Synthesis method of boric acid methyl iminodiacetate compound
By using N,N-dimethylformamide as a solvent in the synthesis of methyliminodiacetate boric acid as a solvent and using the beating steps of water and organic solvents, the problem of using prone toxin in the existing methods is solved, and an efficient and safe synthesis process is achieved, which is suitable for large-scale production.
Patent Information
- Application Number
- CN202510210743.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-25
- Publication Date
- 2025-05-30
AI Technical Summary
The existing synthesis methods of boric acid methyliminodiacetate compounds use toluene as a solvent, which is a prevalent drug controlled by the state, limiting the scope of synthesis.
Boric acid compounds, N,N-dimethylformamide and methyliminodiacetic acid are used to form boric acid methyliminodiacetic acid compounds by dehydration and condensation reaction, and excess solvents and impurities are removed by beating steps of water and organic solvents.
It replaces toluene that is prone to poison production, expands the synthesis range, improves the purity and yield of the product, and is suitable for large-scale production.
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Figure CN120058757A_ABST
Abstract
Description
Technical Field
[0001] This application relates to the technical field of organic synthesis, and more specifically, it relates to a method for synthesizing boronic acid methyliminodiacetate compounds. Background Art
[0002] N-methyliminodiacetic acid (MIDA) boronate is a nucleophilic reagent that can replace classical boronic acid reagents for Suzuki coupling reactions. During drug development, MIDA boronate can be used as a building block to introduce specific functional groups into target molecules. In addition, they can also be used as precursors for polymers or other functional materials.
[0003] Boronic acid methyliminodiacetate compounds can react specifically within biological systems without interfering with other cellular processes, and thus are also used for bioorthogonal reactions, which helps to label or modify biomolecules in living cells.
[0004] Currently, the synthesis method of boronic acid methyliminodiacetate compounds mainly uses toluene and dimethyl sulfoxide as solvents. However, toluene is a controlled substance in China and belongs to drugs precursor chemicals, resulting in the need for relevant qualifications to use this synthesis method. Summary of the Invention
[0005] In order to expand the synthesis scope of boronic acid methyliminodiacetate compounds, this application provides a method for synthesizing boronic acid methyliminodiacetate compounds.
[0006] A method for synthesizing boronic acid methyliminodiacetate compounds, comprising the following steps: S1: Mix a boronic acid compound and N,N-dimethylformamide, then add methyliminodiacetic acid and stir to react to obtain a reaction solution; S2: Add the reaction solution to ice water, filter to obtain a crude product; first slurry the crude product with water, filter and dry it, then slurry it with an organic solvent for a second time, filter to obtain the boronic acid methyliminodiacetate compound; The synthesis reaction equation of the above boronic acid methyliminodiacetate compound is as follows: R 1 is selected from any one of I, Br, CH 3 、CHCH 2 and OH.
[0007] Preferably, in the step S1, the boronic acid compound is any one of 4-iodophenylboronic acid, 4-methylphenylboronic acid, 4-vinylphenylboronic acid, 4-bromophenylboronic acid, 3-bromophenylboronic acid and 4-hydroxyphenylboronic acid.
[0008] Preferably, in step S1, the feed ratio of the boric acid compound to methyliminodiacetic acid is 1 mol:(1-2) mol.
[0009] Preferably, in step S1, the stirring reaction temperature is 100 to 140° C. and the time is 12 to 20 hours.
[0010] Preferably, in step S2, the organic solvent is one or both of petroleum ether and ethyl acetate.
[0011] Preferably, the organic solvent is composed of a mixture of petroleum ether and ethyl acetate in a volume ratio of (3-5):1.
[0012] Preferably, in step S1, the boronic acid compound is any one of 4-methylphenylboronic acid, 4-vinylphenylboronic acid, 4-bromophenylboronic acid and 3-bromophenylboronic acid; In the step S2, the organic solvent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1.
[0013] Preferably, in step S1, the boronic acid compound is 4-hydroxyphenylboric acid; In the step S2, the organic solvent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1.
[0014] In summary, this application has the following beneficial effects: The present application uses boric acid compounds and methyliminodiacetic acid to form boric acid methyliminodiacetic acid ester compounds through dehydration condensation reaction. Since low-toxic N,N-dimethylformamide is used as a solvent to replace the state-controlled easy-to-make drug toluene, not only the synthesis range of boric acid methyliminodiacetic acid ester compounds is expanded, but also excess N-methyliminodiacetic acid and a small amount of raw materials are removed by water beating, and some water-insoluble impurities are removed by organic solvent beating, so high-yield boric acid methyliminodiacetic acid ester compounds are successfully synthesized, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 is the LCMS spectrum of 4-iodophenylboronic acid methyliminodiacetate; Figure 2 is the HNMR spectrum of 4-iodophenylboronic acid methyliminodiacetate; Figure 3 is the LCMS spectrum of 4-tolylboronic acid methyliminodiacetate; Figure 4 is the HNMR spectrum of 4-tolylboronic acid methyliminodiacetate; Figure 5 is the LCMS spectrum of 4-vinylbenzeneboronic acid methyliminodiacetate; Figure 6 is the HNMR spectrum of methyliminodiacetic acid ester of 4-vinylbenzeneboronic acid; Figure 7 is the LCMS spectrum of methyliminodiacetic acid ester of 4-bromophenylboronic acid; Figure 8 is the HNMR spectrum of methyliminodiacetic acid ester of 4-bromophenylboronic acid; Figure 9 is the LCMS spectrum of 2-(3-bromophenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione; Figure 10 is the HNMR spectrum of 2-(3-bromophenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione; Figure 11 is the LCMS spectrum of methyliminodiacetic acid ester of 4-hydroxybenzeneboronic acid; Figure 12 is the HNMR spectrum of methyliminodiacetic acid ester of 4-hydroxybenzeneboronic acid. Detailed implementation manners
[0016] The following further describes the present application in detail with reference to the accompanying drawings and embodiments. Embodiment
[0017] Embodiment 1 A synthesis method of a methyliminodiacetic acid ester boronic acid compound, and the synthesis reaction equation is as follows:
[0018] The reagents used in the above synthesis method and their corresponding feeding amounts are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 4-Iodobenzene boronic acid <![CDATA[C 6 H 6 BIO 2 > 248 250g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 223g 1.5eq. DMF / / 2500mL /
[0019] The above synthesis method includes the following steps: S1: Add 223 g of methyliminodiacetic acid to a 5000 mL round-bottom flask. First, add 2500 mL of the solvent DMF, and then add 250 g of 4-iodobenzeneboronic acid. Stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, obtain the reaction solution.
[0020] S2: Add the reaction solution to 10000 ml of ice water, and filter to obtain a yellow solid crude product; first slurry the crude product with 3000 ml of water for 1 - 3 h (1 h in the embodiment of the present application), filter and dry it, and then slurry it with 2000 ml of ethyl acetate for 1 - 3 h (1 h in the embodiment of the present application), filter and dry it to obtain 315 g of a yellow solid.
[0021] Refer toFigure 1 and Figure 2 , after detection, the yellow solid is 4-iodophenylboronic acid methyliminodiacetate (purity 98+%, yield 87%).
[0022] Example 2 A method for synthesizing a boronic acid methyliminodiacetate compound, and the synthesis reaction equation is as follows:
[0023] The reagents used in the above synthesis method and their corresponding feeding amounts are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 4-Methylphenylboronic acid <![CDATA[C 7 H 6 BO 2 > 136 520g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 823g 1.5eq. DMF / / 5000mL /
[0024] The above synthesis method includes the following steps: S1: Add 823 g of methyliminodiacetic acid to a 10 L round-bottom flask. First, add 5000 mL of the solvent DMF, then add 520 g of 4-methylphenylboronic acid, and stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, a reaction solution is obtained.
[0025] S2: Add the reaction solution to 15000 ml of ice water, and filter to obtain a crude white solid; first slurry the crude product with 10000 ml of water for 1 - 3 h (2 h in the embodiment of the present application), filter and dry it, then slurry it with 5000 ml of an organic solvent (PE:EA = 3:1) for 1 - 3 h (2 h in the embodiment of the present application), filter, and dry to obtain 910 g of a white solid.
[0026] Refer to Figure 3 and Figure 4 , after detection, the white solid is 4-tolylboronic acid methyliminodiacetate (purity 99+%, yield 96%).
[0027] Example 3 A method for synthesizing a boronic acid methyliminodiacetate compound, and the synthesis reaction equation is as follows:
[0028] The reagents used in the above synthesis method and their corresponding feeding amounts are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 4-Vinylphenylboronic acid <![CDATA[C 8 H 9 BO 2 > 148 100g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 150g 1.5eq. DMF / / 1000mL /
[0029] The above synthesis method includes the following steps: S1: Add 150 g of methyliminodiacetic acid to a 10 L round-bottom flask. First, add 1000 mL of the solvent DMF, then add 100 g of 4-vinylphenylboronic acid, and stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, a reaction solution is obtained.
[0030] S2: Add the reaction solution to 5000 ml of ice water, and filter to obtain the crude white solid; first, slurry the crude product with 3000 ml of water for 1 - 3 h (3 h in the examples of this application), filter and dry it, then slurry it with 3000 ml of organic solvent (PE:EA = 3:1) for 1 - 3 h (3 h in the examples of this application), filter and dry it to obtain 158 g of white solid.
[0031] Refer to Figure 5 and Figure 6 , after detection, the white solid is 4 - vinylphenylboronic acid methyliminodiacetate (purity 98+%, yield 90%).
[0032] Example 4 A method for synthesizing a boronic acid methyliminodiacetate compound, and the synthesis reaction equation is as follows:
[0033] The reagents used in the above - mentioned synthesis method and their corresponding feeding amounts are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 4-Bromophenylboronic acid <![CDATA[C 6 H 6 BBrO 2 > 200 520g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 572g 1.5eq. DMF / / 5000mL /
[0034] The above - mentioned synthesis method includes the following steps: S1: Add 572 g of methyliminodiacetic acid to a 10 L round - bottom flask, first add 5000 mL of solvent DMF, then add 520 g of 4 - bromophenylboronic acid, stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, obtain the reaction solution.
[0035] S2: Add the reaction solution to 15000 ml of ice water, and filter to obtain the crude white solid; first, slurry the crude product with 5000 ml of water for 1 - 3 h (2 h in the examples of this application), filter and dry it, then slurry it with 5000 ml of organic solvent (PE:EA = 3:1) for 1 - 3 h (2 h in the examples of this application), filter and dry it to obtain 750 g of white solid.
[0036] Refer to Figure 7 and Figure 8 , after detection, the white solid is 4 - bromophenylboronic acid methyliminodiacetate (purity 98+%, yield 91%).
[0037] Example 5 A method for synthesizing a boronic acid methyliminodiacetate compound, and the synthesis reaction equation is as follows:
[0038] The reagents used in the above - mentioned synthesis method and their corresponding feeding amounts are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 3-Bromophenylboronic acid <![CDATA[C 6 H 6 BBrO 2 > 200 320g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 352g 1.5eq. DMF / / 3000mL /
[0039] The above synthesis method includes the following steps: S1: Add 352 g of methyliminodiacetic acid to a 10 L round-bottom flask. First, add 3000 mL of the solvent DMF, then add 320 g of 3-bromophenylboronic acid, and stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, a reaction solution is obtained.
[0040] S2: Add the reaction solution to 10000 ml of ice water, and filter to obtain a crude white solid; first, slurry the crude product with 3000 ml of water for 1 - 3 h (2 h in the embodiment of the present application), filter and dry it, then slurry it with 3000 ml of an organic solvent (PE:EA = 3:1) for 1 - 3 h (2 h in the embodiment of the present application), filter, and dry to obtain 463 g of a white solid.
[0041] Refer to Figure 9 and Figure 10 , after detection, the white solid is 2-(3-bromophenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (purity 98+%, yield 91%).
[0042] Example 6 A synthesis method of a boronic acid methyliminodiacetate compound, and the synthesis reaction equation is as follows:
[0043] The reagents and their corresponding feeding amounts used in the above synthesis method are shown in the following table. Reagent Molecular formula Molecular weight Dosage Dosage ratio 4-Hydroxyphenylboronic acid <![CDATA[C 6 H 7 BO 3 > 138 600g 1.0eq. Methyliminodiacetic acid <![CDATA[C 5 H 9 NO 4 > 147 960g 1.5eq. DMF / / 6000mL /
[0044] The above synthesis method includes the following steps: S1: Add 960 g of methyliminodiacetic acid to a 10 L round-bottom flask. First, add 6000 mL of the solvent DMF, then add 600 g of 4-hydroxyphenylboronic acid, and stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, a reaction solution is obtained.
[0045] S2: Add the reaction solution to 20000 ml of ice water, and filter to obtain a crude brown solid; first, slurry the crude product with 10000 ml of water for 1 - 3 h (2 h in the embodiment of the present application), filter and dry it, then slurry it with 10000 ml of an organic solvent (PE:EA = 5:1) for 1 - 3 h (2 h in the embodiment of the present application), filter, and dry to obtain 1027 g of a brown solid.
[0046] Refer to Figure 11 and Figure 12, after detection, the brown solid was 4-hydroxyphenylboronic acid methyliminodiacetate (purity 99+%, yield 95%).
[0047] Comparative Example Comparative Example 1 A method for synthesizing a boronic acid methyliminodiacetate compound, comprising the following steps: (1) Mix 40 g of sodium hydroxide and 18.65 g of water, add 54.56 g of (methylimine)di-acetonitrile within 2.5 h at 45 °C, raise the temperature to 130 °C within 4.5 h, keep the temperature for 0.6 h, then add hydrochloric acid to adjust the pH to 3.5, keep the temperature at 60 °C for 0.5 h, add activated carbon, keep the temperature for 20 min, filter by suction to obtain a filtrate, extract with toluene, and take the organic layer; (2) Control the temperature below 40 °C, dissolve 32.93 g of methylboronic acid in acetonitrile, then add the organic layer from step (1), then raise the temperature to 120 °C within 3 h, control the pressure at 1.8 MPa, and keep the reaction until no water vapor is distilled out as the end point, then vacuum distill the organic solvent to obtain 73.68 g of the product methylboronic acid methyliminodiacetate, with a yield of 86.2%.
[0048] Comparative Example 2 A method for synthesizing a boronic acid methyliminodiacetate compound, comprising the following steps: Add 3,5-dibromophenylboronic acid (8.40 g, 30.0 mmol) and N-methyliminodiacetic acid (5.29 g, 36.0 mmol) to a 1000 mL round-bottom flask, pour in toluene (500 mL) and dimethyl sulfoxide (50.0 mL), and connect the flask to a Dean-Stark receiver filled with toluene and a condenser. After the reaction mixture was immersed in an oil bath at 130 °C for 6 h, the toluene was removed and the product was precipitated and dried in water to obtain 11.4 g of a white powdery product, with a purity of 93+% and a yield of 97.4%.
[0049] By comparing Examples 1-6 with Comparative Examples 1-2, it can be seen that the boronic acid methyliminodiacetate compounds prepared in Examples 1-6 have a purity as high as 98+% and a yield as high as over 87%. Compared with Comparative Examples 1-2, Examples 1-6 use N,N-dimethylformamide as a solvent, avoiding the use of toluene which is controlled by the state, have a wider range of use, and are suitable for large-scale production.
[0050] Comparative Example 3 A method for synthesizing a boronic acid methyliminodiacetate compound, which is different from Example 1 in that only water is used for pulping.
[0051] The above method for synthesizing a boronic acid methyliminodiacetate compound, comprising the following steps: S1: Add 223 g of methyliminodiacetic acid into a 5000 mL round-bottom flask. First, add 2500 mL of the solvent DMF, and then add 250 g of 4-iodophenylboronic acid. Stir and react at 120 °C for 16 h. After detecting the completion of the reaction by TLC and LCMS, obtain the reaction solution.
[0052] S2: Add the reaction solution into 10000 ml of ice water, and filter to obtain the crude yellow solid; first, slurry the crude product with 3000 ml of water for 1 h, filter and dry it, then slurry it with 3000 ml of water for the second time for 1 h, filter and dry it to obtain 347 g of yellow solid.
[0053] After detection, the yellow solid is 4-iodophenylboronic acid methyliminodiacetate (purity 90+%, yield 88%).
[0054] By comparing Example 1 and Comparative Example 3, it can be seen that Example 1 prepared 4-iodophenylboronic acid methyliminodiacetate with a purity as high as 98+%. Compared with Comparative Example 3, Example 1 adopted water slurrying combined with organic solvent slurrying, which improved the purity of 4-iodophenylboronic acid methyliminodiacetate.
[0055] This specific embodiment is only an interpretation of the present application, and it is not a limitation of the present application. Those skilled in the art can make modifications without creative contributions to this embodiment according to needs after reading this specification, but as long as it is within the scope of the claims of the present application, it is protected by the patent law.
Claims
1. A method for synthesizing boric acid methyliminodiacetate compounds, characterized in that: The following steps are involved: S1: After mixing the boric acid compound and N,N-dimethylformamide, adding methyliminodiacetic acid and stirring to react, obtaining a reaction solution; S2: adding the reaction solution into ice water and filtering to obtain a crude product; beating the crude product with water for the first time, filtering and drying, beating the crude product with an organic solvent for the second time, filtering, and obtaining a boric acid methyliminodiacetate compound; R1 is selected from any one of I, Br, CH3, CHCH2 and OH.
2. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 1, characterized in that: In the step S1, the boronic acid compound is any one of 4-iodophenylboric acid, 4-methylphenylboric acid, 4-vinylphenylboric acid, 4-bromophenylboric acid, 3-bromophenylboric acid and 4-hydroxyphenylboric acid.
3. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 1, characterized in that: In the step S1, the feed ratio of the boric acid compound to methyliminodiacetic acid is 1 mol:(1-2) mol.
4. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 1, characterized in that: In the step S1, the stirring reaction temperature is 100 to 140° C. and the time is 12 to 20 hours.
5. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 1, characterized in that: In the step S2, the organic solvent is one or both of petroleum ether and ethyl acetate.
6. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 5, characterized in that: The organic solvent is composed of a mixture of petroleum ether and ethyl acetate in a volume ratio of (3-5):
1.
7. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 6, characterized in that: In step S1, the boronic acid compound is any one of 4-methylphenylboronic acid, 4-vinylphenylboronic acid, 4-bromophenylboronic acid and 3-bromophenylboronic acid; In the step S2, the organic solvent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:
1.
8. The method for synthesizing boric acid methyliminodiacetate compounds according to claim 6, characterized in that: In step S1, the boronic acid compound is 4-hydroxyphenylboric acid; In the step S2, the organic solvent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1.