Alpha-deuterated carboxylic acid compound and preparation method thereof

Abstract

The invention discloses an alpha-deuterated carboxylic acid compound and a preparation method thereof. The preparation method comprises the following steps: adding a malonic acid derivative, an acridine photocatalyst and diphenyl disulfide into a reaction flask, and adding pyridine and 1, 2-dichloroethane / deuterium water (5 / 1) in a nitrogen atmosphere; placing the reaction bottle in a 5W photoreactor, and reacting at 50 DEG C for 12 hours; and after the reaction is finished, separating and purifying by using a preparation plate or column chromatography. According to the alpha-deuterated carboxylic acid compound obtained by the preparation method disclosed by the invention, the deuteration rate is greater than or equal to 95%. The reaction conditions are relatively mild, the operation is simple and convenient, green and cheap deuterium water is used as a deuterium source, the substrate application range is wide (can be directly used for later derivatization of some drug molecules or natural products), the functional group compatibility is good, the obtained alpha-deuterated carboxylic acid compound can be used for preparing other deuterium-containing compounds with high additional values through functional group conversion, and the method is suitable for industrial production. 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] This invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for efficiently preparing α-deuterated carboxylic acid compounds through a visible-light-induced decarboxylation / deuteration tandem reaction using malonic acid as a raw material, under the synergistic catalysis of an organic acridine photocatalyst and a thioether hydrogen atom transfer reagent, and utilizing deuterated water as an economical deuterium source. This strategy achieves precise deuterium labeling of the α-site of the carboxylic acid through deuteration of the α-carboxyl radical, followed by deuterium atom transfer, achieving a deuteration rate of 95% or greater. Background Art

[0002] α-Deuterated carboxylic acids possess unique physicochemical properties and diverse synthetic transformation potential due to their special structure (a deuterium atom and a carboxyl group are attached to the same carbon). Organic deuterated molecules have a wide range of applications in pharmaceutical research and organic synthesis. In medicinal chemistry, replacing one or more carbon-hydrogen bonds at specific metabolic sites of a drug molecule with carbon-deuterium bonds can improve the drug's metabolic stability without changing its efficacy. In organic synthesis, the introduction of deuterium atoms at specific carbon sites can help understand or elucidate the course of reactions. Therefore, how to efficiently and gently introduce deuterium atoms into complex drugs or organic molecules is a topic of great interest to both medicinal chemists and organic chemists.

[0003] Based on the above background, the inventors plan to construct a versatile platform for preparing deuterated compounds. Carboxylic acid compounds are ideal starting materials in organic synthesis. Inspired by the powerful functional group transformation potential of carboxylic acid compounds, the inventors envisioned the development of an efficient and highly selective method for preparing α-deuterated carboxylic acid compounds. This approach could leverage the diverse synthetic transformation capabilities of the carboxyl functional group in carboxylic acids, such as condensation to form esters and amides, reduction to form alcohols, and Curtius rearrangement to form amines. Furthermore, the free radical decarboxylation reaction of carboxylic acids could be utilized to synthesize a series of α-deuterated α-functional compounds with potential applications in medicinal chemistry and organic chemistry. Since the derivatization of carboxylic acids is well established, the key to establishing a platform for preparing a series of α-deuterated compounds lies in the development of a simple and convenient method for synthesizing α-deuterated carboxylic acids.

[0004] At present, there are mainly the following methods for synthesizing α-deuterated carboxylic acid compounds (such as the following Figure 8 ) : oxidation of deuterated aldehydes and ketones, conversion of α-bismuth / bromine-substituted carboxylate, reduction of unsaturated carboxylic acids, H / D exchange at the α-position of carboxylic acids, and thermal decarboxylation of malonic acid. However, each of these methods has limitations, which are described below with examples.

[0005] For example, in the method disclosed in Document 1 (GUO, Q.; REN X.; LU, Z. Org Lett. 2019, 21, 880), the acidity of the aldehyde α-H is utilized to undergo H / D exchange at 100 ° C under the action of 4-dimethylaminopyridine (DMAP) and deuterated water to obtain an α-deuterated aldehyde, and then an α-deuterated carboxylic acid compound is obtained under oxidative conditions. The specific reaction conditions are shown below.

[0006]

[0007] In the method disclosed in Reference 2 (YAMAGO S.; KAYAHARA E.; KOTANI M. Angew Chem Int Ed, 2007, 46, 1304), an α-bismuth-substituted carboxylate is reacted in the highly toxic system of Bu3SnD and C6D6 at 80°C for 1 hour to produce an α-deuterated carboxylate. Further hydrolysis of the α-deuterated carboxylate can also yield an α-deuterated carboxylic acid compound. The specific reaction scheme is shown below.

[0008]

[0009] In the method disclosed in Document 3 (OHTA T.; TAKAYA H.; NOYORI R. Tetrahedron Letters, 1990, 31, 7189), Ru(OCOCH3)2[(R)-Binap] is used as a catalyst, and α,β-unsaturated carboxylic acids are reacted in a D2 (4atm) atmosphere for 168 hours to obtain some simple α,β-dideuterated carboxylic acid compounds. The specific reaction conditions are shown below.

[0010]

[0011] In the method disclosed in Reference 4 (ATKINSON JG.; CSAKVARY JJ.; HERBERT GT. Journal of the American Chemical Society, 1968, 90, 498), a potassium carboxylate is heated to reflux (120-180° C.) in an alkaline deuterium oxide system to cause H / D exchange of the α-position proton of the carboxyl group, thereby preparing some α-deuterated carboxylic acid compounds. The specific reaction is shown below.

[0012]

[0013] In the method disclosed in document 5 (WENNERBERG J.; DREISCH K. J Labelled Comp Radiopharm, 2023, 66, 138), a monosubstituted malonic acid derivative is subjected to hydrogen-deuterium exchange in D2O at 55°C, and then heated to 160°C for decarboxylation to obtain an α-deuterated carboxylic acid. The specific reaction is shown below.

[0014]

[0015] Existing literature indicates that some progress has been made in the synthesis of α-deuterated carboxylic acids. However, traditional methods generally involve reactions in strongly alkaline media, and suffer from common problems such as high reaction temperatures, expensive and difficult-to-obtain deuterated reagents, and cumbersome procedures. While synthetic pathways using malonic acid as a precursor have achieved significant success, they suffer from harsh reaction conditions and poor substrate functional group compatibility. Given the widespread application of organic deuterated molecules in pharmaceutical research and organic synthesis, there is an urgent need to develop novel synthetic strategies for α-deuterated carboxylic acids that exhibit mild, green reaction conditions, broad substrate adaptability, and high deuteration efficiency. Summary of the Invention

[0016] The primary objective of the present invention is to provide a novel method for preparing α-deuterated carboxylic acid compounds by utilizing the photocatalytic free radical monodecarboxylation deuteration reaction of malonic acid derivatives. This method aims to overcome certain limitations of existing synthesis methods for such compounds, such as harsh reaction conditions (high temperature, strong alkalinity), toxic or expensive deuterated reagents, or the use of high-value-added raw materials.

[0017] Another object of the present invention is to provide a novel α-deuterated carboxylic acid compound, and based on the excellent functional group conversion properties of the carboxylic acid group in its structure, to construct a universal synthetic platform to achieve modular preparation of diversified α-deuterated-α-functional group compounds.

[0018] The present invention is achieved by providing an α-deuterated carboxylic acid compound, the chemical structure of which is shown in the following formula (I):

[0019]

[0020] In formula (I), R 1 4-chlorophenethyl, benzyl, 4-iodobenzyl, 4-sulfonebenzyl, 4-boronatebenzyl, 4-nitrobenzyl, cyclobutyl, oxacyclopentyl, cycloheptyl and other linear, branched, cyclic alkyl groups, as well as drug molecular fragments such as clofibrate, isoxetine, dehydroepiandrosterone, formononetin, naproxen and ethinylestradiol; R 2 It is hydrogen, methyl, ethyl, isopropyl, etc.

[0021] The present invention further discloses a method for preparing the above-mentioned α,-deuterated carboxylic acid compounds, which comprises the following steps:

[0022] (1) Under a nitrogen atmosphere, malonic acid, a photocatalyst, a hydrogen transfer reagent and a base are sequentially added to a mixed solvent of 1,2-dichloroethane / deuterated water (5 / 1) in a molar ratio of (1.0): (0.01): (0.05): (1) to obtain a mixture; wherein the photocatalyst is an acridine photocatalyst, the hydrogen transfer reagent is p-phenylene disulfide, and the base is pyridine.

[0023] (2) stirring the mixture of step (1) at a suitable temperature until the reaction is completed, extracting, drying and removing the low-boiling point solvent from the reaction mixture under reduced pressure to obtain a crude reaction product, and separating the crude product by silica gel column chromatography or preparative chromatography to obtain the expected α-deuterated carboxylic acid compound.

[0024] Preferably, in step (1), the malonic acid is R 1 and R 2 Alkyl carboxylic acid substituted with a group; R 1 4-chlorophenethyl, benzyl, 4-iodobenzyl, 4-sulfonebenzyl, 4-boronatebenzyl, 4-nitrobenzyl, cyclobutyl, oxacyclopentyl, cycloheptyl and other linear, branched, cyclic alkyl groups, as well as drug molecular fragments such as clofibrate, isoxetine, dehydroepiandrosterone, formononetin, naproxen and ethinylestradiol; R 2 It is hydrogen, methyl, ethyl, isopropyl, etc.

[0025] Preferably, in step (1), the reaction solvent is dichloroethane and deuterated water, and the volume ratio of the two is 5:1; in step (2), the mixture is stirred at 50 degrees Celsius for 12 to 48 hours under 5W 460nm blue light irradiation.

[0026] The present invention further discloses a method for preparing various α-deuterated carboxylic acid compounds and the structures of related compounds, using cheap and readily available malonic acid as a free radical precursor, undergoing monodecarboxylation under photocatalytic conditions to produce an α-carboxyl free radical, which then intercepts a deuterium atom to produce an α-deuterated carboxylic acid.

[0027] The present invention overcomes the shortcomings of the prior art and provides a new method for preparing α-deuterated carboxylic acid compounds by utilizing the monodecarboxylation deuteration of malonic acid derivatives. Under a nitrogen atmosphere, malonic acid, a photocatalyst, a hydrogen transfer agent, and a base are sequentially added to a reaction solvent in a molar ratio of (1.0):(0.01):(0.05):(1) to obtain a mixture; wherein the photocatalyst is an acridine photocatalyst, the hydrogen transfer agent is p-phenylene disulfide, and the base is pyridine. The mixture is stirred at a suitable temperature and under light until the reaction is completed. After the reaction is completed, the reaction mixture is quenched, extracted, dried, and the low-boiling point solvent is removed by decompression to obtain a crude reaction product. The crude product can be separated by silica gel column chromatography or preparative chromatography to obtain the desired α-deuterated carboxylic acid compound.

[0028] In the preparation method of the present invention, when malonic acid with different structures is used as a free radical precursor, the preparation reaction equation of α-deuterated carboxylic acid compounds is as follows:

[0029]

[0030] In the preparation method of the present invention, when a disubstituted malonic acid derivative derived from dehydroepiandrosterone is used as a free radical precursor, the preparation reaction equation of the α-deuterated carboxylic acid compound is as follows:

[0031]

[0032] In the preparation method of the present invention, when the monosubstituted malonic acid derivative derived from ethinylestradiol is used as a free radical precursor, the preparation reaction equation of the α-deuterated carboxylic acid compound is as follows:

[0033]

[0034] Disubstituted malonic acid and monosubstituted malonic acid generate α-deuterated carboxylic acids (e.g., compound 12) and α-dideuterated carboxylic acids (e.g., compound 16), respectively. The formation of dideuterated carboxylic acids in the monosubstituted malonic acid derivatives in this reaction system is due to the initial H / D exchange of the α-hydrogen of the malonic acid. Subsequently, under alkaline conditions, a single electron transfer occurs between one of the carboxyl anions of the malonic acid anion and the excited photocatalyst, followed by decarboxylation to generate an α-carboxyl radical. This α-carboxyl radical then undergoes a hydrogen atom transfer reaction with deuterated thiol to yield an α-dideuterated monocarboxylic acid compound.

[0035] In the present invention, malonic acid, which has a stable structure and a wide range of sources, is used as a free radical precursor. Under photocatalytic conditions, monodecarboxylation is performed to obtain α-carboxyl free radicals, and the α-carboxyl free radicals intercept deuterium atoms, thereby enabling the convenient and rapid preparation of important α-deuterated carboxylic acid compounds.

[0036] α-Deuterated carboxylic acid compounds have multi-dimensional application value in drug discovery and mechanism research. The α-deuterated carboxylic acid compounds prepared in this invention contain both deuterium atoms and carboxyl groups and are expected to have broad applications in materials science, organic synthesis, and small molecule drug development.

[0037] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following advantages:

[0038] (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. The malonate substrate used is widely available, easily accessible, stable, and low-cost. In addition, the functional group compatibility of the reaction is good, and the substrate is applicable to a wide range of applications (both disubstituted and monosubstituted malonates can participate well in this chemical transformation).

[0039] (2) Different from the commonly used methods for preparing α-deuterated carboxylic acid compounds, this invention provides a new reaction mode, namely, the photocatalytic monodecarboxylation deuteration reaction of malonic acid derivatives free radicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Schematic diagram of representative α-deuterated carboxylic acid compounds of the present invention;

[0041] Figure 2 is the hydrogen spectrum of compound 3 in the embodiment of the present invention;

[0042] Figure 3 is the carbon spectrum of compound 3 in the examples of the present invention;

[0043] Figure 4 is the hydrogen spectrum of compound 15 in the examples of the present invention;

[0044] Figure 5 This is the carbon spectrum of compound 15 in the examples of the present invention.

[0045] Figure 6 is the hydrogen spectrum of compound 19 in the examples of the present invention;

[0046] Figure 7 is the carbon spectrum of compound 19 in the examples of the present invention; Figure 8 This is a traditional synthesis method of α-deuterated carboxylic acid compounds in the present invention; Figure 9 A series of α-deuterated-α-functional group compounds are prepared from compound 9 in the present invention. DETAILED DESCRIPTION

[0047] 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.

[0048] Example 2

[0049] (1) Under a nitrogen atmosphere, 2-(4-chloroethylbenzene)-2-ethylmalonic acid, an acridine photocatalyst, p-phenylene disulfide, and pyridine were added in a molar ratio of (1.0):(0.01):(0.05):(1) in sequence to dichloroethane and deuterated water in a volume ratio of 5:1 to obtain a mixture.

[0050] (2) The mixture of step (1) was reacted in a 5W photochemical reactor at a constant temperature of 50°C for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and quenched, extracted, dried, and the low-boiling point solvent was removed by vacuum rotation to obtain a crude reaction product. The crude product was separated by silica gel column chromatography or preparative chromatography to obtain the expected α-deuterated carboxylic acid compound 3 with a yield of 93% and a deuteration rate (D-lnc)>95%. Its structural formula is shown below:

[0051]

[0052] The H NMR spectrum and C NMR spectrum of the α-deuterated carboxylic acid compound 3 are as follows: Figure 2 、 Figure 3 .

[0053] Examples 1 to 15

[0054] Examples 1 to 15 are substantially the same as Example 2, except that the substituent R 1 、R 2 The specific structures of different α-deuterated carboxylic acids and the numbers of the corresponding synthetic compounds are shown in the table below:

[0055] Table 1 Examples 1 to 15

[0056]

[0057]

[0058] Example 14

[0059] (1) Under nitrogen atmosphere, a naproxen-derived monosubstituted malonic acid derivative, an acridine photocatalyst, p-phenylene disulfide and pyridine were added in a molar ratio of (1.0):(0.01):(0.05):(1) in sequence to dichloroethane and deuterated water in a volume ratio of 5:1 to obtain a mixture.

[0060] (2) The mixture of step (1) is reacted in a 5W photochemical reactor at a constant temperature of 50°C for 48 hours. After the reaction is completed, the reaction mixture is cooled to room temperature, quenched, extracted, dried, and the low-boiling point solvent is removed by vacuum rotation to obtain a crude reaction product. The crude product is separated by silica gel column chromatography or preparative chromatography to obtain the expected α-deuterated carboxylic acid compound with a yield of 90% and a deuteration rate (D-lnc)>95%. Its structural formula is shown below:

[0061]

[0062] The H NMR and C NMR spectra of the α-deuterated carboxylic acid compound 15 are shown in Figure 2. Figure 4 、 Figure 5 .

[0063] Example 16

[0064] This example is essentially the same as Example 8, except that the reaction scale was scaled up from 0.1 mmol to 3.7 mmol. The yield of the scaled-up reaction was essentially the same as that of the 0.1 mmol reaction, and the deuteration rate was greater than 95%. This further demonstrates the excellent practicality of the preparation method of the present invention.

[0065] The reaction equation involved in the embodiment of the present invention is as follows:

[0066] Gram-scale reactions

[0067]

[0068] The above-developed photocatalytic monodecarboxylation reaction of malonic acid derivatives provides a new route for the synthesis of α-deuterated carboxylic acids. The synthesized α-deuterated carboxylic acids, with the help of the powerful functional group conversion ability of carboxylic acids, have constructed a multifunctional platform for the preparation of a series of α-deuterated-α-functional group compounds (such as the attached Figure 9). Starting from the α-deuterated carboxylic acid compound 9, a series of α-deuterium-α-functionalized compounds were successfully synthesized using the carboxylic acid free radical decarboxylation functionalization strategy. For example, in the catalytic system of silver and potassium persulfate, it can undergo a decarboxylation azidation reaction with an azide reagent (TsN3) to obtain an α-deuterium-substituted azide compound (Compound 17); under the conditions of carboxylic acid reductive decarboxylation functionalization, the α-deuterated carboxylic acid compound 9 can also smoothly undergo a decarboxylation borylation reaction to obtain an α-deuterium-substituted borate compound (Compound 18). And a decarboxylation alkynylation reaction with an alkyne reagent obtains an α-deuterium-substituted alkynyl compound (Compound 19); and reacts with a trifluoromethylcopper reagent [(bpy)Cu(CF3)2] to obtain an α-deuterium-substituted trifluoromethyl compound (Compound 20). The α-deuterated carboxylic acid compound 9 can react with a selective fluorine reagent under photocatalytic conditions to obtain an α-deuterium-substituted fluorinated compound (Compound 21). The α-deuterated carboxylic acid compound 9 reacts with tert-butyl hypochlorite in the presence of silver to produce the α-deuterated chloro compound (compound 22). Organic deuterated compounds have a wide range of applications in medicinal chemistry and organic synthesis. Using readily available malonic acid as a starting material, this method provides a new method for the preparation of various deuterated compounds by controlling the differential conversion abilities of the two carboxyl groups in the malonic acid substrate.

[0069] Example 19

[0070] (1) Under nitrogen atmosphere, compound 9, AgNO3, K2S2O8, and TIPS-EBX were added sequentially with acetonitrile and water in a molar ratio of (1.0):(0.1):(1.5):(1.5) in a volume ratio of 1:1 to obtain a mixture.

[0071] (2) The mixture of step (1) was stirred at 50° C. for 24 h. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched, extracted, dried, and the low-boiling point solvent was removed by vacuum evaporation to obtain a crude reaction product. The crude product was separated by silica gel column chromatography or preparative chromatography to obtain the expected α-deuterium-substituted alkynyl compound 19 in a yield of 62%. Its structural formula is shown below:

[0072]

[0073] The H NMR and C NMR spectra of the α-deuterium substituted alkynyl compound 19 are shown in Figure 2. Figure 6 、 Figure 7 .

[0074] 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 raw materials, monodecarboxylation is performed under photocatalytic conditions to obtain α-carboxyl radicals, which intercept deuterium atoms to obtain α-deuterated carboxylic acids. The chemical structure of this type of compound is shown in the following structural formula (I): In formula (I), R 1 4-chlorophenethyl, benzyl, 4-iodobenzyl, 4-sulfonebenzyl, 4-boronatebenzyl, 4-nitrobenzyl, cyclobutyl, oxacyclopentyl, cycloheptyl and other linear, branched, cyclic alkyl groups, as well as drug molecular fragments such as clofibrate, isoxetine, dehydroepiandrosterone, formononetin, naproxen and ethinylestradiol; R 2 It is hydrogen, methyl, ethyl, isopropyl, etc.

2. The malonic acid derivative according to claim 1 is a derivative having the above-mentioned R 1 、R 2 Group, malonic acid after functional group.

3. The suitable photocatalytic malonic acid derivative free radical monodecarboxylation deuteration system according to claim 1 is an organic acridine compound / thioether (thiophenol) type hydrogen atom transfer reagent synergistically catalyzed under light, a suitable reaction additive (such as a base, etc.) is added to the reaction system, and deuterated water is used as a deuterium source.

4. The method for preparing the α-deuterated carboxylic acid compound according to claim 1, wherein The method comprises the following steps: (1) Under a nitrogen atmosphere, malonic acid, a photocatalyst, a hydrogen transfer reagent and a base are sequentially added to a mixed solvent of 1,2-dichloroethane / deuterated water (5 / 1) in a molar ratio of (1.0): (0.01): (0.05): (1) to obtain a mixture; wherein the photocatalyst is an acridine photocatalyst, the hydrogen transfer reagent is p-phenylene disulfide, and the base is pyridine. (2) The mixture of step (1) is stirred at 50° C. under blue light irradiation until the reaction is completed, the reaction mixture is extracted, dried, and the low-boiling point solvent is removed by decompression to obtain a crude reaction product, and the crude product is separated by silica gel column chromatography or preparative chromatography to obtain an α-deuterated carboxylic acid compound with a deuteration rate greater than or equal to 95% and a yield of 73-96%.

5. The method for preparing an α-deuterated carboxylic acid compound according to claim 4, wherein: In step (1), the carboxylic acid is R 1 and R 2 Alkyl carboxylic acid substituted with a group; wherein R 1 4-chlorophenethyl, benzyl, 4-iodobenzyl, 4-sulfonebenzyl, 4-boronatebenzyl, 4-nitrobenzyl, cyclobutyl, oxacyclopentyl, cycloheptyl and other linear, branched, cyclic alkyl groups, as well as drug molecular fragments such as clofibrate, isoxetine, dehydroepiandrosterone, formononetin, naproxen and ethinylestradiol; R 2 It is hydrogen, methyl, ethyl, isopropyl, etc.

6. The method for preparing the α-deuterated carboxylic acid compound according to claim 4, wherein: In step (1), the reaction solvent is dichloroethane and deuterated water, and the volume ratio of the two is 5:1; in step (2), the mixture is stirred at 50 degrees Celsius for 12 to 48 hours under 5W 460nm blue light irradiation.

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