Deuterated betaine methyl esters, methods for their preparation, and uses thereof

Abstract

The application provides a kind of deuterated betaine methyl ester and its preparation method and its application, it is related to betaine methyl ester technical field, under suitable alkaline conditions, the positive charge of methyl in deuterated methyl iodide attacks the nitrogen atom containing lone pair electron in N,N-dimethyl glycine, generates deuterated betaine by forming quaternary amine nitrogen, then, methoxy negative ion attacks the carbonyl carbon of deuterated betaine carboxyl group to form deuterated betaine methyl ester, then remove sodium salt by adjusting pH to neutral, remove impurities by beating the solid with predetermined beating liquid, filter, and obtain the solid compound by concentrating the filtrate under reduced pressure, to obtain deuterated betaine methyl ester, the above preparation method is simple, and separation is simple.

Description

Technical Field

[0001] This invention belongs to the technical field of betaine methyl ester preparation, specifically relating to a deuterated betaine methyl ester, its preparation method, and its application. Background Technology

[0002] Betaine is a quaternary ammonium salt alkaloid with excellent biological activity and wide applications in the pharmaceutical, pesticide, feed additive, and cosmetic industries. Betaine methyl ester is an essential key intermediate in the preparation of betaine, and its preparation directly affects the preparation of betaine. At the same time, betaine methyl ester is also a derivative of betaine, and its lipid solubility and in vivo action time are superior to those of betaine.

[0003] Existing literature reports a synthetic strategy for preparing betaine methyl ester via the reaction of chloroacetic acid, calcium hydroxide, and trimethylamine, followed by acidification to prepare betaine methyl ester hydrochloride. Deuterium atoms can not only serve as tracer atoms for labeling compounds but also effectively improve the absorption, distribution, metabolism, and excretion pathways of candidate drug molecules. Introducing trideuteryl groups into drug molecules significantly improves the biological processes of candidate drug molecules, affecting efficacy and holding significant importance for the pharmaceutical industry. Betaine's metabolic site is on the nitrogen atom; substituting the methyl group on the nitrogen atom with a trideuteryl group can improve the pharmacokinetics and / or toxicity of betaine, potentially leading to improvements in efficacy and safety compared to non-deuterated counterparts. Furthermore, betaine esterification improves its lipophilicity and prolongs the duration of drug action. Therefore, we hope to modify the pharmacokinetic properties of betaine and improve its efficacy by using deuterated betaine methyl ester. At the same time, deuterated betaine methyl ester is also an important scientific research biochemical reagent. However, the preparation of deuterated betaine methyl ester has not been reported, so it is necessary to find a method for its preparation. Summary of the Invention

[0004] In view of this, the present invention provides a deuterated betaine methyl ester.

[0005] It is also necessary to provide a method for preparing deuterated betaine methyl ester.

[0006] It is also necessary to provide an application for deuterated betaine methyl ester.

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

[0008] A deuterated betaine methyl ester, the structural formula of which is:

[0009]

[0010] The preparation method of deuterated betaine methyl ester as described above includes the following steps:

[0011] S1: N,N-dimethylglycine and deuterated iodomethyl methyl ester are dissolved in an organic solvent, and the pH is adjusted to alkaline to obtain a mixture containing deuterated betaine methyl ester.

[0012] S2: Adjust the pH of mixture one containing deuterated betaine methyl ester to neutral, filter, and the filtrate is mixture two containing deuterated betaine methyl ester;

[0013] S3: The mixture containing deuterated betaine methyl ester is concentrated to dryness under reduced pressure, and then the solid is pulped with a predetermined pulping solution. The mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain solid deuterated betaine methyl ester.

[0014] The synthetic route is:

[0015]

[0016] Preferably, in step S1, the organic solvent is selected from methanol.

[0017] Preferably, in step S1, adjusting the pH to alkaline specifically means that the pH is 9 to 11.

[0018] Preferably, the pH adjustment is alkaline: specifically, it is adjusted by adding a metal alkali.

[0019] Preferably, the metal alkali is added dropwise.

[0020] Preferably, in step S2, the pH of the mixture containing deuterated betaine methyl ester is adjusted to neutral: specifically by adjusting with dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.

[0021] Preferably, in step S3, the predetermined slurry is prepared by mixing dichloromethane and methanol in a predetermined volume ratio.

[0022] Preferably, the predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:1.

[0023] The applications of deuterated betaine methyl ester as described above, including its use as a raw material for the preparation of deuterated betaine and its use as a raw material for the preparation of deuterated betaine hydrochloride.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] This invention provides a deuterated betaine methyl ester, its preparation method, and its application. Under suitable alkaline conditions, the positively charged methyl group in deuterated iodomethane attacks the nitrogen atom containing a lone pair of electrons in N,N-dimethylglycine, forming a quaternary ammonium nitrogen to generate deuterated betaine. Then, the methoxy anion attacks the carbonyl carbon of the carboxyl group of deuterated betaine to form deuterated betaine methyl ester. The sodium salt is removed by adjusting the pH to neutral, and impurities are effectively removed by slurrying the solid with a predetermined slurry. After filtration and concentration of the filtrate under reduced pressure, a solid compound is obtained, yielding deuterated betaine methyl ester. The above preparation method is simple and easy to separate. Attached Figure Description

[0026] Figure 1 This is the 1H NMR spectrum of deuterated betaine methyl ester.

[0027] Figure 2 This is the mass spectrum of deuterated betaine methyl ester. Detailed Implementation

[0028] The technical solutions and effects of the embodiments of the present invention will be further described in detail below with reference to the accompanying drawings.

[0029] A deuterated betaine methyl ester, the structural formula of which is:

[0030]

[0031] The preparation method of deuterated betaine methyl ester as described above includes the following steps:

[0032] S1: N,N-dimethylglycine and deuterated iodomethyl methyl ester are dissolved in an organic solvent, and the pH is adjusted to alkaline to obtain a mixture containing deuterated betaine methyl ester.

[0033] S2: Adjust the pH of mixture one containing deuterated betaine methyl ester to neutral, filter, and the filtrate is mixture two containing deuterated betaine methyl ester, to neutralize sodium hydroxide, and filter to remove inorganic salts NaCl and NaI.

[0034] S3: The mixture containing deuterated betaine methyl ester is concentrated to dryness under reduced pressure, and then the solid is pulped with a predetermined pulping solution. The mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain solid deuterated betaine methyl ester. The predetermined pulping solution effectively removes side reaction impurities and reduces the loss of the target product.

[0035] The synthetic route is:

[0036]

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] This invention provides a deuterated betaine methyl ester, its preparation method, and its application. Under suitable alkaline conditions, the positively charged methyl group in deuterated iodomethane attacks the nitrogen atom containing a lone pair electron in N,N-dimethylglycine, forming a quaternary ammonium nitrogen to generate deuterated betaine. Then, the methoxy anion attacks the carbonyl carbon of the carboxyl group of deuterated betaine to form deuterated betaine methyl ester. The sodium salt is removed by adjusting the pH to neutral, and impurities are effectively removed by slurrying the solid with a predetermined slurry. The solid compound is obtained by filtration and concentration of the filtrate under reduced pressure, yielding deuterated betaine methyl ester. The above preparation method is simple and easy to separate.

[0039] The synthesis mechanism is as follows:

[0040]

[0041] Furthermore, the molar ratio of N,N-dimethylglycine to deuterated iodomethyl is 1:1 to 1:2.

[0042] Furthermore, in step S1, the organic solvent is selected from methanol.

[0043] Furthermore, in step S1, adjusting the pH to alkaline specifically means setting the pH to 9-11. If the alkalinity is too low, no reaction will occur; if the alkalinity is too high, it will cause the deuterated iodomethyl to hydrolyze, resulting in the consumption and waste of raw materials.

[0044] Furthermore, the pH is adjusted to be alkaline by adding sodium hydroxide or potassium hydroxide, specifically by adding 10% sodium hydroxide. The sodium hydroxide is added dropwise to avoid hydrolysis of deuterated iodomethane.

[0045] Furthermore, in step S2, the pH of the mixture containing deuterated betaine methyl ester is adjusted to neutral: this can be achieved by dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.

[0046] Furthermore, in step S3, the predetermined pulping solution is prepared by mixing dichloromethane and methanol in a predetermined volume ratio, which can effectively remove impurities. It is easy to operate through simple pulping and does not require recrystallization. Other types of solvents cannot effectively remove impurities, or they may cause product loss while removing impurities, resulting in a decrease in yield.

[0047] Furthermore, the predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:1 to effectively remove impurities and avoid product dissolution and loss.

[0048] Furthermore, as described above, deuterated betaine methyl ester has applications in which it alters the pharmacokinetic properties of betaine and enhances its efficacy. At the same time, deuterated betaine methyl ester is also an important scientific research biochemical reagent.

[0049] Furthermore, the deuterated betaine methyl ester is used as a raw material for preparing deuterated betaine, and as a raw material for preparing deuterated betaine hydrochloride.

[0050] The synthetic route and reaction mechanism are as follows:

[0051] Preparation of deuterated betaine and its hydrochloride from deuterated betaine methyl ester:

[0052]

[0053] Reaction mechanism:

[0054]

[0055] Specifically: Under reflux and alkaline conditions (pH>12), deuterated betaine methyl ester undergoes a process where hydroxide ions attack the carbonyl carbon of the ester (which is positively charged), and the methoxy group leaves with a negative charge, thus generating deuterated betaine.

[0056] Deuterated betaine is acidified with hydrochloric acid (pH<2), which releases the carboxyl group of the inner salt, forming deuterated betaine hydrochloride.

[0057] Example 1:

[0058] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours, and the reaction was monitored by TLC until complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then slurried with a predetermined slurry (dichloromethane:methanol volume ratio of 5:1), filtered, and the filtrate was concentrated under reduced pressure to obtain the solid compound, deuterated betaine methyl ester, a pale yellow powder with a yield of 30%.

[0059] The prepared pale yellow deuterated betaine methyl ester powder was characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS), such as... Figure 1 and Figure 2 As shown, the results are as follows:

[0060] 1 H NMR(400MHz,D2O)δ4.53(2H),3.83(3H),3.56(6H).HRMS calcd for C5H8D3NO2[M+H] + 135.1, found 135.0.

[0061] Based on the above characterization, it can be concluded that deuterated betaine methyl ester was prepared.

[0062] Comparative Example 1:

[0063] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then pulped with a predetermined pulping solution (dichloromethane:methanol volume ratio of 8:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 8%). The Rf value of the compound was consistent with that of deuterated betaine methyl ester as monitored by TLC.

[0064] Comparative Example 2:

[0065] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then pulped with a predetermined pulping solution (dichloromethane:methanol volume ratio of 1:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 53%). TLC monitoring showed that a large amount of impurities were still present, and the impurities could not be effectively removed.

[0066] Comparative Example 3:

[0067] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then slurried with a predetermined slurry (ethyl acetate:methanol volume ratio of 5:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 46%). TLC monitoring showed that a large amount of impurities were still present, and the impurities could not be effectively removed.

[0068] Comparative Example 4:

[0069] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then slurried with a predetermined slurry (ethyl acetate:methanol volume ratio of 1:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 58%). TLC monitoring showed that a large amount of impurities were still present, and the impurities could not be effectively removed.

[0070] Comparative Example 5:

[0071] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and then deuterated iodomethane (0.9 mL, 14.2 mmol) was added. 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was then adjusted to 7 with 10% dilute hydrochloric acid. The precipitated solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The solid was then slurried with a predetermined slurry (ethyl acetate:methanol volume ratio of 8:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 23%). TLC monitoring showed that a large amount of impurities were still present, and the impurities could not be effectively removed.

[0072] As can be seen from Comparative Examples 1 to 5, different proportions or types of the intended pulping solution result in low reaction yields or ineffective removal of impurities.

[0073] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the invention. Those skilled in the art will understand that implementing all or part of the above-described embodiments and making equivalent changes in accordance with the claims of the present invention are still within the scope of the invention.

Claims

1. A method for preparing deuterated betaine methyl ester, characterized in that, The structural formula of the deuterated betaine methyl ester is: ； Includes the following steps: S1: N,N-dimethylglycine and deuterated iodomethyl methyl ester are dissolved in an organic solvent, the pH is adjusted to alkaline, and the reaction yields a mixture containing deuterated betaine methyl ester; the organic solvent is methanol; the pH is 9-11; S2: Adjust the pH of mixture one containing deuterated betaine methyl ester to neutral, filter, and the filtrate is mixture two containing deuterated betaine methyl ester; Adjust the pH of mixture one containing deuterated betaine methyl ester to neutral: specifically by adjusting with dilute hydrochloric acid. S3: The mixture containing deuterated betaine methyl ester is concentrated to dryness under reduced pressure, and then the solid is pulped with a predetermined pulping solution. The mixture is filtered, and the filtrate is concentrated under reduced pressure to obtain solid deuterated betaine methyl ester. The predetermined pulping solution is a mixture of dichloromethane and methanol at a predetermined volume ratio of 4:1 to 6:

1. The synthesis route is as follows: 。 2. The method for preparing deuterated betaine methyl ester as described in claim 1, characterized in that: In step S1, the pH is adjusted to be alkaline: specifically by adding sodium hydroxide or potassium hydroxide.

3. The method for preparing deuterated betaine methyl ester as described in claim 2, characterized in that: The sodium hydroxide or potassium hydroxide needs to be added dropwise.

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