A method for preparing an oxalic acid derivative by visible light catalyzed decarboxylation of an oxamidic acid derivative

Abstract

The application discloses a method for preparing a mesotartaric acid derivative by visible light catalyzed decarboxylation of oxamic acid derivative, and belongs to the technical field of chemical synthesis. In the method, a light catalyst is used, and oxamic acid derivative reacts with alpha-keto acid ester under light catalysis to obtain the mesotartaric acid derivative at a medium yield. The method has mild process conditions and simple operation, does not need to add a stoichiometric oxidant, and is safe and high in safety, and meanwhile, the method avoids generation of stoichiometric waste. The method is different from existing synthesis technologies in reaction type, starting material and reverse synthesis bond breaking selection, and provides a new synthesis path for the mesotartaric acid derivative.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing a tartronic acid derivative by visible light catalysis of decarboxylation of oxamic acid derivative. BACKGROUND

[0002] Tartronic acid, also known as hydroxymalonic acid, is an organic compound with carboxyl and hydroxyl functional groups. Tartronic acid and its derivatives have a wide range of uses, such as as reverse peptide substitutes (J. Med. Chem., 1998, 41, 339-345) and as synthesis building blocks of biodegradable surfactants (Polym. Adv. Technol. 2001, 12, 697-710). The classic method for preparing tartronic acid derivatives is through an oxidation reaction between malonate and a chemical oxidant (such as a heavy metal oxidant or a peroxy acid). Under the catalysis of a transition metal, malonate can also react with oxygen to introduce a hydroxyl functional group to obtain malonate, and the general chemical reaction formula is as follows: However, the traditional method has problems such as generation of stoichiometric waste, use of special catalysts or low yield. In view of the above problems, some new methods have been developed to synthesize tartronic acid derivatives. Carlos F. Marcos et al. reported that tartronic acid derivatives can be prepared by a continuous process of Passerini three-component reaction of glyoxylic ester or amide and zinc-catalyzed hydrolysis reaction (Green Chem., 2006, 8, 787-789), and the general chemical reaction formula is as follows Akichika Itoh et al. found that beta-keto ester can react with oxygen under visible light irradiation to obtain tartronic acid derivatives through a tandem oxidation and rearrangement process (Org. Lett. 2010, 12, 1948-1951; RSC Adv. 2016, 6, 42596-42599), and the general chemical reaction formula is as follows However, these methods still have deficiencies in raw material availability, ease of operation or reaction efficiency, and therefore it is necessary to develop new efficient methods for synthesizing tartronic acid derivatives. SUMMARY

[0003] In view of the problems in the prior art that the synthesis of tartronic acid derivatives mainly relies on some oxidation reactions, which produces stoichiometric waste, and that the use of oxygen in chemical production has certain safety risks, the application provides a method for preparing a tartronic acid derivative by visible light catalysis of decarboxylation of oxamic acid derivative, which realizes efficient synthesis of tartronic acid derivative through an oxidation-reduction neutral reaction.

[0004] A method for preparing a mesotartaric acid derivative by visible light catalyzed decarboxylation of oxamic acid derivative, comprising the following steps: mixing alpha-keto acid ester, oxamic acid derivative, photocatalyst and base in an organic solvent, removing oxygen, and synthesizing the mesotartaric acid derivative by free radical coupling reaction under visible light irradiation.

[0005] The method of the present application utilizes oxamic acid derivative and alpha-keto acid ester as starting materials to synthesize mesotartaric acid derivative through one-step oxidation-reduction neutral photocatalytic process. On one hand, the photocatalyst is excited to oxidize the oxamic acid derivative to obtain an amide radical intermediate. On the other hand, the alpha-keto acid ester is reduced by the reduced photocatalyst to generate an alpha-hydroxy radical intermediate. The coupling of the above two radicals constructs C-C(CO) bond, realizing the synthesis of mesotartaric acid derivative.

[0006] The free radical coupling reaction is as follows:

[0007]

[0008] wherein, R 1 is selected from Ph or 4-Cl-Ph; R 2 is selected from Et or Me; R 3 is selected from N( n Pr)2 or N(Et)2.

[0009] The molar ratio of the alpha-keto acid ester and the oxamic acid derivative is 3:2.

[0010] The amount of the photocatalyst is 2 mol% of the oxamic acid derivative.

[0011] The photocatalyst is selected from 4CzIPN, 3DPA2FBN or [Ir(dtbbpy)(ppy)2]PF6; the chemical structural formula of the photocatalyst is as follows:

[0012]

[0013] The molar ratio of the base to the oxamic acid derivative is 2:1.

[0014] The base is cesium carbonate.

[0015] The organic solvent is selected from acetonitrile or dichloromethane.

[0016] The time of the free radical coupling reaction is 24 h, and the temperature is 25-55℃; preferably, the temperature of the free radical coupling reaction is 35℃.

[0017] The present application realizes photocatalysis by placing Kessil led lamps on one side or both sides of the reaction device, and controls the reaction temperature by adjusting the number of Kessil led lamps and the positional relationship with the reaction device.

[0018] Compared with the prior art, the present application has the following advantages and technical effects:

[0019] The present application uses a photocatalyst, and under the photocatalysis, oxamic acid derivatives react with alpha-keto esters to obtain hypomalic acid derivatives in a medium yield. The process has mild conditions and simple operation, and does not need to add stoichiometric oxidants, and no oxygen is involved in the whole synthesis process, so the safety is high, and stoichiometric waste is avoided. The present application is different from the prior synthesis technology in reaction type, starting material and reverse synthesis bond breaking selection, and provides a new synthesis path for hypomalic acid derivatives. BRIEF DESCRIPTION OF DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments will be briefly introduced as follows. Obviously, the drawings in the following description only constitute some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor under the premise of the drawings.

[0021] Figure 1 Chemical principle diagram for synthesizing hypomalic acid derivatives of the present application;

[0022] Figure 2 Nuclear magnetic resonance hydrogen spectrum diagram for synthesizing hypomalic acid derivative III-a in Example 1;

[0023] Figure 3 Nuclear magnetic resonance hydrogen spectrum diagram for synthesizing hypomalic acid derivative III-b in Example 2;

[0024] Figure 4 Nuclear magnetic resonance hydrogen spectrum diagram for synthesizing hypomalic acid derivative III-c in Example 3;

[0025] Figure 5 Nuclear magnetic resonance hydrogen spectrum diagram for synthesizing hypomalic acid derivative III-d in Example 4. DETAILED DESCRIPTION

[0026] The various exemplary embodiments of the present application will be described in detail below, and the detailed description should not be considered as limiting the present application, but should be understood as a more detailed description of some aspects, characteristics and embodiments of the present application.

[0027] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. In addition, where a range of values is provided, it is understood that each intervening value, to the upper and lower limit of the range is also specifically disclosed. Each smaller range between any stated value or intervening value in the stated range and any other stated or intervening value in that stated range is encompassed. The upper and lower limits of these smaller ranges can independently be included or excluded in the range.

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned herein are incorporated by reference to disclose and describe in detail the methods and / or materials which are described in them. In case of conflict, the content of the present specification will control.

[0029] Various modifications and changes can be made to the specific embodiments of the present application described herein without departing from the scope or spirit of the application. Other embodiments of the application will be apparent to those of ordinary skill in the art from the description and examples herein. The description and examples are illustrative only and are not intended to limit the scope of the application.

[0030] As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or variations thereof, are intended to be open-ended terms that mean including, but not limited to.

[0031] The present application utilizes oxamidate derivatives and α-keto esters as starting materials to synthesize sub-tartaric acid derivatives through a one-step oxidation-reduction neutral photocatalytic process. On the one hand, the photo-catalyst is excited to oxidize the oxamidate derivative to obtain an amide radical intermediate. On the other hand, the α-keto ester is reduced by the reduced photo-catalyst to generate an α-hydroxy radical intermediate. The coupling of the above two radicals constructs a C-C(CO) bond, realizing the synthesis of sub-tartaric acid derivatives, Figure 1 Chemical principle diagram for synthesizing sub-tartaric acid derivatives of the present application.

[0032] In some embodiments of the present application, the route map for synthesizing sub-tartaric acid derivatives is as follows:

[0033]

[0034] The α-keto ester, photo-catalyst and base used in the embodiments of the present application are all obtained through conventional commercial channels, and the oxamidate derivative can be synthesized in one step according to the literature method (Org. Lett. 2023, 25, 1829-1833).

[0035] Example 1

[0036] Into a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxaline derivative I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a polytetrafluoroethylene septum, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lights were placed 7 cm apart from the glass vial (one on each side of the glass vial, in a three-point-one-line arrangement), and a fan was placed 10 cm above the vial to maintain the temperature of the interior of the glass vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-a (37.0 mg, 42% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0037] The NMR spectrum of the sub-tartaric acid derivative III-a prepared in Example 1 is shown in Figure 2 , and the hydrogen spectrum data are as follows:

[0038] 1 H NMR (400 MHz, CDC13) δ 7.54-7.29 (m, 5H), 5.03 (s, 1H), 4.35-4.15 (m, 2H), 3.39-3.32 (m, 1H), 3.18-3.11 (m, 1H), 3.08-3.01 (m, 1H), 2.96-2.88 (m, 1H), 1.64-1.53 (m, 2H), 1.28-1.21 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.10-1.00 (m, 1H), 0.89 (t, J = 7.4 Hz, 3H), 0.53 (t, J = 7.4 Hz, 3H).

[0039] Example 2

[0040] Into a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-b (0.3 mmol, 1.5 eq), oxaline derivative I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a polytetrafluoroethylene septa, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lights were placed 7 cm apart from the glass vial (one on each side of the glass vial, in a three-point-one-line arrangement), and a fan was placed 10 cm above the vial to maintain the temperature of the interior of the glass vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-b (43.7 mg, 55%, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 5:1).

[0041] The nuclear magnetic resonance hydrogen spectrum of the sub-tartaric acid derivative III-b prepared in Example 2 is shown in Figure 3 , and the hydrogen spectrum data are as follows:

[0042] 1 H NMR (400 MHz, CDC13) δ 7.56-7.27 (m, 5H), 5.03 (s, 1H), 3.79 (s, 3H), 3.43-3.27 (m, 1H), 3.20-3.09 (m, 1H), 3.09-2.99 (m, 1H), 2.94-2.86 (m, 1H), 1.70-1.48 (m, 2H), 1.36-1.18 (m, 1H), 1.15-0.98 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H), 0.54 (t, J = 7.4 Hz, 3H).

[0043] Example 3

[0044] Into a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-c (0.3 mmol, 1.5 eq), oxaline derivative I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a PTFE septum, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lights were placed 7 cm apart from the glass vial (one on each side of the glass vial, in a three-point-one-line arrangement), and a fan was placed 10 cm above the vial to maintain the temperature of the interior of the glass vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 2 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-c (39.8 mg, 40% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0045] The NMR spectrum of the sub-tartaric acid derivative III-c prepared in Example 3 is shown in Figure 4 , and the hydrogen spectrum data are as follows:

[0046] 1 H NMR (400 MHz, CDC13) δ 7.49 - 7.30 (m, 5H), 4.97 (s, 1H), 4.33 - 4.12 (m, 2H), 3.38 - 3.31 (m, 1H), 3.15 - 3.08 (m, 1H), 3.07 - 2.99 (m, 1H), 2.92 - 2.84 (m, 1H), 1.63 - 1.50 (m, 2H), 1.39 - 1.22 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.16 - 1.07 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H), 0.58 (t, J = 7.4 Hz, 3H).

[0047] Example 4

[0048] Into a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxaline derivative I-b (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). The glass vial was sealed with a PTFE septum, degassed using the freeze-pump-thaw method, placed two 440 nm Kessil led lights (one on each side of the vial, three points in a line) 7 cm from the vial and a fan 10 cm above the vial to maintain the temperature of the interior of the vial at 35 °C ± 1 °C, and the reaction mixture was stirred and irradiated for 24 h. The reaction mixture was directly concentrated under reduced pressure and the sub-tartaric acid derivative III-d (36.2 mg, 50% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 5:1).

[0049] The NMR spectrum of the sub-tartaric acid derivative III-d prepared in Example 4 is shown in Figure 5 , and the hydrogen spectrum data are as follows:

[0050] 1 H NMR (400 MHz, CDC13) δ 7.52-7.30 (m, 5H), 5.03 (s, 1H), 4.34-4.15 (m, 2H), 3.51-3.42 (m, 1H), 3.30-3.22 (m, 1H), 3.21-3.14 (m, 1H), 3.08-3.01 (m, 1H), 1.25 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H), 0.76 (t, J = 7.0 Hz, 3H).

[0051] Example 5

[0052] Into a 20 mL vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidic acid derivative I-a (0.2 mmol, 1.0 eq), Ir(dtbbpy)(ppy)2]PF6(0.004 mmol, 3.7 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the vial was sealed with a polytetrafluoroethylene septum, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lamps were placed 7 cm apart from the vial (two Kessil led lamps were placed on both sides of the vial in a three-point-one-line manner), and a fan was placed 10 cm above the vial to keep the temperature inside the vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-a (34.4 mg, 39% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0053] Example 6

[0054] Into a 20 mL vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidic acid derivative I-a (0.2 mmol, 1.0 eq), Ir(dtbbpy)(ppy)2]PF6(0.004 mmol, 3.7 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the vial was sealed with a polytetrafluoroethylene septum, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lamps were placed 7 cm apart from the vial (two Kessil led lamps were placed on both sides of the vial in a three-point-one-line manner), and a fan was placed 10 cm above the vial to keep the temperature inside the vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-a (34.4 mg, 39% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0055] Example 7

[0056] To a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidate I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a PTFE septa, it was degassed using the freeze-pump-thaw method, and a 440 nm Kessil led lamp was placed 7 cm away from the glass vial (two Kessil led lamps were placed on both sides of the glass vial in a three-point-one-line manner), and the temperature inside the glass vial was maintained at 55 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-a (31.7 mg, 36% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0057] Example 8

[0058] To a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidate I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a PTFE septa, it was degassed using the freeze-pump-thaw method, and a 440 nm Kessil led lamp was placed 7 cm away from the glass vial, and a fan was placed 10 cm above the vial, and the temperature inside the glass vial was maintained at 25 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure, and the sub-tartaric acid derivative III-a (28.2 mg, 32% NMR yield, yellow oil) was isolated by column chromatography (petroleum ether / ethyl acetate = 10:1).

[0059] Comparative Example 1

[0060] To a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidic acid derivative I-a (0.2 mmol, 1.0 eq), (Ir{dF(CF3)ppy}2(dtbpy))PF6(0.004 mmol, 4.5 mg, 2 mol%), Cs2CO3(0.4 mmol, 130.3 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a PTFE septa, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lights were placed 7 cm away from the glass vial and a fan was placed 10 cm above the vial to keep the temperature inside the glass vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the tartronic acid derivative III-a (9.69 mg, 11% NMR yield, yellow oil).

[0061] Comparative Example 2

[0062] To a 20 mL glass vial equipped with a stir bar was added sequentially a-ketoester II-a (0.3 mmol, 1.5 eq), oxamidic acid derivative I-a (0.2 mmol, 1.0 eq), 3DPA2FBN (0.004 mmol, 2.6 mg, 2 mol%), CsF (0.4 mmol, 60.8 mg, 2.0 eq) and acetonitrile (4 mL). After the glass vial was sealed with a PTFE septa, it was degassed using the freeze-pump-thaw method, two 440 nm Kessil led lights were placed 7 cm away from the glass vial and a fan was placed 10 cm above the vial to keep the temperature inside the glass vial at 35 °C ± 1 °C. After the reaction mixture was stirred and irradiated for 24 h, it was directly concentrated under reduced pressure and separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the tartronic acid derivative III-a (4.4 mg, 5% NMR yield, yellow oil).

[0063] The above merely shows the preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and any changes or replacements within the technical scope disclosed by the present application can be easily thought of by those skilled in the art, which shall be covered within the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.

Claims

1. A method for the photocatalytic decarboxylation of oxamates derivatives to produce aminomalonates derivatives by visible light, characterized in that, The method comprises the following steps: The α-keto ester, oxamic acid derivative, photocatalyst and base are mixed in an organic solvent, oxygen is removed, and a sub-rubidic acid derivative is synthesized through a free radical coupling reaction under visible light irradiation; The synthesis route of the sub-rubidic acid derivative is as follows: 。 2. The method for preparing tartaric acid derivatives by visible light photocatalysis of oxalic acid derivatives according to claim 1, characterized in that, The molar ratio of the α-keto ester and the oxamic acid derivative is 3:

2.

3. The method for preparing tartaric acid derivatives by visible light photocatalysis of oxalic acid derivatives according to claim 1, characterized in that, The amount of the photocatalyst is 2 mol% of the oxamic acid derivative.

4. The method of claim 3, wherein the method is a method of preparing an isoracemic acid derivative by decarboxylation of a visible light catalytic oxamic acid derivative, characterized in that, The photocatalyst is selected from 4CzIPN, 3DPA2FBN or [Ir(dtbbpy)(ppy)2]PF6.

5. The method for preparing tartaric acid derivatives by visible light-catalyzed decarboxylation of oxaline derivatives according to claim 1, characterized in that, The molar ratio of the base to the oxamic acid derivative is 2:

1.

6. The method of decarboxylation of oxamates derivatives to produce aminomalonates derivatives by visible light catalysis according to claim 1, characterized in that, The base is cesium carbonate.

7. The method of decarboxylation of oxamates derivatives to produce aminomalonates derivatives by visible light catalysis according to claim 1, characterized in that, The organic solvent is selected from acetonitrile or dichloromethane.

8. The method for preparing tartaric acid derivatives by visible light-catalyzed decarboxylation of oxaline derivatives according to claim 1, characterized in that, The time of the free radical coupling reaction is 24 h, and the temperature is 25-55℃.

9. The method for preparing tartaric acid derivatives by visible light-catalyzed decarboxylation of oxaline derivatives according to claim 8, characterized in that, The temperature of the free radical coupling reaction is 35℃.

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