CN118063338A - Deuterated betaine methyl ester, preparation method and application thereof - Google Patents
Deuterated betaine methyl ester, 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 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 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
- 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
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 230000007935 neutral effect Effects 0.000 claims abstract description 9
- 238000004537 pulping Methods 0.000 claims abstract description 6
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical class C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims abstract 2
- 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 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 15
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 7
- 238000010009 beating Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical class [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 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
- 238000002156 mixing 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 39
- 229960003237 betaine Drugs 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 17
- 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
- 159000000000 sodium salts Chemical class 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000005611 electricity Effects 0.000 abstract 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical class IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 abstract 1
- 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
- 230000000052 comparative effect Effects 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000012544 monitoring process Methods 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
- 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
- 230000009471 action Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 101001121408 Homo sapiens L-amino-acid oxidase Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100026388 L-amino-acid oxidase Human genes 0.000 description 1
- 101100012902 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) FIG2 gene Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 125000004429 atom Chemical group 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
- 238000012512 characterization method Methods 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
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002632 lipids Chemical class 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
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- 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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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域Technical Field
本发明属于甜菜碱甲酯制备的技术领域，具体涉及一种氘代甜菜碱甲酯及其制备方法及其应用。The invention belongs to the technical field of betaine methyl ester preparation, and specifically relates to deuterated betaine methyl ester, a preparation method thereof and application thereof.
背景技术Background technique
甜菜碱是一种季铵盐型生物碱，拥有优异的生物活性，在医药、农药、饲料添加剂和化妆品等行业具有广泛的应用，而甜菜碱甲酯是制备甜菜碱的必不可少的关键中间产物，它的制备直接影响甜菜碱的制备；同时，甜菜碱甲酯也是甜菜碱的衍生物，脂溶性和生物体内作用时间优于甜菜碱。Betaine is a quaternary ammonium alkaloid with excellent biological activity. It is widely used in the pharmaceutical, pesticide, feed additive and cosmetic industries. Betaine methyl ester is an indispensable 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 fat solubility and in vivo action time are better than betaine.
现有文献报道采用氯乙酸、氢氧化钙和三甲胺反应制备甜菜碱甲酯，然后再酸化制备甜菜碱甲酯盐酸盐的合成策略；氘原子不仅可以作为示踪原子对化合物进行标记，还可以有效地改善候选药物分子的吸收、分布、代谢和排泄途径。在药物分子中引入三氘甲基会显著的改善候选药物分子的生物学过程，影响药效，对制药行业的发展有着重要的意义。甜菜碱的代谢位点是在氮原子上，对氮原子上的甲基进行三氘甲基取代，能够改善甜菜碱的药动力学和/或毒性特征，潜在地转化为与非氘化对应物相比在功效和安全性方面的改善；另外，甜菜碱酯化，能改善其脂溶性，延长药物的作用时间。为此我们希望通过氘代甜菜碱甲酯，改变甜菜碱的药动学性质，提高甜菜碱的药效，与此同时，氘代甜菜碱甲酯也是重要的科研生化试剂；但是对于氘代甜菜碱甲酯的制备尚未报道，因此需要寻找氘代甜菜碱甲酯的制备方法。Existing literature reports a synthetic strategy of preparing betaine methyl ester by reacting chloroacetic acid, calcium hydroxide and trimethylamine, and then acidifying to prepare betaine methyl ester hydrochloride; deuterium atoms can not only be used as tracer atoms to label compounds, but also effectively improve the absorption, distribution, metabolism and excretion pathways of candidate drug molecules. The introduction of trideuterium methyl groups into drug molecules will significantly improve the biological processes of candidate drug molecules, affect drug efficacy, and have important significance for the development of the pharmaceutical industry. The metabolic site of betaine is on the nitrogen atom. Substituting the methyl group on the nitrogen atom with trideuterium methyl can improve the pharmacokinetic and/or toxicity characteristics of betaine, potentially translating into improvements in efficacy and safety compared to non-deuterated counterparts; in addition, betaine esterification can improve its lipid solubility and prolong the duration of drug action. To this end, we hope to change the pharmacokinetic properties of betaine and improve the efficacy of betaine through 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 preparing deuterated betaine methyl ester.
发明内容Summary of the invention
有鉴于此，本发明提供一种氘代甜菜碱甲酯。In view of this, the present invention provides a deuterated betaine methyl ester.
还有必要提供一种氘代甜菜碱甲酯的其制备方法。It is also necessary to provide a method for preparing deuterated betaine methyl ester.
还有必要提供一种氘代甜菜碱甲酯的应用。It is also necessary to provide an application of deuterated betaine methyl ester.
本发明解决其技术问题所采用的技术方案是：The technical solution adopted by the present invention to solve the technical problem is:
一种氘代甜菜碱甲酯，其结构式为：A deuterated betaine methyl ester, the structural formula of which is:
如上所述氘代甜菜碱甲酯的制备方法，包括以下步骤：The preparation method of deuterated betaine methyl ester as described above comprises the following steps:
S1：将N,N-二甲基甘氨酸、氘代碘甲烷溶解在有机溶剂中，调节pH为碱性反应得到含有氘代甜菜碱甲酯的混合物一；S1: dissolving N,N-dimethylglycine and deuterated iodomethane in an organic solvent, adjusting the pH to an alkaline reaction to obtain a mixture containing deuterated betaine methyl ester;
S2：将含有氘代甜菜碱甲酯的混合物一的pH调节为中性、过滤，滤液为含有氘代甜菜碱甲酯的混合物二；S2: adjusting the pH of the mixture 1 containing deuterated betaine methyl ester to neutral, filtering, and obtaining a filtrate as the mixture 2 containing deuterated betaine methyl ester;
S3：将含有氘代甜菜碱甲酯的混合物二减压浓缩至干，再用预定打浆液对固体进行打浆，过滤、滤液减压浓缩得到氘代甜菜碱甲酯的固体；S3: concentrating the mixture containing deuterated betaine methyl ester under reduced pressure to dryness, beating the solid with a predetermined beating liquid, filtering, and concentrating the filtrate under reduced pressure to obtain a solid of deuterated betaine methyl ester;
合成路线是：The synthetic route is:
优选地，所述S1步骤中，所述有机溶剂选自甲醇。Preferably, in step S1, the organic solvent is selected from methanol.
优选地，所述S1步骤中，所述调节pH为碱性具体为所述pH为9～11。Preferably, in the step S1, the pH is adjusted to be alkaline, specifically the pH is 9-11.
优选地，所述调节pH为碱性：具体通过加入金属碱调节。Preferably, the pH is adjusted to be alkaline: specifically, by adding a metal base.
优选地，所述金属碱需滴加。Preferably, the metal base needs to be added dropwise.
优选地，所述S2步骤中，将含有氘代甜菜碱甲酯的混合物一的pH调节为中性：具体通过稀盐酸或氢溴酸或氢碘酸调节。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.
优选地，所述S3步骤中，所述预定打浆液为二氯甲烷与甲醇以预定的体积比配置而成。Preferably, in the step S3, the predetermined pulping liquid is prepared by mixing dichloromethane and methanol in a predetermined volume ratio.
优选地，所述二氯甲烷与甲醇的预定体积比为4:1～6:1。Preferably, the predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:1.
如上所述的氘代甜菜碱甲酯的其应用，所述氘代甜菜碱甲酯作为制备氘代甜菜碱原料的应用，以及作为制备氘代甜菜碱盐酸盐原料的应用。The application of the deuterated betaine methyl ester as described above, the application of the deuterated betaine methyl ester as a raw material for preparing deuterated betaine, and the application of the deuterated betaine methyl ester as a raw material for preparing deuterated betaine hydrochloride.
与现有技术相比，本发明的有益效果在于：Compared with the prior art, the present invention has the following beneficial effects:
本发明提供的一种氘代甜菜碱甲酯及其制备方法及其应用，在适宜的碱性条件下，氘代碘甲烷中显正电性的甲基进攻N,N-二甲基甘氨酸中含孤对电子的氮原子，通过形成季胺氮，生成氘代甜菜碱，然后，甲氧基负离子进攻氘代甜菜碱的羧基的羰基碳形成氘代甜菜碱甲酯；再通过调节pH为中性去除钠盐，通过预定打浆液对固体进行打浆有效除去杂质，过滤、滤液减压浓缩得到固体化合物，得到氘代甜菜碱甲酯，上述制备方法简单、分离简便。The invention provides deuterated betaine methyl ester, a preparation method thereof and an application thereof. Under suitable alkaline conditions, a positively charged methyl group in deuterated iodomethane attacks a nitrogen atom containing a lone pair of electrons in N,N-dimethylglycine to form quaternary amine nitrogen to generate deuterated betaine, and then a methoxyl anion attacks the carbonyl carbon of the carboxyl group of the deuterated betaine to form deuterated betaine methyl ester; then, the pH is adjusted to be neutral to remove sodium salt, a solid is beaten with a predetermined beating liquid to effectively remove impurities, and the solid compound is obtained by filtering and concentrating the filtrate under reduced pressure to obtain the deuterated betaine methyl ester. The preparation method is simple and the separation is simple.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为氘代甜菜碱甲酯的核磁共振氢谱图。FIG1 is a hydrogen nuclear magnetic resonance spectrum of deuterated betaine methyl ester.
图2为氘代甜菜碱甲酯的质谱图。FIG2 is a mass spectrum of deuterated betaine methyl ester.
具体实施方式Detailed ways
以下结合本发明的附图，对本发明实施例的技术方案以及技术效果做进一步的详细阐述。The technical solutions and technical effects of the embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings of the present invention.
一种氘代甜菜碱甲酯，其结构式为：A deuterated betaine methyl ester, the structural formula of which is:
如上所述氘代甜菜碱甲酯的制备方法，包括以下步骤：The preparation method of deuterated betaine methyl ester as described above comprises the following steps:
S1：将N,N-二甲基甘氨酸、氘代碘甲烷溶解在有机溶剂中，调节pH为碱性反应得到含有氘代甜菜碱甲酯的混合物一；S1: dissolving N,N-dimethylglycine and deuterated iodomethane in an organic solvent, adjusting the pH to an alkaline reaction to obtain a mixture containing deuterated betaine methyl ester;
S2：将含有氘代甜菜碱甲酯的混合物一的pH调节为中性、过滤，滤液为含有氘代甜菜碱甲酯的混合物二，以中和氢氧化钠，过滤除去无机盐NaCl和NaI；S2: adjusting the pH of the mixture containing deuterated betaine methyl ester to neutral, filtering, and the filtrate is the mixture containing deuterated betaine methyl ester, so as to neutralize the sodium hydroxide, and filtering to remove the inorganic salts NaCl and NaI;
S3：将含有氘代甜菜碱甲酯的混合物二减压浓缩至干，再用预定打浆液对固体进行打浆，过滤、滤液减压浓缩得到氘代甜菜碱甲酯的固体；通过预定打浆液有效除去副反应杂质，减少目标产物的损失；S3: The mixture containing deuterated betaine methyl ester is concentrated under reduced pressure to dryness, and then the solid is pulped with a predetermined pulping liquid, filtered, and the filtrate is concentrated under reduced pressure to obtain a solid of deuterated betaine methyl ester; the predetermined pulping liquid is used to effectively remove side reaction impurities and reduce the loss of the target product;
合成路线是：The synthetic route is:
与现有技术相比，本发明的有益效果在于：Compared with the prior art, the present invention has the following beneficial effects:
本发明提供的一种氘代甜菜碱甲酯及其制备方法及其应用，在适宜的碱性条件下，氘代碘甲烷中显正电性的甲基进攻N,N-二甲基甘氨酸中含孤对电子的氮原子，通过形成季胺氮，生成氘代甜菜碱，然后，甲氧基负离子进攻氘代甜菜碱羧基的羰基碳形成氘代甜菜碱甲酯；再通过调节pH为中性去除钠盐，通过预定打浆液对固体进行打浆有效除去杂质，过滤、滤液减压浓缩得到固体化合物，得到氘代甜菜碱甲酯，上述制备方法简单、分离简便。The invention provides a deuterated betaine methyl ester, a preparation method thereof and an application thereof. Under suitable alkaline conditions, a positively charged methyl group in deuterated iodomethane attacks a nitrogen atom containing a lone pair of electrons in N,N-dimethylglycine to form quaternary amine nitrogen to generate deuterated betaine, and then a methoxyl anion attacks the carbonyl carbon of the carboxyl group of the deuterated betaine to form deuterated betaine methyl ester; then, the pH is adjusted to be neutral to remove sodium salt, a solid is beaten with a predetermined beating liquid to effectively remove impurities, and the solid compound is obtained by filtering and concentrating the filtrate under reduced pressure to obtain the deuterated betaine methyl ester. The preparation method is simple and the separation is simple.
合成机理如下：The synthesis mechanism is as follows:
进一步的，N,N-二甲基甘氨酸与氘代碘甲烷的摩尔比1:1～1:2。Furthermore, the molar ratio of N,N-dimethylglycine to deuterated iodomethane is 1:1 to 1:2.
进一步的，所述S1步骤中，所述有机溶剂选自甲醇。Furthermore, in the step S1, the organic solvent is selected from methanol.
进一步的，所述S1步骤中，所述调节pH为碱性具体为所述pH为9～11，碱性太低，不发生反应；碱性太强会引起氘代碘甲烷水解，导致原料的消耗浪费。Furthermore, in the step S1, the pH is adjusted to be alkaline, specifically the pH is 9 to 11. If the alkalinity is too low, no reaction will occur; if the alkalinity is too strong, deuterated iodomethane will be hydrolyzed, resulting in the waste of raw materials.
进一步的，所述调节pH为碱性具体通过加入氢氧化钠或氢氧化钾调节，具体通过加入10％氢氧化钠调节，氢氧化钠采用滴加方式，采用滴加方式避免氘代碘甲烷水解。Furthermore, the pH is adjusted to be alkaline by adding sodium hydroxide or potassium hydroxide, and specifically by adding 10% sodium hydroxide. The sodium hydroxide is added dropwise to avoid hydrolysis of deuterated iodomethane.
进一步的，所述S2步骤中，将含有氘代甜菜碱甲酯的混合物一的pH调节为中性：可通过稀盐酸或氢溴酸或氢碘酸调节。Furthermore, in the step S2, the pH of the mixture containing deuterated betaine methyl ester is adjusted to neutral: it can be adjusted by dilute hydrochloric acid, hydrobromic acid or hydroiodic acid.
进一步的，所述S3步骤中，所述预定打浆液为二氯甲烷与甲醇以预定的体积比配置而成，能有效除去杂质，通过简单打浆，操作便捷，不用重结晶；其它种类溶剂不能有效除去杂质，或者除去杂质的同时，引起产物的流失，导致收率降低。Furthermore, in the step S3, the predetermined slurrying liquid is composed of dichloromethane and methanol in a predetermined volume ratio, which can effectively remove impurities through simple slurrying, is easy to operate, and does not require recrystallization; other types of solvents cannot effectively remove impurities, or while removing impurities, cause the loss of product, resulting in a decrease in yield.
进一步的，所述二氯甲烷与甲醇的预定体积比为4:1～6:1，以有效除去杂质，避免引起产物的溶解流失。Furthermore, the predetermined volume ratio of dichloromethane to methanol is 4:1 to 6:1, so as to effectively remove impurities and avoid dissolution and loss of the product.
进一步的，如上所述的氘代甜菜碱甲酯的其应用，所述氘代甜菜碱甲酯改变甜菜碱的药动学性质，提高甜菜碱的药效，与此同时，氘代甜菜碱甲酯也是重要的科研生化试剂。Furthermore, the application of the deuterated betaine methyl ester as described above changes the pharmacokinetic properties of betaine and improves the efficacy of betaine. At the same time, the deuterated betaine methyl ester is also an important scientific research biochemical reagent.
进一步的，所述氘代甜菜碱甲酯作为制备氘代甜菜碱原料的应用，以及作为制备氘代甜菜碱盐酸盐原料的应用。Furthermore, the deuterated betaine methyl ester is used as a raw material for preparing deuterated betaine, and is used as a raw material for preparing deuterated betaine hydrochloride.
合成路线及反应机理如下：The synthetic route and reaction mechanism are as follows:
氘代甜菜碱甲酯制备氘代甜菜碱及其盐酸盐：Preparation of deuterated betaine and its hydrochloride from deuterated betaine methyl ester:
反应机理：Reaction mechanism:
具体的：氘代甜菜碱甲酯在回流、碱性(pH>12)条件下，氢氧根负离子进攻酯羰基碳(显正电性)，甲氧基带着负电荷离去，生成氘代甜菜碱。Specifically: under reflux and alkaline (pH>12) conditions, the hydroxide anion attacks the carbonyl carbon (positively charged) of the ester, and the methoxyl group leaves with a negative charge to generate deuterated betaine.
氘代甜菜碱用盐酸酸化(pH<2)，内盐的羧基游离，生成氘代甜菜碱盐酸盐。Deuterated betaine is acidified with hydrochloric acid (pH < 2), and the carboxyl group of the inner salt is freed to form deuterated betaine hydrochloride.
实施例一：Embodiment 1:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(二氯甲烷：甲醇的体积比为5:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物，氘代甜菜碱甲酯，淡黄色粉末，产率30％。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was slurried with a predetermined slurry (the volume ratio of dichloromethane: methanol was 5:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound, deuterated betaine methyl ester, a light yellow powder, with a yield of 30%.
将制备得到的淡黄色氘代甜菜碱甲酯粉末，进行核磁共振(NMR)和质谱(MS)表征，如图1和图2所示，结果如下：The prepared light yellow deuterated betaine methyl ester powder was characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS), as shown in Figures 1 and 2. The results 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。 1 H NMR (400 MHz, D 2 O) δ 4.53 (2H), 3.83 (3H), 3.56 (6H). HRMS calcd for C 5 H 8 D 3 NO 2 [M+H] + 135.1, found 135.0.
根据上述表征，可知制备得到氘代甜菜碱甲酯。According to the above characterization, it can be known that deuterated betaine methyl ester is prepared.
对比例一：Comparative Example 1:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(二氯甲烷：甲醇的体积比为8:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物(收率8％)，经TLC监测，和氘代甜菜碱甲酯的Rf值一致。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was slurried with a predetermined slurry (the volume ratio of dichloromethane: methanol was 8:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 8%), which was consistent with the Rf value of deuterated betaine methyl ester monitored by TLC.
对比例二：Comparative Example 2:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(二氯甲烷：甲醇的体积比为1:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物(收率53％)，经TLC监测，还有大量的杂质存在，不能有效除去杂质。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was slurried with a predetermined slurry (the volume ratio of dichloromethane: methanol was 1:1), filtered, and the filtrate was concentrated under reduced pressure to obtain a solid compound (yield 53%). According to TLC monitoring, a large amount of impurities were still present, and the impurities could not be effectively removed.
对比例三：Comparative Example 3:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(乙酸乙酯:甲醇的体积比为5:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物(收率46％)，经TLC监测，还有大量的杂质存在，不能有效除去杂质。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was 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%). According to TLC monitoring, a large amount of impurities were still present, and the impurities could not be effectively removed.
对比例四：Comparative Example 4:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(乙酸乙酯:甲醇的体积比为1:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物(收率58％)，经TLC监测，还有大量的杂质存在，不能有效除去杂质。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was 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%). According to TLC monitoring, a large amount of impurities were still present, and the impurities could not be effectively removed.
对比例五：Comparative Example 5:
在室温下，取N,N-二甲基甘氨酸(1.0023g，9.7mmol)溶解在20mL甲醇中，再加入氘代碘甲烷(0.9mL，14.2mmol)，缓慢滴加10％NaOH，调节pH＝10，室温反应24小时，TLC监测反应至完全，再用10％稀盐酸调节反应液pH＝7，析出固体过滤，滤液减压浓缩至干，用预定打浆液(乙酸乙酯:甲醇的体积比为8:1)对固体进行打浆，过滤，滤液减压浓缩得固体化合物(收率23％)，经TLC监测，还有大量的杂质存在，不能有效除去杂质。At room temperature, N,N-dimethylglycine (1.0023 g, 9.7 mmol) was dissolved in 20 mL of methanol, and deuterated iodomethane (0.9 mL, 14.2 mmol) was added, and 10% NaOH was slowly added dropwise to adjust the pH to 10. The reaction was allowed to react at room temperature for 24 hours. The reaction was monitored by TLC until it was complete. The pH of the reaction solution was adjusted to 7 with 10% dilute hydrochloric acid, and the precipitated solid was filtered. The filtrate was concentrated to dryness under reduced pressure, and the solid was 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%). According to TLC monitoring, a large amount of impurities were still present, and the impurities could not be effectively removed.
由对比例一至对比例五可知，预定打浆液的配比或种类不同，反应产率低，或不能有效除去杂质。It can be seen from Comparative Examples 1 to 5 that the ratio or type of the predetermined pulping liquid is different, the reaction yield is low, or the impurities cannot be effectively removed.
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，本领域普通技术人员可以理解实现上述实施例的全部或部分流程，并依本发明权利要求所作的等同变化，仍属于发明所涵盖的范围。The above disclosure is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of the present invention. A person skilled in the art can understand that all or part of the processes of the above embodiments and equivalent changes made according to the claims of the present invention still fall within the scope of the invention.
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