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Preparation method of chiral alpha-amino acid derivatives

A technology for amino acids and derivatives, applied in the field of preparation of chiral α-amino acid derivatives, which can solve the problem of inability to obtain chiral α-amino acids and their derivatives with high efficiency and high stereoselectivity, low diastereoselectivity, and applicable The scope is limited and other problems, to achieve the effect of avoiding the use of precious metals and highly toxic drugs, high selectivity, and avoiding cumbersome steps

Inactive Publication Date: 2012-04-11
LANZHOU UNIVERSITY
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Problems solved by technology

However, this method also has serious disadvantages and cannot be used as a general preparation method for chiral α-amino acids and their derivatives: (1) The scope of application is extremely limited, and it is only used for the preparation of pyrrole, thiophene, indole or p-methoxyphenyl, etc. Such extremely electron-rich aryl substituted chiral α-amino acids and derivatives thereof cannot be used for the preparation of weak electron donor aryl substituted or aliphatic substituted chiral α-amino acids and derivatives thereof; (2 ) requires stoichiometric TMSOTf as a necessary reaction accelerator, but the reagent is expensive, making the method extremely costly; (3) low diastereoselectivity and long reaction time, it is impossible to obtain chirality with high efficiency and high stereoselectivity α-amino acid and its derivatives; (4) Franklin A. Davis et al. reported that simply adding ZnCl 2 Combinations with alkyl (or aryl) magnesium chloride Grignard reagents cannot be used for this method

Method used

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  • Preparation method of chiral alpha-amino acid derivatives
  • Preparation method of chiral alpha-amino acid derivatives
  • Preparation method of chiral alpha-amino acid derivatives

Examples

Experimental program
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Effect test

Embodiment 1-9

[0036] Examples 1-9: Add the chiral sulfinyl ester imine compound (0.2 mmol) into the organic reaction solvent, add the halogenated metal reagent at the reaction temperature listed in Table 1, and the reaction time is 0.2~2 hours. After the thin-plate chromatography detects the reaction, add it The ammonium chloride solution was quenched, the aqueous phase was extracted with an organic solvent, the combined organic phases were washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography with petroleum ether and ethyl acetate (volume Ratio 2:1~1:1) Purify, and obtain chiral α-amino acid derivatives. The yield and diastereoselectivity are shown in Table 1.

[0037] The structural formula of chiral sulfinyl ester imine compound is:

[0038]

[0039] R 2 Is ethyl, R 3 It is tert-butyl.

[0040] The structural formula of halogenated metal reagent is: R 1 -ZnX·MgX' 2 ·LiX''

[0041...

Embodiment 10-14

[0047] Example 10-14: The chiral sulfinyl ester imine compound (0.2 mmol) was added to DCM, and the metal halide reagent was added at -78°C. The reaction time was 0.2 to 2 hours. After the reaction was detected by thin plate chromatography After adding ammonium chloride solution to quench, the aqueous phase was extracted with organic solvent, the combined organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and subjected to silica gel column chromatography with petroleum ether and ethyl acetate (2:1~1:1) Purification to obtain chiral α-amino acid derivatives 。 The yield and diastereoselectivity are shown in Table 2.

[0048] The structural formula of chiral sulfinyl ester imine compound is:

[0049]

[0050] R 2 Is ethyl, R 3 It is tert-butyl.

[0051] The structural formula of halogenated metal reagent is: R 1 -ZnX·MgX' 2 ·LiX''

[0052] R 1 , X is shown in Table 2, or X’ and X’’ are both chlorine. ...

Embodiment 10

[0057] Example 10: 1 H NMR (300 MHz, CDCl 3 ) δ 4.23 (q, J = 7.1, 2H), 3.52 (d, J = 9.5, 1H), 2.06 (d, J = 3.7, 1H), 1.30 (t, J = 5.4, 3H), 1.27 (s, 9H), 0.97 (s, 9H).

[0058] Its structural formula is:

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Abstract

The invention discloses a preparation method of chiral alpha-amino acid derivatives, which belongs to the field of organic intermediate synthesis. The preparation method comprises the following steps of: taking chiral sulphinyl ester imine compound and halide metal reagent as raw materials, and carrying out one-step addition reaction to obtain various different substituted chiral alpha-amino acid derivatives. The preparation method has the characteristics of simple process, high non enantioselectivitiy, moderate reaction condition, quick synthesis speed, high production rate and low cost; the used materials are cheap, easy to get and stable for photo-thermal chemical properties; noble metal and highly toxic product can be avoided being used and produced; the preparation method has remarkable operation safety and general applicability and can be used for preparation of various different substituted chiral alpha-amino acids and derivatives thereof; and the preparation method has greatly important application value for organic intermediate synthesis, non natural chiral alpha-amino acid synthesis and multi-peptide drug research and development.

Description

technical field [0001] The invention belongs to the field of synthesis of organic intermediates, and relates to a preparation method of chiral α-amino acid derivatives. Background technique [0002] Unnatural chiral α-amino acids are not only an important class of chiral precursors in organic synthesis, but also serve as structural units of polypeptides and proteins, have a variety of biological activities, and play an important role in the origin and evolution of life. effect. [0003] At present, countries around the world have extensive research on polypeptide drugs containing unnatural amino acid skeletons. These drugs are mostly used in analgesia, antibacterial, anti-inflammatory, improving immunity, inhibiting cell growth, and anti-tumor. Many drugs have entered clinical research. stage. More importantly, the configuration of amino acids has a crucial impact on the biological activity of the polypeptides or proteins they consist of. Therefore, how to efficiently synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B53/00C07C313/06C07D333/24C07D317/30
Inventor 王锐林利伏旭
Owner LANZHOU UNIVERSITY
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