized in that, aryl acetate diazonium, pure and mild α, β-unsaturated imines ester reacts synthetic described α-amido, δ-hydroxyl hexanodioic acid derivative under the catalysis of acetic acid rhodium;
In the formula (I), Ar
1For phenyl, have the phenyl of substituted radical; R is benzyl, have substituent benzyl, methyl, ethyl, sec.-propyl; Ar
3For phenyl, have the phenyl of substituted radical; Ts is p-toluenesulfonyl;
Described preparation method's reaction formula is:
Wherein, Ar
1For phenyl, have the phenyl of substituted radical; R is benzyl, have substituent benzyl, methyl, ethyl, sec.-propyl; Ar
3For phenyl, have the phenyl of substituted radical; Ts is p-toluenesulfonyl.
2. preparation method as claimed in claim 1 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).
3. preparation method as claimed in claim 1 is characterized in that, described aryl acetate diazonium: alcohol: α, β-unsaturated
Imines: the mol ratio of acetic acid rhodium=1.5: 1.5: 1.0: 0.01.
4. preparation method as claimed in claim 1 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 1 is characterized in that, described α, β-unsaturated imines ester is 4-rubigan α, β-unsaturated imines ester, the bromophenyl α of 4-, β-unsaturated imines ester, bromophenyl α between 4-, β-unsaturated imines ester, the fluorophenyl α of 4-, 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 1, it is characterized in that, described aryl acetate diazonium is the 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 1 is characterized in that, described preparation method comprises: with alcohol, and α, β-unsaturated imines ester, acetic acid rhodium and organic solvent add in the 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, the nitranilide ester is dissolved in obtains diazonium solution in the organic solvent, wherein, the amount that is used for the organic solvent of dissolving diazonium is 10-30ml/mmol; Then at room temperature, by peristaltic pump the diazonium drips of solution is added in the 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.
8. preparation method as claimed in claim 7 is characterized in that, described organic solvent is chloroparaffin, toluene or dimethylbenzene.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310090604 CN103242209A (en) | 2013-03-20 | 2013-03-20 | Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives |
| CN201310573510.3A CN104058998B (en) | 2013-03-20 | 2013-11-15 | α-amido, δ-hydroxyl hexanodioic acid derivative and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310090604 CN103242209A (en) | 2013-03-20 | 2013-03-20 | Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103242209A true CN103242209A (en) | 2013-08-14 |
Family
ID=48922115
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201310090604 Pending CN103242209A (en) | 2013-03-20 | 2013-03-20 | Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives |
| CN201310573510.3A Expired - Fee Related CN104058998B (en) | 2013-03-20 | 2013-11-15 | α-amido, δ-hydroxyl hexanodioic acid derivative and its preparation method and application |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310573510.3A Expired - Fee Related CN104058998B (en) | 2013-03-20 | 2013-11-15 | α-amido, δ-hydroxyl hexanodioic acid derivative and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN103242209A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104649917A (en) * | 2015-01-09 | 2015-05-27 | 华东师范大学 | Ternary cyclobutane derivative containing beta-amino acid as well as synthesis method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245809B1 (en) * | 1996-12-09 | 2001-06-12 | Cor Therapeutics Inc. | Integrin antagonists |
| US8445706B2 (en) * | 2008-09-05 | 2013-05-21 | Board Of Trustees Of Northern Illinois University | Unnatural amino acids capable of covalently modifying protein phosphatases and their use as general and specific inhibitors and probes |
| CN102234231B (en) * | 2010-04-26 | 2015-01-07 | 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 |
| CN102491931B (en) * | 2011-11-11 | 2014-04-16 | 华东师范大学 | 3-substituted indolone derivative and preparation method and application thereof |
-
2013
- 2013-03-20 CN CN 201310090604 patent/CN103242209A/en active Pending
- 2013-11-15 CN CN201310573510.3A patent/CN104058998B/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104649917A (en) * | 2015-01-09 | 2015-05-27 | 华东师范大学 | Ternary cyclobutane derivative containing beta-amino acid as well as synthesis method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104058998B (en) | 2016-04-06 |
| CN104058998A (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102040625B (en) | Chiral spiro pyridylamidophosphine ligand compounds and synthesis method and application thereof | |
| CN101657462B (en) | The preparation method and intermediates of capecitabine | |
| CN102984945B (en) | An enantioselective process for cycloalkenyl [beta]-substituted alanines | |
| CN111072605B (en) | Preparation method of fluoroalkyl-substituted benzofuran derivative or indole derivative | |
| CN103910676B (en) | A kind of synthetic method of polysubstituted tetrahydro isoquinoline derivative | |
| CN105175365B (en) | A kind of method of the β benzyl butyrolactone efficiently synthesized with particular configuration | |
| CN103242209A (en) | Preparation method of alpha-amido, delta-hydroxyl adipic acid derivatives | |
| CN1724519B (en) | Indole kind compound with insuline sensitizing activity and its preparation method and use | |
| CN101575298A (en) | Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol | |
| CN107445935A (en) | A kind of hesperetin analog derivative of amide groups substitution and its preparation and as the application in the medicine of anti-inflammatory | |
| CN103044277B (en) | Preparation method of optical pure alpha-hydroxyl-beta-aminopropionic acid ester derivative | |
| CN101318896B (en) | Method for synthesizing cis-alpha-allyl-beta, gamma-unsaturated carboxylic acid ester | |
| CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
| CN102887808B (en) | Preparation method of multi-substituted indanol derivatives | |
| CN107266311B (en) | Method for continuously preparing α -keto ester by using microfluid chip reactor | |
| CN103274957B (en) | The synthetic method of α, α-disubstituted amido acid derivative | |
| CN104059049A (en) | Benzo dioxy heterocyclic derivatives with optical activity and preparation method and application thereof | |
| CN114702425A (en) | Preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and intermediate | |
| CN103204786A (en) | Co-catalyzing preparation method of alpha, betal-diamino acid derivative of alpha-quaternary carbon | |
| CN104058980A (en) | Alpha-amino beta-hydroxy amino acid derivative with optical activity and preparation method and application thereof | |
| CN105085278A (en) | Method for preparing 2-methyl-1-substituted phenyl-2-propyl amine compound | |
| CN106866511A (en) | A kind of preparation method of polysubstituted pyridine derivative | |
| CN115697968A (en) | Preparation method of (S) -2-amino-3- (4- (2, 3-dimethylpyridin-4-yl) phenyl methyl propionate and salt thereof | |
| CN103204833A (en) | Preparation method of fully-substituted tetrahydrofuran derivative | |
| CN105294471A (en) | Synthetic method of alpha-amido-gamma-nitro succinate derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130814 |