Continuous Flow Synthesis of 4-Substituted-1,2,5-Oxadiazolecarboxylic Acids

Abstract

The present invention discloses a continuous flow synthesis method for 4-substituted-1,2,5-oxadiazolecarboxylic acid, belonging to the field of applied organic synthesis technology. A mixed solution of compound 1 and hydrochloric acid and a sodium nitrite solution are added to a premixing module M1 via metering pumps, mixed, and then transferred to a reaction module R1 for reaction to produce a reaction solution containing compound 2. The resulting reaction solution containing compound 2 is then mixed with a sodium hydroxide solution in a T-shaped premixing module M2, followed by a reaction in reaction module R2. After the reaction is completed, the effluent is collected in a product collection module P. This synthesis method offers advantages such as easy purification, high conversion rate, continuous safety, and precise control of reaction conditions, enabling safe, environmentally friendly, and efficient production of the target product. #imgabs0#

Description

Technical Field

[0001] The invention relates to a continuous flow synthesis method for 4-substituted-1,2,5-oxadiazolecarboxylic acid, and belongs to the technical field of organic synthesis application. Background Art

[0002] 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds, as bioisosteres of amide bonds, have important applications in the field of medicinal chemistry. Currently, the synthesis methods of 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds are as follows:

[0003] Patent WO2004058763A reports that 2,3-butanedione dioxime is cyclized with succinic anhydride and then reacted with potassium permanganate to oxidize one of the two adjacent methyl groups to obtain 4-substituted-1,2,5-oxadiazolecarboxylic acid, as shown in the following reaction formula:

[0004]

[0005] Patent CN113286795A reports that ethyl 3-substituted-3-oxopropanoate (I) is reacted with aqueous sodium nitrate in a suitable solvent such as acetic acid to obtain ethyl 3-substituted-2-(hydroxyimino)-3-oxopropanoate (II); compound (II) is reacted with hydroxylamine hydrochloride in a suitable solvent such as EtOH using a suitable base such as sodium acetate or a suitable acid solution such as HCl in dioxane at a temperature of about 50-80°C to obtain ethyl 3-substituted-2,3-bis(hydroxyimino)propanoate (III); compound (III) is cyclized with CDI in a suitable solvent such as THF to obtain ethyl 4-substituted 1,2,5-oxadiazole-3-carboxylate (IV); compound (IV) is hydrolyzed with an aqueous base such as lithium hydroxide in a suitable solvent system such as THF and water, or with an aqueous HCl solution at about 100°C in a suitable solvent system such as dioxane and water to obtain 4-substituted-1,2,5-oxadiazolecarboxylic acid (V). As shown in the following reaction formula:

[0006]

[0007] The above method has the following problems: the use of oxidants (potassium permanganate, sodium nitrate) is prone to explosion hazards, has poor regioselectivity, is difficult to control the reaction, is complex to operate, has a low overall yield, and is not suitable for large-scale preparation or industrial production. Summary of the Invention

[0008] In order to solve the above problems, the present invention provides a green, mild, high-yield, and safety-reducing continuous flow synthesis method for 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds, which expands the scope of application of continuous flow chemistry technology and provides a potential path for promoting green development in the field of innovative drug development.

[0009] The technical solution of the present invention:

[0010] The present invention provides a method for synthesizing 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds, which is based on a series-parallel process of continuous flow pipeline reactors, wherein compound 1 is mixed with a sodium nitrite mixed solution and a hydrochloric acid solution to react to obtain compound 2; compound 2 is then reacted with a sodium hydroxide solution to obtain a target compound 3;

[0011]

[0012] Wherein, R is one of C1-8 alkyl, aromatic hydrocarbon, and heterocyclic aromatic hydrocarbon;

[0013] The process of the continuous flow pipeline reactor series-parallel process includes:

[0014] (1) A mixed solution of compound 1 and hydrochloric acid and a sodium nitrite solution are added to the premixing module M1 through metering pumps, mixed, and then transferred to the reaction module R1 for reaction to obtain a reaction solution containing compound 2;

[0015] (2) The resulting reaction solution containing compound 2 is then mixed with a sodium hydroxide solution in a T-type premixing module M2, and then reacted in a reaction module R2; after the reaction is completed, the effluent is collected in a product collection module P.

[0016] In one embodiment of the present invention, the C1-8 alkyl group may specifically be: a C1-8 straight chain or branched chain alkyl group, or a C3-C6 cycloalkyl group.

[0017] In one embodiment of the present invention, the aromatic hydrocarbon group may be a substituted or unsubstituted benzene ring or naphthalene ring.

[0018] In one embodiment of the present invention, the heterocyclic aromatic hydrocarbon group may be optionally substituted or unsubstituted pyridine.

[0019] In one embodiment of the present invention, the substituents on the aromatic hydrocarbon group and the heterocyclic aromatic hydrocarbon group are selected from: C1-4 alkyl, C1-4 alkoxy, and halogen (F, Cl, Br, I).

[0020] In an embodiment of the present invention, in step (1), the molar ratio of compound 1 to hydrochloric acid in the mixed solution of compound 1 and hydrochloric acid is 1:1.

[0021] In an embodiment of the present invention, in step (1), the mixed solution of compound 1 and hydrochloric acid is added to the premixing module M1 at a flow rate of 24 μL / min.

[0022] In an embodiment of the present invention, the molar ratio of compound 1 to sodium nitrite is 1:1.2-1.5.

[0023] In an embodiment of the present invention, in step (1), the sodium nitrite solution is added to the premixing module M1 at a flow rate of 24 μL / min.

[0024] In an embodiment of the present invention, in step (1), the reaction temperature of the reaction module R1 is 20-30°C.

[0025] In an embodiment of the present invention, in step (2), the sodium hydroxide solution is added to the T-type premixing module M2 at a flow rate of 48 μL / min to mix with the reaction solution containing compound 2.

[0026] In an embodiment of the present invention, in step (2), the reaction solution is added to the T-type premixing module M2 at a flow rate of 48 μL / min to mix with the sodium hydroxide solution.

[0027] In an embodiment of the present invention, in step (2), the reaction temperature of the reaction module R2 is 50°C.

[0028] In an embodiment of the present invention, the molar ratio of compound 1 to sodium hydroxide is 1:8-10.

[0029] In an embodiment of the present invention, EG solution (ethylene glycol solution) may be further added to the mixed solution of Compound 1 and hydrochloric acid to replenish the volume when preparing the mixed solution of Compound 1 and hydrochloric acid.

[0030] In an embodiment of the present invention, the collected effluent is subjected to extraction, separation, and drying of the organic phase over anhydrous sodium sulfate, followed by rotary evaporation to obtain the target compound.

[0031] In the embodiments of the present invention, the continuous flow series-parallel process is a microchemical technology based on microreactors. It features mobility, miniaturization, and environmental friendliness, making it a highly promising alternative to batch chemical reactions. Microreactors are continuous flow tubular reactors with inner diameters between micrometers and millimeters. Compared to conventional reactors, these reactors have significantly larger surface areas and excellent heat and mass transfer efficiencies. They enable instant mixing of raw materials in precise proportions, improving product yields and meeting the demands of the green manufacturing era.

[0032] Beneficial effects of the present invention:

[0033] The synthesis method provided by the present invention features easy purification, high conversion rate, continuous safety, and precise control of reaction conditions. It can safely, environmentally friendly, and efficiently produce 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds. The method is safe and controllable, reacting under normal pressure, addressing the technical issues of existing preparation methods that are prone to explosion and other safety hazards, making them unsuitable for large-scale preparation or industrial production.

[0034] The reaction of the present invention is carried out in a continuous flow pipeline reactor, which has a very large specific surface area and excellent heat exchange and mass transfer efficiency, and can instantly mix the raw materials in a precise ratio, which is beneficial to improving the yield and quality of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is a continuous synthesis route for 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds; wherein A is a mixed solution of compound 1 and hydrochloric acid, B is a sodium nitrite solution, and C is a sodium hydroxide solution; M1 and M2 are premixing modules; P1, P2, and P3 are metering pumps; R1 and R2 are reaction modules; and P is a product collection module.

[0036] Figure 2 The reaction formula is for preparing 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds. DETAILED DESCRIPTION

[0037] The following reaction examples are used to illustrate the present invention, which includes but is not limited to the following related contents. All simple modifications obtained based on this method belong to the technology protected by the present invention.

[0038] Example 1

[0039] Synthesis of 4-cyclopropyl-1,2,5-oxadiazolecarboxylic acid:

[0040] A mixture of 3-cyclopropylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) was mixed in T-type mixing module M1 (temperature 20-30°C) and retained in pipeline reaction module R1 for 30 minutes. The reaction mixture was then mixed in T-type mixing module M2 (flow rate 48 μL / min) with sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min), retained in pipeline reaction module R2 for 10 minutes (temperature 50°C), and finally flowed into collection module P. The mixture was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain 4-cyclopropyl-1,2,5-oxadiazolecarboxylic acid (91 mg, 0.594 mmol / mL) as a white solid in an overall yield of 45%.

[0041] 1 H NMR(400MHz, DMSO-d6)δ:2.40(tt,J=8.4,5.2Hz,1H),1.21–1.10(m,2H),1.03–0.94(m,2H).MS(ESI):m / z calcd.for C6H7N2O3[M+H] +155.0,found:155.0.

[0042] Example 2

[0043] Synthesis of 4-methyl-1,2,5-oxadiazolecarboxylic acid:

[0044] A mixture of 3-methylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) was mixed in T-type mixing module M1 (temperature 20-30°C) and allowed to react in pipeline reaction module R1 for 30 minutes. The reaction mixture (flow rate 48 μL / min) and sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min) were then mixed in T-type mixing module M2 and allowed to react in pipeline reaction module R2 for 10 minutes (temperature 50°C). The resulting mixture was then transferred to collection module P. The mixture was extracted with water and ethyl acetate, separated, and the organic phase dried over anhydrous sodium sulfate and rotary evaporated to yield 4-methyl-1,2,5-oxadiazolecarboxylic acid (80 mg, 0.622 mmol / mL) as a white solid in an overall yield of 47%.

[0045] 1 H NMR(400MHz, DMSO-d6)δ:12.11(s,1H),2.10(s,3H).MS(ESI):m / z calcd.forC4H5N2O3[M+H] + 129.0,found:129.0.

[0046] Example 3

[0047] Synthesis of 4-phenyl-1,2,5-oxadiazolecarboxylic acid:

[0048] A mixture of 3-phenylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) was mixed in T-type mixing module M1 (temperature 20-30°C) and retained in pipeline reaction module R1 for 30 minutes. The reaction mixture was then mixed in T-type mixing module M2 (flow rate 48 μL / min) with sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min), retained in pipeline reaction module R2 for 10 minutes (temperature 50°C), and finally flowed into collection module P. The mixture was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain 4-phenyl-1,2,5-oxadiazolecarboxylic acid (120 mg, 0.635 mmol / mL) as a white solid in an overall yield of 47%.

[0049] 1 H NMR(400MHz, DMSO-d6)δ:12.23(s,1H),7.70–7.58(m,2H),7.55–7.39(m,3H).MS(ESI):m / z calcd.for C9H7N2O3[M+H] + 191.0,found:191.0.

[0050] Example 4

[0051] Synthesis of 4-(4-methoxyphenyl)-1,2,5-oxadiazolecarboxylic acid:

[0052] A mixed solution of 3-(4-methoxyphenyl)isoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and a sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in the T-type mixing module M1 (temperature 20-30°C), and stayed in the pipeline reaction module R1 for 30 minutes. Subsequently, the reaction liquid after the reaction was completed (flow rate was 48 μL / min) and a sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min) were mixed in the T-type mixing module M2, and stayed in the pipeline reaction module R2 for 10 minutes (temperature 50°C). Finally, the mixed solution flowed into the collection module P. The mixture was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to give 4-(4-methoxyphenyl)-1,2,5-oxadiazolecarboxylic acid (121 mg, 0.554 mmol / mL) as a white solid with a total yield of 42%.

[0053] 1H NMR(400MHz, DMSO-d6)δ:12.23(s,1H),7.63–7.22(m,2H),7.19–6.83(m,2H),3.79(s,3H).MS(ESI):m / z calcd.for C 10 H9N2O4[M+H] + 221.0,found:221.0.

[0054] Example 5

[0055] Synthesis of 4-(3-pyridyl)-1,2,5-oxadiazolecarboxylic acid:

[0056] A mixture of 3-(3-pyridyl)isoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) was mixed in T-type mixing module M1 (temperature 20-30°C) and retained in pipeline reaction module R1 for 30 minutes. The reaction mixture was then mixed in T-type mixing module M2 (flow rate 48 μL / min) and sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min), retained in pipeline reaction module R2 for 10 minutes (temperature 50°C), and finally flowed into collection module P. The mixture was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain 4-(3-pyridyl)-1,2,5-oxadiazolecarboxylic acid as a white solid. (92 mg, 0.48 mmol / mL), total yield 36%.

[0057] 1 H NMR(400MHz, DMSO-d6)δ:12.22(s,1H),8.80(d,J=1.2Hz,1H),8.41(dd,J=5.2,1.2Hz, 1H),7.93(dt,J=8.0,1.2Hz,1H),7.46(dd,J=8.0,5.2Hz,1H).MS(ESI):m / zcalcd.for C8H5N3O3[M+H] + 192.0,found:192.0.

[0058] Comparative Example 1

[0059] 4-Cyclopropyl-1,2,5-oxadiazolecarboxylic acid was synthesized by referring to the process of Example 1, except that the introduction conditions of the sodium hydroxide solution were changed to sodium hydroxide solution (12.80 mmol / mL, flow rate 24 μL / min), and the other conditions remained unchanged:

[0060] A mixed solution of 3-cyclopropylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in a T-shaped mixing module M1 (temperature 20-30°C) and allowed to react in a pipeline reaction module R1 for 30 minutes. The reaction solution was then mixed in a T-shaped mixing module M2 (flow rate 48 μL / min) and sodium hydroxide solution (12.80 mmol / mL, flow rate 24 μL / min). The reaction continued in the pipeline reaction module R2 for 10 minutes (temperature 50°C). The resulting mixed solution flowed into a collection module P. The mixed solution was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the product with an overall yield of 10%.

[0061] Comparative Example 2

[0062] 4-Cyclopropyl-1,2,5-oxadiazolecarboxylic acid was synthesized by referring to the process of Example 1, except that the introduction conditions of the sodium hydroxide solution were changed to sodium hydroxide solution (3.20 mmol / mL, flow rate 96 μL / min), and the other conditions remained unchanged:

[0063] A mixed solution of 3-cyclopropylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in a T-shaped mixing module M1 (temperature 20-30°C) and allowed to react in a pipeline reaction module R1 for 30 minutes. The reaction mixture (flow rate 48 μL / min) and sodium hydroxide solution (3.20 mmol / mL, flow rate 96 μL / min) were then mixed in a T-shaped mixing module M2 and allowed to react in a pipeline reaction module R2 for 10 minutes (temperature 50°C). The resulting mixed solution flowed into a collection module P. The mixed solution was extracted with water and ethyl acetate, separated, and the organic phase dried over anhydrous sodium sulfate and rotary evaporated to obtain the product with an overall yield of 13%.

[0064] Comparative Example 3

[0065] 4-Cyclopropyl-1,2,5-oxadiazolecarboxylic acid was synthesized by referring to the process of Example 1, except that the residence time of the R1 reaction module was changed to 10 minutes, and the other conditions remained unchanged:

[0066] A mixed solution of 3-methylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and a sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in a T-type mixing module M1 (temperature 20-30°C), then allowed to react in a pipeline reaction module R1 for 10 minutes. The reaction mixture (flow rate 48 μL / min) and a sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min) were then mixed in a T-type mixing module M2, allowed to react in a pipeline reaction module R2 for 10 minutes (temperature 50°C), and the resulting mixed solution flowed into a collection module P. The mixed solution was extracted with water and ethyl acetate, separated, and the organic phase dried over anhydrous sodium sulfate and rotary evaporated to obtain the product with an overall yield of 20%.

[0067] Comparative Example 4

[0068] 4-Cyclopropyl-1,2,5-oxadiazolecarboxylic acid was synthesized by referring to the process of Example 1, except that the temperature of the R2 reaction module was changed (20° C.), and the other parameters remained unchanged:

[0069] A mixed solution of 3-methylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in a T-shaped mixing module M1 (temperature 20-30°C) and allowed to react in a pipeline reaction module R1 for 30 minutes. The reaction mixture (flow rate 48 μL / min) and sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min) were then mixed in a T-shaped mixing module M2 and allowed to react in a pipeline reaction module R2 for 10 minutes (temperature 20°C). The resulting mixed solution flowed into a collection module P. The mixed solution was extracted with water and ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated to obtain the product with an overall yield of 13.5%.

[0070] Comparative Example 5

[0071] 4-Cyclopropyl-1,2,5-oxadiazolecarboxylic acid was synthesized by referring to the process of Example 1, except that the temperature of the R2 reaction module was changed (70° C.), and all other conditions remained unchanged:

[0072] A mixed solution of 3-methylisoxazol-5(4H)-one (1.33 mmol / mL) and hydrochloric acid (1.33 mmol / mL) (flow rate 24 μL / min) and a sodium nitrite solution (1.92 mmol / mL, flow rate 24 μL / min) were mixed in a T-shaped mixing module M1 (temperature 20-30°C), then allowed to react in a pipeline reaction module R1 for 30 minutes. The reaction mixture (flow rate 48 μL / min) and a sodium hydroxide solution (6.40 mmol / mL, flow rate 48 μL / min) were then mixed in a T-shaped mixing module M2, allowed to react in a pipeline reaction module R2 for 10 minutes (temperature 70°C), and the resulting mixed solution flowed into a collection module P. The mixed solution was extracted with water and ethyl acetate, separated, and the organic phase dried over anhydrous sodium sulfate and rotary evaporated to obtain the product with an overall yield of less than 10%.

[0073] The embodiments provided above are not intended to limit the scope of the present invention, nor are the steps described to limit their execution order. Any obvious improvements to the present invention made by those skilled in the art in combination with existing common knowledge shall fall within the scope of protection defined by the claims of the present invention.

Claims

1. A method for synthesizing 4-substituted-1,2,5-oxadiazolecarboxylic acid compounds, characterized in that Based on a continuous flow pipeline reactor series-parallel process, compound 1 is mixed with a sodium nitrite mixed solution and a hydrochloric acid solution to react to obtain compound 2; compound 2 is then reacted with a sodium hydroxide solution to obtain the target compound 3; ， ， ， Wherein, R is one of C1-8 alkyl, aromatic hydrocarbon, and heterocyclic aromatic hydrocarbon; the aromatic hydrocarbon is a substituted or unsubstituted benzene ring or naphthalene ring; the heterocyclic aromatic hydrocarbon is a substituted or unsubstituted pyridine ring; the substituents on the aromatic hydrocarbon and heterocyclic aromatic hydrocarbon are selected from: C1-4 alkyl, C1-4 alkoxy, and halogen; The process of the continuous flow pipeline reactor series-parallel process includes: (1) The mixed solution of compound 1 and hydrochloric acid and the sodium nitrite solution were added to the premixing module M1 through metering pumps, and then transferred to the reaction module R1 for 30 minutes to react to obtain a reaction solution containing compound 2; (2) The resulting reaction solution containing compound 2 is then mixed with a sodium hydroxide solution in a T-type premixing module M2, and then reacted in a reaction module R2; after the reaction is completed, the effluent is collected in a product collection module P; In step (2), sodium hydroxide solution is added to the T-type premixing module M2 at a flow rate of 48 μL / min to mix with the reaction solution containing compound 2; the reaction temperature of the reaction module R2 is 50°C.

2. The method according to claim 1, characterized in that The C1-8 alkyl group is selected from: a C1-8 straight chain or branched chain alkyl group, and a C3-C6 cycloalkyl group.

3. The method according to claim 1, characterized in that In step (1), the molar ratio of compound 1 to hydrochloric acid in the mixed solution of compound 1 and hydrochloric acid is 1:1; the molar ratio of compound 1 to sodium nitrite is 1:1.2-1.

5.

4. The method according to claim 1, wherein In step (1), a mixed solution of compound 1 and hydrochloric acid was added to the premixing module M1 at a flow rate of 24 μL / min.

5. The method according to claim 1, wherein In step (1), sodium nitrite solution was added to the premixing module M1 at a flow rate of 24 μL / min.

6. The method according to claim 1, characterized in that In step (1), the reaction temperature of the reaction module R1 is 20-30°C.

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