CN115521266A - A kind of preparation method of vinyl isoxazolidine derivative - Google Patents

Abstract

The invention discloses a preparation method of a vinyl isoxazolidine derivative, which comprises the following steps: when a copper catalyst and alkali are added into an organic solvent, stirring O-propinyl oxime ether compound and sulfonyl azide for reaction to obtain a 2-vinyl isoxazolidine derivative; the structural formula of the O-propinyl oxime ether compound is shown as

(ii) a The structural formula of the sulfonyl azide is

(ii) a The structural formula of the 2-vinyl isoxazolidine derivative is shown in the specification

(ii) a The preparation method is simple, and the effects of mild reaction conditions, high yield and high purity can be achieved by optimizing the reaction conditions.

Description

A kind of preparation method of vinyl isoxazolidine derivative

technical field

The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of vinyl isoxazolidine derivatives.

Background technique

Isoxazole rings as mimetics of nucleoside, carbohydrate, PNA, amino acid and steroid analogues, as well as their anticancer, antitumor, antibacterial, inhibitory cell cycle cleavage protein 25 (Cdc25A/Cdc25B) enzymes and SH2-containing structures domain protein tyrosine phosphatase 1 (SHP-1) has attracted much attention due to its wide range of biological activities. Studies have shown that introducing several different functional groups or molecular skeletons into certain molecules for modification can improve the biological activity of the parent molecule in order to find highly active pharmaceutical precursor compounds. In recent years, there have been more and more studies on isoxazolidines and compounds containing isoxazolidine rings, and new compounds involving isoxazolidine rings and their reactions have been used to achieve total synthesis or obtain biologically active compounds. compound.

The present invention takes isoxazolidine as the molecular skeleton, introduces vinyl to obtain a new type of 2-vinyl isoxazolidine derivatives, and synthesizes various types of 2-vinyl isoxazolidine derivatives through a copper-catalyzed method. and enrich the library of isoxazole ring compounds.

Contents of the invention

The purpose of the present invention is to provide a preparation method of vinyl isoxazolidine derivatives, the preparation method is simple, and the effects of mild reaction conditions, high yield and high purity can be achieved by optimizing the reaction conditions.

The purpose of the present invention can be achieved through the following technical solutions:

磺酰基叠氮的结构式为

；2-乙烯基异噁唑烷衍生物的结构式为

A method for preparing vinyl isoxazolidine derivatives, comprising the following steps: when an organic solvent is added with a copper catalyst and a base, stirring and reacting an O-propynyl oxime ether compound with a sulfonyl azide to obtain 2-ethylene isoxazolidine derivatives; the structural formula of O-propynyl oxime ether compounds is

The structural formula of sulfonyl azide is

; The structural formula of 2-vinyl isoxazolidine derivatives is

Among them, R ¹ , R ² , and R ³ in the structural formulas of O-propynyl oxime ether compounds, sulfonyl azide and 2-vinyl isoxazolidine derivatives are independently selected from phenyl, substituted phenyl, naphthyl , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, halogen, halogenated C ₁ -C ₆ alkyl or halogenated C ₁ -C ₆ alkoxy any one;

Described copper catalyst is copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, Any one of copper thiophene-2-carboxylate and cuprous acetate;

The base is any one of triethylamine, n-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, diisopropylethylamine, pyridine, 2-picoline, sodium hydroxide;

The organic solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, benzene, and xylene.

As a further solution of the present invention: the molar ratio of the O-propynyl oxime ether compound, copper catalyst, and base is 1:0.05-0.4:0.1-2; the O-propynyl oxime ether compound, sulfonyl alkene The nitrogen molar ratio is 1:1-3.

As a further solution of the present invention: the stirring reaction temperature is 0-60° C. and the reaction time is 0.5-8 hours.

Beneficial effects of the present invention:

The present invention uses copper catalysts and amine compounds as bases to react O-propynyl oxime ether compounds and sulfonyl azide to obtain 2-vinylisoxazolidine derivatives in one step, with mild reaction conditions and high yield , high purity, high atom economy and many other advantages provide a new route and new ideas for 2-vinylisoxazolidine derivatives, which can play an important role in the fields of synthetic intermediates, pharmaceutical intermediates, pesticide intermediates, etc. It has good application value and potential in industry and scientific research.

Description of drawings

In order to facilitate the understanding of those skilled in the art, the present invention will be further described below in conjunction with the accompanying drawings.

Fig. 1 is the reaction mechanism diagram of O-propynyl oxime ether compound and sulfonyl azide of the present invention.

detailed description

The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Apparently, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

磺酰基叠氮的结构式为

；2-乙烯基异噁唑烷衍生物的结构式为

As shown in Figure 1, a kind of preparation method of vinyl isoxazolidine derivative, comprises the steps: when organic solvent is added with copper catalyst and alkali, O-propynyl oxime ether compound is stirred with sulfonyl azide Reaction, obtains 2-vinyl isoxazolidine derivative; The structural formula of O-propynyl oxime ether compound is

The structural formula of sulfonyl azide is

; The structural formula of 2-vinyl isoxazolidine derivatives is

Among them, R ¹ , R ² , and R ³ in the structural formulas of O-propynyl oxime ether compounds, sulfonyl azide and 2-vinyl isoxazolidine derivatives are independently selected from phenyl, substituted phenyl, naphthyl , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, halogen, halogenated C ₁ -C ₆ alkyl or halogenated C ₁ -C ₆ alkoxy any one;

The copper catalyst is copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, thiophene- Any one of copper 2-formate and cuprous acetate;

The base is any one of triethylamine, n-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, diisopropylethylamine, pyridine, 2-picoline, sodium hydroxide; most preferably triethylamine;

The organic solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, benzene, and xylene; preferably acetonitrile;

The molar ratio of O-propynyl oxime ether compound, copper catalyst and base is 1:0.05-0.4:0.1-2; the molar ratio of O-propynyl oxime ether compound and sulfonyl azide is 1:1-3;

The temperature of the stirring reaction is 0-60°C and the reaction time is 0.5-8 hours;

C ₁ -C ₆ alkyl refers to straight chain or branched chain alkyl with 1-6 carbon atoms, which includes C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkane Base or C ₆ alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl, etc. ;

C ₁ -C ₆ alkoxy refers to the group after the C ₁ -C ₆ alkyl is connected to the O atom;

The meaning of halogen refers to halogen elements, which can be F, Cl, Br or I;

The meaning of halogenated C ₁ -C ₆ alkyl refers to C ₁ -C ₆ alkyl substituted by halogen, which can be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, etc.;

The meaning of halogenated C ₁ -C ₆ alkoxy refers to C ₁ -C ₆ alkoxy substituted by halogen, which can be trifluoromethoxy, pentafluoroethoxy, difluoromethoxy, chloromethoxy Base etc.;

The preparation steps are as follows: mix the O-propynyl oxime ether compound with the sulfonyl azide for reaction, and in the reaction process, firstly, the sulfonyl azide and the terminal alkyne compound undergo 1,3-dipolar cycloaddition reaction to obtain three Azole complex, followed by ring-opening rearrangement, and intramolecular nucleophilic addition and isomerization with O-propynyl oxime ether compound to obtain 2-vinylisoxazolidine derivatives;

Reaction is carried out under the catalysis of copper catalyst and the effect of alkali, and under the effect of copper catalyst and alkali, the reaction mechanism of O-propynyl oxime ether compound and the sulfonyl azide is shown in Figure 1;

First, under the action of copper catalyst and base, O-propynyl oxime ether compound and sulfonyl azide undergo 1,3-dipolar cycloaddition to obtain copper complex triazole A, followed by ring-opening rearrangement to obtain Enketimine intermediate B, enketimine intermediate B undergoes intramolecular nucleophilic attack, and at the same time, the carbon-nitrogen double bond undergoes isomerization, and finally 2-vinylisoxazolidine derivatives are obtained;

Copper catalysts include copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper triflate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, thiophene- Any one or more of 2-copper formate and cuprous acetate, preferably cuprous iodide or cuprous chloride, most preferably cuprous iodide;

The mol ratio of O-propynyl oxime ether compound and copper catalyst is 1:0.05-0.4;

The molar ratio of propynyl oxime ether compound and base is 1:0.1-2;

The ratio of O-propynyl oxime ether compound to organic solvent is 1mmol: 5-15mL, such as 1mmol: 5mL, 1mmol: 8mL, 1mmol: 10mL, 1mmol: 12mL or 1mmol: 15mL;

After the reaction is finished, a post-treatment step is also included, and the post-treatment includes extraction, concentration, crystallization, recrystallization, any one of treatment means or a combination of multiple treatment means in column chromatography purification;

As an exemplary post-treatment method, for example, the reaction system is cooled to room temperature, the solvent is evaporated by a rotary evaporator, the residue is passed through a 200-300 mesh silica gel column, and ethyl acetate/petroleum ether is used as the eluent , wherein the volume ratio of ethyl acetate to petroleum ether is 1:5-15, thereby obtaining the target product of 2-vinyl isoxazolidine derivatives;

As another exemplary post-treatment method, for example, after the reaction is complete, cool the reaction system to room temperature naturally, add a mixture of ethyl acetate and saturated saline in an equal volume ratio, shake and extract for 2-4 times , collect the organic layer, dry, and concentrate by rotary evaporation to obtain a crude product, which is subjected to 200-300 mesh silica gel column chromatography, using ethyl acetate and petroleum ether mixture as eluent, wherein ethyl acetate and petroleum ether The volume ratio is 1:5-10, so as to obtain the target product of 2-vinyl isoxazolidine derivatives.

Example 1

Add O-propynyl oxime ether compound, sulfonyl azide, cuprous iodide, and triethylamine to acetonitrile, then stir and seal the reaction at room temperature for 4 hours.

Among them, the molar ratio of O-propynyl oxime ether compound to cuprous iodide is 1:0.10; the molar ratio of O-propynyl oxime ether compound to triethylamine is 1:1.0; O-propynyl oxime ether the molar ratio of compound to sulfonyl azide is 1:1.5; and the ratio of O-propynyl oxime ether compound in millimoles to acetonitrile in milliliters is 1:5;

After the reaction, the reaction system was naturally cooled to room temperature, and concentrated by rotary evaporation to obtain a crude product, which was subjected to 300-400 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as the eluent, wherein acetic acid The volume ratio of ethyl ester to sherwood oil is 1: 5, thereby obtaining the target product 2-vinylisoxazolidine derivative as light yellow viscous liquid, the yield is 92%, and the purity is 99.0%;

NMR: ¹ HNMR (400MHz, deuterated chloroform CDCl ₃ ) δ7.76 (d, J=7.8Hz, 1H), 7.64-7.60 (m, 1H), 7.56-7.54 (m, 2H), 7.44-7.40 ( m, 2H), 7.27-7.17(m, 5H), 7.15-7.11(m, 1H), 7.02-7.03(m, 1H), 6.63(d, J=8.6Hz, 1H), 4.52(s, 2H) .

¹³ CNMR (400MHz, deuterated chloroform CDCl3) δ7.59(d, J=8.4Hz, 2H), 7.31(s, 5H), 7.18(d, J=8.0Hz, 2H), 5.61(s, 1H), 5.51(s, 1H), 4.40(t, J=8.2Hz, 2H), 3.71(t, J=8.2Hz, 2H), 2.38(s, 3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ160.4, 142.6, 140.7, 139.6, 134.1, 129.3(2C), 129.2, 128.5(2C), 126.6(2C), 126.4(2C), 112.4, 67.4, 34.6, 21.6 .

Example 2

Add O-propynyl oxime ether compound and sulfonyl azide, cuprous iodide, triethylamine to acetonitrile, then raise the temperature to 30°C, and stir and seal the reaction at this temperature for 6 hours;

Among them, the molar ratio of O-propynyl oxime ether compound to cuprous iodide is 1:0.15; the molar ratio of O-propynyl oxime ether compound to triethylamine is 1:1.2; O-propynyl oxime ether compound the molar ratio of compound to sulfonyl azide is 1:1.2; and the ratio of O-propynyl oxime ether compound in millimoles to acetonitrile in milliliters is 1:7;

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate to petroleum ether is 1:7, thereby obtaining the target product 2-vinylisoxazolidine derivative as a yellow solid, with a yield of 88% and a purity of 98.3%;

Melting point: 129-156°C;

NMR: ¹ HNMR (400MHz, deuterated chloroform CDCl ₃ ) δ7.73-7.82(m, 4H), 7.47-7.53(m, 2H), 7.40(t, J=8.4Hz, 3H), 6.92(d, J=5.6Hz, 2H), 5.65(s, 1H), 5.56(s, 1H), 4.48(t, J=8.2Hz, 2H), 3.76(t, J=8.2Hz, 2H), 2.30(s, 3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ160.1, 142.5, 141.1, 139.4, 133.6, 133.1, 131.7, 129.1 (2C), 128.4, 128.1, 127.8, 126.8, 126.6, 126.22 (2C), 126.18, 114.8, 1 , 67.5, 34.6, 21.5.

Example 3

Add O-propynyl oxime ether compound, sulfonyl azide, cuprous iodide, and triethylamine to acetonitrile, then raise the temperature to 40°C, and stir and seal the reaction at this temperature for 5 hours; The molar ratio of the alkynyl oxime ether compound to cuprous iodide is 1:0.2; the molar ratio of the O-propynyl oxime ether compound to triethylamine is 1:1.0; the O-propynyl oxime ether compound and the sulfonyl alkene The molar ratio of nitrogen is 1:1.5; and the ratio of O-propynyl oxime ether compound in millimoles to acetonitrile in milliliters is 1:9;

After the reaction was complete, the reaction system was naturally cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to 200-300 mesh silica gel column chromatography, using a mixture of ethyl acetate and petroleum ether as an eluent, wherein The volume ratio of ethyl acetate and petroleum ether is 1:5, thereby obtaining the target product 2-vinylisoxazolidine derivative as light yellow liquid, the yield is 85%, and the purity is 96.8%;

NMR: ¹ HNMR (400MHz, deuterated chloroform CDCl ₃ ) δ7.80(d, J=8.8Hz, 2H), 7.27(d, J=6.4Hz, 2H), 5.28(s, 1H), 4.80(s , 1H), 4.35(t, J=7.0Hz, 2H), 3.66(t, J=7.0Hz, 2H), 2.40(d, J=7.6Hz, 5H), 1.35-1.41(m, 2H), 1.16 -1.26(m, 4H), 0.84(t, J=5.8Hz, 3H);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 158.5, 142.8, 142.1, 139.9, 129.4 (2C), 126.6 (2C), 105.6, 67.2, 35.0, 32.8, 31.2, 27.6, 22.5, 21.6, 14.1.

The copper catalyst cuprous iodide of embodiment 1-3 is replaced with other copper catalysts of the same molar amount, and other operations are identical, and the product yield obtained is as follows respectively: copper catalyst is cuprous chloride, and product yield is 91; The catalyst is copper bromide, and the product yield is 82%; the copper catalyst is copper trifluoromethanesulfonate, and the product yield is 65%;

It can be seen that under the catalysis of different copper catalysts, the corresponding products can be obtained. Generally, the reaction effect of the monovalent copper compound is better than that of the divalent copper compound, and the catalytic effect of the CuI pair is the best.

The base triethylamine of embodiment 1-3 is replaced with other bases of the same molar amount, and other operations are the same, and the product yields obtained are as follows respectively: the base is triethylamine, and the product yield is 92%; the base is tri-tert-butylamine, and the product yield The yield is 90; the base is 2-fluoropyridine, and the product yield is 82; it can be seen that in the base, the reaction effect of the tertiary amine very similar to triethylamine is also better, and the base of pyridines can also be obtained to a certain extent. The product, the productive rate of inorganic base then significantly reduces.

The organic solvent acetonitrile of Example 1-3 is replaced by other solvents of the same volume, and other operations are the same, and the product yields obtained are as follows: the organic solvent is MeOH, and the product yield is a trace amount; the organic solvent is THF, and the product yield is Be 87; Organic solvent is DMF, and product yield is 76;

It can be seen that organic solvents also have a certain impact on the final result, wherein acetonitrile has the best effect, followed by THF, and the yields of other solvents are greatly reduced.

In summary, it can be clearly seen from all the above examples that when the method of the present invention is adopted, the O-propynyl oxime ether compound and the sulfonyl azide can be reacted smoothly, thereby obtaining the target product, and the yield Good, simple post-treatment, the achievement of these effects depends on the comprehensive synergy of multiple factors such as catalysts, ligands, and solvents.

The preferred embodiments of the invention disclosed above are only to help illustrate the invention. The preferred embodiments are not exhaustive in all detail, nor are the inventions limited to specific embodiments described. Obviously, many modifications and variations can be made based on the contents of this specification. This description selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The invention is to be limited only by the claims, along with their full scope and equivalents.

Claims (3)

1. A preparation method for vinyl isoxazolidine derivatives, characterized in that it comprises the steps of: stirring the O-propynyl oxime ether compound with sulfonyl azide when the organic solvent is added with copper catalyst and alkali Reaction, obtains 2-vinyl isoxazolidine derivative; The structural formula of O-propynyl oxime ether compound is

The structural formula of sulfonyl azide is

; The structural formula of 2-vinyl isoxazolidine derivatives is

Among them, R ¹ , R ² , and R ³ in the structural formulas of O-propynyl oxime ether compounds, sulfonyl azide and 2-vinyl isoxazolidine derivatives are independently selected from phenyl, substituted phenyl, naphthyl , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkoxy, halogen, halogenated C ₁ -C ₆ alkyl or halogenated C ₁ -C ₆ alkoxy any one; Described copper catalyst is copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, Any one of copper thiophene-2-carboxylate and cuprous acetate; The base is any one of triethylamine, n-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, diisopropylethylamine, pyridine, 2-picoline, sodium hydroxide; The organic solvent is one of methanol, ethanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, benzene, and xylene. 2. the preparation method of vinyl isoxazolidine derivative according to claim 1, is characterized in that, the mol ratio of described O-propynyl oxime ether compound, copper catalyst, alkali is 1:0.05-0.4: 0.1-2; the molar ratio of the O-propynyl oxime ether compound and sulfonyl azide is 1:1-3. 3. The preparation method of vinyl isoxazolidine derivatives according to claim 1, characterized in that the stirring reaction temperature is 0-60°C and the reaction time is 0.5-8 hours.

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