CN118063338A - Deuterated betaine methyl ester and preparation method and application thereof - Google Patents
Deuterated betaine methyl ester and preparation method and application thereof Download PDFInfo
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- CN118063338A CN118063338A CN202410064603.1A CN202410064603A CN118063338A CN 118063338 A CN118063338 A CN 118063338A CN 202410064603 A CN202410064603 A CN 202410064603A CN 118063338 A CN118063338 A CN 118063338A
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- -1 Deuterated betaine methyl ester Chemical class 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000007787 solid Substances 0.000 claims abstract description 30
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 claims abstract description 26
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical class C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims abstract description 24
- 239000000706 filtrate Substances 0.000 claims abstract description 21
- 108700003601 dimethylglycine Proteins 0.000 claims abstract description 13
- 229940078490 n,n-dimethylglycine Drugs 0.000 claims abstract description 13
- 238000004537 pulping Methods 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 230000007935 neutral effect Effects 0.000 claims abstract description 9
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical class [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 238000010979 pH adjustment Methods 0.000 claims description 3
- 238000004513 sizing Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract description 17
- 229960003237 betaine Drugs 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 16
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 5
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001412 amines Chemical group 0.000 abstract description 3
- 230000005611 electricity Effects 0.000 abstract description 3
- 159000000000 sodium salts Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides deuterated betaine methyl ester and a preparation method and application thereof, and relates to the technical field of betaine methyl ester, wherein under a proper alkaline condition, methyl with positive electricity in deuterated methyl iodide attacks nitrogen atoms containing lone pair electrons in N, N-dimethylglycine, and deuterated betaine is generated through formation of quaternary amine nitrogen; then, methoxy anions attack the carbonyl carbon of the deuterated betaine carboxyl group to form deuterated betaine methyl ester; and then the pH value is adjusted to be neutral to remove sodium salt, the solid is pulped by preset pulping liquid to effectively remove impurities, the solid compound is obtained by filtering and concentrating filtrate under reduced pressure, and the deuterated betaine methyl ester is obtained.
Description
Technical Field
The invention belongs to the technical field of betaine methyl ester preparation, and particularly relates to deuterated betaine methyl ester, a preparation method and application thereof.
Background
Betaine is a quaternary ammonium salt type alkaloid, has excellent biological activity, and has wide application in industries such as medicines, pesticides, feed additives, cosmetics and the like, while betaine methyl ester is an essential key intermediate product for preparing betaine, and the preparation of the betaine directly influences the preparation of the betaine; meanwhile, the betaine methyl ester is also a derivative of betaine, and the fat solubility and the in-vivo action time are superior to those of betaine.
The prior literature reports a synthetic strategy for preparing betaine methyl ester hydrochloride by adopting chloroacetic acid, calcium hydroxide and trimethylamine to react and then acidizing; deuterium atoms can not only be used as trace atoms to label compounds, but also can effectively improve absorption, distribution, metabolism and excretion pathways of candidate drug molecules. The introduction of the tridentate methyl into the drug molecules can obviously improve the biological process of candidate drug molecules, influence the drug effect and have important significance for the development of the pharmaceutical industry. The metabolic site of betaine is a tridentate methyl substitution on the nitrogen atom, with methyl groups on the nitrogen atom, which can improve the pharmacokinetic and/or toxicity profile of betaine, potentially converting to improvements in efficacy and safety compared to non-deuterated counterparts; in addition, the esterification of betaine can improve the fat solubility and prolong the acting time of the medicine. Therefore, the deuterated betaine methyl ester is expected to change the pharmacokinetic property of the betaine to improve the drug effect of the betaine, and is also an important scientific and biochemical reagent; however, the preparation of deuterated betaine methyl ester has not been reported, and thus a preparation method of deuterated betaine methyl ester needs to be found.
Disclosure of Invention
In view of this, the present invention provides a deuterated betaine methyl ester.
It is also necessary to provide a method for preparing deuterated betaine methyl ester.
It is also desirable to provide for the use of deuterated betaine methyl esters.
The technical scheme adopted for solving the technical problems is as follows:
A deuterated betaine methyl ester having the structural formula:
the preparation method of the deuterated betaine methyl ester comprises the following steps:
s1: dissolving N, N-dimethyl glycine and deuterated methyl iodide in an organic solvent, and regulating the pH value to be alkaline for reaction to obtain a mixture I containing deuterated betaine methyl ester;
S2: adjusting the pH of the first mixture containing deuterated betaine methyl ester to be neutral, and filtering to obtain a filtrate which is a second mixture containing deuterated betaine methyl ester;
s3: concentrating the mixture II containing deuterated betaine methyl ester under reduced pressure to dryness, pulping the solid by using preset pulping liquid, filtering, and concentrating the filtrate under reduced pressure to obtain the deuterated betaine methyl ester solid;
The synthetic route is as follows:
preferably, in the step S1, the organic solvent is selected from methanol.
Preferably, in the step S1, the pH adjustment is specifically performed at a pH of 9 to 11.
Preferably, the pH adjustment is alkaline: in particular by adding a metal base.
Preferably, the metal base is added dropwise.
Preferably, in the step S2, the pH of the first deuterated betaine methyl ester-containing mixture is adjusted to be neutral: in particular by dilute hydrochloric acid or hydrobromic acid or hydroiodic acid.
Preferably, in the step S3, the predetermined sizing liquid is formed by configuring dichloromethane and methanol in a predetermined volume ratio.
Preferably, the predetermined volume ratio of the dichloromethane to the methanol is 4:1-6:1.
The use of deuterated betaine methyl esters as described above as a starting material for the preparation of deuterated betaines and as a starting material for the preparation of deuterated betaines hydrochloride.
Compared with the prior art, the invention has the beneficial effects that:
According to the deuterated betaine methyl ester and the preparation method and application thereof, under a proper alkaline condition, the methyl group with positive electricity in the deuterated methyl iodide attacks the nitrogen atom containing lone pair electrons in N, N-dimethyl glycine, the deuterated betaine is generated by forming quaternary amine nitrogen, and then methoxy anions attack carbonyl carbon of carboxyl of the deuterated betaine to form the deuterated betaine methyl ester; and then the pH value is adjusted to be neutral to remove sodium salt, the solid is pulped by preset pulping liquid to effectively remove impurities, the solid compound is obtained by filtering and concentrating filtrate under reduced pressure, and the deuterated betaine methyl ester is obtained.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of deuterated betaine methyl ester.
FIG. 2 is a mass spectrum of deuterated betaine methyl ester.
Detailed Description
The technical scheme and technical effects of the embodiments of the present invention are further described in detail below with reference to the accompanying drawings.
A deuterated betaine methyl ester having the structural formula:
the preparation method of the deuterated betaine methyl ester comprises the following steps:
s1: dissolving N, N-dimethyl glycine and deuterated methyl iodide in an organic solvent, and regulating the pH value to be alkaline for reaction to obtain a mixture I containing deuterated betaine methyl ester;
s2: adjusting the pH of the first mixture containing deuterated betaine methyl ester to be neutral, filtering, wherein the filtrate is the second mixture containing deuterated betaine methyl ester, neutralizing sodium hydroxide, and filtering to remove inorganic salt NaCl and NaI;
S3: concentrating the mixture II containing deuterated betaine methyl ester under reduced pressure to dryness, pulping the solid by using preset pulping liquid, filtering, and concentrating the filtrate under reduced pressure to obtain the deuterated betaine methyl ester solid; the impurities of side reactions are effectively removed through preset slurry beating, so that the loss of target products is reduced;
The synthetic route is as follows:
Compared with the prior art, the invention has the beneficial effects that:
According to the deuterated betaine methyl ester and the preparation method and application thereof, under a proper alkaline condition, the methyl group with positive electricity in the deuterated methyl iodide attacks the nitrogen atom containing lone pair electrons in N, N-dimethyl glycine, the deuterated betaine is generated by forming quaternary amine nitrogen, and then methoxy anions attack carbonyl carbon of the carboxyl of the deuterated betaine to form the deuterated betaine methyl ester; and then the pH value is adjusted to be neutral to remove sodium salt, the solid is pulped by preset pulping liquid to effectively remove impurities, the solid compound is obtained by filtering and concentrating filtrate under reduced pressure, and the deuterated betaine methyl ester is obtained.
The synthesis mechanism is as follows:
Further, the molar ratio of N, N-dimethyl glycine to deuterated methyl iodide is 1:1-1:2.
Further, in the step S1, the organic solvent is selected from methanol.
Further, in the step S1, the pH is adjusted to be alkaline, specifically, the pH is 9 to 11, and the alkalinity is too low to react; too strong basicity causes hydrolysis of deuterated iodomethane, resulting in waste of raw materials.
Furthermore, the pH value is regulated by adding sodium hydroxide or potassium hydroxide, and is regulated by adding 10% sodium hydroxide, wherein the sodium hydroxide adopts a dropwise adding mode, and the deuterated methyl iodide is prevented from hydrolyzing by adopting the dropwise adding mode.
Further, in the step S2, the pH of the mixture one containing deuterated betaine methyl ester is adjusted to be neutral: can be regulated by dilute hydrochloric acid or hydrobromic acid or hydroiodic acid.
In the step S3, the predetermined pulping liquid is formed by configuring dichloromethane and methanol according to a predetermined volume ratio, so that impurities can be effectively removed, and the operation is convenient and fast through simple pulping without recrystallization; other types of solvents are not effective in removing impurities or, while removing impurities, cause loss of the product, resulting in reduced yields.
Further, the predetermined volume ratio of the dichloromethane to the methanol is 4:1-6:1, so that impurities are effectively removed, and dissolution loss of a product is avoided.
Furthermore, the application of the deuterated betaine methyl ester changes the pharmacokinetic property of the betaine, improves the drug effect of the betaine, and is also an important scientific and biochemical reagent.
Further, the deuterated betaine methyl ester is used as a raw material for preparing the deuterated betaine and is used as a raw material for preparing the deuterated betaine hydrochloride.
The synthetic route and reaction mechanism are as follows:
Deuterated betaine methyl ester preparation deuterated betaine and hydrochloride thereof:
reaction mechanism:
Specific: under the conditions of reflux and alkalinity (pH > 12), the hydroxyl anions attack the ester carbonyl carbon (positive charge), and the methoxy groups leave with negative charges, so that the deuterated betaine is generated.
Deuterated betaine is acidified with hydrochloric acid (pH < 2), and the carboxyl groups of the inner salt are free to form deuterated betaine hydrochloride.
Embodiment one:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was taken and dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted by 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (methylene chloride: methanol volume ratio: 5:1), and the filtrate was filtered and concentrated under reduced pressure to obtain a solid compound, deuterated betaine methyl ester, pale yellow powder, yield 30%.
The prepared yellowish deuterated betaine methyl ester powder is subjected to Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) characterization, and the results are shown in fig. 1 and 2, and are as follows:
1H NMR(400MHz,D2O)δ4.53(2H),3.83(3H),3.56(6H).HRMS calcd for C5H8D3NO2[M+H]+135.1,found 135.0.
from the above characterization, it can be seen that deuterated betaine methyl ester was prepared.
Comparative example one:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was taken and dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted with 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (methylene chloride: methanol volume ratio of 8:1), filtered, and the filtrate was concentrated under reduced pressure to give a solid compound (yield 8%) which was consistent with the Rf value of deuterated betaine methyl ester via TLC monitoring.
Comparative example two:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted with 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (methylene chloride: methanol volume ratio of 1:1), and filtered, and the filtrate was concentrated under reduced pressure to give a solid compound (yield 53%) which was monitored by TLC and was also present as a large amount of impurities, failing to effectively remove the impurities.
Comparative example three:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted with 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (ethyl acetate: methanol: volume ratio: 5:1), filtered, and the filtrate was concentrated under reduced pressure to give a solid compound (yield 46%) which was monitored by TLC and was also present as a large amount of impurities, failing to effectively remove the impurities.
Comparative example four:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted with 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (ethyl acetate: methanol volume ratio: 1:1), filtered, and the filtrate was concentrated under reduced pressure to give a solid compound (yield 58%) which was monitored by TLC and was also present as a large amount of impurities, failing to effectively remove the impurities.
Comparative example five:
N, N-dimethylglycine (1.0023 g,9.7 mmol) was dissolved in 20mL of methanol at room temperature, deuterated iodomethane (0.9 mL,14.2 mmol) was added thereto, 10% NaOH was slowly added dropwise thereto, pH=10 was adjusted, the reaction was carried out at room temperature for 24 hours, TLC was monitored until the reaction was completed, pH=7 was adjusted with 10% diluted hydrochloric acid, solid was precipitated and filtered, the filtrate was concentrated to dryness under reduced pressure, the solid was slurried with a predetermined slurry (ethyl acetate: methanol: volume ratio: 8:1), filtered, and the filtrate was concentrated under reduced pressure to give a solid compound (yield 23%) which was monitored by TLC and was not effectively removed by the presence of a large amount of impurities.
As is clear from comparative examples one to five, the proportions or kinds of the predetermined sizing agents are different, the reaction yield is low, or impurities cannot be removed effectively.
The foregoing disclosure is illustrative of the preferred embodiments of the present invention, and is not to be construed as limiting the scope of the invention, as it is understood by those skilled in the art that all or part of the above-described embodiments may be practiced with equivalents thereof, which fall within the scope of the invention as defined by the appended claims.
Claims (10)
1. A deuterated betaine methyl ester, which is characterized by the structural formula:
2. the method for preparing deuterated betaine methyl ester according to claim 1, comprising the steps of:
s1: dissolving N, N-dimethyl glycine and deuterated methyl iodide in an organic solvent, and regulating the pH value to be alkaline for reaction to obtain a mixture I containing deuterated betaine methyl ester;
S2: adjusting the pH of the first mixture containing deuterated betaine methyl ester to be neutral, and filtering to obtain a filtrate which is a second mixture containing deuterated betaine methyl ester;
s3: concentrating the mixture II containing deuterated betaine methyl ester under reduced pressure to dryness, pulping the solid by using preset pulping liquid, filtering, and concentrating the filtrate under reduced pressure to obtain the deuterated betaine methyl ester solid;
The synthetic route is as follows:
3. the deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 2, wherein: in the step S1, the organic solvent is methanol.
4. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 2, wherein: in the step S1, the pH adjustment is specifically performed to adjust the pH to 9 to 11.
5. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 4, wherein: the pH is adjusted to be alkaline: in particular by adding a metal base.
6. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 5, wherein: the metal base needs to be added dropwise.
7. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 2, wherein: in the step S2, the pH of the first mixture containing deuterated betaine methyl ester is adjusted to be neutral: in particular by dilute hydrochloric acid or hydrobromic acid or hydroiodic acid.
8. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 2, wherein: in the step S3, the preset sizing liquid is formed by configuring methylene dichloride and methanol according to a preset volume ratio.
9. The deuterated betaine methyl ester and the preparation method and the application thereof as described in claim 8, wherein: the preset volume ratio of the dichloromethane to the methanol is 4:1-6:1.
10. Use of deuterated betaine methyl ester as described in any of the claims 1-9, characterized in that: the application of the deuterated betaine methyl ester as the raw material for preparing the deuterated betaine and the application of the deuterated betaine methyl ester as the raw material for preparing the deuterated betaine hydrochloride.
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