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Method for synthesizing alpha, alpha-dideuterated alcohol and deuterated medicine through reduction deuteration of acyl fluoride compound

A synthesis method and compound technology, applied in the field of reductive deuteration of acyl fluoride compounds, can solve problems such as poor selectivity and poor atom economy

Inactive Publication Date: 2021-08-24
CHINA AGRI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to solve the problems existing in the preparation of α,α-dideuterated alcohols in the prior art, such as the use of flammable reducing agents, poor selectivity, and poor atom economy, the present invention establishes a deuterated reaction based on single electron transfer reduction Reductive deuteration method of fluorine compounds

Method used

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  • Method for synthesizing alpha, alpha-dideuterated alcohol and deuterated medicine through reduction deuteration of acyl fluoride compound
  • Method for synthesizing alpha, alpha-dideuterated alcohol and deuterated medicine through reduction deuteration of acyl fluoride compound
  • Method for synthesizing alpha, alpha-dideuterated alcohol and deuterated medicine through reduction deuteration of acyl fluoride compound

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Experimental program
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Effect test

Embodiment 1

[0039]

[0040] Into a 100mL single-necked round-bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) in tetrahydrofuran (0.100mol / L) 50.0mL, compound 1a 150mg (1.00mmol), heavy water 601mg (30.0mmol). The reaction mixture was stirred at room temperature for 30.0 min, after which time the reaction was quenched by bubbling air. Ethyl acetate and 1.00M hydrochloric acid solution were added for extraction, the organic phase was dried, concentrated, and separated by column chromatography to obtain 131 mg of the target compound 2a with a yield of 95% and a deuteration rate of more than 98%.

[0041] The target product 2a obtained by the above synthesis method was detected by proton nuclear magnetic resonance spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (500MHz, CDCl 3 )δ7.33–7.24(m,2H),7.21–7.16(m,3H),2.71(t,J=7.7Hz,2H),1.88(t,J=7.7Hz,2H),1.43(br,1H ); 13 C{ 1 H}NMR (126MHz, CDCl 3 )δ141.9, 128.5(×2), 125.9, 61.6(m), 34.1,...

Embodiment 2

[0043]

[0044] Into a 50mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) in tetrahydrofuran (0.100mol / L) 15.0mL, compound 1b 54.7mg (0.300mmol), heavy water 180mg (9.00mmol). The reaction mixture was stirred at room temperature for 30.0 min, after which time the reaction was quenched by bubbling air. Ethyl acetate and 1.00M hydrochloric acid solution were added for extraction, the organic phase was dried, concentrated, and separated by column chromatography to obtain 49.5 mg of the target compound 2b, with a yield of 98% and a deuterium substitution rate greater than 98%.

[0045]The target product 2b obtained by the above synthesis method was detected by proton nuclear magnetic resonance spectrum and carbon spectrum, and the test results are as follows: 1 H NMR (500MHz, CDCl 3 )δ7.11(m, 2H), 6.83(m, 2H), 3.78(s, 3H), 2.64(t, J=7.7Hz, 2H), 1.84(t, J=7.7Hz, 2H), 1.70( br,1H); 13 C{ 1 H}NMR (126MHz, CDCl 3 )δ157.8, 133.9,...

Embodiment 3

[0047]

[0048] Into a 50mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) in tetrahydrofuran (0.100mol / L) 15.0mL, compound 1c 49.9mg (0.300mmol), heavy water 180mg (9.00mmol). The reaction mixture was stirred at room temperature for 30.0 min, after which time the reaction was quenched by bubbling air. Ethyl acetate and 1.00M hydrochloric acid solution were added for extraction, the organic phase was dried, concentrated, and separated by column chromatography to obtain 44.8 mg of the target compound 2c with a yield of 98% and a deuterium substitution rate of 98%.

[0049] The target product 2c obtained by the above synthesis method was detected by proton nuclear magnetic resonance spectrum and carbon spectrum, and the test results were as follows: 1 H NMR (500MHz, CDCl 3 )δ7.11–7.07 (m, 4H), 2.66 (t, J = 7.8Hz, 2H), 2.31 (s, 3H), 1.85 (t, J = 7.8Hz, 2H), 1.65 (br, 1H); 13 C{ 1 H}NMR (126MHz, CDCl 3 )δ138.8, 135.4, 129.1, 1...

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Abstract

The invention relates to an alpha, alpha-dideuterated alcohol compound and a reduction deuteration method of an acyl fluoride compound for preparing the alpha, alpha-dideuterated alcohol compound. The acyl fluoride compound as shown in the general formula (1) reacts with a divalent lanthanide transition metal compound and a deuterium donor reagent in an organic solvent I to generate the alpha, alpha-dideuterated alcohol compound as shown in the general formula (2). In order to solve the problems of use of a flammable reducing agent, poor selectivity, poor atom economy and the like in the preparation of alpha, alpha-dideuterated alcohol compounds in the prior art, the invention establishes a single electron transfer reduction deuteration reaction-based acyl fluoride compound reduction deuteration method. The method can be used for preparing the alpha, alpha-dideuterated alcohol compound, and has the advantages of high deuteration rate of the product, good regioselectivity, good chemical selectivity, low reagent price, simplicity in operation, mild conditions and wide substrate application range.

Description

technical field [0001] The present invention relates to α, α-dideuterated alcohols, deuterated medicines and a reduction deuteration method of acyl fluoride compounds used for synthesizing α, α-dideuterated alcohols. Background technique [0002] Deuterated organic compounds are widely used in the fields of life science, material science, instrumental analysis, and organic reaction mechanism research. Due to the kinetic isotope effect (DKIE), the C-D bond is more stable, and the introduction of deuterium into the drug molecule can improve the kinetic characteristics of the drug, reduce metabolic toxicity and enhance the activity of the drug. The research and development of deuterated drugs has gradually become a hot field. Alcohol compounds and their derivatives are important fragments in the synthesis of many active compounds. The synthesis of deuterium-labeled drugs and other active molecules is of great significance for drug metabolism and toxicology research and the de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/147
CPCC07C29/147C07C41/26C07C319/20C07C213/00C07C67/31C07D317/54C07C17/16C07C209/08C07C51/60C07C67/14C07B59/001C07B59/002C07C2603/74C07B2200/05
Inventor 方冰李恒朝彭梦琪宁磊陈星月安杰
Owner CHINA AGRI UNIV
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