CN112194548B - Alpha-amino-gamma-butyrolactone compound and preparation method thereof - Google Patents
Alpha-amino-gamma-butyrolactone compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses aα-amino-γA-butyrolactone compound and a preparation method thereof belong to the field of organic chemical synthesis, and the preparation method comprises the steps of dissolving azlactone (II), copper salt and organic base in an organic solvent, then adding 4-ethynyl carbonate (I), stirring and reacting at-20 to 30 ℃, and directly separating and purifying after the reaction is finished to obtain a product; decarboxylation of 4-ethynylcarbonate and azlactone [3+2] in the present invention]Cycloaddition reactions effecting simultaneous inclusion of two adjacent consecutive quaternary carbon centersα-amino-γThe construction of the butyrolactone compound, the main skeleton of which exists in a plurality of natural products and drug molecules, can provide more useful candidate molecules for the screening of lead compounds and the research and development of new drugs; the preparation method has the advantages of novelty, simple operation, mild reaction conditions, good substrate universality, high yield, high diastereoselectivity, easy conversion of products into other useful molecules and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to an alpha-amino-gamma-butyrolactone compound and a preparation method thereof.
Background
The α -amino- γ -butyrolactone backbone is a very useful class of structures, which are widely found in natural products and pharmaceutical molecules. Compounds having the α -amino- γ -butyrolactone structure often exhibit a wide variety of biological activities, for example: antibacterial, anticonvulsive, analgesic, and local anesthetic.
Furthermore, the α -amino- γ -butyrolactone backbone is a very important class of intermediates for the synthesis of a variety of natural products, such as: myriocin, melokhanine E, α -Amanitin, funebrine et al (bioorg.med.chem.lett.2013, 23,4154.j.org.chem.2004,69,1475.Tetrahedron lett.2011,52,5744.Bioorg.med.chem.2012,20, 6533.).
Therefore, the development of a highly efficient synthesis method of α -amino- γ -butyrolactone structural skeleton and the improvement of the pharmacological properties of the compounds by structural modification of α -amino- γ -butyrolactone are beneficial to the discovery of new drugs, and have attracted extensive attention from organic chemists and medicinal chemists.
Although α -amino- γ -butyrolactone frameworks are very important, we have found that there are only two methods currently used to construct such frameworks (eur.j.med.chem.2019, 163,500.Eur.j.med.chem.2020,185,111800.J.org.chem.2019,84,7066.Tetrahedron lett.2013,54, 1071) whose synthesis method is as follows:
in the above-mentioned synthesis method, the synthesis method,
the first method is to take gamma-hydroxy-alpha-amino acid as a key intermediate and prepare the compound through intramolecular cyclization. The intermediate gamma-hydroxy-alpha-amino acid is usually prepared by a multi-step reaction, and the reaction condition of one step of cyclization is harsh.
The second method is by the iodine catalyzed cyclization of azlactone with ethylene oxide in ionic liquids. However, this method has the following disadvantages: 1. the ionic liquid [ Bmim ] OH is used as a solvent and alkali in the reaction, the dosage is large, and the ionic liquid is expensive and the use cost is high; 2. elemental iodine is used as a catalyst in the reaction, the iodine elemental iodine has toxicity and corrosivity and is easy to sublimate, and a large amount of sodium thiosulfate solution is required to be added to wash and remove iodine after the reaction is finished; 3. the ethylene oxide substrate used in the reaction is unstable, difficult to purify and store and inconvenient to use; 4. the method has narrow application range on azlactone substrates, and the constructed alpha-amino-gamma-butyrolactone has a relatively single structure; 5. the alpha-amino-gamma-butyrolactone compound synthesized by the method is difficult to be converted into the alpha-amino-gamma-butyrolactone compound with other structural frameworks by a simple method.
Therefore, in view of the importance of the alpha-amino-gamma-butyrolactone framework, the development of a simple and efficient synthesis method with the characteristics of mild reaction conditions, easy operation, easily obtained substrate, wide application range and the like for constructing a series of alpha-amino-gamma-butyrolactone compounds containing continuous quaternary carbon centers is of great significance.
Disclosure of Invention
One of the objectives of the present invention is to provide a novel class of α -amino- γ -butyrolactone compounds to solve the above problems.
In order to achieve the purpose, the invention adopts the technical scheme that: a novel alpha-amino-gamma-butyrolactone compound has a structure shown in the following structural formula (III):
in the above structural formula, R 1 The substituent is selected from at least one of aryl or alkyl; r 2 And R 3 The substituents are selected from aryl groups.
The invention provides a novel alpha-amino-gamma-butyrolactone compound, which has a gamma-butyrolactone structural unit, wherein alpha and beta positions of the compound have two continuous quaternary carbon centers.
The application value of the compound of the invention is as follows: the existing gamma-butyrolactone and alpha-amino-gamma-butyrolactone derivatives generally have good biological activity; therefore, the novel compounds provided by the invention have great potential application value, can enrich a lead compound library, and provide sufficient compound sources for discovery of drug candidate molecules. In addition, such compounds have an alkynyl group that is easily functionalized and can be readily converted into other useful compounds, such as: the indole derivatives provide a rapid method for synthesizing other alpha-amino-gamma-butyrolactone derivative molecular libraries.
The second object of the present invention is to provide a process for preparing the above compound, which comprises the steps of,
the method comprises the following steps:
(1) Dissolving azlactone (II), copper salt and organic base in an organic solvent, adding 4-ethynyl carbonate (I), stirring and reacting at-20-30 ℃, and directly separating and purifying after the reaction is finished to obtain an alpha-amino-gamma-butyrolactone product;
wherein the 4-ethynylcarbonate (I) has the structure:
the azlactone (II) has the following structure:
the synthetic route is as follows:
the invention adopts the synthesis method to synthesize a series of novel alpha-amino-gamma-butyrolactone derivatives.
As a preferred technical scheme: the organic solvent is at least one of toluene, mesitylene, dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetonitrile, methyl tert-butyl ether, 1,4-dioxane, chlorobenzene, ethyl acetate, methyl acetate, isopropyl acetate, ethyl butyrate and methanol.
As a preferred technical scheme: the copper salt is at least one selected from copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, cuprous chloride, cuprous bromide and cuprous iodide.
As a preferred technical scheme: the dosage of the copper salt is minimum 10mol%.
As a preferred technical scheme: the organic base is at least one of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, tributylamine, triethylenediamine and 1,8-diazabicycloundec-7-ene.
As a preferable technical scheme: the organic base is used in an amount of at least 1.0 equivalent.
As a preferred technical scheme: the reaction time was 1.5h.
As a preferred technical scheme: the separation and purification method is column chromatography.
Compared with the prior art, the invention has the advantages that: the invention adopts the decarboxylation [3+2] cyclization reaction of copper salt catalyzed 4-ethynyl carbonic ester with azlactone to synthesize a series of alpha-amino-gamma-butyrolactone compounds with high yield and high diastereoselectivity; the compound prepared by the method enriches the types of alpha-amino-gamma-butyrolactone compounds, thereby providing sufficient compound sources for screening lead compounds and drug candidate molecules; the method has the advantages of high reaction speed, mild reaction conditions, easy commercial availability of the catalyst and the alkali, simple operation, wide application range of the substrate, good universality, high yield (up to 98%), and very good diastereoselectivity (up to >95: 5dr).
Drawings
FIG. 1 is a hydrogen spectrum of III-a obtained in example 1;
FIG. 2 is a carbon spectrum of III-a obtained in example 1;
FIG. 3 is a single crystal diagram of III-a obtained in example 1.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1: synthesis of Compound (III-a)
Synthesis of Compound III-a:
dissolving copper salt (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of solvent in a dry reaction tube, then sequentially adding organic base (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) under the protection of argon, and stirring the reaction mixture at-20-30 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1) to obtain compound iii-a, under different reaction conditions as shown in table 1, in the following specific reaction conditions:
TABLE 1 different reaction conditions
| Numbering | Copper salts | Organic base | Solvent(s) | Temperature (. Degree.C.) | dr | Yield (%) |
| 1 | CuI | DMAP | CH 2 Cl 2 | 0 | 77:23 | 99 |
| 2 | [Cu(MeCN) 4 ]PF 6 | DMAP | CH 2 Cl 2 | 0 | 78:22 | 89 |
| 3 | Cu(OAc) 2 ·H 2 O | DMAP | CH 2 Cl 2 | 0 | 80:20 | 90 |
| 4 | [Cu(MeCN) 4 ]BF 4 | DMAP | CH 2 Cl 2 | 0 | 80:20 | 93 |
| 5 | Cu(OTf) 2 | DMAP | CH 2 Cl 2 | 0 | 81:19 | 95 |
| 6 | Cu(OTf) 2 | -- | CH 2 Cl 2 | 0 | -- | -- |
| 7 | Cu(OTf) 2 | pyridine | CH 2 Cl 2 | 0 | 67:33 | 99 |
| 8 | Cu(OTf) 2 | NEt 3 | CH 2 Cl 2 | 0 | 30:70 | 99 |
| 9 | Cu(OTf) 2 | DABCO | CH 2 Cl 2 | 0 | 60:40 | 91 |
| 10 | Cu(OTf) 2 | DMAP | CH 2 Cl 2 | -20 | 75:25 | 97 |
| 11 | Cu(OTf) 2 | DMAP | CH 2 Cl 2 | 30 | 81:19 | 78 |
| 12 | Cu(OTf) 2 | DMAP | toluene | 0 | 43:57 | 52 |
| 13 | Cu(OTf) 2 | DMAP | THF | 0 | 74:26 | 99 |
| 14 | Cu(OTf) 2 | DMAP | CH 3 CN | 0 | 85:15 | 97 |
| 15 | Cu(OTf) 2 | DMAP | EtOAc | 0 | 74:26 | 93 |
| 16 | Cu(OTf) 2 | DMAP | MeOH | 0 | -- | Trace amount of |
As can be seen from Table 1, the influence of different kinds of copper salts on the diastereoselectivity and activity of the reaction is slightly different; by way of comparison, copper trifluoromethanesulfonate (Cu (OTf) 2 ) The reaction effect of (3) is the best. The influence of alkali on the reaction is large, when alkali is absent, the reaction is not carried out, and the effect on Dimethylaminopyridine (DMAP) is optimal through comparison. In addition, temperature and solvent have certain influence on the reaction. Finally, it is a more preferable scheme to use copper trifluoromethanesulfonate as a catalyst, p-dimethylaminopyridine as a base, acetonitrile as a solvent, and a reaction temperature of 0 ℃.
In the best case, the following III-a results:
white solid, 37.1mg, yield 97%;85, 15dr; m.p.218.0-220.4 deg.c; 1 H NMR(300MHz,DMSO-d 6 )δ(major diastereomer)8.73(s,1H),7.88(d,J＝7.0Hz,2H),7.60(m,1H),7.52(m,2H),7.16-7.10(m,2H),7.09-7.01(m,8H),5.15(d,J＝9.0Hz,1H),4.93(d,J＝9.0Hz,1H),3.99(s,1H)； 13 C NMR(150MHz,DMSO-d 6 )δ(major diastereomer)171.9,167.1,138.9,134.9,133.8,131.8,128.3,127.9,127.8,127.5,127.45,127.36,127.3,127.2,81.1,80.8,75.7,69.4,54.6；HRMS(ESI)Calcd.for C 25 H 20 NO 3 [M+H] + :382.1443；found:382.1436.
the hydrogen spectrum, carbon spectrum and single crystal spectrum of III-a are shown in FIGS. 1 to 3, respectively.
Example 2: synthesis of Compound (III-b)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-b (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 39.1mg, yield 99%; 89; m.p.183.4-185.5 deg.C; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.91-7.82(m,2H),7.60-7.52(m,1H),7.47(m,2H),7.36(s,1H),7.16-7.06(m,5H),7.01(d,J＝8.4Hz,2H),6.89(d,J＝8.1Hz,2H),5.00(d,J＝8.9Hz,1H),4.86(d,J＝8.9Hz,1H),2.87(s,1H),2.22(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.2,166.5,138.0,135.0,134.0,133.7,132.2,128.9,128.8,128.4,128.3,127.5,127.3,127.1,81.6,78.2,75.4,69.7,55.1,21.0；HRMS(ESI)Calcd.for C 26 H 22 NO 3 [M+H] + :396.1600；found:396.1595。
example 3: synthesis of Compound (III-c)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynylcarbonate I-c (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after the reaction is complete, the solvent is evaporated off under reduced pressure and the crude product residue is subjected to column chromatographyAnd (1) separating and purifying (petroleum ether: ethyl acetate: dichloromethane = 15). A white solid; 35.5mg, yield 86%;91 dr; m.p.168.0-171.9 deg.c; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.91-7.81(m,2H),7.60-7.52(m,1H),7.51-7.42(m,2H),7.34(s,1H),7.17-7.07(m,5H),7.04(d,J＝8.9Hz,2H),6.61(d,J＝8.9Hz,2H),4.99(d,J＝9.0Hz,1H),4.83(d,J＝9.0Hz,1H),3.71(s,3H),2.86(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.1,166.5,159.3,135.0,134.0,132.2,128.9,128.8,128.6,128.4,128.3,127.3,127.1,113.5,81.7,78.2,75.3,69.8,55.4,54.8；HRMS(ESI)Calcd.for C 26 H 22 NO 4 [M+H] + :412.1549；found:412.1544。
example 4: synthesis of Compound (III-d)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-d (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 32.1mg, yield 73%;85 parts by weight; m.p.135.4-137.3 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ(major diastereomer)8.72(s,1H),7.91-7.84(m,2H),7.65-7.56(m,1H),7.55-7.48(m,2H),7.10-7.01(m,5H),7.01-6.94(m,4H),5.13(d,J＝9.0Hz,1H),4.94(d,J＝9.0Hz,1H),3.98(s,1H),1.14(s,9H)； 13 C NMR(100MHz,DMSO-d 6 )δ(major diastereomer)171.9,166.9,149.9,135.4,134.8,133.8,131.9,128.4,127.9,127.4,127.3,127.2,126.9,124.5,81.1,80.5,75.1,69.4,54.3,34.0,30.9；HRMS(ESI)Calcd.for C 29 H 28 NO 3 [M+H] + :438.2069；found:438.2062。
example 5: synthesis of Compound (III-e)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-e (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 41.7mg, yield 99%; 84; m.p.120.4-125.0 ℃; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.91-7.82(m,2H),7.60-7.52(m,1H),7.53-7.41(m,2H),7.33(s,1H),7.15-7.06(m,5H),7.01-6.94(m,2H),6.93-6.84(m,2H),5.05(d,J＝8.9Hz,1H),4.89(d,J＝8.9Hz,1H),2.87(s,1H),2.14(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.0,166.6,137.9,137.0,135.1,133.9,132.3,128.9,128.7,128.3,128.2,128.1,127.3,127.0,124.6,81.5,78.4,75.6,69.7,55.2,21.4；HRMS(ESI)Calcd.for C 26 H 22 NO 3 [M+H] + :396.1600；found:396.1594。
example 6: synthesis of Compound (III-f)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-f (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was evaporated under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 43.0mg, yield 99%;86, 14dr; m.p.190.2-191.2℃； 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.86(d,J＝7.5Hz,2H),7.59-7.52(m,1H),7.51-7.43(m,2H),7.30(s,1H),7.21-7.07(m,5H),7.06-6.97(m,1H),6.81(d,J＝8.7Hz,1H),6.72-6.58(m,2H),5.07(d,J＝8.9Hz,1H),4.88(d,J＝8.9Hz,1H),3.62(s,3H),2.87(s,1H)； 13 C NMR(101MHz,CDCl 3 )δ(major diastereomer)171.9,166.6,159.2,138.8,135.1,133.8,132.3,129.3,128.9,128.4,128.3,127.3,127.0,119.7,113.9,113.5,81.3,78.5,75.7,69.6,55.3,55.2；HRMS(ESI)Calcd.for C 26 H 22 NO 4 [M+H] + :412.1549；found:412.1546。
Example 7: synthesis of Compound (III-g)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynylcarbonate I-g (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 41.0mg, yield 99%; 84; m.p.178.3-179.5 ℃; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.82(dd,J＝8.3,1.4Hz,2H),7.60(d,J＝7.3Hz,1H),7.55-7.48(m,1H),7.47-7.38(m,2H),7.26(dd,J＝3.8,3.2Hz,2H),7.17-7.00(m,5H),6.80(dd,J＝8.2Hz,1H),6.55-6.41(m,1H),5.03(d,J＝8.4Hz,1H),4.77(d,J＝8.4Hz,1H),3.60(s,3H),2.83(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.7,166.8,155.9,136.4,134.2,132.0,129.8,129.1,128.7,128.1,127.6,127.5,127.3,127.2,120.4,111.0,82.9,78.5,76.5,69.7,54.6,53.8；HRMS(ESI)Calcd.For C 26 H 22 NO 4 [M+H] + :412.1549；found:412.1538。
example 8: synthesis of Compound (III-h)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynylcarbonate I-h (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after the reaction was completed, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 40.5mg, yield 99%;80, 20dr; m.p.147.0-154.5 deg.c; 1 H NMR(300MHz,DMSO-d 6 )δ(major diastereomer)8.85(s,1H),7.87(d,J＝7.4Hz,2H),7.65-7.56(m,1H),7.56-7.46(m,2H),7.21-6.99(m,7H),6.96-6.85(m,2H),5.14(d,J＝9.1Hz,1H),4.94(d,J＝9.1Hz,1H),4.03(s,1H)； 13 C NMR(100MHz,DMSO-d 6 )δ(major diastereomer)172.0,167.3,161.0(d,J＝244.8Hz,1C),135.4(d,J＝3.2Hz,1C),135.0,133.7,131.9,129.4(d,J＝8.2Hz,1C),128.3,128.0,127.7,127.6,127.5,114.6(d,J＝21.5Hz,1C),81.0,80.9,75.8,69.6,54.2；HRMS(ESI)Calcd.for C 25 H 19 NO 3 F[M+H] + :400.1349；found:400.1345。
example 9: synthesis of Compound (III-i)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynylcarbonate I-I (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane = 15. A white solid; 35.2mg, yield 85%;85 parts by weight; m.p.170.1-172.4℃； 1 H NMR(300MHz,DMSO-d 6 )δ(major diastereomer)8.90(s,1H),7.87(d,J＝7.5Hz,2H),7.65-7.57(m,1H),7.54-7.54(m,2H),7.21-7.12(m,4H),7.12-7.02(m,5H),5.14(d,J＝9.0Hz,1H),4.92(d,J＝9.0Hz,1H),4.04(s,1H)； 13 C NMR(100MHz,DMSO-d 6 )δ(major diastereomer)172.0,167.4,138.5,135.0,133.7,131.9,131.8,129.1,128.3,128.1,127.8,127.7,127.6,127.5,81.1,80.8,76.0,69.6,54.3；HRMS(ESI)Calcd.for C 25 H 19 NO 3 Cl[M+H] + :416.1053；found:416.1053。
Example 10: synthesis of Compound (III-j)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-j (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 44.1mg, yield 96%;85, 15dr; m.p.165.3-167.8 ℃; 1 H NMR(300MHz,DMSO-d 6 )δ(major diastereomer)8.90(s,1H),7.87(d,J＝7.0Hz,2H),7.63-7.57(m,1H),7.51(dd,J＝8.3,6.7Hz,2H),7.26(d,J＝8.6Hz,2H),7.13-7.09(m,5H),7.07(d,J＝8.8Hz,2H),5.13(d,J＝9.0Hz,1H),4.91(d,J＝9.0Hz,1H),4.03(s,1H)； 13 C NMR(100MHz,DMSO-d 6 )δ(major diastereomer)172.0,167.5,139.0,135.0,133.7,131.9,130.6,129.4,128.3,128.1,127.8,127.6,127.5,120.5,81.1,80.7,76.0,69.5,54.4；HRMS(ESI)Calcd.for C 25 H 19 NO 3 Br[M+H] + :460.0548；found:460.0544。
example 11: synthesis of Compound (III-k)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-k (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane = 15. A white solid; 38.0mg, yield 87%;80, 20dr; m.p.158.5-162.2 ℃; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.88-7.82(m,2H),7.62-7.50(m,1H),7.53-7.41(m,2H),7.35-7.28(s,4H),7.23(s,1H),7.20-7.08(m,5H),5.16(d,J＝9.0Hz,1H),4.85(d,J＝9.0Hz,1H),2.89(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.1,167.0,142.2,135.5,133.6,132.5,130.1(q,J＝32.9Hz,1C),129.0,128.9,128.8,128.2,127.3,127.0,125.0(q,J＝3.7Hz,1C),123.8(q,J＝272.1Hz,1C),80.7,79.0,76.5,70.1,55.3；HRMS(ESI)Calcd.for C 26 H 19 NO 3 F 3 [M+H] + :450.1317；found:450.1314。
example 12: synthesis of Compound (III-l)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-l (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 37.7mg, yield 84%; 76; m.p.159.8-160.5 ℃; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.88-7.79(m,2H),7.60-7.52(m,1H),7.51-7.43(m,2H),7.23(d,J＝2.2Hz,1H),7.22-7.16(m,6H),7.14(d,J＝8.6Hz,1H),7.04(dd,J＝8.5,2.3Hz,1H),5.14(d,J＝9.0Hz,1H),4.78(d,J＝9.0Hz,1H),2.87(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.2,167.1,138.6,135.6,133.5,132.5,132.2,132.1,130.0,129.9,129.1,129.0,128.9,127.3,127.0,126.9,80.5,79.1,76.6,70.1,54.8；HRMS(ESI)Calcd.for C 25 H 18 NO 3 Cl 2 [M+H] + :450.0664；found:450.0660。
example 13: synthesis of Compound (III-m)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-m (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 37.5mg, yield 87%; 88; m.p.201.3-202.7 ℃; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.92-7.85(m,2H),7.72-7.64(m,3H),7.60-7.47(m,4H),7.47-7.41(m,2H),7.35(s,1H),7.20(dd,J＝8.8,2.0Hz,1H),7.18-7.13(m,2H),7.04-6.99(m,3H),5.17(d,J＝9.0Hz,1H),4.99(d,J＝9.0Hz,1H),2.94(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.2,166.7,135.2,134.8,133.9,132.6,132.5,132.3,128.9,128.5,128.4,128.3,127.9,127.4,127.3,127.1,126.8,126.7,126.5,125.1,81.5,78.7,76.1,69.8,55.5；HRMS(ESI)Calcd.for C 29 H 22 NO 3 [M+H] + :432.1600；found:432.1601。
example 14: synthesis of Compound (III-n)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-a (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynylcarbonate I-n (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 38.0mg, yield 98%; 88; m.p.177.7-179.9 deg.C; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.85(d,J＝7.3Hz,2H),7.59-7.52(m,1H),7.51-7.43(m,2H),7.29(s,1H),7.25-7.16(m,5H),7.07(dd,J＝4.9,1.4Hz,1H),6.79-6.71(m,2H),4.99(d,J＝8.8Hz,1H),4.77(d,J＝8.8Hz,1H),2.87(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.0,166.6,140.3,134.6,133.9,132.3,128.9,128.7,128.5,127.3,126.8,126.7,126.0,125.3,81.0,77.6,75.8,70.0,52.8；HRMS(ESI)Calcd.for C 23 H 18 NO 3 S[M+H] + :388.1007；found:388.1003。
example 15: synthesis of Compound (III-o)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-b (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 30.0mg, yield 75%; 71; m.p.201.5-203.9 ℃; 1 H NMR(400MHz,CDCl 3 )δ(major diastereomer)7.89-7.82(m,2H),7.57-7.52(m,1H),7.49-7.44(m,2H),7.30(s,1H),7.17(dd,J＝7.8,1.9Hz,2H),7.13-7.06(m,3H),6.96(d,J＝8.4Hz,2H),6.90(d,J＝8.2Hz,2H),5.04(d,J＝8.9Hz,1H),4.87(d,J＝8.9Hz,1H),2.86(s,1H),2.20(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.3,166.6,138.2,137.3,134.0,132.2,132.0,129.0,128.9,128.2,128.1,127.6,127.3,126.9,81.6,78.3,75.6,69.7,55.2,21.1；HRMS(ESI)Calcd.for C 26 H 22 NO 3 [M+H] + :396.1600；found:396.1591。
example 16: synthesis of Compound (III-p)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-c (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 35.8mg, yield 86%;>20:1dr；m.p.163.6-166.8℃； 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)8.04(s,1H),7.94-7.87(m,2H),7.59-7.52(m,1H),7.51-7.40(m,4H),7.29-7.22(m,1H),7.11-7.06(m,1H),7.05-6.96(m,5H),5.25(d,J＝8.6Hz,1H),4.92(d,J＝8.6Hz,1H),2.73(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.7,167.2,139.7,133.4,133.0,132.6,132.3,132.2,131.5,129.7,128.9,128.7,127.8,127.4,127.2,126.7,82.1,80.0,78.5,72.3,54.6；HRMS(ESI)Calcd.for C 25 H 19 NO 3 Cl[M+H] + :416.1053；found:416.1054。
example 17: synthesis of Compound (III-q)
In a dry reaction tube, the mixture isDissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-d (0.2 mmol) in 1mL of acetonitrile, sequentially adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 40.5mg, yield 99%; 76; m.p.185.3-187.0 deg.C; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.76(d,J＝8.1Hz,2H),7.31-7.23(m,3H),7.21-7.14(m,2H),7.13-7.04(m,8H),5.09(d,J＝8.9Hz,1H),4.89(d,J＝8.9Hz,1H),2.86(s,1H),2.42(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)172.1,166.6,142.9,137.5,135.3,131.0,129.6,128.34,128.32,128.2,128.0,127.5,127.3,127.0,81.4,78.4,75.8,69.6,55.3,21.7；HRMS(ESI)Calcd.for C 26 H 22 NO 3 [M+H] + :396.1600；found:396.1590。
example 18: synthesis of Compound (III-r)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-e (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane = 15. A white solid; 38.5mg, yield 93%; 89; m.p.214.9-216.5 ℃;1H NMR (400mhz, cdcl3) δ (major diastereomer) 7.72 (d, J =8.5hz, 2h), 7.37 (d, J =8.5hz, 2h), 7.25-7.18 (m, 2H), 7.12-7.07 (m, 2H), 7.07-7.01 (m, 7H), 4.98 (d, J =8.9hz, 1h), 4.82 (d, J =8.9hz, 1h), 2.82 (s, 1H); 13C NMR (100MHz, CDCl3) delta (major diastereomer) 172.0,165.6,138.6,137.1,134.9,132.2,129.2,128.7,128.5,128.4,128.2,128.1,127.5,127.0,81.4,78.5,75.7,69.8,55.2; HRMS (ESI) Calcd. For C25H19NO3Cl [ M + H ] +:416.1053; found 416.1043.
Example 19: synthesis of Compound (III-s)
Dissolving copper trifluoromethanesulfonate (0.01 mmol) and azlactone II-f (0.2 mmol) in 1mL of acetonitrile in a dry reaction tube, adding p-dimethylaminopyridine (0.1 mmol) and 4-ethynyl carbonate I-a (0.1 mmol) in sequence under the protection of argon, and stirring the reaction mixture at 0 ℃; after completion of the reaction, the solvent was distilled off under reduced pressure, and the crude product residue was purified by column chromatography (petroleum ether: ethyl acetate: dichloromethane =15: 1. A white solid; 20.1mg, yield 52% yield; 81; m.p.231.8-233.2 deg.C; 1 H NMR(300MHz,CDCl 3 )δ(major diastereomer)7.62(dd,J＝3.7Hz,1.2Hz,1H),7.53(dd,J＝4.9Hz,1.2Hz,1H),7.20(s,1H),7.15-7.09(m,8H),7.09-7.04(m,1H),5.02(d,J＝9.0Hz,1H),4.88(d,J＝9.0Hz,1H),2.89(s,1H)； 13 C NMR(100MHz,CDCl 3 )δ(major diastereomer)171.9,161.0,138.0,136.7,134.7,130.9,129.3,128.5,128.4,128.3,128.2,128.0,127.5,127.0,81.3,78.6,75.2,69.8,55.2；HRMS(ESI)Calcd.for C 23 H 18 NO 3 S[M+H] + :388.1007；found:388.1000.
the present invention is not intended to be limited to the particular embodiments shown and described, and all changes, equivalents and modifications that come within the spirit and scope of the invention are desired to be protected.
Claims (7)
1. The preparation method of the alpha-amino-gamma-butyrolactone compound is characterized by comprising the following steps:
dissolving azlactone (II), copper salt and organic base in an organic solvent, adding 4-ethynyl carbonate (I), stirring and reacting at-20-30 ℃, and directly separating and purifying after the reaction is finished to obtain an alpha-amino-gamma-butyrolactone product; wherein the 4-ethynylcarbonate (I) has the structure:
the azlactone (II) has the following structure:
the alpha-amino-gamma-butyrolactone has the following structure:
in the above structural formula, R 1 The substituent is selected from at least one of aryl or alkyl; r 2 And R 3 The substituents are selected from aryl; the organic solvent is at least one selected from toluene, dichloromethane, tetrahydrofuran, acetonitrile and ethyl acetate.
2. The method of claim 1, wherein: the copper salt is at least one selected from copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate, cuprous chloride, cuprous bromide and cuprous iodide.
3. The method of claim 1, wherein: the organic base is at least one selected from triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, tributylamine, triethylenediamine and 1, 8-diazabicycloundec-7-ene.
4. The method of claim 1, wherein: the dosage of the copper salt is minimum 10mol%.
5. The method of claim 1, wherein: the organic base is used in an amount of at least 1.0 equivalent.
6. The production method according to claim 1, characterized in that: the reaction time was 1.5h.
7. The method of claim 1, wherein: the separation and purification method is column chromatography.
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