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Preparation method of deuterated amino acid ester compound

A technology for ester compounds and amino acid esters, which is applied in the field of preparation of chiral deuterated amino acid esters, can solve the problems of complex synthesis conditions, harshness, inability to meet application value and market value, etc., and achieves the effect of simple operation.

Inactive Publication Date: 2021-08-06
CHONGQING ACAD OF CHINESE MATERIA MEDICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the synthesis of deuterated amino acids is not well developed, the synthesis steps are complex or the synthesis conditions are harsh, and selective deuteration is not possible (J.Biol.Chem, 1937,120,531-536; BBA-Gen Subject, 1977,497,1 -13; Biochim Biophys Acta, 1976, 446, 479-485.)
Therefore, the synthesis of traditional deuterated amino acids has been unable to meet its huge application value and market value

Method used

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  • Preparation method of deuterated amino acid ester compound
  • Preparation method of deuterated amino acid ester compound
  • Preparation method of deuterated amino acid ester compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026]

[0027] In an anhydrous and oxygen-free glove box under argon atmosphere, (R)-SEGPHOS (0.012mmol)Pd(OAc) 2 (0.005mmol) into the reaction tube in turn, then add 1ml 1,2-dichloroethane ring and stir for 30min, then add Zn(OTf) 2 (Zinc trifluoromethanesulfonate) (0.02mmol) was stirred for 10min, and then 0.2mmol of imidate derivative, deuterated methanol (1.0mmol), and 1ml of 1,2-dichloroethane were added. React in an oil bath at 70°C, monitor and detect the reaction by TLC, concentrate after the completion of the reaction, and pass through a column with silica gel to obtain a white solid with a yield of 89% and an ee value of 87%. The income rate is 97%.

[0028] 1 H NMR (400MHz, CDCl 3 ):δ7.49-7.44(m,2H),7.38-7.29(m,3H),6.74-6.71(m,2H),6.55-6.51(m,2H),5.01(s,0.03H),4.66( s, 1H), 3.71 (d, J=7.16Hz, 6H).

Embodiment 2

[0030]

[0031] In an anhydrous and oxygen-free glove box under argon atmosphere, (R)-SEGPHOS (0.012mmol)Pd(OAc) 2 (0.005mmol) into the reaction tube in turn, then add 1ml 1,2-dichloroethane ring and stir for 30min, then add Zn(OTf) 2 (Zinc trifluoromethanesulfonate) (0.02 mmol) was stirred for 10 min, and then 0.2 mmol of imidate derivatives, deuterated methanol (1.0 mmol), and 1 ml of 1,2-dichloroethane were added. React in an oil bath at 70°C, monitor and detect the reaction by TLC, concentrate after the completion of the reaction, and pass through a column with silica gel to obtain a white solid with a yield of 92% and an ee value of 88%. The income rate is 78%. 1 H NMR (400MHz, DMSO-d 6 )δ8.33 (s, 1H), 7.63–6.97 (m, 5H), 4.45 (dd, J=9.3, 7.8Hz, 0.21H), 3.59 (s, 3H), 3.00 (d, J=13.7Hz, 0.24H), 2.87(d,J=13.2Hz,1H), 1.79(s,3H).

Embodiment 3

[0033]

[0034] In an anhydrous and oxygen-free glove box under argon atmosphere, (R)-SEGPHOS (0.012mmol)Pd(OAc) 2 (0.005mmol) into the reaction tube in turn, then add 1ml 1,2-dichloroethane ring and stir for 30min, then add Zn(OTf) 2 (Zinc trifluoromethanesulfonate) (0.02 mmol) was stirred for 10 min, and then 0.2 mmol of imidate derivatives, deuterated methanol (1.0 mmol), and 1 ml of 1,2-dichloroethane were added. React in an oil bath at 70°C, TLC monitors and detects the reaction. After the reaction is completed, concentrate and pass through a column with silica gel to obtain a white solid with a yield of 95% and an ee value of 90%. The income rate is 78%. 1H NMR (400MHz, Chloroform-d) δ8.33 (d, J = 7.8Hz, 1H), 7.19 (td, J = 7.5, 1.0Hz, 1H), 6.78 (dt, J = 9.0, 1.4Hz, 3H) ,4.44(ddd,J=9.4,7.7,5.4Hz,022H),3.72(s,3H),3.60(s,3H),2.98(dd,J=13.7,5.5Hz,0.20H),2.84(dd, J=13.7,9.4Hz,1H),1.79(s,3H).

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Abstract

The invention discloses a method for efficiently preparing chiral deuterated amino acid ester, which is characterized in that in a common organic solvent, asymmetric transfer deuterization of imidic acid ester is realized by taking imidic acid ester as a raw material and taking deuterated methanol as a deuterium source and adopting transition metal catalysis. The target product namely chiral deuterated amino acid ester is obtained. The reaction general formula of the chiral deuterated amino acid ester is shown in the specification. The method for preparing the chiral deuterated amino acid ester by taking the deuterated methanol as the deuterium source comprises the steps of reaction system establishment, main reaction and post treatment. The preparation method of the deuterated chiral amino acid ester is simple to operate, mild, efficient, green and high in deuteration rate.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of chiral deuterated amino acid ester. Background technique [0002] Deuterium (D or 2 H) is an isotope of hydrogen (H) with twice the atomic mass of hydrogen, also known as heavy hydrogen. Deuterium, non-toxic, non-radioactive. Deuterated compounds are a very important class of high value-added chemicals. At present, the preparation methods of deuterated compounds mainly include hydrogen-deuterated exchange, direct deuterated and dehalogenated deuterated methods (J.Am.Chem.Soc.2019, 141, 1467-1472; J.Am.Chem.Soc. 2018, 140, 10970-10974; Adv. Synth. Catal. 2018, 360, 637-641.). In the field of medicinal chemistry, the role of deuterated compounds has become increasingly prominent. When the C-H bond at one or several positions in the drug molecule is replaced by a C-D bond, the selectivity and activity of the drug can still be maintained. Mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/36C07D333/24C07B59/00
CPCC07B59/001C07B59/002C07B2200/05C07B2200/07C07C227/18C07D333/24C07C229/36
Inventor 罗阳樵新芳杨大坚苏智敏樊保敏
Owner CHONGQING ACAD OF CHINESE MATERIA MEDICA
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