Alpha-alkynyl carboxylic acid (ester) compound and preparation method thereof

Abstract

The invention discloses an alpha-alkynyl carboxylic acid (ester) compound and a preparation method thereof. The preparation method comprises the following steps: adding a reaction solvent into weighed malonic acid substrate, 1-(2-aryl alkynyl)-1, 2-benzioyl-3 (1H)-ketone and iron trifluoromethanesulfonate in a nitrogen atmosphere to obtain a mixture, then reacting the mixture for 12 hours under the irradiation of blue light, and carrying out methyl esterification treatment on a crude product obtained by the reaction to obtain the 1, 2, 4-trimethyl-1, 3, 5-trimethyl-1, 3, 5-trimethyl-1, 3, 5-trimethyl-1, 3, 5-trimethyl-1, 3, 5-trimethyl-1, 3, 5-trimethyl-1, 3-diketone. And carrying out silica gel column chromatography or preparative chromatography separation to obtain the alpha-alkynyl carboxylic ester compound. The preparation method disclosed by the invention is mild in reaction condition and simple and convenient to operate, the used chemicals are simple, easily available and commercialized reagents or can be prepared by a reported synthesis method, the reaction cost is relatively low, the functional group compatibility is good, the substrate application range is wide, and the method can also be used for later derivatization of some drug molecules or natural products; the reaction intermediate alpha-alkynyl carboxylic acid can also be directly separated, and various types of compounds are prepared through a decarboxylation functionalization reaction; the method is expected to have wide application prospects in the related fields of synthetic chemistry, drug research and development, life science and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing α-alkynyl carboxylic acid (ester) compounds by using malonic acid derivatives as free radical precursors, utilizing the carbon free radicals obtained by decarboxylation under photocatalytic conditions and capturing them through 1-(2-phenylalkynyl)-1,2-benzidoxyl-3(1H)-one. Background Art

[0002] α-Alkynyl carboxylates possess unique physical and chemical properties and diverse synthetic transformations due to their unique structure (an alkyne and a carboxylic acid attached to the same carbon). First, the malonic acid derivatives used as starting materials are inexpensive and readily available. Second, the carboxyl group in the resulting α-alkynyl carboxylates can participate in a wide range of decarboxylation reactions, enabling further functional group transformations. Furthermore, the alkyne fragment can also undergo reactions such as addition and cyclization. Therefore, the preparation of α-alkynyl carboxylates can become a strategy for constructing complex molecules.

[0003] Currently, there are two main methods for synthesizing α-alkynyl carboxylic acid (ester) compounds: 1. Synthesis by reacting carboxylic acid esters with halogenated alkynes in the presence of a strong base; 2. Preparation by ionic decarboxylation alkynylation of α-cyanocarboxylic acids under high temperature conditions. The following examples illustrate each of these methods:

[0004] In the method disclosed in Document 1 (I. Scheipers, C. Mück-Lichtenfeld, A. Studer, Angew. Chem. Int. Ed. 2019, 58, 6545), the carboxylate raw material is subjected to hydrogen extraction using a strong base, lithium N, N-diisopropylamine, at -78 ° C to obtain an enolate, which is then used as a nucleophile to attack the haloalkyne to obtain an α-alkynylation product. Subsequently, the carboxylate is alkaline hydrolyzed to a salt, and then acidified to obtain a carboxylic acid product. The specific reaction conditions are shown in the figure below.

[0005]

[0006] In the method disclosed in Document 2 (Yi-Si Feng, Zhong-Qiu Xu, Long Mao, Feng-Feng Zhang, and Hua-Jian Xu, Organic Letters 201315, 1472), a potassium salt of an α-cyanocarboxylate, a bromoalkyne, a catalytic amount of silver carbonate, copper bromide, and a ligand are added to a solvent and mixed, and the mixture is reacted at 130° C. for 16 hours to obtain a decarboxylation alkynylated product. The product can then be subjected to alkaline hydrolysis and acidification to obtain an α-alkynyl carboxylic acid. The specific reaction conditions are shown in the figure below.

[0007]

[0008] However, these strategies also have limitations, such as relatively harsh reaction conditions (using strong bases or high temperatures), a narrow substrate range, and relatively limited functional group compatibility. Therefore, the development of simple, practical, sustainable, and easily scalable strategies for the preparation of α-alkynyl carboxylates remains of great importance. Such research is expected to find widespread application in organic synthesis and drug discovery. Summary of the Invention

[0009] The present invention aims to provide a new method for preparing α-alkynyl carboxylic acid (ester) compounds by utilizing a free radical monodecarboxylation coupling reaction involving malonic acid derivatives, aiming to solve the problems existing in the synthesis methods of such compounds, such as severe reaction conditions, narrow substrate application range, relatively limited functional group compatibility, and difficulty in large-scale preparation in actual synthesis.

[0010] The present invention is achieved by providing an α-alkynyl carboxylate compound, the chemical structure of which is shown in the following structural formula (I):

[0011]

[0012] In formula (I), R 1 is methyl, ethyl, isopropyl, benzyl, 4-iodobenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-carboxybenzyl, 4-chlorophenethyl, or a drug molecule fragment such as estrone or progesterone, as well as an alkyl group with an ester, ether, ketone, alkene, or alkyne fragment; R 2 is methyl, ethyl, isopropyl, benzyl or hydrogen; in addition, R 1 、R 2 It can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and piperidine ring with benzoyl protection; and R 3 It is benzene, a benzene ring substituted with halogen, methyl or methoxy, or 2-naphthyl.

[0013] The present invention further discloses a method for preparing the above-mentioned α-alkynyl carboxylic acid (ester) compound, which comprises the following steps:

[0014] (1) Under a nitrogen atmosphere, malonic acid, 1-(2-phenylalkynyl)-1,2-benzidoxyl-3(1H)-one, and an iron catalyst are weighed in a molar ratio of (1.0):(0.5-2.0):(0.05-0.2), and then a reaction solvent is added to obtain a mixture; wherein the iron catalyst is iron trifluoromethanesulfonate or other suitable iron salts such as iron nitrate.

[0015] (2) The mixture of step (1) is stirred under blue light irradiation until the reaction is completed, and the reaction mixture is extracted, dried and evaporated under reduced pressure to remove the low-boiling point solvent to obtain a crude reaction product, which is first esterified and separated by silica gel column chromatography or preparative chromatography to obtain the expected α-alkynyl carboxylate compound.

[0016] Preferably, in step (1), the malonic acid is R 1 、R 2 Alkylmalonic acid substituted with a group; wherein R 1 is methyl, ethyl, isopropyl, benzyl, 4-iodobenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-carboxybenzyl, 4-chlorophenethyl, or a drug molecule fragment such as estrone or progesterone, as well as an alkyl group with an ester, ether, ketone, alkene, or alkyne fragment; R 2 is methyl, ethyl, isopropyl, benzyl or hydrogen; in addition, R 1 、R 2 It can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and piperidine ring with benzoyl protection;

[0017] Preferably, in step (1), the 1-(2-arylalkynyl)-1,2-benzidoyl-3(1H)-one is an aromatic ring structure R with different substituents. 3 , benzene, a benzene ring substituted with halogen or methyl, methoxy, or 2-naphthalene.

[0018] Preferably, in step (1), the reaction solvent is N-methylpyrrolidone / water = 3 / 1 (v / v), or a mixed solvent of other highly polar solvents (such as DMF, DMSO, etc.) and water in a volume ratio of 10 / 1 to 1 / 1; in step (2), the mixture is stirred and reacted under blue light irradiation and 30 to 60° C. for 6 to 24 hours, and has good adaptability to the light source, and the reaction can be achieved under blue light or near-blue light of various intensities.

[0019] The present invention further discloses a method for preparing a variety of α-alkynyl carboxylic acid ester compounds using malonic acid derivatives that are easy to prepare and have diverse structures as free radical precursors and 1-(2-phenylalkynyl)-1,2-benzidoyl-3(1H)-one as a free radical scavenger, as well as the structures of related compounds.

[0020] The present invention overcomes the deficiencies of the prior art and provides a new method for preparing α-alkynyl carboxylic acid (ester) compounds by utilizing the free radical decarboxylation functionalization reaction of malonic acid derivatives. Under a nitrogen atmosphere, malonic acid, 1-(2-phenylalkynyl)-1,2-benzidoyl-3(1H)-one, and an iron catalyst are weighed in a molar ratio of (1.0):(0.5-2.0):(0.05-0.2), and then a reaction solvent is added to obtain a mixture; wherein the iron catalyst is iron trifluoromethanesulfonate or other suitable iron salts. The above mixture is stirred at 30-60°C under blue light irradiation until the reaction is completed, and the reaction mixture is extracted, dried, and subjected to reduced pressure rotary evaporation to remove the low-boiling point solvent to obtain a crude reaction product. After esterification, the crude product is subjected to silica gel column chromatography or preparative chromatography to obtain the expected α-alkynyl carboxylic acid ester compound.

[0021] In the preparation method of the present invention, when malonic acid of different structures is used as a free radical precursor and 1-(2-phenylalkynyl)-1,2-benzidoyl-3(1H)-one is used as a free radical scavenger, the preparation reaction equation of α-alkynyl carboxylic acid (ester) compounds is as follows:

[0022]

[0023] In the preparation method of the present invention, when benzylmethylmalonic acid is used as a free radical precursor and 1-(2-arylalkynyl)-1,2-benzidoyl-3(1H)-one with different substitutions on the aryl group is used as a free radical scavenger, the preparation reaction equation of the α-alkynyl carboxylic acid (ester) compound is as follows:

[0024]

[0025] Therefore, in the present invention, stable, structurally diverse, and easily prepared alkyl-substituted malonic acid derivatives are used as free radical precursors. By means of iron-mediated ligand-to-metal charge transfer (LMCT) decarboxylation radical generation and subsequent free radical addition reactions, important α-alkynyl carboxylic acid (ester) compounds can be prepared conveniently and quickly.

[0026] Carboxyl and alkyne structural units have a wide range of applications in materials, functional building blocks, pharmaceuticals, and active molecules. The α-alkynyl carboxylic acid (ester) compounds prepared in this invention contain both carboxyl and alkyne groups. These compounds are expected to be further studied and applied in a wider range of fields, including materials science, organic synthesis, and small molecule drug development.

[0027] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following advantages:

[0028] (1) The preparation method of the present invention is simple to operate and easy to scale up. The developed reaction can occur under mild conditions, utilizing an iron-mediated ligand-to-metal charge transfer (LMCT) strategy under light irradiation. Malonic acid can efficiently generate alkyl radicals. The malonic acid substrate used is widely available, easily available, stable, and low-cost. In addition, the functional group compatibility of the reaction is good, and the substrate has a wide range of applicability (both disubstituted and monosubstituted malonic acids can participate well in this chemical transformation).

[0029] (2) The preparation method of the present invention is applicable to the decarboxylation alkynylation reaction of a malonic acid substrate derived from a drug molecule or a complex natural product. Unlike the commonly used preparation methods of α-alkynyl carboxylic acid (ester) compounds, this invention provides a new reaction mode, namely, LMCT-driven malonic acid free radical decarboxylation to initiate the reaction, and subsequent free radical reactions can be used to conveniently synthesize the desired compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 is a summary drawing of the present invention;

[0031] Figure 2 is the hydrogen spectrum of compound 1 in Example 1 of the present invention;

[0032] Figure 3 is the carbon spectrum of compound 1 in Example 1 of the present invention;

[0033] Figure 4 is the hydrogen spectrum of the compound in Example 9 of the present invention;

[0034] Figure 5 is the carbon spectrum of the compound in Example 9 of the present invention;

[0035] Figure 6 is the hydrogen spectrum of the compound in Example 10 of the present invention;

[0036] Figure 7 is the carbon spectrum of the compound in Example 10 of the present invention; DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solutions and advantages of the present invention more clearly presented, the present invention is further described in detail below in conjunction with the embodiments and drawings. It should be understood that the specific embodiments described herein are only used to illustrate the present invention and are not used to limit the present invention.

[0038] Example 1

[0039] (1) Under a nitrogen atmosphere, 2-(4-chlorophenethyl)-2-ethylmalonic acid, 1-(2-phenylalkynyl)-1,2-benzidoxyl-3(1H)-one, and an iron catalyst are weighed in a molar ratio of (1.0):(1.5):(0.1), and then a reaction solvent is added to obtain a mixture; wherein the iron catalyst is iron trifluoromethanesulfonate or other suitable iron salt.

[0040] (2) The mixture of step (1) is irradiated with 5W, 460nm blue light and stirred at 50°C until the reaction is complete. The reaction mixture is extracted, dried, and subjected to reduced pressure rotary evaporation to remove the low-boiling point solvent to obtain a crude product. The crude product is separated by silica gel column chromatography or preparative chromatography to obtain the expected α-alkynyl carboxylic acid compound as an intermediate product in a yield of 68%. Its structural formula is shown in the figure below:

[0041]

[0042] (3) In step (2), in order to obtain an α-alkynyl carboxylate compound, the crude product of step (2) is subjected to methyl esterification and then subjected to silica gel column chromatography or preparative chromatography for separation and purification, to obtain an α-alkynyl carboxylate compound with a yield of 66%. Its structural formula 1 is shown in the figure below:

[0043]

[0044] Examples 2 to 5

[0045] Examples 2 to 5 are substantially the same as Example 1, except that the substituent R 1 and R 2 The specific structures of malonic acid derivatives and the structures of the corresponding synthetic compounds are shown in the table below:

[0046]

[0047] Examples 6 to 8

[0048] Examples 6 to 8 are basically the same as Example 2, except that the benzene ring of the phenylethynyl group is replaced by a different substituent R. The specific structure of the acetylenic reagent and the number of the corresponding compound synthesized are shown in the following table:

[0049]

[0050]

[0051] Examples 9-10

[0052] Examples 9 to 10 are substantially the same as Example 1, except that the substituent R 1It is a drug molecule derivative. The structure of malonic acid and the structure of the corresponding synthetic compound are shown in the table below:

[0053]

[0054] Example 11

[0055] This example is essentially the same as Example 4, except that the reaction scale was scaled up from 0.1 mmol to 3.6 mmol. Methyl esterification was omitted, and the α-alkynyl carboxylic acid product was directly isolated. The yield of the scaled-up reaction was 63%, which was almost the same as the 64% yield of the 0.1 mmol reaction. This further demonstrates the excellent practicality of the preparation method of the present invention.

[0056] The reaction equation involved in the embodiment of the present invention is as follows:

[0057]

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. Using malonic acid derivatives as free radical precursors, photocatalytic decarboxylation is used to generate α-carboxyl radicals, which are then captured by 1-(2-arylalkynyl)-1,2-benzidoyl-3(1H)-one to obtain α-alkynyl carboxylic acid compounds. α-alkynyl carboxylate compounds can be obtained through esterification. The chemical formula of this type of compound is shown in the following structural formula (I): In formula (I), R 1 is methyl, ethyl, isopropyl, benzyl, 4-iodobenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-carboxybenzyl, 4-chlorophenethyl, or a drug molecule fragment such as estrone or progesterone, as well as an alkyl group with an ester, ether, ketone, alkene, or alkyne fragment; R 2 is methyl, ethyl, isopropyl, benzyl or hydrogen; in addition, R 1 、R 2 It can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and piperidine ring with benzoyl protection; and R 3 It is benzene, a benzene ring substituted with halogen, methyl or methoxy, or 2-naphthyl.

2. The malonic acid derivative according to claim 1 is a derivative having the above-mentioned R 1 、R 2 Substituted malonic acid.

3. The suitable photocatalytic system according to claim 1 is an iron-catalyzed free radical decarboxylation system based on a ligand-to-metal charge transfer strategy, wherein an iron salt is added to the reaction system as a catalyst without the need for additional reaction additives (such as bases, etc.).

4. The method for preparing the α-alkynyl carboxylic acid (ester) compound according to claim 1, characterized in that: The method comprises the following steps: (1) Under a nitrogen atmosphere, malonic acid, 1-(2-arylalkynyl)-1,2-benzidoyl-3(1H)-one, and an iron catalyst are weighed in a molar ratio of (1.0):(0.5-2.0):(0.05-0.2), and then a reaction solvent is added to obtain a mixture; wherein the iron catalyst is iron trifluoromethanesulfonate or other suitable iron salts such as iron nitrate. (2) The mixture of step (1) is stirred under blue light irradiation until the reaction is completed, and the reaction mixture is extracted, dried, and subjected to reduced pressure rotary evaporation to remove the low-boiling point solvent to obtain a crude reaction product. The crude product is subjected to esterification treatment and silica gel column chromatography or preparative chromatography to obtain the expected α-alkynyl carboxylate compound.

5. The method for preparing an α-alkynyl carboxylic acid (ester) compound according to claim 4, wherein: In step (1), the malonic acid is R 1 、R 2 Alkylmalonic acid substituted with a group; wherein R 1 is methyl, ethyl, isopropyl, benzyl, 4-iodobenzyl, 4-phenylbenzyl, 4-trifluoromethylbenzyl, 4-carboxybenzyl, 4-chlorophenethyl, or a drug molecule fragment such as estrone or progesterone, as well as an alkyl group with an ester, ether, ketone, alkene, or alkyne fragment; R 2 is methyl, ethyl, isopropyl, benzyl or hydrogen; in addition, R 1 、R 2 It can also form cyclic structures such as cyclobutane, pyran, benzo five-membered ring and piperidine ring with benzoyl protection; In step (1), the 1-(2-arylalkynyl)-1,2-benzidoyl-3(1H)-one is an aromatic ring structure R with different substituents. 3 , is benzene, a benzene ring substituted with halogen or methyl, methoxy, or 2-naphthyl.

6. The method for preparing an α-alkynyl carboxylic acid (ester) compound according to claim 4, wherein: In step (1), the reaction solvent is N-methylpyrrolidone / water = 3 / 1 (v / v), or a mixed solvent of other highly polar solvents (such as DMF, DMSO, etc.) and water in a volume ratio of 10 / 1 to 1 / 1; in step (2), the mixture is stirred and reacted under blue light irradiation and 30 to 60° C. for 6 to 24 hours, and has good adaptability to light sources, and the reaction can be achieved under blue light or near-blue light of various intensities.

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