CN114933516A - Method for synthesizing deuterated compound in ionic liquid medium - Google Patents
Method for synthesizing deuterated compound in ionic liquid medium Download PDFInfo
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- CN114933516A CN114933516A CN202210685307.4A CN202210685307A CN114933516A CN 114933516 A CN114933516 A CN 114933516A CN 202210685307 A CN202210685307 A CN 202210685307A CN 114933516 A CN114933516 A CN 114933516A
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- compound
- deuterium
- ionic liquid
- bmim
- boric acid
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 38
- 239000002608 ionic liquid Substances 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 46
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 44
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004327 boric acid Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 12
- -1 ketone compound Chemical class 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 3
- WJGNDSKDYFZIRF-UHFFFAOYSA-L 1-butyl-3-methylimidazol-3-ium trifluoromethanesulfonate Chemical compound S(=O)(=O)(C(F)(F)F)[O-].FC(S(=O)(=O)[O-])(F)F.C(CCC)[N+]1=CN(C=C1)C.C(CCC)[N+]1=CN(C=C1)C WJGNDSKDYFZIRF-UHFFFAOYSA-L 0.000 claims description 2
- XFYRJHANHCHCTK-HMTLIYDFSA-N BF 6 Chemical compound O([C@@H](CC(=O)C=1C(O)=C(C=2OC3=C4C(C(C)(C)C(=O)C3(C)C)=O)C)C=3C=CC=CC=3)C=1C=2C4C1=CC=CC=C1 XFYRJHANHCHCTK-HMTLIYDFSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 claims description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000003814 drug Substances 0.000 description 8
- 238000006467 substitution reaction Methods 0.000 description 8
- 238000010183 spectrum analysis Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- LUZDYPLAQQGJEA-UHFFFAOYSA-N 2-Methoxynaphthalene Chemical compound C1=CC=CC2=CC(OC)=CC=C21 LUZDYPLAQQGJEA-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- LUZDYPLAQQGJEA-BNEYPBHNSA-N 1-deuterio-2-methoxynaphthalene Chemical compound C1=CC=C2C([2H])=C(OC)C=CC2=C1 LUZDYPLAQQGJEA-BNEYPBHNSA-N 0.000 description 1
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical compound N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- PKIMEAAUKQKNFH-UHFFFAOYSA-N C1=CC=C2NC([CH2+])=CC2=C1 Chemical compound C1=CC=C2NC([CH2+])=CC2=C1 PKIMEAAUKQKNFH-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000005619 boric acid group Chemical group 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 230000005445 isotope effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- 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
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- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- 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
- C07B59/007—Steroids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07—ORGANIC CHEMISTRY
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- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
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Abstract
The invention discloses a method for synthesizing a deuterated compound in an ionic liquid medium, which comprises the following steps: deuterium water is used as a deuterium source, and the compound and boric acid are heated and reacted in an ionic liquid solvent under the air to obtain a compound with hydrogen and deuterium exchanged at corresponding sites. The invention takes deuterium water which is relatively cheap and easy to obtain as a deuterium source and takes [ bmim]PF 6 The ionic liquid is a solvent, and the exchange of hydrogen and deuterium of the compound is realized in one step under the condition that boric acid is used as an additive. The method has the advantages of mild conditions, high atom economy, environmental protection and the like, and has good theoretical value and application prospect.
Description
Technical Field
The invention relates to organic synthesis, in particular to a method for synthesizing a deuterated compound in an ionic liquid medium.
Background
Deuterium labeled compounds are important compounds that are widely used in the fields of medicine and chemistry, etc. The method can be used for simplifying nuclear magnetic resonance hydrogen spectroscopy, can also be used as a standard substance for mass spectrometry, and is widely applied to analysis of high-order structures such as organic compound structures, protein polypeptides and the like. Meanwhile, in the research of medicines, experiments prove that the deuterium labeled compound can influence the pharmacokinetic characteristics of the medicines, so that the deuterium labeled compound can be used as a favorable tool for improving the absorption, distribution, metabolism and excretion of the medicines. Deuterium labeled compounds have great potential in pharmacokinetics since the first deuterium drug (deutetrabenzine) was approved in 2017, after which various deuterium drugs were subsequently released in advanced clinical stages. In addition, in the field of organic chemistry, kinetic isotope effects of deuterium can be used to elucidate the mechanism of the reaction. In addition, deuterium labeled compounds are widely used in the fields of agriculture, environment, medicine, polymer materials and the like. At present, a plurality of methods for synthesizing deuterium labeled compounds are available, but most of the methods need to remove other functional groups such as halogen, boric acid and the like, and often need to rely on the catalysis of transition metals and have harsh reaction conditions. Although the hydrogen-deuterium exchange reaction has the advantages of no change of the original structure, atom economy and the like, the selectivity of the deuterated sites is generally difficult to control by the method.
The methods currently available in the literature by synthesis of deuterated compounds include:
zinc is used as a catalyst to catalyze alkyl halide to prepare a deuterated compound by using deuterium water as a deuterium source. (Liu, Z.Chen, C.Su, X.ZHao, Q.Gao, G.H.Ning, H.Zhu, W.Tang, K.Leng, W.Fu, B.Tian, X.Peng, J.Li, Q.H.xu, W.Zhou and K.P.Loh, nat.Commun, 2018,9,80.)
Brookfield acid as catalyst with C 6 D 6 As a source of deuterium to catalyze aryl compounds to produce deuterated compounds. (X.Liang, S.Duttwyler, Asian J.org.chem.,2017,6, 1063-
As can be seen from the above examples, the occurrence of such reactions depends on the use of transition metal catalysts such as zinc and palladium, which inevitably causes heavy metal residues in practical production, especially in the process of synthesizing drugs. In addition, the literature reports that the exchange of hydrogen and deuterium is not selective at the deuterium position.
Disclosure of Invention
In order to solve the technical problems that the existing compound has harsh reaction conditions in the deuteration process, depends on an expensive transition metal catalyst and the like, the invention aims to provide a method for synthesizing a deuterated compound in an ionic liquid medium, avoids the use of high temperature and transition metal, reduces pollution, saves cost, synthesizes the deuterated compound at a specific site in a high-selectivity mode, realizes high-selectivity deuterium exchange of the compound, and is more efficient and environment-friendly.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a method for synthesizing a deuterated compound in an ionic liquid medium comprising the steps of: taking deuterium water as a deuterium source, and heating and reacting the compound and boric acid in an ionic liquid solvent under the air to obtain a compound with hydrogen and deuterium exchange at a corresponding site.
The synthesis method specifically comprises the following steps: in an ionic liquid solvent solution containing a compound and boric acid, deuterium water is used as a deuterium source, and the reaction temperature is 50-100 ℃ and the reaction time is 2-8 hours under the stirring condition; after the reaction is finished, a crude product is obtained, and then the crude product is purified by a column chromatography method to obtain a target deuterated product.
The present invention is directed to a method for preparing a compound of the present invention]PF 6 Reacting in ionic liquid solution at 70 ℃ for about 6 hours under the condition of stirring, obtaining a crude product after the reaction is completed, and purifying by using a column chromatography method to obtain a target product.
The specific synthetic route involved in the reaction is shown below:
boron spectrum by nuclear magnetic resonance shows that [ bmim ] in the ionic liquid]PF 6 The fluoride anion in (b) combines with the boronic acid to produce BF x (OH) 4-x Anion substances generate an acidic environment and simultaneously realize hydrogen and deuterium exchange of selected sites of the compound, and the method realizes the synthesis of the deuterated compound simply and efficiently by one-step reaction.
One of the preferable technical solutions is: the ionic liquid solvent is [ bmim]BF 6 ，[bmim]OTf，[bmim]PF 6 ，[bmim]NTf 2 Etc., more preferably [ bmim ]]PF 6 An ionic liquid.
One of the preferable technical solutions is: the reaction temperature is 50-100 ℃, and the reaction time is 2-8 hours; more preferably, the reaction temperature is 70 ℃ and the reaction time is 6 to 10 hours.
One of the preferable technical solutions is: the molar ratio of the compound to the boric acid to the deuterium oxide solution is 1:0.2:20-1:2:20, and more preferably 1:1: 20.
The compound can be prepared by hydrogen deuterium exchange reaction in one step.
The compound type is shown as a formula I, and the boric acid structure is shown as a formula II:
wherein, the formula I contains electron-rich aromatic hydrocarbon, indole nitrogen-containing heteroaromatic hydrocarbon, olefin and ketone compounds.
Compared with the prior art, the invention has the following advantages:
1. the use of transition metal is avoided, the cost is reduced, and heavy metal residue is not caused in the reaction process. 2. The selective site deuterated compound is synthesized by one step of reaction, and the reaction is efficient and rapid. 3. The method uses a cheap and easily-obtained deuterium source, has mild reaction conditions and simple operation, and has good application prospect. Therefore, the invention has higher theoretical innovation value and implementation value.
The specific implementation mode is as follows:
example 1
Taking deuterium water as a deuterium source, and heating and reacting the compound and boric acid in an ionic liquid solvent under the air to obtain a compound with hydrogen and deuterium exchange at a corresponding site. The method comprises the following specific steps:
2-methoxynaphthalene-1-d(2a)：
2-Methaxynephthalene (1a, 0.3mmol), boric acid (0.3mmol), D 2 The three starting materials O (6mmol) were dissolved in [ bmim ] in the above ratio 1:1:20]PF 6 (0.2mL), a reaction system was formed. The system reacts in the air, after the reaction is completed by stirring for 6 hours at 70 ℃, the solvent is evaporated out to obtain a crude product, and then the crude product is purified by a column chromatography method to obtain the target product with the yield of 94 percent. Deuterium substitution rate: 94 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.84–7.79(m,3H),7.50–7.49(m,1H),7.42–7.41(m,1H),7.23–7.21(m,1H),3.97(s,1H). 13 C NMR(100MHz,CDCl 3 ):δ＝157.61,134.57,129.42,129.01,127.71,126.73,126.41,123.63,118.76,105.53(t,J＝24Hz),55.32.
example 2
1,6-dimethoxynaphthalene-2,4,5-d 3 (2b)：
1, 6-dimethoxynaphalene shown in a structural formula 1b is used for replacing 2-dimethoxynaphalene shown in a structural formula 1a in example 1, and the three raw materials are dissolved in [ bmim ] in a ratio of 1:0.2:20]PF 6 (0.2mL), a reaction system was formed. The remaining procedure was as in example 1, yield: and 90 percent. Deuterium substitution rate: d 1 ：92％,D 2 ：95％,D 3 : 90 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝8.24(d,J＝9.2Hz,1H),7.40(s,1H),7.19(d,J＝9.2Hz,1H),7.15(d,J＝2.5Hz,1H),6.73–6.71(m,0.08H),4.01(s,3H),3.94(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ＝158.16,155.70,135.86,126.64,126.61,126.51,123.77,120.84,118.95(t,J＝24Hz),117.57,105.47(t,J＝24Hz),101.82(t,J＝24Hz),55.46,55.27.HRMS(EI)m/z:(M)+Calc.for:C 12 H 9 D 3 O 2 + ,191.1020,Found 191.1022.
example 3
(S)-2-(6-methoxynaphthalen-2-yl-5-d)propanoic acid(2c)：
(R) -2- (6-methoxynhahalen-2-yl) propanoic acid shown in the structural formula 1c is used instead of 2-methoxynhahalene shown in the structural formula 1a in example 1, and the three raw materials are dissolved in the ratio of 1:0.6:20 in the [ bmim [, [ bmim ] ]]PF 6 (0.2mL), a reaction system was formed. The remaining procedure was as in example 1, yield: 91 percent. Deuterium substitution rate: 50 percent. Product spectral analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.74–7.71(m,3H),7.46–7.43m,1H),7.18–7.13(m,1.5H),4.01–3.80(m,4H),1.62(d,J＝7.1Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ＝180.71,157.73,157.68,134.91,133.84,133.78,129.33,128.92,127.25,127.20,126.22,126.17,119.05,105.64,55.32,45.30,18.16.
example 4
N-(2-(7-methoxynaphthalen-1-yl-8-d)ethyl)acetamide(2d)：
The 2-methoxylphthalene shown in the structural formula 1a in example 1 is replaced by N- (2- (7-methoxylphthalen-1-yl) ethyl) acetamide shown in the structural formula 1d, and the three raw materials are dissolved in the ratio of 1:1.2:20 in the [ bmim [, the mixture is then dissolved in the solvent]PF 6 (0.2mL), a reaction system was formed. The remaining procedure was as in example 1, yield: and 76 percent. Deuterium substitution rate: 94 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.77–7.70(m,1H),7.68–7.67(m,1H),7.47–7.46(m,0.06H),7.28–7.26(m,2H),7.18–7.15(m,1H),5.62(br,1H),3.99(s,3H),3.61(t,J＝7.3Hz,2H),3.25(t,J＝7.3Hz,2H),1.95(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ＝170.35,157.96,133.61,133.17,130.24,129.30,127.12,127.08,123.16,118.43,55.55,40.14,33.23,23.41.HRMS(EI)m/z:(M)+Calc.for:C 15 H 16 DNO 2 + ,244.1326,Found 244.1322.
example 5
d 2 -dehydroepiandrosterone(2e)：
The 2-methoxynaphthalene of formula 1a in example 1 was replaced with dehydroepisteristerone of formula 1e, and the three materials were dissolved in a ratio of 1:1.8:20 in [ bmim [ ]]PF 6 (0.2mL), a reaction system was formed. The remaining procedure was as in example 1, yield: 54 percent. Deuterium substitution rate: 80 percent. Product spectrumAnd (3) analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝5.37–5.30(m,1H),3.53–3.51(m,1H),2.44–2.43(m,0.4H),2.36–2.18(m,2H),2.14–2.00(m,2H),1.93(dd,J＝12.3,5.8Hz,1H),1.89–1.78(m,3H),1.67(dt,J＝13.7,6.3Hz,3H),1.58–1.40(m,3H),1.33–1.19(m,2H),1.14–0.95(m,5H),0.88(s,3H). 13 C NMR(100MHz,CDCl 3 ):δ＝141.10,120.83,71.48,51.75,50.23,47.55,42.17,37.19,36.64,35.49,31.53,31.50,31.42,30.77,21.76,21.67,20.35,19.42,13.53,13.51.
example 6
(ethene-1,1-diyl-2,2-d 2 )dibenzene(2f)：
The ethene-1, 1-diyldibezene shown in the structural formula 1f is used to replace the 2-methoxynaphthalene shown in the structural formula 1a in the example 1, and the three raw materials are dissolved in the [ bmim ] in the ratio of 1:2:20]PF 6 (0.2mL), a reaction system was formed. The remaining procedure was as in example 1, yield: 74 percent. Deuterium substitution rate: 90 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.42–7.38(m,10H),5.51(s,0.20H). 13 CNMR(100MHz,CDCl 3 ):δ＝149.97,141.51,128.31,128.21,127.74,114.02,113.80.
example 7
2-(methyl-d 3 )-1H-indole-4,5,6,7-d 4 (2g)：
The same procedure as in example 1 was carried out except that (1H-indol-2-yl) methylium represented by the formula 1g was used instead of 2-methoxynhaththalene represented by the formula 1a in example 1, in terms of yield: 88 percent. Deuterium substitution rate: d 1 ：84％,D 2 ：40％,D 3 ：23％,D 4 : 70 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.81(br,1H),7.52–7.50(m,0.60H),7.28–7.24(m,0.77H),7.12–7.04(m,0.60H),6.22(d,J＝1.4Hz,1H),2.45–2.36(m,0.47H). 13 C NMR(100MHz,CDCl 3 ):δ＝136.10,135.05,129.11,120.84,119.66,119.55,110.17,100.40,13.19(m).HRMS(EI)m/z:(M)+Calc.for:C 9 H 2 D 7 N + ,138.1169,Found 138.1155.
example 8
2,3,4,9-tetrahydro-1H-carbazole-1,1,5,6,7,8-d 6 (2h)：
The same procedure as in example 1 was carried out except that 2,3,4,9-tetrahydro-1H-carbazole of the formula 1H was used instead of 2-methoxynapthalene of the formula 1a in example 1, in the same manner as in example 1, except that the yield: 91 percent. Deuterium substitution rate: d 1 ：50％,D 2 ：95％,D 3 ：50％,D 4 : 86 percent. Product spectrum analysis: 1 H NMR(400MHz,CDCl 3 ):δ＝7.50–7.44(m,4H),7.41–7.31(m,2H),7.15(t,J＝5.3Hz,2H),7.09(d,J＝8.3Hz,2H),7.02–6.95(m,2H),3.92(d,J＝2.9Hz,3H),2.42(s,3H). 13 C NMR(101MHz, 13 C NMR(100MHz,CDCl 3 ):δ＝160.11,145.20,133.00,132.62,131.47,131.07,129.35,128.99,127.61,127.34,122.24,113.05,55.29,21.68. 1 H NMR(400MHz,CDCl 3 ):δ＝7.57(s,1H),7.30(s,0.5H),7.23–7.16(m,0.28H),2.87–2.63(m,3H),2.06–1.87(m,4H). 13 C NMR(100MHz,CDCl 3 ):δ＝135.73,134.17,127.79,120.87,118.88,117.66,110.36,110.11,23.36,23.29,23.26,23.19,22.91(t,J＝20Hz),21.01.HRMS(EI)m/z:(M)+Calc.for:C 12 H 7 D 6 N + ,177.1419,Found177.1406.
it should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (8)
1. A method for synthesizing a deuterated compound in an ionic liquid medium, comprising the steps of: taking deuterium water as a deuterium source, and heating and reacting the compound and boric acid in an ionic liquid solvent under the air to obtain a compound with hydrogen and deuterium exchange at a corresponding site.
2. The method of claim 1, wherein the method comprises: in an ionic liquid solvent solution containing a compound and boric acid, deuterium water is used as a deuterium source, and the reaction temperature is 50-100 ℃ and the reaction time is 2-8 hours under the stirring condition; after the reaction is finished, a crude product is obtained, and then the crude product is purified by a column chromatography method to obtain a target deuterated product.
3. The method of claim 2, wherein the compound comprises an electron-rich aromatic hydrocarbon, an indole-azaaromatic hydrocarbon, an olefin, or a ketone compound.
4. The method for synthesizing deuterated compounds in ionic liquid media according to claim 2 wherein the ionic liquid solvent is [ bmim [ ]]BF 6 、[bmim]OTf、[bmim]PF 6 Or [ bmim]NTf 2 A solvent.
5. The method of claim 2, wherein the reaction temperature is 70 ℃ and the reaction time is 6-8 hours.
6. The method of claim 2, wherein the molar ratio of the compound to the boric acid to the deuterium oxide is 1:0.2:20 to 1:2: 20.
7. The method of claim 6, wherein the molar ratio of the compound to the boric acid to the deuterium oxide is 1:1: 20.
8. The method of claim 2, wherein the compound is of the type shown in formula I, and the boronic acid is of the formula II:
wherein, the formula I contains electron-rich arene, indole nitrogen-containing arene, olefin and ketone compounds.
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| CN1887829A (en) * | 2006-06-23 | 2007-01-03 | 郭启勇 | Synthesis process of 18F lebeled positive electron radioactive tracer with ionic liquid as phase transfer catalyst |
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| CN114213206A (en) * | 2021-12-30 | 2022-03-22 | 华东理工大学 | Preparation method of alpha-deuterated enal |
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| US20070276042A1 (en) * | 2006-05-26 | 2007-11-29 | Auspex Pharmaceuticals, Inc. | Preparation and utility of substituted carboxylic acid compounds |
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| EP3892602A1 (en) * | 2020-04-08 | 2021-10-13 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Method for the preparation of deuterated or tritiated compounds |
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