A kind of method of synthesizing chiral amine

A technology for chiral amines and compounds, applied in the field of synthesizing chiral amines, can solve the problems of low yield of deuterated products, expensive deuterated reagents, complicated reaction systems, etc., and achieves high reaction economic benefits, high atom utilization, The effect of simple reaction system

Active Publication Date: 2020-11-17
SHAANXI NORMAL UNIV
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Problems solved by technology

[0024] In summary, due to factors such as expensive deuterated reagents, complex reaction systems for synthesizing deuterated chiral amines, low yields of deuterated products, and low deuterated rates, the development of reaction systems is simple, deuterium sources are cheap, and yields are high. The method of synthesizing deuterated chiral amines with high deuterium rate and good stereoselectivity has become a relatively challenging research direction.

Method used

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  • A kind of method of synthesizing chiral amine
  • A kind of method of synthesizing chiral amine
  • A kind of method of synthesizing chiral amine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] In the glove box, 183 mg (1.5 mmol) of 1-phenylethanol, 60.5 mg (0.5 mmol) of R-(+)-tert-butylsulfinamide, 9 mg (0.075 mmol) of acetophenone, and 10 mg of sodium hydroxide ( 0.25 mmol) and 2 mL of toluene were added to the reaction tube, the reaction tube was sealed and taken out of the glove box, and the sealed tube was placed in a parallel reactor with a set temperature of 120 ° C and water condensed and refluxed for 12 h. After the reaction was finished, the diatomaceous earth was filtered to remove the alkali, the solvent was distilled off under reduced pressure, and column chromatography was separated to obtain a light yellow oily liquid with the following structural formula:

[0040]

[0041] Its yield is 72%, and the dr value measured by high performance liquid chromatography is 98.5:1.5. Its spectral data are: 1 H NMR (CDCl 3 ,400MHz)δ(ppm):7.36-7.27(m,1H),4.58-4.52(m,1H),3.41(brs,1H),1.51(d,J=6.4Hz,3H),1.24(s,9H ); 13 C NMR (CDCl 3 ,100MHz) δ (ppm): 144...

Embodiment 2

[0043] In the glove box, 302 mg (1.5 mmol) of 1-(4-bromophenyl) ethanol, 60.5 mg (0.5 mmol) of R-(+)-tert-butylsulfinamide, 15 mg (0.075 mmol) of 4-bromoacetophenone mmol), sodium hydroxide 10mg (0.25mmol), and toluene 2mL were added to the reaction tube, and the reaction tube was sealed and taken out of the glove box. . After the reaction was finished, diatomaceous earth was filtered to remove the alkali, the solvent was distilled off under reduced pressure, and column chromatography was separated to obtain a white solid with the following structural formula:

[0044]

[0045] Its yield is 78%, and the dr value measured by high performance liquid chromatography is 98.7:1.3. Its spectral data are: 1 H NMR (CDCl 3 ,400MHz)δ(ppm):7.47(d,J=8.4Hz,2H),7.23(d,J=8.4Hz,2H),4.53-4.48(m,1H),3.37(brd,J=2.0Hz, 1H), 1.49(d, J=6.4Hz, 3H), 1.23(s, 9H); 13 C NMR (CDCl 3 ,100MHz) δ (ppm): 143.1, 131.8, 128.4, 121.6, 55.6, 53.5, 22.6; HRMS (ESI) m / z theoretical value C 12 h 18 BrNOS[...

Embodiment 3

[0047] In the glove box, 228 mg (1.5 mmol) of 1-(4-methoxyphenyl) ethanol, 60.5 mg (0.5 mmol) of R-(+)-tert-butylsulfinamide, 4-methoxyphenyl ethyl Add 11.3mg (0.075mmol) of ketone, 10mg (0.25mmol) of sodium hydroxide, and 2mL of toluene into the reaction tube, seal the reaction tube and take it out of the glove box. The reactor was reacted for 12h. After the reaction was finished, the diatomaceous earth was filtered to remove the alkali, the solvent was distilled off under reduced pressure, and column chromatography was separated to obtain a light yellow oily liquid with the following structural formula:

[0048]

[0049] Its yield is 75%, and the dr value measured by high performance liquid chromatography is 98.5:1.5. Its spectral data are: 1 H NMR (CDCl 3 ,400MHz)δ(ppm):7.27(dt,J=8.8,2.4Hz,2H),6.88(dt,J=8.8,2.6Hz,2H),4.53-4.48(m,1H),3.8(s,1H ),3.33(brs,1H),1.48(d,J=6.4Hz,3H),1.22(s,9H); 13 C NMR (CDCl 3 ,100MHz) δ (ppm): 159.1, 136.2, 127.7, 114.0, 55.4, 55.2, 53.3...

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Abstract

The invention discloses a method for synthesizing chiral amine. According to the method, a catalytic amount of ketone is used as a self-catalyst, alkali which is cheap and easy to get is used as a synergistic catalyst, a 1-aryl-alcoho compound is used as a substrate, chiral methylpropane-2-sulfinamide is used as an amine source, in an inert gas atmosphere, asymmetric amination reaction of alcoholis completed, and through a one-pot method, the chiral amine is obtained. According to the method for synthesizing the chiral amine, a reaction system is simple, operation is simple and convenient, economic benefits are high, transition metal catalysts or other auxiliary additives are not needed, a chiral product does not contain transition metal residues, and the method for synthesizing the chiral amine is clean, safe and efficient; moreover, the target product yield (41%-82%) is high, the stereoselectivity is good (a dr is 99:1), the defects that traditional raw material agents are expensive, a reaction system is complex, synthesis steps are tedious, a deuterated ratio is low, the stereoselectivity is low, and the like are overcome, and the method for synthesizing the chiral amine has very important application prospects in medicine synthesis especially.

Description

technical field [0001] The invention belongs to the technical field of synthesizing chiral amines, and specifically relates to the synthesis of chiral amines through the asymmetric N-alkylation of chiral tert-butylsulfinamide under the synergistic action of 1-arylethanol with a catalytic amount of ketone and base method. Background technique [0002] Chiral amines are an important class of amine compounds, which widely exist in drugs, pesticides, synthetic intermediates, natural products and compounds with biological activity, especially occupy an extremely important position in the field of chiral drugs. The enantiomers of chiral drugs have very similar physical properties, but their metabolism, transformation or activation pathways in organisms are different, resulting in very different drug effects, so obtain high enantioselectivity or high diastereoselectivity Single isomers are of great significance. [0003] The traditional chemical synthesis method is to resolve the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C313/06C07D333/20C07F17/02
CPCC07B2200/07C07C313/06C07D333/20C07F17/02
Inventor 王超肖苗许瑞瑞肖建良
Owner SHAANXI NORMAL UNIV
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