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Method for introducing gamma-deuteration into carbonyl compound
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A carbonyl compound and compound technology, applied in the field of molecular labeling, can solve the problems of high reaction temperature, poor regioselectivity of deuterium substitution, limited wide application, etc., and achieves good functional group tolerance, wide range of substrate selection, and reaction conditions. simple effect
Pending Publication Date: 2022-08-02
SHANGHAI JIAO TONG UNIV
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However, although the acid / base catalyzed hydrogenisotope exchange process can selectively deuterium replace the acidic or basic C–H bonds in the molecule, it usually requires a higher reaction temperature, which is likely to destroy or affect other sensitive components in the reaction substrate. Functional group; the main disadvantage of transition metalcatalysis is that the regioselectivity of deuterium substitution is not good and the deuterium substitution rate of different substrates is unstable, which limits its wide application in organic synthetic chemistry, and, in the specific position of the carbon chain Selective introduction of deuterium, still challenging and practical
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Embodiment 1
[0028]
[0029] Use 0.5mmol styrene, 1.5mmol benzyl thioglycolate, PPh according to the general operation procedure 3 (4.0 equiv.), DTBP (4.5 equiv.), and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V=2:1). After the reaction was completed, 115 mg of colorless liquid was obtained after treatment and purification, which was the product with a yield of 90% and a deuteration rate of 85%. NMR and mass spectrometry data: 1 H NMR (400MHz, CDCl 3 )δ7.43-7.29(m, 5H), 7.29-7.21(m, 2H), 7.21-7.08(m, 3H), 5.10(s, 2H), 2.70-2.56(m, 1H), 2.37(t, J=7.5 Hz, 2H), 2.03-1.90 (m, 2H). 13 C NMR (101MHz, CDCl 3 )δ173.3,141.3,136.1, 128.6,128.5,128.4,128.2,126.0,66.2,34.7(t,J=19.4Hz),33.6,26.4.HRMS (ESI)([M+H] + )Calcd.for C 17 H 17 DO 2 :256.1442;found:256.1444.
Embodiment 2
[0031]
[0032] Use 0.5mmol styrene, 1.5mmol benzyl thioglycolate, PPh according to the general operation procedure 3 (3.0 equiv.), DTBP (4.0 equiv.), and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V=2:1). After the reaction was completed, 93 mg of colorless liquid was obtained after treatment and purification, which was the product, with a yield of 73% and a deuteration rate of 86%. The NMR data were consistent with Example 1.
Embodiment 3
[0034]
[0035] Use 0.5mmol styrene, 1.0mmol benzyl thioglycolate, PPh according to the general operation procedure 3 (4.0 equiv.), DTBP (4.5 equiv.), and the reaction solvent was a mixed solvent of ethyl acetate and deuterium water (6 mL, V:V=2:1). After the reaction, 79 mg of colorless liquid was obtained after treatment and purification, which was the product, the yield was 62%, and the deuteration rate was 88%. The NMR data were consistent with Example 1.
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Abstract
The invention provides a method for introducing gamma-deuteration into a carbonyl compound, which comprises the following steps: dissolving an olefin compound and an alpha-carbonyl thiol compound in a mixed solvent of an organic solvent and deuterium water to obtain a mixed solution; adding a phosphinereagent and a free radical initiator into the mixed solution, and reacting under an illumination condition, so as to convert the substrate into the corresponding gamma-deuterated carbonyl compound. The method for introducing the deuteration has the characteristics of high deuteration efficiency, good selectivity, good functional group tolerance, high yield, mild reaction conditions, no need of metal participating in the reaction and wide substrate range, and is particularly suitable for selectively introducing the deuteration at a specific position of a carbon chain.
Description
technical field [0001] The present invention relates to the technical field of molecular labeling, in particular, to a method for introducing γ-deuterium into carbonyl compounds. Background technique [0002] As an important labeling method, deuterium has important applications in drugmetabolism, new reaction mechanism research, nuclear magnetic resonance, mass spectrometry and other research. The introduction of deuterium at the appropriate position of the drug molecule can greatly alter the metabolism and pharmacokinetic properties of the drug. In 2017, the FDA approved the first deuterated drug, deutetrabenazine, which greatly facilitated the research on deuterated drugs and the development of deuterated methods. [0003] The traditional synthesis of deuterium-substituted compounds often uses a hydrogenisotope exchange strategy. The deuterium isotope is introduced into the compound in a single step without re-synthesis. It has advantages in terms of atom and step econo...
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