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Synthetic method of alpha-monodeuterated alcohol compound and deuterated drug

A synthesis method and compound technology, applied in the field of reductive deuteration of new aldehydes and ketones, can solve the problems of expensive ruthenium catalysts, poor chemoselectivity, and low deuteration rate of products, and achieve small dosage, good chemoselectivity, and deuterium The effect of high generation rate

Inactive Publication Date: 2021-06-11
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 product deuteration rate, poor regioselectivity, poor chemoselectivity, need to use expensive ruthenium catalysts or expensive and flammable metal deuterides in the preparation of α-deuterated alcohol compounds in the prior art, The present invention establishes a method for the reduction deuteration of aldehydes and ketones based on the single electron transfer reduction deuteration reaction for the preparation of α-deuterated alcohols and aldehydes and ketones represented by the general formula (2) , hormones, deuterated derivatives of natural products

Method used

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  • Synthetic method of alpha-monodeuterated alcohol compound and deuterated drug
  • Synthetic method of alpha-monodeuterated alcohol compound and deuterated drug
  • Synthetic method of alpha-monodeuterated alcohol compound and deuterated drug

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Experimental program
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Effect test

Embodiment 1

[0042]

[0043] Add dodiodis in a 25 mL single-mouth round bottom flask under argon protected (SMI) 2 The solution (0.100 mol / L) in tetrahydrofuran (0.100 mol / L) was 7.50 ml, and the compound 1a was 44.5 mg (0.300 mmol), and 150 mg (7.50 mmol) was overwater. The reaction mixture was stirred at room temperature for 15 min, followed by air to quench the reaction. Ethyl acetate was added to 1 M hydrochloric acid solution, and the organic phase was dried, concentrated, and the column chromatography was separated to obtain 44.5 mg of the target compound 2a, the yield was 98%, and the deuterated rate was 98%.

[0044] The target product 2a obtained by the above synthesis method is used to detect the nuclear magnetic resonance spectrum and carbon spectrum detection. The test results are as follows. 1 H NMR (300MHz, CDCL 3 Δ7.31-7.24 (m, 2H), 7.23-7.14 (m, 3H), 2.71 (m, 2H), 1.75 (M, 2H), 1.22 (BR, 1H), 1.22 (S, 3H); 13 C { 1 H} NMR (75MHz, CDCL 3 ) δ142.2, 128.5 (× 2), 125.9, 67.1 ...

Embodiment 2

[0046]

[0047] Add dodiodis in a 25 mL single-mouth round bottom flask under argon protected (SMI) 2 The solution (0.100 mol / L) in tetrahydrofuran (0.100 mol / L) was 7.50 mL, and the compound 1b was 48.7 mg (0.300 mmol), and 150 mg (7.50 mmol) was overwater. The reaction mixture was stirred at room temperature for 15 min, followed by air to quench the reaction. EtOAc.

[0048] The target product 2b obtained by the above synthesis method was used to detect the nuclear magnetic resonance spectrum and carbon spectrum detection, and the test results were as follows: 1 H NMR (300MHz, CDCL 3 Δ7.19-7.09 (m, 4H), 2.75 (D, J = 13.5 Hz, 1H), 2.67-2.58 (M, 3H), 1.57 (Br, 1H), 1.29-1.19 (m, 6H); 13 C { 1 H} NMR (75MHz, CDCL 3 ) δ142.5, 135.7, 129.4, 128.1, 68.5 (t, j C-D = 21.8Hz), 45.4, 28.5, 22.7, 15.6.

Embodiment 3

[0050]

[0051] Add dodiodis in a 25 mL single-mouth round bottom flask under argon protected (SMI) 2 The solution (0.100 mol / L) in tetrahydrofuran (0.100 mol / L) was 7.50 ml, and Compound 1C 63.1 mg (0.300 mmol) was 100 mg (7.50 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by air to quench the reaction. EtOAc.

[0052] The target product 2c obtained by the above synthesis method is used to detect the nuclear magnetic resonance spectrum and carbon spectrum detection, and the test results are as follows: 1 H NMR (300MHz, CDCL 3 Δ7.41-7.14 (m, 10H), 3.79 (S, 1H), 1.69 (S, 1H), 1.17 (S, 3H); 13 C { 1 H} NMR (75MHz, CDCL 3 Δ142.6, 141.6, 128.9, 128.7, 128.7, 128.3, 126.9, 126.6, 69.7 (T, J C-D = 22.0 Hz), 60.6, 21.4.

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Abstract

The invention provides an alpha-monodeuterated alcohol compound and a reduction deuteration method of an aldehyde ketone compound for preparing the alpha-monodeuterated alcohol compound. The aldoketone compound 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 alcohol compound shown in a general formula (2). The invention establishes a reduction deuteration method of an aldehyde ketone compound based on a single electron transfer reduction deuteration reaction, and the method is used for preparing the alpha-monodeuterated alcohol compound shown in a general formula (2) as well as deuterated derivatives of aldehyde ketone drugs, hormones and natural products of the alpha-deuterated alcohol compounds. The method has the advantages of high product deuteration rate, good regioselectivity, good chemical selectivity, low reagent price, simple operation, mild conditions and wide substrate application range. Compared with an existing H / D exchange method, the deuterium donor reagent is small in dosage, the cost can be remarkably reduced, and the utilization rate of deuterium atoms is increased.

Description

Technical field [0001] The present invention relates to a reduction deuteration method for alpha-a deutenol, deuterated drug, and a novel aldone organic matter for synthesizing α-a deutenol. Background technique [0002] The organic compounds of markers in drug metabolism and toxicology, mass spectrometry, new materials development, and organic chemical reaction mechanisms have extensive applications. In particular, in drug development and improvement, due to the kinetic isotope effect (DKIE), the CD button is more stable, which makes the introduction of 氘 in the improvement of pharmacokinetic characteristics, the decrease in metabolism, and the improvement of drug activity. potential. Furthermore, the development of deuterated drugs has become a hot field (J. MED.CHEM.2019, 62, 5276-5297). During the pharmaceutical metabolism, the chiral center of the chiral center contains an acid-based drug molecule is prone to configuration conversion and racemation, resulting in an increase ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C29/145C07C41/26C07C51/367C07C67/31C07C253/30C07C33/20C07C33/24C07C33/46C07C31/125C07C35/32C07C35/20C07C35/37C07C31/137C07C69/675C07C69/757C07C255/53C07C43/23C07C59/54C07C33/025C07C31/135C07C33/44C07D473/10C07J1/00C07J7/00C07D335/02
CPCC07C29/145C07C41/26C07C51/367C07C67/31C07C253/30C07D473/10C07J1/0022C07J7/007C07D335/02C07B59/001C07B59/002C07B59/007C07B2200/05C07C2601/14C07C2601/16C07C2601/08C07C2601/18C07C2602/08C07C2603/74
Inventor 安杰李恒朝彭梦琪宁磊赖泽敏
Owner CHINA AGRI UNIV
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