A one-pot method for synthesizing 3-substituted glutaric acid

Abstract

The present invention relates to the technical field of organic synthesis, and more particularly to a method for synthesizing 3-substituted glutaric acid by a one-pot method, comprising the following steps: S1, dissolving compound A, diethyl malonate and an inorganic base in an organic solvent, heating to reflux until compound A is completely reacted, and obtaining a reaction solution; S2, adding a strong acid reagent and a weak acid reagent to the reaction solution in step S1, heating to reflux, and obtaining 3-substituted glutaric acid by post-treatment. In the present invention, the one-step preparation of 3-substituted glutaric acid can be achieved by the above-mentioned preparation method, and the cumbersome operation of multi-step synthesis is avoided, which greatly improves the selectivity and yield of the whole synthesis process, and compared with the multi-step synthesis in the prior art, the one-pot method of the present invention reduces the separation and purification requirements of the intermediate, further shortens the reaction time, improves the reaction yield, and realizes a more simple, efficient and economical synthesis preparation of 3-substituted glutaric acid.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 3-substituted glutaric acid in a one-pot process. Background Art

[0002] As an important pharmaceutical and chemical intermediate, 3-substituted glutaric acid can be used as the basic skeleton of drug molecules. By introducing different substituents thereon, compounds with different activities and bioavailabilities can be synthesized, providing flexibility for drug design. The synthesis method of 3-substituted glutaric acid generally involves a variety of reaction pathways, the most common of which include (1) condensation reaction: glutaric acid can undergo a condensation reaction with a suitable reagent to form a 3-substituted derivative; (2) alkylation or arylation: glutaric acid can be alkylated or arylated at the third carbon using an alkylating agent or an arylating agent, respectively, which generally involves a substitution reaction in which the substituent replaces the hydrogen atom on the third carbon of the glutaric acid molecule; (3) hydrogenation of unsaturated derivatives: if the precursor of 3-substituted glutaric acid contains unsaturation, such as an unsaturated derivative of glutaric acid, it can be hydrogenated to introduce a substituent at the third carbon, and this process involves the addition of hydrogen to the double bond or triple bond present in the unsaturated precursor; (4) ring-opening reaction: glutaric acid derivatives containing a ring structure can undergo a ring-opening reaction under appropriate conditions to produce 3-substituted glutaric acid derivatives. These methods provide multiple routes to the synthesis of 3-substituted glutaric acid derivatives with different substituents attached to the third carbon atom, allowing the production of a wide range of compounds with potential applications in various fields such as medicine, material science and organic synthesis.

[0003] At present, existing research has reported a method for synthesizing 3-substituted glutaric acid from aldehydes. The synthesis route is as follows:

[0004]

[0005] Although the above scheme can synthesize and prepare 3-substituted glutaric acid, the synthesis preparation method requires multiple steps of reaction, which increases the complexity and cost of the preparation, and also increases the steps and operation difficulty of the reaction; on the other hand, the above synthesis method contains toxic or environmentally hazardous substances as reagents or catalysts, which is not conducive to environmental protection and sustainable development. Summary of the invention

[0006] In view of this, the present invention proposes a one-pot method for synthesizing 3-substituted glutaric acid to solve the technical problems of the prior art such as the complex synthesis method of 3-substituted glutaric acid and the low reaction yield.

[0007] The technical solution of the present invention is achieved as follows: The present invention provides a one-pot method for synthesizing 3-substituted glutaric acid, comprising the following steps:

[0008] S1, dissolving compound A, diethyl malonate and an inorganic base in an organic solvent, heating and refluxing until compound A is completely reacted to obtain a reaction solution;

[0009] S2, adding a strong acid reagent and a weak acid reagent to the reaction solution in step S1, heating to reflux, and obtaining 3-substituted glutaric acid through post-treatment;

[0010] Wherein, the molecular structure formula of compound A is:

[0011] R is an alkyl group having 1 to 8 carbon atoms, an aryl group, or an alkylene oxide group having 1 to 5 carbon atoms;

[0012] The molecular structure of 3-substituted glutaric acid is:

[0013] R is an alkyl group having 1 to 8 carbon atoms, an aryl group, or an alkylene oxide group having 1 to 5 carbon atoms.

[0014] In the present invention, compound A and diethyl malonate are subjected to a condensation reaction in an alkaline environment to form an intermediate, and the reaction of compound A is completely monitored by a TLC plate, i.e., the generation of the intermediate is determined; and then a further hydrolysis reaction is directly carried out in an acidic environment to generate 3-substituted glutaric acid. In the present invention, the preparation method can realize one-step preparation of 3-substituted glutaric acid, avoiding the cumbersome operation of multi-step synthesis, which greatly improves the selectivity and yield of the entire synthesis process; compared with the multi-step synthesis in the prior art, the one-pot method of the present invention reduces the separation and purification requirements of the intermediate, further shortens the reaction time, improves the reaction yield, and realizes a more simple, efficient and economical synthesis preparation of 3-substituted glutaric acid.

[0015] Based on the above technical solution, preferably, in step S1, the molar ratio of compound A, diethyl malonate and inorganic base is 1:2.0-3.0:2.5-3.5. Particularly preferably, the molar ratio of compound A, diethyl malonate and inorganic base is 1:2.5:3.

[0016] Based on the above technical solution, preferably, in step S1, the inorganic base includes but is not limited to one or more of Na2CO3, Li2CO3, K2CO3, NaHCO3, KHCO3, CaCO3 and Ca(HCO3)2. The selection of the above inorganic base can more effectively promote the condensation reaction and improve the efficiency of the formation of the intermediate.

[0017] Based on the above technical solution, preferably, in step S1, the molar ratio of the strong acid reagent to the inorganic base is 2 to 3:1, and the volume ratio of the strong acid reagent to the weak acid reagent is 1:1 to 1.5. Particularly preferably, the volume ratio of the strong acid reagent to the weak acid reagent is 1:1.

[0018] In the present invention, the strong acid reagent is added in excess relative to the inorganic base. The excess strong acid reagent can react with the unreacted inorganic base in step S1 to produce a salt by acid-base neutralization reaction. The salt is retained in the reaction system, which helps the hydrolysis and decarboxylation steps of the intermediate ester and helps to drive the reaction forward.

[0019] On the basis of the above technical solution, preferably, the strong acid reagent is any one or more of concentrated hydrochloric acid, concentrated sulfuric acid or concentrated nitric acid, and the weak acid reagent is one or more of acetic acid, citric acid, oxalic acid and benzoic acid.

[0020] More preferably, the strong acid reagent is concentrated hydrochloric acid, and the weak acid reagent is acetic acid.

[0021] In step S2, the strong acid effectively promotes the hydrolysis reaction of the intermediate ester group by providing a large amount of hydrogen ions to generate a carboxylic acid group; the weak acid forms a buffer system with the strong acid on the one hand to maintain suitable acidic conditions, and on the other hand, the weak acid can enhance the solubility of the intermediate, which is more conducive to the reaction. The amount of the strong acid reagent added is based on the amount of the inorganic base added, and the amount added is much larger than the amount of the inorganic base added, and its purpose is to neutralize the inorganic base in step S1, and the addition of acetic acid and the strong acid synergistically help to establish an acidic environment that can dissolve the substrate.

[0022] On the basis of the above technical solution, preferably, in step S1, the organic solvent is an alcohol solvent. Alcohol solvents have good solubility and can dissolve the reaction raw materials. In the present invention, the alcohol solvent includes but is not limited to one or more of methanol, ethanol, and isopropanol.

[0023] On the basis of the above technical scheme, preferably, the temperature of heating reflux in step S1 is 80-120°C; the temperature of heating reflux in step S2 is 80-120°C, and the time is 16-18h. From the viewpoint of reaction speed, the reaction temperature in step S1 and step S2 is not particularly limited, and the temperature at which the reflux reaction can be achieved can be appropriately set, preferably 80-120°C; the reaction time in steps S1 and S2 is not particularly limited, wherein the reaction time in step S1 is the time when the reaction of compound A is completely monitored by the TLC plate, and the reaction in step S2 is overnight, which can be appropriately set, but preferably 16-18h.

[0024] On the basis of the above technical scheme, preferably, in step S2, the post-treatment specifically includes: after the reaction is completed, the solvent is removed under reduced pressure to obtain a crude product, the crude product is extracted with water and an organic solvent, and the organic phase is concentrated and recrystallized to obtain 3-substituted pentanedioic acid.

[0025] The above-mentioned post-treatment is only the most preferred solution. After the reaction, it is sufficient to carry out conventional treatment for obtaining the product from the reaction solution. For example, the reaction solvent can be distilled off from the reaction solution by operations such as reduced pressure heating to obtain the target product. In addition, the target product can also be obtained by extracting with an organic solvent after adding water to the reaction solution for dilution. The above-mentioned 3-substituted pentanedioic acid thus obtained has sufficient purity to be used in subsequent steps, but in order to further improve the purity, the purity can also be further improved by conventional purification means such as crystallization, fractionation, solvent conversion washing, column chromatography, etc.

[0026] On the basis of the above technical scheme, preferably, in the extraction process, the organic solvent includes but is not limited to butyl acetate, ethyl acetate, dichloromethane, tetrahydrofuran and 1,2-dichloroethane. The present invention does not specifically limit the organic solvent for extraction, and any reagent that can achieve the extraction of the target product can be used. However, it is preferably one or more of butyl acetate, ethyl acetate, dichloromethane, tetrahydrofuran and 1,2-dichloroethane, and ethyl acetate is particularly preferred.

[0027] On the basis of the above technical solution, preferably, in the recrystallization treatment, the recrystallization agent includes one or more of diethyl ether, methyl tert-butyl ether and ethyl acetate, and diethyl ether is particularly preferred.

[0028] The one-pot method for synthesizing 3-substituted glutaric acid of the present invention has the following beneficial effects compared with the prior art:

[0029] (1) The preparation method of the present invention can realize the one-step preparation of 3-substituted glutaric acid, avoiding the cumbersome operation of multi-step synthesis, which greatly improves the selectivity and yield of the entire synthesis process. Compared with the multi-step synthesis in the prior art, the one-pot method of the present invention reduces the separation and purification requirements of the intermediates, further shortens the reaction time, improves the reaction yield, and realizes a more simple, efficient and economical synthesis preparation of 3-substituted glutaric acid;

[0030] (2) During the hydrolysis reaction of step S2, the synergistic effect of strong acid and weak acid is used to establish an acidic environment in which the substrate can be dissolved, which can further promote the formation of 3-substituted glutaric acid and realize the one-pot preparation of 3-substituted glutaric acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0032] Figure 1Compound 2 prepared in Example 1 of the present invention 1 HNMR spectra;

[0033] Figure 2 Compound 2 prepared in Example 1 of the present invention 13 CNMR images;

[0034] Figure 3 This is the LC-MS chart of compound 2 prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0035] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] For all the following examples, standard operations and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in ° C (Celsius). The structure of the compound is confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The melting point of the compound is determined by a RY-1 melting point instrument, and the thermometer is uncalibrated and is given in ° C. 1HNMR is measured by a JEOL JNM-ECA-400 nuclear magnetic resonance instrument. The mass spectrum is measured by an API3000 (ESI) mass spectrometer. All reaction solvents are pre-treated by standardization unless otherwise specified.

[0037] In the following examples, unless otherwise specified, % refers to mass percentage.

[0038] Example 1

[0039] This embodiment provides a one-pot method for synthesizing 3-substituted glutaric acid, which specifically comprises the following steps:

[0040]

[0041] The reaction mixture of compound 1 (2.9 g, 25.4 mmol), diethyl malonate (10.35 g, 64.6 mmol) and K2CO3 (10.7 g, 77.5 mmol) was dissolved in ethanol (30 ml) and heated to 100°C under reflux until compound 1 was no longer detected by the TLC plate. Subsequently, concentrated hydrochloric acid (20 ml) and acetic acid (20 ml) were added to the reaction mixture, which was then heated to 100°C under reflux for 16 h. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. After concentration, the extract was recrystallized from ether to obtain compound 2, which was 4.75 g as a gray solid with a yield of 86.52%. 1 H NMR spectra, 13 CNMR and LC-MS images are shown in Figure 1-3 shown.

[0042] It should be noted that this embodiment is only an exemplary description of the technical solution of the present invention, wherein the molar ratio of compound 1, diethyl malonate and K2CO3 is 1:2.0~3.0:2.5~3.5, the molar ratio of concentrated hydrochloric acid and K2CO3 is 2~3:1, and the volume ratio of concentrated hydrochloric acid and acetic acid is 1:1~1.5. The adjustment of the dosage within the above range can achieve the one-pot preparation of compound 2.

[0043] Example 2

[0044] This embodiment provides a one-pot method for synthesizing 3-substituted glutaric acid, which specifically comprises the following steps:

[0045]

[0046] The reaction mixture of compound 1 (2.9 g, 25.4 mmol), diethyl malonate (8.13 g, 50.8 mmol) and Na2CO3 (6.73 g, 63.5 mmol) was dissolved in methanol (40 ml) and heated to 80°C and refluxed until compound 1 was no longer detected by the TLC plate. Subsequently, concentrated hydrochloric acid (16.5 ml) and acetic acid (19.8 ml) were added to the reaction mixture, which was then heated to 80°C and refluxed for 18 h. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. After concentration, the extract was recrystallized from methyl tert-butyl ether to obtain compound 2, which was 4.52 g, a gray solid, with a yield of 82.33%.

[0047] Example 3

[0048] This embodiment provides a one-pot method for synthesizing 3-substituted glutaric acid, which specifically comprises the following steps:

[0049]

[0050] The reaction mixture of compound 1 (2.9 g, 25.4 mmol), diethyl malonate (12.19 g, 76.2 mmol) and Li2CO3 (6.59 g, 88.9 mmol) was dissolved in ethanol (50 ml) and heated to 120° C. and refluxed until compound 1 was no longer detected by the TLC plate. Subsequently, concentrated hydrochloric acid (28 ml) and acetic acid (42 ml) were added to the reaction mixture, which was then heated to 120° C. and refluxed for 18 h. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. After concentration, the extract was recrystallized from ether to obtain compound 2, which was 4.788 g, a gray solid, with a yield of 87.07%.

[0051] Example 4

[0052] This embodiment provides a one-pot method for synthesizing 3-substituted glutaric acid. The specific preparation steps are the same as those in Example 1, except that concentrated hydrochloric acid (20 ml) is added to the reaction mixture, and then heated to reflux for 16 h. Compound 2 is obtained, and the compound 2 is 2.85 g, a gray solid, and the yield is 51.95%. Compared with Example 1, it can be seen that the reaction yield is significantly reduced by adding only concentrated hydrochloric acid, which may be due to the fact that no weak acid reagent is added, resulting in poor solubility of the intermediate prepared in step S1.

[0053] Example 5

[0054] This example provides a one-pot method for synthesizing 3-substituted glutaric acid. The specific preparation steps are the same as those in Example 1, except that concentrated hydrochloric acid (20 ml) and acetic acid (10 ml) are added to the reaction mixture, and then heated under reflux for 16 hours. Compound 2 is obtained, and the compound 2 is 3.85 g, a gray solid, with a yield of 70.36%. Compared with Example 1, it can be seen that the ratio of the strong acid reagent to the weak acid reagent also affects the reaction yield.

[0055] Example 6

[0056] This embodiment provides a one-pot method for synthesizing 3-substituted glutaric acid, which specifically comprises the following steps:

[0057]

[0058] The reaction mixture of compound 1 (2.28 g, 21.5 mmol), diethyl malonate (10.35 g, 64.6 mmol) and K2CO3 (10.7 g, 77.5 mmol) was dissolved in ethanol (25 ml) and heated to 100 ° C. and refluxed until compound 1 was no longer detected by the TLC plate. Subsequently, concentrated hydrochloric acid (20 ml) and acetic acid (30 ml) were added to the reaction mixture, and then heated to reflux for 16 h. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate. After concentration, the extract was recrystallized from ether to obtain compound 2. Compound 2 was obtained, and compound 2 was 4.05 g, with a yield of 90.60%.

[0059] The above embodiments are merely exemplary illustrations of the technical solutions of the present invention and do not constitute a limitation on the technical solutions of the present invention. When the R group in Example 1 is an epoxy alkyl group and the R group in Example 6 is an aryl group, the preparation of 3-substituted glutaric acid can be prepared by a one-pot method. The R group is an epoxy alkyl group with a carbon number of 1-5 such as ethylene oxide and butylene oxide, and the epoxy alkyl group has a high reactivity and can react with diethyl malonate to achieve the one-pot method for preparing 3-substituted glutaric acid; the reactivity of the alkyl group is between the epoxy alkyl group and the aryl group, so the alkyl group with a carbon number of 1-8 also has a good reactivity and can react with diethyl malonate to achieve the one-pot method for preparing 3-substituted glutaric acid.

[0060] 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, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A one-pot method for synthesizing 3-substituted glutaric acid, characterized in that: The following steps are involved: S1, dissolving compound A, diethyl malonate and an inorganic base in an organic solvent, heating and refluxing until compound A is completely reacted to obtain a reaction solution; S2, adding a strong acid reagent and a weak acid reagent to the reaction solution in step S1, heating to reflux, and obtaining 3-substituted glutaric acid through post-treatment; Wherein, the molecular structure formula of compound A is: , R is an alkyl group having 1 to 8 carbon atoms, an aryl group, or an alkylene oxide group having 1 to 5 carbon atoms; The molecular structure of 3-substituted glutaric acid is: , R is an alkyl group having 1 to 8 carbon atoms, an aryl group, or an alkylene oxide group having 1 to 5 carbon atoms; The heating reflux temperature in step S1 is 80-120°C, and the inorganic base is one or more of Na2CO3, Li2CO3, K2CO3, NaHCO3, KHCO3, CaCO3 and Ca(HCO3)2; The heating reflux temperature in step S2 is 80-120° C. and the time is 16-18 hours; The molar ratio of the strong acid reagent to the inorganic base is 2-3:1, and the volume ratio of the strong acid reagent to the weak acid reagent is 1:1-1.5; The strong acid reagent is any one or more of concentrated hydrochloric acid, concentrated sulfuric acid and concentrated nitric acid, and the weak acid reagent is one or more of acetic acid, citric acid, oxalic acid and benzoic acid.

2. The one-pot method for synthesizing 3-substituted glutaric acid according to claim 1, characterized in that: In step S1, the molar ratio of compound A, diethyl malonate and inorganic base is 1:2.0-3.0:2.5-3.

5.

3. The one-pot method for synthesizing 3-substituted glutaric acid according to claim 1, characterized in that: In step S1, the organic solvent is an alcohol solvent.

4. The one-pot method for synthesizing 3-substituted glutaric acid according to claim 1, characterized in that: In step S2, the post-treatment specifically includes: after the reaction is completed, the solvent is removed under reduced pressure to obtain a crude product, the crude product is extracted with water and an organic solvent, and the organic phase is concentrated and recrystallized to obtain 3-substituted glutaric acid.

5. The one-pot method for synthesizing 3-substituted glutaric acid according to claim 4, characterized in that: During the extraction process, the organic solvent is at least one of butyl acetate, ethyl acetate, dichloromethane, tetrahydrofuran and 1,2-dichloroethane.

6. The one-pot method for synthesizing 3-substituted glutaric acid according to claim 4, characterized in that: In the recrystallization treatment, the recrystallization agent is one or more of diethyl ether, methyl tert-butyl ether and ethyl acetate.

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