(R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compounds as well as preparation method and application thereof

A technology of azaaryl and compound, which is applied in the field of synthesis of chiral deuterated compounds, can solve the problem of low stereoselectivity, and achieve the effects of environmental friendliness, metal-free participation, and mild reaction conditions

Active Publication Date: 2019-07-12
HENAN NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] One of the objects of the present invention is to solve the problem of low stereoselectivity in the synthesis of chiral deuterated compounds in the prior art, and provide a kind of (R)-2-(α-deuterium-α-alkyl-α-aryl) The preparation method of azaaryl compound

Method used

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  • (R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compounds as well as preparation method and application thereof
  • (R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compounds as well as preparation method and application thereof
  • (R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] ( R )-2-(2-methyl-1-phenylpropyl-1-d) The concrete preparation steps of quinoline are as follows:

[0027]

[0028] Preparation process: Take a dry 25 mL schlenk tube, add 29.6 mg (0.1 mmol) 2-(1-chloro-2-methyl-1-phenylpropyl) quinoline, DPZ (0.35 mg, 0.001 mmol), CPA ( 1.16 mg, 0.02 mmol), HEH (38 mg, 0.15 mmol), D 2 O (200 mg, 10 mmol), sodium bicarbonate (12.6 mg, 0.15 mmol), then add 3 mL of mesitylene, cover the bottle, and degas with a vacuum pump 2-3 times at no higher than -78°C , each time for 5 to 10 min, then placed at 25°C, irradiated with a 3 W blue light, and reacted for 20 minutes. After the reaction, column chromatography separated (petroleum ether / ethyl acetate = 20~4:1, volume ratio ), concentrated by rotary evaporation, and dried in vacuo (dried at 25°C for 1 hour) to obtain 19.8 mg of white solid ( R )-2-(2-methyl-1-phenylpropyl-1-d)quinoline with a yield of 75%, an enantiomeric excess of 93%, and a deuterated rate of >99%. NMR and mass spect...

Embodiment 2

[0030] ( R )-2-(2-methyl-1-(4-(trifluoromethyl)phenyl) propyl-1-d) quinoline The specific preparation steps are as follows:

[0031]

[0032]In the present example, 2-(1-chloro-2-methyl-1-phenylpropyl)quinoline in Example 1 was used 2-(1-chloro-2-methyl-1-(4-( s trifluoromethyl)) propyl) quinoline replacement, other steps are identical with embodiment 1, obtain 22.4 mg colorless oil ( R )-2-(2-methyl-1-(4-(trifluoromethyl)phenyl)propyl-1-d)quinoline, yield 68%. The enantiomeric excess is 95%, and the deuteration rate is >99%. NMR and mass spectrometry data are: 1 H NMR (300 MHz, CDCl 3 ) δ 8.28 – 7.95 (m, 2H), 7.81 – 7.59 (m,4H), 7.51 – 7.45 (m, 3H), 7.34 (d, J = 8.4 Hz, 1H), 2.89 – 2.85 (m, 1H), 0.93– 0.85 (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) Δ 162.8, 147.0, 136.5, 129.4, 129.2,128.8, 127.4, 126.9, 126.0, 125.3, 125.2, 125.2, 121.2,32.2, 21.6, 21.3; HRMS (ESI) M / Z 331.1519 (m +H + ), calc. for C 20 h 18 DF 3 N331.1527.

Embodiment 3

[0034] ( R )-2-(2-methyl-1-(2-naphthyl) propyl-1-d) The concrete preparation steps of quinoline are as follows:

[0035]

[0036] In this example, the 2-(1-chloro-2-methyl-1-phenylpropyl)quinoline in Example 1 was used 2-(1-chloro-2-methyl-1-(2-naphthyl) base) propyl) quinoline to give 22.5 mg colorless oil ( R )-2-(2-methyl-1-(2-naphthyl)propyl-1-d)quinoline in 72% yield, 88% enantiomeric excess, and >99% deuterated rate. NMR and mass spectrometry data are: 1 H NMR (300 MHz, CDCl 3 )δ 8.13 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.84 –7.63 (m, 6H), 7.50 –7.33 (m, 4H), 3.00 – 2.90 (m, 1H), 0.96 (d, J = 6.4 Hz,6H); 13 C NMR (75 MHz, CDCl 3 ) Δ 163.7, 147.6, 140.4, 136.3, 133.5, 132.3,129.3, 129.1, 127.7, 127.5, 127.0, 126.8, 125.8, 125.4,121.3, 31.7, 21.5; HRMS (ESI) m / z 313.1802 (M+H + ), calc. for C 23 h 21 DN313.1810.

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Abstract

The invention provides a preparation method of (R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compounds. The compounds are prepared by the following steps: dispersing one 2-(alpha-chloro-alpha-alkyl-alpha-aryl)aza arene, photosensitizer DPZ, chiral catalyst CPA, Hantzsch ester HEH, a deuterium source and sodium bicarbonate into an organic solvent, performing degassing treatment at a temperature not higher than -78 DEG C, placing the degassed product at 20-30 DEG C, performing a reaction for 20-40 min under irradiation of a blue light with powder of 3-10 W, and after the reaction is completed, performing separation, and performing purification to obtain one corresponding (R)-2-(alpha-deuterio-alpha-alkyl-alpha-aryl)azaaryl compound. According to the compounds provided by the invention, the enantiomeric excess of the obtained target product is about 90%, the deuteration rate is as high as 99% or more, the yield is high, and the method has mild reaction conditions and no pollution.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chiral deuterated compounds, in particular to (R)-2-(α-deuterium-α-alkyl-α-aryl) azaaryl compounds and their preparation methods and applications. Background technique [0002] Deuterium-substituted drugs replace the hydrogen atoms in the molecule with deuterium atoms on the basis of the original drug. Many drugs involve the breaking of the C-H bond in the metabolic clearance mechanism in the body. Therefore, the introduction of deuterium atoms at the metabolic site of the drug can slow down or prevent the breaking of the C-D bond, thereby achieving the purpose of changing the drug metabolism rate or metabolic pathway. Compared with non-deuterated drugs, deuterium-banded drugs can slow down drug metabolism, improve pharmacokinetics, and reduce toxic metabolites. Therefore, the synthesis of deuterated compounds has received a certain amount of attention, especially in April 2017, when the FDA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/12C07D217/02C07D277/64A61P35/00
CPCC07D215/12C07D217/02C07D277/64A61P35/00
Inventor 江智勇
Owner HENAN NORMAL UNIV
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