Preparation method of methylboronic acid-d3

Abstract

The invention discloses a preparation method of methylboronic acid-d3, which comprises the following steps: taking iodomethane-d3 as a raw material, carrying out Grignard reaction on the iodomethane-d3 and magnesium chips to generate methyl magnesium iodine-d3, further reacting the methyl magnesium iodine-d3 and trimethyl borate to generate dimethyl methylboronic acid, adding acid, quenching, hydrolyzing, and purifying to obtain the methylboronic acid-d3. The product prepared by the method is high in purity, high in yield and high in deuteration degree.

Description

Technical Field

[0001] The 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 many 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: In patent CN104163825B, sodium borohydride and boron trifluoride are used to prepare borane, and then carbon monoxide is introduced 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 atomic economy of this process are not guaranteed. In the related art, methyl Grignard reagent or methyl lithium reagent is also often used to react with trimethyl borate, and methylboric acid is obtained after hydrolysis; for example, patent CN103030660A, but its post-treatment process also only uses alkanes for pulping, and it is difficult to guarantee the yield of methylboric acid.

[0004] Methylboronic acid-d3 refers to the substitution of deuterium (D) for hydrogen (H) on the methyl group in the methylboronic acid molecule. Methylboronic acid-d3 is an important drug intermediate and can be used to synthesize different deuterated drugs.

[0005] Regarding the preparation method of methylboronic acid-d3, the related art discloses that it is prepared by reacting methylmagnesium iodide-d3 with trimethyl borate, but does not involve a post-treatment process. The hydrogen isotope effect also has a certain influence on the preparation of methylmagnesium iodide-d3, and methylboronic acid-d3 has good solubility in water and is easy to remain in the aqueous phase and difficult to purify; in the absence of a suitable purification process, the yield of the prepared methylboronic acid-d3 is often very low, and it is difficult to meet the subsequent reaction requirements. Summary of the invention

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

[0007] The technical solution adopted by the present invention to solve its technical problem is: A preparation method of methylboric acid-d3, which comprises taking iodomethane-d3 as a raw material, reacting with magnesium chips to generate methylmagnesium iodide-d3, further reacting methylmagnesium iodide-d3 with trimethyl borate to generate dimethyl methylborate, adding acid to quench and hydrolyze, and purifying to obtain methylboric acid-d3; 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 alkaline solution, and the aqueous phase is obtained by separation; The above aqueous phases are combined, acid is added under a protective atmosphere to adjust the pH to 1-7, ether is added for extraction, and then n-hexane is added for slurrying, filtered, washed and dried to obtain methylboric acid-d3.

[0008] In the present invention, the timing of adding n-hexane and the use of ether are very important. In the process of purification, 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 methylboric acid-d3. Specifically, when the mass proportion of n-hexane is higher, the yield of methylboric 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 the preferred n-hexane pulping: the mass ratio of ether, theoretical methylboric acid-d3, and n-hexane is (0.2-0.7): 1: (1-6).

[0009] Preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid.

[0010] Preferably, the ether is tertiary methyl ether or ethyl ether.

[0011] 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.

[0012] Preferably, after adding ether for extraction, rotary evaporation is performed, and when the mass of 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.

[0013] 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.

[0014] Preferably, the base is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

[0015] Preferably, the molar ratio of methyl iodide-d3: magnesium chips: trimethyl borate is 1:1-1.5:0.5-1.

[0016] Preferably, the reaction temperature for the reaction of methylmagnesium iodide-d3 and trimethyl borate to generate dimethyl methylborate is below -60°C.

[0017] Preferably, the acid addition quenching hydrolysis is specifically: warming 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.

[0018] The invention has the beneficial effects that the yield of methylboric acid-d3 is greater than 42%, the purity is greater than 95%, and the deuteration degree is greater than 99.5%. DETAILED DESCRIPTION

[0019] The technical solution of the present invention is further described in detail below through specific embodiments.

[0020] 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 embodiments, unless otherwise specified, are all conventional methods in the art.

[0021] Example 1 A method for preparing methylboronic acid-d3 comprises the following steps: 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 bottle, and then add iodomethane-d3-ether solution to carry out Grignard reaction to obtain methylmagnesium iodide-d3.

[0022] 2. Place the reaction bottle 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 and add it into the reaction bottle under N2 protection, then warm it up at room temperature for 18 hours; add hydrochloric acid to adjust the pH to 3 and stir for 2 hours.

[0023] 3. Separate the reaction solution to obtain an organic phase and an aqueous phase; add a 50% by mass potassium hydroxide aqueous solution to the organic phase, adjust the pH to 12, and separate to obtain an aqueous phase.

[0024] 4. Combine the above aqueous phases, add 6 mol / L hydrochloric acid under N2 protection to adjust the pH to 3, add tert-methyl ether for extraction, 250 g each time, and extract 3 times.

[0025] 5. The theoretical mass of methylboric acid-d3 in this embodiment is 50g (0.8mol). Rotary evaporation is performed until tertiary methyl ether is about 35g, 300g of n-hexane is added for pulping, filtration, washing with n-hexane, and drying to obtain methylboric acid-d3 29.0g, with a yield of 58.0%, a deuteration degree of 99.8%, and a purity of 95.4%. The product has been confirmed to be methylboric acid-d3 by nuclear magnetic resonance.

[0026] Embodiment 2-10 A method for preparing methylboronic acid-d3, the specific steps are shown in Example 1, the difference lies in the ratio of reactants and process conditions, see Table 1 for details; Among them, 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. The quenching conditions of Example 4: the reaction solution was warmed up at 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.

[0027] Comparative Examples 1-3 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, see Table 1.

[0028] 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.

[0029] Table 1

[0030] The above-described embodiment is only a preferred solution of the present invention and does not limit the present invention in any form. There are other variations and modifications 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 a raw material, reacting with magnesium chips to generate methylmagnesium iodide-d3, methylmagnesium iodide-d3 further reacting with trimethyl borate to generate dimethyl methylborate, adding acid to quench hydrolysis, and purifying to obtain methylboric acid-d3; 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 alkaline solution, and the aqueous phase is obtained by separation; The above aqueous phases are combined, acid is added under a protective atmosphere to adjust the pH to 1-7, ether is added for extraction, and then n-hexane is added for slurrying, filtered, washed and dried to obtain methylboric acid-d3.

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 tertiary methyl ether or ethyl ether.

4. The preparation method according to claim 1 or 3, characterized in that: The number of extractions with ether is 3-5 times, and in each extraction, the amount of ether added is 1-5 times the theoretical mass of methylboric acid-d3.

5. The preparation method according to claim 1 or 3, characterized in that: After adding ether for extraction, rotary evaporation is performed. When the mass of 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.

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

7. The preparation method according to claim 1 or 6, characterized in that: The alkali is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

8. 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.

9. 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.

10. The preparation method according to claim 1, characterized in that: The acid addition quenching hydrolysis is specifically as follows: warming 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.

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