A kind of preparation method of nickel-catalyzed α-deuterated chiral sulfonamide compound

A technology for sulfonamides and compounds, which is applied in the field of preparation of α-deuterated chiral sulfonamide compounds, can solve the problems of small reaction scale and range, high price, low selectivity, etc., and save experimental steps and costs, and catalyst consumption Low, high enantioselectivity effect

Active Publication Date: 2022-04-15
SHANDONG NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After research by the inventors of the present invention, it has been found that the existing problems in the preparation of chiral amine compounds by transition metal-catalyzed transfer deuteration reaction are as follows: (1) generally only one model reaction is done, mainly for the purpose of studying the reaction mechanism, reaction scale and scope Generally smaller; (2) most of the catalysts adopted are based on expensive and highly toxic precious metals, such as ruthenium, rhodium, palladium and iridium, etc., but based on abundant and environmentally friendly cheap metal catalysts are very few; ( 3) The deuterium source is not ideal. Deuterium gas is expensive and requires high-pressure steel cylinders for storage and transportation. It is flammable and explosive when used, and the risk factor is high
At the same time, in the preparation process of the deuterated reagent, there are also the following defects: when using deuterated formic acid, on the one hand, the reaction intermediate metal-negative deuterium [M-D] is easy to exchange with the hydrogen in the solvent or reagent in the system to form metal-negative deuterium [M-D]. Hydrogen [M-H], resulting in a low deuteration rate in the product. On the other hand, ketimine has tautomerism between imine and enamine under acidic conditions, so the hydrogen at the β position is also easily deuterated, and formic acid reacts Afterwards, carbon dioxide will be released, and the acidity of formic acid will also cause corrosion and other damage to the reaction vessel.
Deuterated water is the most ideal reagent, but there are not many reactions that can use deuterated water, and the selectivity is not high, and deuterated at multiple positions in the molecule

Method used

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  • A kind of preparation method of nickel-catalyzed α-deuterated chiral sulfonamide compound
  • A kind of preparation method of nickel-catalyzed α-deuterated chiral sulfonamide compound
  • A kind of preparation method of nickel-catalyzed α-deuterated chiral sulfonamide compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation of (R)-N-tosyl-1-phenyl-1-d-ethylamine (2a)

[0053]

[0054] Under nitrogen protection, add Ni(OTf) into a 10mL Schlenk reaction tube 2 (0.72mg, 0.002mmol), (S)-Binapine (1.84mg, 0.0025mmol), Molecular sieves (50 mg) and isopropanol-d8 (0.3 mL), stirred for 10 minutes, added sulfonylimide 1a (27.4 mg, 0.1 mmol). The reaction tube was sealed and heated in an oil bath at 60°C for 24 hours. After the reaction stopped, cool down, the distillation device recovered the solvent, the residue was added to a silica gel column, and eluted with petroleum ether and ethyl acetate (volume ratio 10:1) to obtain pure (R)-N-p-toluenesulfonyl-1- Phenyl-1-d-ethylamine (2a), yield 99%, enantiomeric excess (ee) 94%, deuterated rate>98%. NMR, HPLC, and high-resolution mass spectrometry data are as follows:

[0055] 1 H NMR (400MHz, CDCl 3 ): δ7.61(d, J=8.3Hz, 2H), 7.19-7.16(m, 5H), 7.11-7.08(m, 2H), 5.06(s, 1H, NH), 4.45(pseudopentet, J=7.1 Hz, 0.02H), 2.38(...

Embodiment 2

[0059] Example 2: Preparation of (R)-N-p-toluenesulfonyl-1-(3-methylphenyl)-1-d-ethylamine (2b)

[0060]

[0061] Under nitrogen protection, add Ni(OTf) into a 10mL Schlenk reaction tube 2 (0.72mg, 0.002mmol), (S)-Binapine (1.84mg, 0.0025mmol), Molecular sieves (5 mg) and isopropanol-d8 (0.3 mL), stirred for 10 minutes, added sulfonylimide 1b (28.8 mg, 0.1 mmol). The reaction tube was sealed and heated in an oil bath at 60°C for 24 hours. After the reaction stopped, cool down, the distillation device recovered the solvent, the residue was added to a silica gel column, and eluted with petroleum ether and ethyl acetate (volume ratio 10:1) to obtain pure (R)-N-p-toluenesulfonyl-1- (3-methylphenyl)-1-d-ethylamine (2b), yield 99%, enantiomeric excess (ee) 93%, deuteration rate 98%. NMR, HPLC, and high-resolution mass spectrometry data are as follows:

[0062] 1 H NMR (400MHz, CDCl 3 ): δ7.60(d, J=8.3Hz, 2H), 7.16(d, J=8.1Hz, 2H), 7.08(t, J=7.6Hz, 1H), 6.96(d, J=7.5Hz, 1H ...

Embodiment 3

[0066] Example 3: Preparation of (R)-N-p-toluenesulfonyl-1-(4-fluorophenyl)-1-d-ethylamine (2c)

[0067]

[0068] Under nitrogen protection, add Ni(OTf) into a 10mL Schlenk reaction tube 2 (0.72mg, 0.002mmol), (S)-Binapine (1.84mg, 0.0025mmol), Molecular sieves (5 mg) and isopropanol-d8 (0.3 mL), stirred for 10 minutes, and sulfonylimide 1c (29.2 mg, 0.1 mmol) was added. The reaction tube was sealed and heated in an oil bath at 60°C for 24 hours. After the reaction stopped, cool down, the distillation device recovered the solvent, the residue was added to a silica gel column, and eluted with petroleum ether and ethyl acetate (volume ratio 10:1) to obtain pure (R)-N-p-toluenesulfonyl-1- (4-fluorophenyl)-1-d-ethylamine (2c), yield 99%, enantiomeric excess (ee) 93%, deuteration rate 97%. NMR, HPLC, and high-resolution mass spectrometry data are as follows:

[0069] 1 H NMR (400MHz, CDCl 3): δ7.59(d, J=8.2Hz, 2H), 7.18(d, J=8.0Hz, 2H), 7.11-7.01(m, 2H), 6.85(m, 2H), 5.22...

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Abstract

The invention discloses a method for preparing a nickel-catalyzed α-deuterated chiral sulfonamide compound. Under an inert atmosphere, a chiral complex is used as a catalyst, and a deuterated alcohol is used as a deuterium source and a solvent. Under ℃, N-sulfonyl imine undergoes asymmetric transfer deuteration reaction to obtain α-deuterated chiral sulfonamide compound; the chemical structural formula of N-sulfonyl imine is: α-deuterated chiral sulfonamide compound The chemical structural formula is: where, R 1 , R 2 , R 3 from C 1 -C 6 Alkyl, aryl, substituted aryl, heterocyclic aryl, R 1 and R 2 Different; the chiral complex is generated in situ by divalent nickel and chiral phosphine ligands. The invention can not only overcome the shortcomings of the existing transition metal catalyzed deuteration reaction, but also has the advantages of environmental friendliness, simple operation, high reaction efficiency, wide substrate applicability and the like.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a method for preparing a nickel-catalyzed α-deuterated chiral sulfonamide compound. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Deuterated drug development is an excellent strategy to improve drug safety and pharmacokinetics. After the hydrogen atom is replaced by the isotope deuterium, the characteristics of the drug can be changed, such as half-life (which can reduce the therapeutic dose and reduce the number of doses), absorption, distribution and toxicity, while maintaining the original activity and selectivity. This strategy does not change the biological properties of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C303/40C07C311/20C07D333/20C07B53/00C07B59/00
CPCC07C303/40C07D333/20C07B53/00C07B59/001C07B59/002C07B2200/07C07C2602/08C07C2602/10C07C311/20
Inventor 唐波杨朋张力孙雅鑫马瑜王秀华付凯悦王作瑞
Owner SHANDONG NORMAL UNIV
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