A preparation method of methylboronic acid-d3

Abstract

The present invention discloses a method for preparing methylboronic acid d3. The method comprises reacting methyl iodide d3 with magnesium shavings to produce methylmagnesium iodide d3, which is then reacted with trimethyl borate to produce dimethyl methylborate. The product is then quenched with acid for hydrolysis and purified to obtain methylboronic acid d3. The product prepared by the present invention has high purity, high yield, and high degree of deuteration.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing methylboronic acid-d3. Background Art

[0002] Methylboronic acid is the simplest organic boronic acid derivative and an important intermediate in the preparation of many boronic acid derivatives. It has a variety of uses in organic synthesis. In addition, methylboronic acid and its derivatives also have significant advantages in chromatographic analysis and are often used for the separation of cis and trans isomers.

[0003] At present, for the synthesis method of methylboric acid, the prior art discloses the following: Patent CN104163825B uses sodium borohydride and boron trifluoride to prepare borane, then introduces carbon monoxide to react to obtain methylboric anhydride, which is hydrolyzed to obtain methylboric acid. Borane and carbon monoxide in this method are both toxic and flammable gases, and reducing hydrogen is consumed during the preparation process, so the safety and atom economy of this process are not guaranteed. Related technologies also often use methyl Grignard reagents or methyllithium reagents to react with trimethyl borate, and methylboric acid is obtained after hydrolysis; for example, patent CN103030660A, but its post-processing process also only uses alkanes for beating, which makes it difficult to guarantee the yield of methylboric acid.

[0004] Methylboronic acid-d3 refers to a methylboronic acid molecule in which deuterium (D) replaces the hydrogen (H) on the methyl group. Methylboronic acid-d3 is an important pharmaceutical intermediate and can be used to synthesize various deuterated drugs.

[0005] Regarding the preparation of methylboronic acid-d3, related art discloses the reaction of methylmagnesium iodide-d3 with trimethyl borate, but does not address post-processing. The hydrogen isotope effect also has a certain impact on the preparation of methylmagnesium iodide-d3. Furthermore, methylboronic acid-d3 is highly soluble in water, tending to remain in the aqueous phase and making purification difficult. Without a suitable purification process, the yield of the prepared methylboronic acid-d3 is often very low, making it difficult to meet the requirements of subsequent reactions. Summary of the Invention

[0006] The present invention aims to provide a method for preparing methylboronic acid-d3, wherein the prepared product has high purity, high yield and high degree of deuteration.

[0007] The technical solution adopted by the present invention to solve its technical problem is:

[0008] A method for preparing methylboronic acid-d3 comprises: using iodomethane-d3 as a raw material, reacting it with magnesium chips to generate methylmagnesium iodide-d3; further reacting methylmagnesium iodide-d3 with trimethyl borate to generate dimethyl methylborate; quenching the reaction with acid to hydrolyze the reaction product; and purifying the reaction product to obtain methylboronic acid-d3.

[0009] Among them, the purification process includes:

[0010] The reaction solution is separated to obtain an organic phase and an aqueous phase;

[0011] The organic phase is extracted with alkali solution and separated to obtain the aqueous phase;

[0012] The above aqueous phases were combined, acid was added under a protective atmosphere to adjust the pH to 1-7, ether was added for extraction, and then n-hexane was added for slurrying, filtered, washed and dried to obtain methylboric acid-d3.

[0013] In the present invention, the timing of adding n-hexane and the use of ether are very important. During the purification process, ether is a good solvent and n-hexane is a poor solvent. The ratio of good solvent to poor solvent has a significant effect on the yield and purity of methylboronic acid-d3. Specifically, when the mass proportion of n-hexane is higher, the yield of methylboronic acid-d3 increases, but the purity decreases. Therefore, in order to balance the yield and purity of the final product, the mass ratio of the system during n-hexane beating is preferably (0.2-0.7): 1: (1-6).

[0014] Preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid.

[0015] Preferably, the ether is tert-methyl ether or diethyl ether.

[0016] Preferably, the number of ether extractions is 3-5 times, and in each extraction, the amount of ether added is 1-5 times the theoretical mass of methylboric acid-d3.

[0017] Preferably, ether is added for extraction and then rotary evaporation is performed. When the mass of the ether is 20-70% of the theoretical mass of methylboric acid-d3, n-hexane is added for pulping; wherein the amount of n-hexane added is 1-6 times the theoretical mass of methylboric acid-d3.

[0018] Preferably, the organic phase is extracted with alkali by adding 10-50% by mass of an alkali solution to the organic phase, and adjusting the pH to 10-14.

[0019] Preferably, the base is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

[0020] Preferably, the molar ratio of iodomethane-d3:magnesium chips:trimethyl borate is 1:1-1.5:0.5-1.

[0021] Preferably, the reaction temperature for the reaction of methylmagnesium iodide-d3 and trimethyl borate to generate dimethyl methylborate is below -60°C.

[0022] Preferably, the acid-addition quenching hydrolysis is specifically performed by warming the reaction solution at room temperature for 12-18 hours; then adding acid to adjust the pH to 3-5, and stirring for 2-6 hours.

[0023] The invention has the beneficial effects of: the yield of methylboronic acid-d3 is greater than 42%, the purity is greater than 95%, and the deuteration degree is greater than 99.5%. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further described in detail below through specific embodiments.

[0025] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following examples, unless otherwise specified, are all conventional methods in the art.

[0026] Example 1

[0027] A method for preparing methylboronic acid-d3 comprises the following steps:

[0028] 1. Dilute 145 g of iodomethane-d3 (1.0 mol) into 360 ml of ether; under nitrogen protection, add 29 g of magnesium chips (1.2 mol) into the reaction flask, and then add iodomethane-d3-ether solution to carry out Grignard reaction to obtain methylmagnesium iodide-d3.

[0029] 2. Place the reaction flask in a dry ice ethanol bath, cool the Grignard reagent to -65°C, weigh 83g of trimethyl borate (0.8mol), dilute it into 72ml of ether, mix well, add it to the reaction flask under N2 protection, and then warm it to room temperature for 18 hours; add hydrochloric acid to adjust the pH to 3 and stir for 2 hours.

[0030] 3. The reaction solution was separated to obtain an organic phase and an aqueous phase; a 50% by mass potassium hydroxide aqueous solution was added to the organic phase, the pH was adjusted to 12, and the aqueous phase was obtained by separation.

[0031] 4. Combine the above aqueous phases, add 6 mol / L hydrochloric acid under N2 protection to adjust the pH to 3, add methyl tert-ether for extraction, 250 g each time, and extract 3 times.

[0032] 5. The theoretical mass of methylboronic acid-d3 in this embodiment is 50g (0.8mol). Rotary evaporation was performed until methyl tertiary ether was about 35g, 300g of n-hexane was added for pulping, filtration, washing with n-hexane, and drying to obtain methylboronic acid-d3 29.0g, a yield of 58.0%, a deuteration degree of 99.8%, and a purity of 95.4%. The product was confirmed to be methylboronic acid-d3 by nuclear magnetic resonance.

[0033] Example 2-10

[0034] A method for preparing methylboronic acid-d3, the specific steps are as shown in Example 1, except that the ratio of reactants and process conditions are as shown in Table 1;

[0035] In Example 2, the Grignard reagent was cooled to -60°C and 6 mol / L hydrochloric acid was added under N2 protection to adjust the pH to 1. In Example 4, the quenching conditions were as follows: the reaction solution was warmed to room temperature for 12 hours; then, hydrochloric acid was added to adjust the pH to 5 and stirred for 6 hours. In Example 6, the potassium carbonate concentration was 10% and the pH was adjusted to 14; 6 mol / L hydrochloric acid was added under N2 protection to adjust the pH to 7.

[0036] Comparative Examples 1-3

[0037] This comparative example provides a method for preparing methylboronic acid-d3. The specific steps are shown in Example 1, except for the ratio of the raw materials, as shown in Table 1.

[0038] The yield, purity (GC pinacol derivatization detection) and deuteration degree (H-NMR detection) of Examples 1-10 and Comparative Examples 1-2 were calculated, and the results are shown in Table 1.

[0039] Table 1

[0040]

[0041]

[0042] The embodiment described above is only a preferred solution of the present invention and does not limit the present invention in any form. Other variations and modifications are possible without exceeding the technical solution described in the claims.

Claims

1. A method for preparing methylboronic acid-d3, characterized in that, Using iodomethane-d3 as the raw material, it reacts with magnesium chips to produce methylmagnesium iodide-d3, which is then reacted with trimethyl borate to produce dimethyl methylborate. Acid is added to quench the hydrolysis, and after purification, methylboric acid-d3 is obtained. Among them, the purification process includes: The reaction solution is separated to obtain an organic phase and an aqueous phase; The organic phase is extracted with alkali solution and separated to obtain the aqueous phase; Combine the above aqueous phases, add acid to adjust the pH to 1-7 under a protective atmosphere, add ether for extraction, then add n-hexane for pulping, filter, wash and dry to obtain methylboronic acid-d3; The number of ether extractions is 3-5 times, and the amount of ether added in each extraction is 1-5 times the theoretical mass of methylboric acid-d3; After adding ether for extraction, rotary evaporation is performed until the mass of ether is 20-70% of the theoretical mass of methylboric acid-d3, and then n-hexane is added for slurrying; wherein the amount of n-hexane added is 1-6 times the theoretical mass of methylboric acid-d3; The acid addition quenching hydrolysis is specifically as follows: returning the reaction solution to room temperature for 12-18 hours; then adding acid to adjust the pH to 3-5, and stirring for 2-6 hours.

2. The preparation method according to claim 1, characterized in that The acid is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid.

3. The preparation method according to claim 1, characterized in that The ether is tert-methyl ether or ethyl ether.

4. The preparation method according to claim 1, characterized in that The organic phase is extracted with alkali by adding 10-50% by mass of an alkali solution to the organic phase and adjusting the pH to 10-14.

5. The preparation method according to claim 1 or 4, characterized in that The alkali is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

6. The preparation method according to claim 1, characterized in that The molar ratio of iodomethane-d3: magnesium chips: trimethyl borate is 1:1-1.5:0.5-1.

7. The preparation method according to claim 1, characterized in that The reaction temperature for the reaction of methylmagnesium iodide-d3 and trimethyl borate to generate dimethyl methylborate is below -60°C.

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