CN112920066A - Alpha-substituted-alpha-amino acid ester compound and preparation method thereof - Google Patents
Alpha-substituted-alpha-amino acid ester compound and preparation method thereof Download PDFInfo
- Publication number
- CN112920066A CN112920066A CN202110096999.4A CN202110096999A CN112920066A CN 112920066 A CN112920066 A CN 112920066A CN 202110096999 A CN202110096999 A CN 202110096999A CN 112920066 A CN112920066 A CN 112920066A
- Authority
- CN
- China
- Prior art keywords
- amino acid
- alpha
- substituted
- acid ester
- butyl
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention discloses an alpha-substituted-alpha-amino acid ester compound and a preparation method thereof. Adding aromatic amine and alkenyl ether into a reactor, dissolving in a solvent, reacting under the action of a palladium catalyst, a ligand and an oxidant, and separating and purifying to obtain the alpha-substituted-alpha-amino acid ester compound, wherein the reaction formula of the preparation method is shown as the formula (I). The method takes the alkenyl ether and the aromatic amine which are simple and easy to obtain as reaction raw materials to synthesize a series of alpha-substituted-alpha-amino acid ester compounds, and has the characteristics of simple and easy-to-obtain raw materials, convenient operation, mild conditions, high step atom economy, wide substrate applicability, good functional group tolerance and the like.
Description
Technical Field
The invention relates to the technical field of medicine and organic chemical synthesis, in particular to an alpha-substituted-alpha-amino acid ester compound and a preparation method thereof.
Background
The amino acid ester compound has amino and ester functional groups with relatively close space in the structure and a plurality of nitrogen and oxygen atoms with different chemical environments, so the amino acid ester compound is widely applied in the fields of medicine, agriculture, fine chemical engineering and the like. At present, the precise synthesis of multi-substituted and multi-functionalized complex amine compounds is always a very challenging subject.
Currently, there are relatively few methods for synthesizing α -substituted- α -amino acid esters, and three synthetic strategies are generally adopted, namely esterification of α -substituted- α -amino acids (org.lett.2019,21, 4873.; j.med.struc.2020,1209, 127974.; synthesis.2017,49,770.; org.biomol.chem.2020,18,6949.), a second commonly used strategy of nucleophilic substitution with amines at the α -position of the ester group (j.am.chem.soc.2004,126, 10846.; RSC adv.2013,3,17527.; New j.chem.2015,39,2657.), and a third of electrophilic substitution on the α -C of α -amino acid esters (angels.chem.ed.2012, 51,10808.). Although the above synthesis methods have made remarkable research progress in the construction of α -substituted- α -amino acid esters, the three synthesis methods have certain disadvantages, such as the need for pre-functionalization of raw materials (org. lett.2013,13, 3222.; j.am.chem.soc.2004,126,10846.), introduction of halogen atoms into the system (org. lett.2010,12,1936.;), harsh reaction conditions (angelw. chem.int.ed.2012,51,10808.), and the need for deprotection of amine groups (org. biomol.chem.2012,10,1565.), and thus it is very important to develop efficient and convenient synthesis methods for α -substituted- α -amino acid esters. Our group developed a new palladium-catalyzed electron-rich olefin tandem amination/oxidation process without a directing group to synthesize alpha-amino acid esters in 2017 (angelw. chem. int. ed.2017,56,15926.). However, the conditions of this reaction are not suitable for the internal olefin ether, and the synthesis of the α -substituted- α -amino acid ester cannot be carried out. Also, it can be seen from the existing synthesis techniques that the activity of internal olefins tends to be lower than that of terminal olefins, which is a ubiquitous limitation (Angew. chem. int. Ed.2010,49,1238.; org. Lett.2017,19,5717.; Angew. chem. int. Ed.2018,57,14911.).
On the other hand, a wide variety of ionic liquids can improve the homogeneous catalytic efficiency in metal-catalyzed reactions (Nature.2006,439, 831.; science.2003,302, 792.; chem. Commun.2006, 1049.). It is worth mentioning that the cations of ionic liquids are more accessible to charged centers (chem.commun.2018,54,2296.) and this process tends to promote many chemical reactions to proceed smoothly. In palladium-catalyzed reactions, ionic liquids can generally act as solvents or ligands, among others (Catal. Sci. technol.2021, DOI: 10.1039/D0CY01941K.; Catal. A.2020,599, 117599.; Org. Lett.2014,16,3008.; Org. Lett.2006,8,5199.). In the process, if the pure ionic environment of the ionic liquid is applied to the palladium-catalyzed coupling reaction, the mechanism and the route of the coupling reaction are possibly different from those of the traditional molecular solvent, so that a novel synthesis strategy is provided for the synthesis of complex multi-functionalized molecules. Therefore, the palladium-catalyzed olefin double-functionalization process is combined with the advantages of the ionic liquid, so that breakthrough of the traditional technical process can be realized on the synthesis method, and the original barriers of certain reactions are overcome. In conclusion, the development of a synthetic method with simple operation and simple and easily-obtained raw materials by using the alkenyl ether derivative as a substrate to construct the alpha-substituted-alpha-amino acid ester compound with diversified structures still remains a challenging research subject.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention aims to provide an alpha-substituted-alpha-amino acid ester compound and a preparation method thereof. The method takes aromatic amine as a substrate, and alkenyl ether and the aromatic amine react to obtain the alpha-substituted-alpha-amino acid ester compound with diversified structures. The method has the advantages of easily available raw materials, simple operation and strong functional group tolerance, and provides an important technical support for the efficient synthesis of the alpha-substituted-alpha-amino acid ester derivatives with potential biological and pharmacological activities.
The purpose of the invention is realized by the following technical scheme:
an alpha-substituted-alpha-amino acid ester compound, the structural formula of which is:
wherein R is1Hydrogen, methyl, ethyl, pentyl, allyl, benzyl;
R2is benzene, o-methylbenzene, m-methylbenzene, p-methylbenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-tert-butylbenzene, 4-methoxybenzene, 4-trifluoromethylbenzene, 2, 4-dichlorobenzene, mesitylene, naphthalene, benzyl and benzo seven-membered rings;
R3is methyl, ethyl, phenyl, 2, 4-difluorophenyl, 4-methoxyphenyl or benzyl;
R4methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexane, hydroxyethyl, 2-chloroethyl, phenyl, benzyl, allyl, thienylmethyl.
The preparation method of the alpha-substituted-alpha-amino acid ester compound comprises the following steps:
in a solvent, aromatic amine and alkenyl ether react under the action of a palladium catalyst, a ligand and an oxidant to obtain the alpha-substituted-alpha-amino acid ester compound.
The aromatic amine is
Alkenyl ether is
Wherein R is1Hydrogen, methyl, ethyl, pentyl, allyl, benzyl;
R2is benzene, o-methylbenzene, m-methylbenzene, p-methylbenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-tert-butylbenzene, 4-methoxybenzene, 4-trifluoromethylbenzene, 2, 4-dichlorobenzene, mesitylene, naphthalene, benzyl and benzo seven-membered rings;
R3is methyl, ethyl, phenyl, 2, 4-difluorophenyl, 4-methoxyphenyl or benzyl;
R4is methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexane, hydroxyethyl, 2-chloroethyl, phenyl, benzyl, alkenePropyl, thienylmethyl.
Preferably, the aromatic amine is aniline, mesitylene, 3, 4-dichloroaniline, N-methylaniline, N-ethylaniline, N-pentylaniline, N-allylaniline, p-methoxy-N-methylaniline, p-trifluoromethyl-N-methylaniline, o-methyl-N-methyl, m-methyl-N-methylaniline, p-methyl-N-methylaniline, dibenzylamine, N-methylnaphthylamine;
preferably, the alkenyl ether is vinyl ethyl ether, vinyl n-butyl ether, vinyl cyclohexyl ether, vinyl phenyl ether, vinyl benzyl ether, vinyl-2-hydroxyethyl ether, vinyl allyl ether, propenyl ethyl ether, 1-butenylether, styrylether, 2-benzylvinyl ethyl ether.
Preferably, the catalyst is palladium chloride, bis (triphenylphosphine) palladium dichloride (i.e. bis (triphenylphosphine) palladium dichloride), palladium trifluoroacetate, bis (acetonitrile) palladium dichloride, bis (benzonitrile) palladium dichloride, bis (allyl) palladium dichloride (i.e. allyl palladium chloride dimer), or palladium acetate;
preferably, the ligand is 2, 2-bipyridine, 4-dimethoxy-2, 2-bipyridine, 4-dimethyl-2, 2-bipyridine, 6-dimethyl-2, 2-bipyridine, phenanthroline, 5-dimethyl-2, 2-bipyridine or 4, 5-diazafluoren-9-one.
Preferably, the oxidizing agent is one of benzoquinone, o-chloranil, naphthoquinone, iodobenzene acetate, manganese dioxide, sodium periodate and benzoyl peroxide.
Preferably, the solvent is an organic solvent or an ionic liquid, preferably an ionic liquid;
further preferably, the organic solvent is polyethylene glycol, N-dimethylformamide, dimethyl sulfoxide, toluene or 1, 4-dioxane; the ionic liquid is preferably imidazole type ionic liquid;
more preferably, the imidazole type ionic liquid is preferably a 1-butyl-3-methylimidazole type ionic liquid, and includes at least one of 1-butyl-3-methylimidazole chloride salt, 1-butyl-3-methylimidazole tetrafluoroborate, 1-butyl-3-methylimidazole hexafluorophosphate, 1-butyl-3-methylimidazole acetate and 1-butyl-3-methylimidazole bromide salt.
Preferably, the reaction conditions are as follows: the reaction temperature is 0-120 ℃; more preferably 20 to 35 ℃.
Preferably, the reaction time is 8-24 h.
Preferably, the reaction is carried out in an air atmosphere.
Preferably, the molar ratio of the aromatic amine to the alkenyl ether is 1 (2-4).
Preferably, the molar ratio of the catalyst to the aromatic amine is (0.05-0.2): 1.
Preferably, the molar ratio of the oxidant to the aromatic amine is (1-6): 1.
Preferably, the reaction is followed by subsequent treatment (separation and purification): and extracting, concentrating and purifying by column chromatography.
More preferably, the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is (50-500): 1.
The reaction equation of the synthesis method of the invention is as follows:
the principle of the invention is that palladium is used as a catalyst in the air atmosphere, aromatic amine and alkenyl ether are used as raw materials, and a series of alpha-substituted-alpha-amino acid ester compounds are synthesized by a one-step method through amination oxidation reaction catalyzed by palladium. All the raw materials in the method are cheap and easy to obtain, the method is simple and easy to implement, and the operation is safe, so that the method has potential application value.
Compared with the prior art, the invention has the following advantages and effects:
the method successfully synthesizes the alpha-substituted-alpha-amino acid ester compound, and has the advantages of low price of raw materials, easy obtainment, safe and simple operation, strong functional group tolerance, wide substrate universality range, mild reaction conditions and high yield.
Drawings
FIG. 1 is a hydrogen spectrum of the product obtained in example 15;
FIG. 2 is a carbon spectrum of the product obtained in example 15;
FIG. 3 is a hydrogen spectrum of the product obtained in example 16;
FIG. 4 is a carbon spectrum of the product obtained in example 16;
FIG. 5 is a hydrogen spectrum of the product obtained in example 17;
FIG. 6 is a carbon spectrum diagram of the product obtained in example 17;
FIG. 7 is a hydrogen spectrum of the product obtained in example 18;
FIG. 8 is a carbon spectrum of the product obtained in example 18;
FIG. 9 is a hydrogen spectrum of the product obtained in example 19;
FIG. 10 is a carbon spectrum of the product obtained in example 19;
FIG. 11 is a hydrogen spectrum of the product obtained in example 20;
FIG. 12 is a carbon spectrum of the product obtained in example 20;
FIG. 13 is a hydrogen spectrum of the product obtained in example 21;
FIG. 14 is a carbon spectrum of the product obtained in example 21.
Detailed Description
The present invention is described in further detail below with reference to specific examples, but the embodiments and the scope of the present invention are not limited thereto. The high tolerance of the reaction functional group means that groups which are easy to convert such as halogen, chlorine and bromine can be reserved; the compound can also be applicable to heterocyclic rings containing nitrogen, sulfur and oxygen; for substituents containing alkenes, the alkenyl group can also remain unoxidized or converted.
Example 1
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium dichloride, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether and 1mL of [ Bmim ] were added under an air atmosphere]PF60.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying with 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum with a volume ratio of 100:1The yield of the mixed solvent of ether and ethyl acetate was 19%.
Example 2
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] were added under an air atmosphere]PF60.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 28%.
Example 3
In a 15mL test tube, 10% (10% of the molar amount of N-ethylaniline) of palladium acetate, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] were added under an air atmosphere]PF60.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 28%.
Example 4
In an air atmosphere, 5 percent (5 percent of molar amount of N-ethylaniline) palladium acetate, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ether, 1mL of DMF and 0.2mmol of hydrogen peroxide are added into a 15mL test tube, stirring is stopped after stirring reaction is carried out for 12 hours at room temperature, 5mL of water is added, extraction is carried out for 3 times by using ethyl acetate, organic phases are combined and dried by using 0.5g of anhydrous sodium sulfate, filtration and concentration under reduced pressure are carried out, and then separation and purification are carried out by thin layer chromatography, so as to obtain a target product, wherein a thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 9%.
Example 5
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 0.10mmol of N-ethylaniline and 0.20mmol of ethylene were added under an air atmosphereEthyl ether, 1mL [ Bmim ]]BF40.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 38%.
Example 6
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 46%.
Example 7
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 4, 4-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.2mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 44%.
Example 8
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.2mmol of bisAnd (2) adding oxygen water, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 75%.
Example 9
In an air atmosphere, 5 percent (5 percent of molar amount of N-ethylaniline) palladium acetate, 5 percent (5 percent of molar amount of N-ethylaniline) 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ether, 1mL of DMF and 0.2mmol of hydrogen peroxide are added into a 15mL test tube, stirring is stopped after stirring reaction is carried out for 12 hours at room temperature, 5mL of water is added, extraction is carried out for 3 times by using ethyl acetate, organic phases are combined and dried by using 0.5g of anhydrous sodium sulfate, filtration and concentration under reduced pressure are carried out, and then separation and purification are carried out by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 40%.
Example 10
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.1mmol of hydrogen peroxide and 0.1mmol of benzoquinone are stirred at room temperature for 12 hours, then the stirring is stopped, 5mL of water is added, extraction is carried out for 3 times by ethyl acetate, organic phases are combined and dried by 0.5g of anhydrous sodium sulfate, filtration and decompression concentration are carried out, and then separation and purification are carried out by thin layer chromatography, thus obtaining the target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 49%.
Example 11
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.3mmol of hydrogen peroxide, and stirring at room temperatureAfter 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with a volume ratio of 100: 1: ethyl acetate mixed solvent, yield 86%.
Example 12
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.3mmol of hydrogen peroxide, stirring and reacting for 12 hours at 50 ℃, stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 67%.
Example 13
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.3mmol of hydrogen peroxide, stirring and reacting for 12 hours at 120 ℃, stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 31%.
Example 14
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.3mmol of hydrogen peroxide, stirring at room temperature for 24 hours, and stopping stirringAdding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with a volume ratio of 100: 1: ethyl acetate mixed solvent, yield 87%.
Example 15
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethoxy-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.30mmol of vinyl ethyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.3mmol of hydrogen peroxide, stirring and reacting for 12 hours at room temperature, stopping stirring, adding 5mL of water, extracting for 3 times by ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 100: 1: ethyl acetate mixed solvent, yield 91%.
The structural characterization data of the product obtained in example 15 are as follows (nuclear magnetic spectrum as shown in fig. 1 (hydrogen-spectrum) and fig. 2 (carbon-spectrum)):
1H NMR(400MHz,CDCl3)δ7.20(t，J＝7.6Hz,2H),6.70(t,J＝7.2Hz,1H)，6.64(d,J＝7.6Hz,2H)，4.18(q,J＝7.2Hz,2H)，4.00(s，2H),3.46(q,J＝7.2Hz,2H)，1.25(t,J＝7.0Hz,3H)，1.20(t,J＝7.0Hz,3H).
13C NMR(100MHz,CDCl3)δ171.3,147.8,129.2,116.8,112.0,60.8,52.3,46.0,14.2,12.4ppm.
IR(KBr):3554,3304,3073,2976,1747,1605,1508,1192,1027,751cm-1.
HRMS-ESI(m/z):calculated for[C11H15NO2+Na]+:216.0995，found 216.0996.
the structure of the resulting product was deduced from the above data as follows:
example 16
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of 4-bromo-N-methylaniline, 0.20mmol of vinyl ether, and 1mL of [ Bmim ]]BF40.4mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 200: 1: ethyl acetate mixed solvent, yield 50%.
The structural characterization data of the product obtained in example 16 are as follows (nuclear magnetic spectrum as shown in fig. 3 (hydrogen-spectrum) and fig. 4 (carbon-spectrum)):
1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.0Hz,2H),6.54(d,J＝8.4Hz,2H)，4.17(q,J＝7.2Hz,2H),4.02(s,2H),3.03(s,3H),1.24(t,J＝7.4Hz,3H).
13C NMR(100MHz,CDCl3)δ170.5,147.9,131.8,113.9,109.3,61.0,54.4,39.6,14.2ppm.
IR(KBr):3366,2950,1738,1493,1199,805cm-1.
HRMS-ESI(m/z):calculated for[C11H14NO2Br+Na]+:294.0100，found 294.0104.
the structure of the resulting product was deduced from the above data as follows:
example 17
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of dibenzylamine, 0.20mmol of vinyl ethyl ether, and 1mL of [ Bmim ]]BF40.4mmol of hydrogen peroxide, stirring and reacting for 12 hours at room temperature, and stopping reactionStirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with a volume ratio of 500: 1: ethyl acetate mixed solvent, yield 72%.
The structural characterization data of the product obtained in example 17 are as follows (nuclear magnetic spectrum as shown in fig. 5 (hydrogen-spectrum) and fig. 6 (carbon-spectrum)):
1H NMR(500MHz,CDCl3)δ7.38(d,J＝8.0Hz,4H),7.30(t,J＝7.5Hz,4H),7.22(t,J＝7.3Hz,2H),4.13(q,J＝7.2Hz,2H),3.80(s,4H),3.27(s,2H),1.24(t,J＝7.3Hz,3H).
13C NMR(125MHz,CDCl3)δ171.3,139.0,128.8,128.2,127.0,60.1,57.7,53.5,14.2ppm.
IR(KBr):2843,1724,1466,1190,723cm-1.
HRMS-ESI(m/z):calculated for[C18H21NO2+H]+:284.1645，found 284.1650.
the structure of the resulting product was deduced from the above data as follows:
example 18
In a 15mL test tube, 10% (10% of the molar amount of N-ethylaniline) of palladium acetate, 10% (10% of the molar amount of N-ethylaniline) of 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinylphenyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.4mmol of hydrogen peroxide, stirring at room temperature for 16 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 50: 1: ethyl acetate mixed solvent, yield 52%.
The structural characterization data of the product obtained in example 18 are as follows (nuclear magnetic spectrum as shown in fig. 7 (hydrogen-spectrum) and fig. 8 (carbon-spectrum)):
1H NMR(400MHz,CDCl3)δ7.34(t,J＝7.6Hz,2H),7.25(t,J＝7.9Hz,3H),7.06(d,J＝8.0Hz,2H),6.83-6.68(m,3H),4.26(s,2H),3.55(q,J＝7.1Hz,2H),1.26(t,J＝5.3Hz,3H).
13C NMR(100MHz,CDCl3)δ170.1,150.5,147.6,129.4,129.4,125.9,121.3,117.2,112.2,52.6,46.2,29.7,12.6ppm.
IR(KBr):3371,2975,1751,1487,1146,738cm-1.
HRMS-ESI(m/z):calculated for[C16H17NO2+Na]+:278.1151，found 278.1150.
the structure of the resulting product was deduced from the above data as follows:
example 19
In a 15mL test tube, 5% (5% of the molar amount of N-ethylaniline) of palladium acetate, 5% (5% of the molar amount of N-ethylaniline) of 5, 5-dimethyl-2, 2-bipyridine, 0.10mmol of N-ethylaniline, 0.20mmol of vinyl allyl ether, and 1mL of [ Bmim ] in an air atmosphere]BF40.4mmol of hydrogen peroxide, stirring and reacting for 12 hours at room temperature, stopping stirring, adding 5mL of water, extracting for 3 times by using ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 500: 1: ethyl acetate mixed solvent, yield 56%.
The structural characterization data of the product obtained in example 19 are as follows (nuclear magnetic spectrum as shown in fig. 9 (hydrogen-spectrum) and fig. 10 (carbon-spectrum)):
1H NMR(400MHz,CDCl3)δ7.21(t,J＝7.4Hz,2H),6.71(t,J＝7.3Hz,1H),6.65(d,J＝7.9Hz,2H),5.90(ddt,J＝16.7,11.2,5.7Hz,1H),5.26(dd,J＝26.1,13.8Hz,2H),4.63(d,J＝5.6Hz,2H),4.05(s,2H),3.47(q,J＝7.0Hz,2H),1.21(t,J＝7.1Hz,3H).
13C NMR(100MHz,CDCl3)δ171.0,147.7,131.8,129.2,118.5,116.9,112.1,65.5,52.2,46.0,12.4ppm.
IR(KBr):2948,1743,1600,1501,1368,1179,981,747cm-1.
HRMS-ESI(m/z):calculated for[C13H17NO2+Na]+:242.1151,found 242.1156.
the structure of the resulting product was deduced from the above data as follows:
example 20
In a 15mL test tube, 10% (10% of the molar amount of N-ethylaniline) of palladium acetate, 10% (10% of the molar amount of N-ethylaniline) of 4, 5-diazafluoren-9-one, 0.10mmol of N-ethylaniline, 0.20mmol of propylene ethyl ether, and 1mL of [ Bmim ]]BF40.6mmol of hydrogen peroxide, stirring at room temperature for 12 hours, stopping stirring, adding 5mL of water, extracting with ethyl acetate for 3 times, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 200: 1: ethyl acetate mixed solvent, yield 86%.
The structural characterization data of the product obtained in example 20 are as follows (nuclear magnetic spectrum as shown in fig. 11 (hydrogen-spectrum) and fig. 12 (carbon-spectrum)):
1H NMR(500MHz,CDCl3)δ7.28(t,J＝7.9Hz,2H),6.80(dd,J＝8.0Hz,3H),4.48(q,J＝7.2Hz,1H),4.22(dd,J＝3.8,2H),3.47(q,J＝7.2Hz,2H),1.57(d,J＝7.2Hz,3H),1.29(t,J＝6.1Hz,3H),1.27(t,J＝5.7Hz,3H).
13C NMR(125MHz,CDCl3)δ173.7,148.1,129.1,117.2,113.6,60.7,57.1 41.5,15.9,14.4,14.1ppm.
IR(KBr):2973,1732,1598,1500,1190,750cm-1.
HRMS-ESI(m/z):calculated for[C13H19NO2+H]+:222.1489,found 222.1493.
the structure of the resulting product was deduced from the above data as follows:
example 21
In a 15mL test tube, 10% (10% of the molar amount of N-ethylaniline) of palladium acetate, 10% (10% of the molar amount of N-ethylaniline) of 4, 5-diazafluoren-9-one, 0.10mmol of N-ethylaniline, 0.20mmol of styrene ethyl ether, and 1mL of [ Bmim ]]BF40.6mmol of hydrogen peroxide, stirring and reacting for 20 hours at room temperature, stopping stirring, adding 5mL of water, extracting for 3 times by ethyl acetate, combining organic phases, drying by using 0.5g of anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying by thin layer chromatography to obtain a target product, wherein the thin layer chromatography developing agent is petroleum ether with the volume ratio of 400: 1: ethyl acetate mixed solvent, yield 51%.
The structural characterization data of the product obtained in example 21 are as follows (nuclear magnetic spectrum as shown in fig. 13 (hydrogen-spectrum) and fig. 14 (carbon-spectrum)):
1H NMR(400MHz,CDCl3)δ7.35(d,J＝4.9Hz,5H),7.25(t,J＝8.0Hz,2H),6.86(d,J＝8.2Hz,2H),6.79(t,J＝7.3Hz,1H),5.52(s,1H),4.24-4.20(m,1H),3.33(d,J＝7.0Hz,2H),1.23(t,J＝7.1Hz,3H),0.91(t,J＝7.0Hz,3H).
13C NMR(100MHz,CDCl3)δ172.0,148.5,136.1,129.2,128.9,128.5,128.1,118.2,114.5,66.3,61.1,42.5,14.2,13.4ppm.
IR(KBr):2955,1735,1592,1493,1173,748cm-1.
HRMS-ESI(m/z):calculated for[C18H21NO2+H]+:284.1640,found 284.1645.
the structure of the resulting product was deduced from the above data as follows:
the above examples of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. An alpha-substituted-alpha-amino acid ester compound is characterized in that the structural formula is as follows:
wherein R is1Hydrogen, methyl, ethyl, pentyl, allyl, benzyl;
R2is benzene, o-methylbenzene, m-methylbenzene, p-methylbenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-tert-butylbenzene, 4-methoxybenzene, 4-trifluoromethylbenzene, 2, 4-dichlorobenzene, mesitylene, naphthalene, benzyl and benzo seven-membered rings;
R3is methyl, ethyl, phenyl, 2, 4-difluorophenyl, 4-methoxyphenyl or benzyl;
R4methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexane, hydroxyethyl, 2-chloroethyl, phenyl, benzyl, allyl, thienylmethyl.
2. The method for producing an α -substituted- α -amino acid ester compound according to claim 1, comprising the steps of:
in a solvent, aromatic amine and alkenyl ether react under the action of a palladium catalyst, a ligand and an oxidant to obtain an alpha-substituted-alpha-amino acid ester compound;
the aromatic amine is
Alkenyl ether is
Wherein R is1Hydrogen, methyl, ethyl, pentyl, allyl, benzyl;
R2is benzene, o-methylbenzene, m-methylbenzene, p-methylbenzene, 4-fluorobenzene, 4-chlorobenzene, 4-bromobenzene, 4-tert-butylbenzene, 4-methoxybenzene, 4-trifluoromethylbenzene, 2, 4-dichlorobenzene, mesitylene, naphthalene, benzyl and benzo seven-membered rings;
R3is methyl, ethyl, phenyl, 2, 4-difluorophenyl, 4-methoxyphenyl or benzyl;
R4methyl, ethyl, n-butyl, isobutyl, tert-butyl, cyclohexane, hydroxyethyl, 2-chloroethyl, phenyl, benzyl, allyl, thienylmethyl.
3. The method for producing α -substituted- α -amino acid ester compounds according to claim 2,
the palladium catalyst is palladium chloride, dichlorobis (triphenylphosphine) palladium, palladium trifluoroacetate, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, bis (allyl) palladium dichloride or palladium acetate;
the ligand is 2, 2-bipyridyl, 4-dimethoxy-2, 2-bipyridyl, 4-dimethyl-2, 2-bipyridyl, 6-dimethyl-2, 2-bipyridyl, phenanthroline, 5-dimethyl-2, 2-bipyridyl or 4, 5-diazafluoren-9-one;
the oxidant is one of benzoquinone, o-chloranil, naphthoquinone, iodobenzene acetate, manganese dioxide, sodium periodate and benzoyl peroxide.
4. The method for producing α -substituted- α -amino acid ester compounds according to claim 2, wherein the solvent is an organic solvent or an ionic liquid.
5. The method for producing α -substituted- α -amino acid ester compounds according to claim 4, wherein the organic solvent is polyethylene glycol, N-dimethylformamide, dimethyl sulfoxide, toluene or 1, 4-dioxane; the ionic liquid is imidazole type ionic liquid.
6. The method for synthesizing α -substituted- α -amino acid ester compounds according to claim 5, wherein the imidazole-type ionic liquid is 1-butyl-3-methylimidazole-type ionic liquid.
7. The method for producing α -substituted- α -amino acid ester compounds according to claim 6, wherein the 1-butyl-3-methylimidazole-type ionic liquid is one or more of 1-butyl-3-methylimidazole chloride salt, 1-butyl-3-methylimidazole tetrafluoroborate salt, 1-butyl-3-methylimidazole hexafluorophosphate salt, 1-butyl-3-methylimidazole acetate salt, and 1-butyl-3-methylimidazole bromide salt.
8. The method for producing α -substituted- α -amino acid ester compounds according to claim 2,
the reaction is carried out in an air atmosphere;
the reaction temperature is 0-120 ℃, and the reaction time is 8-24 h;
the molar ratio of the aromatic amine to the alkenyl ether is 1 (2-4);
the molar ratio of the palladium catalyst to the aromatic amine is (0.05-0.2) to 1;
the molar ratio of the oxidant to the aromatic amine is (1-6): 1.
9. The method for synthesizing alpha-substituted-alpha-amino acid ester compounds according to claim 8, wherein the reaction temperature is 20-35 ℃.
10. The method for producing α -substituted- α -amino acid ester compounds according to claim 2, wherein the reaction is completed and then subjected to a post-treatment: and extracting, concentrating and purifying by column chromatography.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110096999.4A CN112920066A (en) | 2021-01-25 | 2021-01-25 | Alpha-substituted-alpha-amino acid ester compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110096999.4A CN112920066A (en) | 2021-01-25 | 2021-01-25 | Alpha-substituted-alpha-amino acid ester compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112920066A true CN112920066A (en) | 2021-06-08 |
Family
ID=76167055
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110096999.4A Pending CN112920066A (en) | 2021-01-25 | 2021-01-25 | Alpha-substituted-alpha-amino acid ester compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112920066A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773221A (en) * | 2021-10-08 | 2021-12-10 | 湖北工业大学 | P-benzoquinone compound and preparation method thereof |
| CN115322100A (en) * | 2022-08-30 | 2022-11-11 | 南京工业大学 | Delta, epsilon-alkenyl ketone compound and preparation method and application thereof |
| CN115894299A (en) * | 2022-12-06 | 2023-04-04 | 华南理工大学 | Preparation method of axial chiral carbamate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270076A (en) * | 2008-05-13 | 2008-09-24 | 复旦大学 | Method for preparing natural product (3S,9S)-Ciliatamides C |
| CN103113247A (en) * | 2013-03-13 | 2013-05-22 | 苏州大学 | Method for preparing amino-acid ester |
| CN103896782A (en) * | 2012-12-26 | 2014-07-02 | 北京奥得赛化学股份有限公司 | Method of preparing 2-(N, N- dimethylamino)-2 phenyl butanol |
| CN107011195A (en) * | 2017-03-31 | 2017-08-04 | 华南理工大学 | A kind of method by catalysis oxidation one-step synthesis alpha amino acid ester type compound |
-
2021
- 2021-01-25 CN CN202110096999.4A patent/CN112920066A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270076A (en) * | 2008-05-13 | 2008-09-24 | 复旦大学 | Method for preparing natural product (3S,9S)-Ciliatamides C |
| CN103896782A (en) * | 2012-12-26 | 2014-07-02 | 北京奥得赛化学股份有限公司 | Method of preparing 2-(N, N- dimethylamino)-2 phenyl butanol |
| CN103113247A (en) * | 2013-03-13 | 2013-05-22 | 苏州大学 | Method for preparing amino-acid ester |
| CN107011195A (en) * | 2017-03-31 | 2017-08-04 | 华南理工大学 | A kind of method by catalysis oxidation one-step synthesis alpha amino acid ester type compound |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113773221A (en) * | 2021-10-08 | 2021-12-10 | 湖北工业大学 | P-benzoquinone compound and preparation method thereof |
| CN113773221B (en) * | 2021-10-08 | 2023-09-29 | 湖北工业大学 | P-benzoquinone compound and preparation method thereof |
| CN115322100A (en) * | 2022-08-30 | 2022-11-11 | 南京工业大学 | Delta, epsilon-alkenyl ketone compound and preparation method and application thereof |
| CN115894299A (en) * | 2022-12-06 | 2023-04-04 | 华南理工大学 | Preparation method of axial chiral carbamate |
| CN115894299B (en) * | 2022-12-06 | 2024-03-12 | 华南理工大学 | Preparation method of axial chiral carbamate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112920066A (en) | Alpha-substituted-alpha-amino acid ester compound and preparation method thereof | |
| CN109972165B (en) | Electrochemical preparation method of β -trifluoromethyl amide compound | |
| Wang et al. | Recent advances in fixation of CO2 into organic carbamates through multicomponent reaction strategies | |
| CN110099893B (en) | Preparation method of droxidopa and intermediate thereof | |
| Kadoh et al. | Enhanced structural variety of nonplanar N-oxyl radical catalysts and their application to the aerobic oxidation of benzylic C–H bonds | |
| CN113549062B (en) | Chiral quaternary ammonium salt phase transfer catalyst with high steric hindrance derived from cinchona alkaloid and synthesis method thereof | |
| CN111718372B (en) | Axial chiral phosphine-alkene ligand and preparation method and application thereof | |
| CN106977386B (en) | 2-trifluoroethyl-1-indanone and derivatives and preparation method thereof | |
| CN113620918A (en) | Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction | |
| CN109134320B (en) | Synthesis method of beta-hydroxyl substituted sulfonyl compound | |
| CN112778351B (en) | Preparation method of beta-dimethylphenyl silicon substituted aromatic nitro compound | |
| CN112194559B (en) | Synthesis method of chiral and achiral 2,2' -dihalogenated biaryl compound | |
| CN111892528B (en) | Preparation method of 7-amide indole compound | |
| CN114133373A (en) | Method for synthesizing precursor of vilanterol intermediate | |
| CN113444040A (en) | Method for synthesizing chiral alpha-unnatural amino acid derivative under drive of visible light | |
| JPH04149160A (en) | Production of 1-amino-4-alkoxybenzene compounds | |
| CN111285846B (en) | 2- (2-indolyl) -acetate derivative and synthesis method thereof | |
| CN113277935B (en) | Far-end halogenated alkyl ketone using HX as halogen source and synthesis method thereof | |
| CN113121543B (en) | Preparation method of azepine [4,5-b ] indole compound | |
| CN116041220B (en) | Preparation method of aryl substituted amide compound | |
| CN116199614B (en) | N-axis chiral indole-pyrrole compound and synthesis method thereof | |
| CN115536605B (en) | Preparation method and application of polysubstituted oxazole compound with participation of boron reagent | |
| WO2023097696A1 (en) | Method for synthesizing (1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol | |
| CN114874127B (en) | Preparation method of difluoro carbonyl indolone compound | |
| CN108299236B (en) | Synthetic method of alpha-cyanoacrylate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210608 |
|
| RJ01 | Rejection of invention patent application after publication |