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Alpha-monodeuterated amine compound, deuterated medicine and preparation method of same

A compound and synthetic method technology, applied in the preparation of organic compounds, aminohydroxy compounds, steroids, etc., can solve the problems of expensive reagents, poor regioselectivity, poor chemoselectivity, etc.

Active Publication Date: 2021-05-28
CHINA AGRI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In order to solve the defects of low deuteration rate, poor regioselectivity, poor chemoselectivity and expensive reagents in the preparation of α-deuterated amine compounds in the prior art, the present invention establishes a deuteration reaction based on single electron transfer reduction The reduction deuteration method of the oxime compound is used to prepare the α-deuterated amine compound as shown in the general formula (2), and synthesizes the deuterated pesticide molecule tebufenpyrad with it as a synthetic building block

Method used

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  • Alpha-monodeuterated amine compound, deuterated medicine and preparation method of same
  • Alpha-monodeuterated amine compound, deuterated medicine and preparation method of same
  • Alpha-monodeuterated amine compound, deuterated medicine and preparation method of same

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Experimental program
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Effect test

Embodiment 1

[0044]

[0045] Into a 25 mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) solution (0.1mol / L) in tetrahydrofuran (0.1mol / L) 10mL, add heavy water 160mg (8.00mmol), compound 1a (32.6mg, 0.200mmol), and stir vigorously. The reaction mixture was stirred at room temperature for 15 min, after which time the reaction was quenched by bubbling air. Add ethyl acetate and 1mol / L sodium hydroxide solution for extraction, dry and concentrate the organic phase, add cyclopentyl methyl ether hydrochloride solution (3.0mol / L) to obtain 36.6 mg of the hydrochloride salt of target compound 2a, yield 98% , deuterium rate 96%.

[0046] 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 were as follows: 1 H NMR (300MHz, CDCl 3 )δ8.41(br,3H),7.28–7.14(m,5H),2.75(t,J=7.9Hz,2H),2.15(m,1H),1.92(m,1H),1.41(s,3H ); 13 C{ 1 H}NMR (75MHz, ...

Embodiment 2

[0048]

[0049] Into a 25 mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) in tetrahydrofuran (0.1mol / L) 14mL, add heavy water 224mg (11.2mmol), compound 1b (33.4mg, 0.200mmol), and stir vigorously. The reaction mixture was stirred at room temperature for 15 min, after which time the reaction was quenched by bubbling air. Add ethyl acetate and 1mol / L sodium hydroxide solution for extraction, dry and concentrate the organic phase, add cyclopentyl methyl ether hydrochloride solution (3.0mol / L) to obtain 32.4mg of the hydrochloride salt of target compound 2b, yield 85% , deuterium rate 96%.

[0050] 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 (300MHz, DMSO-d 6 )δ8.25(br,3H),7.29(m,2H),7.15(m,2H),3.03(d,J=13.3Hz, 1H),2.67(d,J=13.3Hz,1H),1.10( s,3H); 13 C{ 1 H}NMR (75MHz, DMSO-d 6 )δ16...

Embodiment 3

[0052]

[0053] Into a 25 mL single-necked round bottom flask under the protection of argon, add samarium diiodide (SmI 2 ) in tetrahydrofuran (0.1mol / L) 10mL, add heavy water 160mg (8.00mmol), compound 1c (36.7mg, 0.200mmol), and stir vigorously. The reaction mixture was stirred at room temperature for 15 min, after which time the reaction was quenched by bubbling air. Add ethyl acetate and 1mol / L sodium hydroxide solution for extraction, dry and concentrate the organic phase, add cyclopentyl methyl ether hydrochloride solution (3.0mol / L) to obtain 35.2mg of the hydrochloride salt of the target compound 2c, yield 85% , deuterium rate 96%.

[0054] 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 are as follows: 1 H NMR (300MHz, DMSO-d 6 )δ8.29(br,3H),7.38(m,2H),7.28(m,2H),3.05(d,J=13.3Hz,1H),2.69(d,J=13.3Hz,1H),1.10( s,3H); 13 C{ 1 H}NMR (75MHz, DMSO-d 6 )...

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Abstract

The invention relates to an alpha-monodeuterated amine compound and a reduction deuteration method of an oxime compound for preparing the alpha-monodeuterated amine compound. The method is characterized in that an oxime compound as shown in a 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-monodeuterated amine compound as shown in a general formula (2), optionally, the compound shown in the general formula (2) is added into an organic acid and / or inorganic acid-organic solvent solution to obtain the ammonium salt shown in the general formula (2). The invention overcomes the defects that the preparation method of the alpha-monodeuterated amine compound in the prior art needs to adopt an expensive and highly toxic transition metal catalyst or an expensive and flammable metal deuteride and generates toxic by-products.

Description

technical field [0001] The invention relates to α-deuterated amine, deuterated medicine and a method for reducing deuterated oxime compound used for synthesizing α-deuterated amine compound. Background technique [0002] In scientific research, deuterated organic compounds are currently widely used as biological probes, internal standards for mass spectrometry, and to study chemical reaction mechanisms (Angew. Chem., Int. Ed. 2018, 57, 1758–1784). In addition, deuterium-labeled drugs and active molecules are more stable due to the deuterium kinetic isotope effect (DKIE), which has great potential in improving pharmacokinetic characteristics, reducing metabolic toxicity, and enhancing drug activity. This makes the development of deuterated drugs a recent hot field (J. Med. Chem. 2019, 62, 5276-5297). In the process of drug metabolism, the chiral center of the drug molecule containing acidic protons is prone to configuration conversion and racemization, resulting in weakened ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/40C07C211/27C07C211/29C07C211/07C07C211/19C07C211/38C07C211/42C07C213/02C07C217/58C07C217/62C07C253/30C07C255/58C07D231/16C07D279/20C07J41/00
CPCC07B59/001C07B59/002C07B59/007C07C209/40C07C213/02C07C253/30C07J41/0088C07D231/16C07D279/20C07B2200/05C07C2602/08C07C2602/10C07C2603/74C07C211/27C07C211/29C07C211/07C07C211/19C07C211/38C07C211/42C07C217/58C07C217/62C07C255/58
Inventor 安杰宁磊马媛李恒朝
Owner CHINA AGRI UNIV
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