Process for the preparation of deuterated betaines
By generating deuterated betaine under alkaline conditions and combining pH adjustment and washing solution treatment, the problem of impurity removal in the synthesis of deuterated betaine was solved, achieving a high yield and a simple separation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NINGXIA MEDICAL UNIV
- Filing Date
- 2024-01-17
- Publication Date
- 2026-05-15
AI Technical Summary
There is currently no effective method for preparing deuterated betaine, which makes its synthetic route complex and impurities difficult to remove, thus affecting the product yield.
Under suitable alkaline conditions, deuterated iodomethane reacts with N,N-dimethylglycine to generate deuterated betaine. By adjusting the pH to neutral and weakly acidic, and combining this with a predetermined washing solution, the separation process is simplified, and side reactions and impurities are avoided.
A high-yield preparation of deuterated betaine was achieved, simplifying the operation process, improving product purity and separation efficiency, and avoiding the use of recrystallization.
Smart Images
Figure BDA0004670056550000021 
Figure BDA0004670056550000041 
Figure BDA0004670056550000051
Abstract
Description
Technical Field
[0001] This invention belongs to the technical field of betaine preparation, specifically relating to a method for preparing deuterated betaine. Background Technology
[0002] Betaine is a quaternary ammonium-type water-soluble alkaloid, short for glycine betaine. It has anti-tumor, antihypertensive, anti-peptic ulcer, and gastrointestinal dysfunction functions, and can also treat liver diseases. Deuterated drugs are new compounds in which some hydrogen atoms in a drug molecule are replaced by its heavy isotope deuterium. This structural modification is called deuteration. Deuterated drugs can improve the pharmacokinetics and / or toxicity characteristics of drugs, potentially resulting in improvements in efficacy and safety compared to non-deuterated counterparts. Therefore, we hope to modify the pharmacokinetic properties of betaine and improve its efficacy through deuterated betaine. In addition, betaine is widely distributed in animals, plants, and microorganisms. When studying the biochemical effects of exogenous betaine in organisms, endogenous betaine can cause interference. The detection and analysis of deuterated betaine can avoid the interference of endogenous betaine, and its synthesis has important application value.
[0003] There are two synthetic routes for betaine: one is natural extraction, which involves adding calcium chloride to the mother liquor from beet sugar production, filtering, adding hydrochloric acid to the filtrate, concentrating and crystallizing to obtain the finished product; the other is chemical synthesis, which involves reacting chloroacetic acid, trimethylamine and sodium hydroxide, concentrating, purifying and crystallizing to obtain betaine. However, the preparation of deuterated betaine has not been reported, so it is necessary to find a method for preparing deuterated betaine. Summary of the Invention
[0004] In view of this, the present invention provides a method for preparing deuterated betaine.
[0005] The technical solution adopted by this invention to solve its technical problem is:
[0006] A method for preparing deuterated betaine includes the following steps:
[0007] S1: Dissolve N,N-dimethylglycine and deuterated iodomethyl methyl ether in an organic solvent, adjust the pH to alkaline, and react to obtain a mixture containing deuterated betaine.
[0008] S2: Adjust the pH of mixture one containing deuterated betaine to neutral, filter, and the filtrate is mixture two containing deuterated betaine;
[0009] S3: The mixture containing deuterated betaine is concentrated under reduced pressure, and the solid after concentration is washed with a predetermined washing solution to obtain a solid containing deuterated betaine.
[0010] S4: Dissolve the solid containing deuterated betaine in an organic solvent, adjust the pH to weakly acidic, filter and dry to obtain deuterated betaine solid powder.
[0011] The synthetic route is:
[0012]
[0013] Preferably, in steps S1 and S4, the organic solvent is selected from methanol, ethanol, ethyl acetate, and acetonitrile.
[0014] Preferably, in step S1, adjusting the pH to alkaline specifically means that the pH is 9 to 11.
[0015] Preferably, the pH adjustment is alkaline: specifically, it is adjusted by adding a metal alkali.
[0016] Preferably, the metal alkali is added dropwise.
[0017] Preferably, in step S2, the pH of the mixture containing deuterated betaine is adjusted to neutral: specifically by adjusting with dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.
[0018] Preferably, in step S3, the predetermined washing solution is prepared by mixing dichloromethane and methanol in a predetermined volume ratio.
[0019] Preferably, the predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:1.
[0020] Preferably, in step S4, adjusting the pH to a weakly acidic state specifically means pH = 4 to 6.
[0021] Preferably, the pH adjustment is weakly acidic: specifically, it is adjusted by dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.
[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0023] This invention provides a method for preparing deuterated betaine. 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. The sodium salt is then removed by adjusting the pH to neutral, followed by effective removal of impurities using a predetermined washing solution. This simple washing process is convenient and does not require recrystallization. Adjusting the pH to weakly acidic conditions prevents the formation of deuterated betaine hydrochloride and effectively releases the deuterated betaine, further removing impurities. The product yield is high, and separation is simple. Attached Figure Description
[0024] Figure 1 This is the 1H NMR spectrum of deuterated betaine.
[0025] Figure 2 This is the 1H NMR spectrum of betaine. Detailed Implementation
[0026] 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.
[0027] A method for preparing deuterated betaine includes the following steps:
[0028] S1: Dissolve N,N-dimethylglycine and deuterated iodomethyl methyl ether in an organic solvent, adjust the pH to alkaline, and react to obtain a mixture containing deuterated betaine.
[0029] S2: Adjust the pH of mixture one containing deuterated betaine to neutral, filter, and the filtrate is mixture two containing deuterated betaine to neutralize sodium hydroxide. Filter to remove inorganic salts NaCl and NaI.
[0030] S3: The mixture containing deuterated betaine is concentrated under reduced pressure, and the solid after concentration is washed with a predetermined washing solution to obtain a solid containing deuterated betaine. The side reaction impurities deuterated N,N-dimethylglycine methyl ester and deuterated betaine methyl ester are removed by the predetermined washing solution to effectively remove impurities and reduce the loss of the target product.
[0031] S4: Dissolve the solid containing deuterated betaine in an organic solvent and adjust the pH to weakly acidic. Filter and dry to obtain deuterated betaine solid powder. By adjusting the pH of the solution to the isoelectric point of deuterated betaine, deuterated betaine is effectively released and precipitated. This further removes the side reaction impurities deuterated N,N-dimethylglycine methyl ester and deuterated betaine methyl ester, while avoiding the formation of deuterated betaine hydrochloride.
[0032] The synthetic route is:
[0033]
[0034] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0035] This invention provides a method for preparing deuterated betaine. 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. Simultaneously, the side reaction of the carboxyl oxygen in N,N-dimethylglycine is suppressed. The sodium salt is then removed by adjusting the pH to neutral, followed by effective removal of impurities using a predetermined washing solution. This simple washing process is convenient and does not require recrystallization. Adjusting the pH to weakly acidic conditions prevents the formation of deuterated betaine hydrochloride and effectively releases deuterated betaine, further removing impurities. The product yield is high, and separation is simple.
[0036] The synthesis mechanism is as follows:
[0037]
[0038] Furthermore, the molar ratio of N,N-dimethylglycine to deuterated iodomethyl is 1:1 to 1:1.5.
[0039] Furthermore, in steps S1 and S4, the organic solvent is selected from methanol, ethanol, ethyl acetate, and acetonitrile.
[0040] Furthermore, in steps S1 and S4, the organic solvent is methanol, which has a high reaction yield and is convenient for subsequent separation.
[0041] 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. Since the carboxyl oxygen in N,N-dimethylglycine also has nucleophilicity, competing side reactions occur. If the alkalinity is too high, the nucleophilicity of the oxygen atom increases, leading to more competing side reactions and a low yield of deuterated betaine. Simultaneously, excessive alkalinity can cause the hydrolysis of deuterated iodomethane, resulting in the waste of raw materials.
[0042] 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.
[0043] Furthermore, in step S2, the pH of the mixture containing deuterated betaine is adjusted to neutral: this can be achieved by dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.
[0044] Furthermore, in step S3, the predetermined washing 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 washing 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.
[0045] 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.
[0046] Furthermore, in step S4, adjusting the pH to a weakly acidic state specifically means pH = 4 to 6. The pH is near the isoelectric point of deuterated betaine, which can effectively precipitate deuterated betaine and further remove the side reaction impurities deuterated N,N-dimethylglycine methyl ester and deuterated betaine methyl ester, while avoiding the formation of deuterated betaine hydrochloride.
[0047] Furthermore, the pH adjustment is weakly acidic: specifically, it is adjusted using dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.
[0048] Example 1:
[0049] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, followed by the addition of deuterated iodomethane (0.9 mL, 14.2 mmol). 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for four hours, 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 under reduced pressure. The solid was washed with a predetermined washing solution (dichloromethane:methanol, volume ratio 5:1), then dissolved in methanol. The pH was adjusted to 5 with 10% dilute hydrochloric acid, and the precipitated solid was filtered and dried to obtain a solid compound, deuterated betaine, as a pale yellow powder with a yield of 80%.
[0050] The prepared pale yellow deuterated betaine powder was characterized by nuclear magnetic resonance (NMR), such as... Figure 1 As shown, the results are as follows:
[0051] 1 H NMR(400MHz,DMSO-d6)δ3.97(s,2H),3.19(s,6H).HRMS calcd for C5H8D3NO2[M+H] + 121.1, found 121.4.
[0052] Based on the nuclear magnetic resonance (NMR) characterization of betaine, such as Figure 2 As shown, 1 ¹H NMR (400MHz, DMSO-d6) δ 4.14 (s, 2H), 3.21 (s, 9H) indicates that deuterated betaine was prepared.
[0053] Comparative Example 1:
[0054] 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 four hours, and 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 under reduced pressure. The solid was washed with a predetermined washing solution (dichloromethane:methanol volume ratio of 1:1). The solid was dissolved in methanol, and the pH was adjusted to 5 with 10% dilute hydrochloric acid. The precipitated solid was filtered, dried, and the solid compound was obtained (yield 10%). The Rf value of the compound was consistent with that of deuterated betaine as monitored by TLC.
[0055] Comparative Example 2:
[0056] 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 four 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, and a solid precipitated. The solid was filtered, and the filtrate was concentrated under reduced pressure. The solid was washed with a predetermined washing solution (dichloromethane:methanol volume ratio of 8:1). TLC monitoring showed that a large amount of impurities (deuterated N,N-dimethylglycine methyl ester or deuterated betaine methyl ester) were still present, and the impurities could not be effectively removed.
[0057] Comparative Example 3:
[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 four 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 under reduced pressure. The solid was washed with a predetermined washing solution (ethyl acetate:methanol volume ratio of 5:1). The solid was dissolved in methanol, and the pH was adjusted to 5 with 10% dilute hydrochloric acid. The precipitated solid was filtered, dried, and dried to obtain a solid compound (yield 15%). The Rf value of the compound was consistent with that of deuterated betaine as monitored by TLC.
[0059] Comparative Example 4:
[0060] 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 four hours, and 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, and the precipitated solid was filtered. The filtrate was concentrated under reduced pressure, and the solid was washed with a predetermined washing solution (ethyl acetate:methanol volume ratio of 1:1). TLC monitoring showed the presence of deuterated betaine and impurities (deuterated N,N-dimethylglycine methyl ester or deuterated betaine methyl ester). TLC monitoring of the solid also showed the presence of deuterated betaine and impurities (deuterated N,N-dimethylglycine methyl ester or deuterated betaine methyl ester). Deuterated betaine was lost along with the impurities.
[0061] Comparative Example 5:
[0062] 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 four hours, and 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, and the precipitated solid was filtered. The filtrate was concentrated under reduced pressure, and the solid was washed with a predetermined washing solution (ethyl acetate:methanol volume ratio of 8:1). TLC monitoring showed the presence of deuterated betaine and impurities (deuterated N,N-dimethylglycine methyl ester or deuterated betaine methyl ester). TLC monitoring of the solid also showed the presence of deuterated betaine and impurities (deuterated N,N-dimethylglycine methyl ester or deuterated betaine methyl ester). Deuterated betaine was lost along with the impurities.
[0063] Comparative Example 6:
[0064] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of ethyl acetate, followed by the addition of deuterated iodomethane (0.9 mL, 14.2 mmol). 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for four hours, 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 under reduced pressure. The solid was washed with a predetermined washing solution (dichloromethane:methanol, volume ratio 5:1), then dissolved in methanol. The pH was adjusted to 5 with 10% dilute hydrochloric acid, and the precipitated solid was filtered and dried to obtain the solid compound deuterated betaine (yield 27%).
[0065] Comparative Example 7:
[0066] At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of acetonitrile, followed by the addition of deuterated iodomethane (0.9 mL, 14.2 mmol). 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was carried out at room temperature for four hours, 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 under reduced pressure. The solid was washed with a predetermined washing solution (dichloromethane:methanol, volume ratio 5:1), dissolved in methanol, and the pH was adjusted to 5 with 10% dilute hydrochloric acid. The precipitated solid was filtered and dried to obtain the solid compound deuterated betaine (yield 56%).
[0067] As can be seen from Comparative Examples 1 to 7, different types of reaction solvents, and different ratios or types of pre-selected washing solutions result in low reaction yields or ineffective removal of impurities.
[0068] 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, characterized in that, Includes the following steps: S1: N,N-dimethylglycine and deuterated iodomethane are dissolved in an organic solvent, and the pH is adjusted to alkaline to obtain a mixture containing deuterated betaine; the pH adjustment to alkaline is specifically achieved by adding a metal alkali. S2: Adjust the pH of mixture one containing deuterated betaine to neutral, filter, and the filtrate is mixture two containing deuterated betaine; Adjust the pH of the mixture containing deuterated betaine to neutral: specifically by adjusting with dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid. S3: The mixture containing deuterated betaine is concentrated under reduced pressure, and the solid after concentration is washed with a predetermined washing solution to obtain a solid containing deuterated betaine. S4: Dissolve the solid containing deuterated betaine in an organic solvent, adjust the pH to weakly acidic, filter and dry to obtain deuterated betaine solid powder; In steps S1 and S4, the organic solvent is selected from methanol, ethanol, ethyl acetate, and acetonitrile. In step S3, the predetermined washing solution is prepared by mixing dichloromethane and methanol in a predetermined volume ratio. The predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:
1.
2. The method for preparing deuterated betaine as described in claim 1, characterized in that: In step S1, adjusting the pH to alkaline specifically means setting the pH to 9-11.
3. The method for preparing deuterated betaine as described in claim 1, characterized in that: The metal alkali needs to be added dropwise.
4. The method for preparing deuterated betaine as described in claim 1, characterized in that: In step S4, adjusting the pH to a weakly acidic state specifically means pH = 4~6.
5. The method for preparing deuterated betaine as described in claim 4, characterized in that: The pH adjustment is weakly acidic: specifically, it is adjusted using dilute hydrochloric acid, hydrobromic acid, or hydroiodic acid.