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Method for preparing chiral alpha-unnatural amino acid by transition metal complex

A technology of unnatural amino acids and transition metals, which is applied in the field of preparation of α-unnatural amino acids, can solve the problems of long synthesis steps, difficulty in control, and limited scope of application, and achieve avoidance of post-processing, easy operation and amplification, and scope of application broad effect

Active Publication Date: 2013-07-24
北京欧凯纳斯生化科技有限公司
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Problems solved by technology

But the shortcoming of this method is: (1) the condition of decomplexing is at 70 ℃, reacts with 3mol / L hydrochloric acid, so this method is only applicable to the chiral α-amino acid that synthetic side chain group is stable to acid, makes The scope of application of this method is limited; (2) decomplexing with strong acid is not complete, there will be a small amount of Ni (II) remaining, therefore need to remove the remaining small amount of Ni (II) by ion exchange resin, this makes preparation step become Complicated, time-consuming and labor-intensive; (3) When this method synthesizes amino acids with relatively long side chains, the e.e value decreases
[0004] In addition, the method of synthesizing chiral α-unnatural amino acids whose side chain groups are sensitive to acid is relatively complicated, and the e.e value is poor
For example, the document Pia Kahnberg, J.Med.Chem.2006, 49 (26), 7611-7611 discloses a method for synthesizing chiral α-unnatural amino acids with tert-butyl ester groups in the side chain, which uses enzyme catalysis To achieve stereoselectivity, its disadvantages are: 1) the synthesis steps are long, the process is complicated, and each step is a small amount of synthesis, which is not easy to enlarge, and is not suitable for industrial production; Control, poor repeatability, and poor e.e value; 3) The raw materials and experimental facilities of this method are not easy to realize, and the cost is higher

Method used

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  • Method for preparing chiral alpha-unnatural amino acid by transition metal complex
  • Method for preparing chiral alpha-unnatural amino acid by transition metal complex
  • Method for preparing chiral alpha-unnatural amino acid by transition metal complex

Examples

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Embodiment 1

[0051] Example 1S-(-6-tert-butoxycarbonyl)-alpha-(N-Fmoc-)-aminocaproic acid synthesis

[0052] The metal complexing agent in this embodiment is heterocyclic metal complexing agent 8-hydroxyquinoline, the halogenated hydrocarbon is aliphatic halogenated hydrocarbon tert-butyl bromobutyrate, and the transition metal is nickel. Proceed as follows:

[0053] 1. Synthesis of S1

[0054] Heat 700mL of isopropanol to 55°C, add 145.9g of potassium hydroxide (2.6mol), after it is completely dissolved, add 100g of L-proline (0.87mol), add 167.5g of o-chlorobenzyl chloride (1.04mol) ); Stir, follow the reaction with thin layer chromatography until the L-proline reaction is complete, the reaction time is 18h; adjust the pH to 6 with 6mol / L hydrochloric acid, add dichloromethane and let stand for 4h; filter, filter cake with dichloromethane (DCM) was washed, and the combined filtrates were recrystallized with acetone after removing the solvent. 185.37 g of white solid S1 was obtained wi...

Embodiment 2

[0068] The synthesis of embodiment 2S-(-8-tert-butoxycarbonyl)-α-(N-Fmoc-)-aminocaprylic acid

[0069] In this embodiment, tert-butyl 6-bromobutyrate is used to replace tert-butyl 4-bromobutyrate in Example 1, and the metal complexing agent and transition metal are the same as in Example 1. The implementation steps of this embodiment are as follows:

[0070] 1.S1, S2, the synthetic method of S3 are identical with embodiment 1;

[0071] 2. Synthesis of S4

[0072] The synthesis method was the same as in Example 1, except that 18.06 g of tert-butyl 6-bromobutyrate (71.89 mmol) was used instead of tert-butyl 4-bromobutyrate in Example 1 to obtain 32 g of solid S4 with a yield of 65%.

[0073] 3. Synthesis of S5

[0074] Dissolve 70g S4 (0.1mol), 38.68g 8-hydroxyquinoline (0.226mol) in 1500mL acetonitrile, add 200mL H under stirring 2 O, keep the temperature at 30°C, stir and react for 12 hours; filter, wash the filter cake with water, combine the filtrates and evaporate aceto...

Embodiment 3

[0078] The synthesis of embodiment 3S-4-(2-ethoxyethoxy)-alpha-(N-Fmoc-)-aminobutyric acid

[0079] The metal complexing agent in this embodiment is ethylenediaminetetrapropionic acid, the halogenated hydrocarbon is 1-ethoxy-2-(2-iodoethoxy)ethane, and the transition metal is copper. Proceed as follows:

[0080] 1. The synthetic method of S1, S2 is identical with embodiment 1;

[0081] 2. Synthesis of S3

[0082] 25g S2 (0.055mol), 26.6g Cu(NO 3 ) 2 ·3H 2 O (0.11mol), 8.26g aminoacetic acid (0.11mol) was dissolved in 300mL methanol, and the methanol solution of KOH (25.3g KOH dissolved in 150mL methanol) was added dropwise under stirring, and the temperature of the system was kept below 50°C during the dropwise addition; After the addition is complete, heat to 60°C, stir and react for 3 hours (the reaction system changes from green to red); cool to room temperature, neutralize with 33g of acetic acid (55mol), adjust pH=6, distill off methanol, and remove the remaining Po...

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Abstract

The invention provides a method for preparing chiral alpha-unnatural amino acid by transition metal complex, comprising the following steps: preparing transition metal complex I with alpha-amino acid, chiral ligand and hydrochloride or nitrate of the transition metal; under the action of alkali, carrying out reaction between transition metal complex I and halohydrocarbon, so as to produce transition metal complex II; and decomplexing the transition metal complex II with metal complex agent, thereby obtaining the chiral alpha-unnatural amino acid. The invention has the following advantages: decomplexing with the metal complex agent instead of a strong acid system, the invention can be used to synthesize the chiral alpha-unnatural amino acid containing an acid-sensing group in a side chain;besides, the invention has a wide range of application and avoids a complicated post-treatment process; raw materials are at low cost and easy to get, and optical selectivity of the product is great;and the reaction condition is relatively mild, easy to operate and amplify, and applicable to a large-scale production.

Description

technical field [0001] The present invention relates to a preparation method of α-unnatural amino acid, in particular to a method for preparing chiral α-unnatural amino acid by utilizing a transition metal complex. Background technique [0002] Unnatural amino acids are not only an important class of drugs, but also an important structural unit of many drugs. Body, therapeutic antibody, recombinant medicinal animal and plant protein, etc.) and preventive or therapeutic vaccines, nucleic acid drugs, small molecule peptide drugs and other biological drugs and vaccines have important applications. At present, countries around the world have extensive research on polypeptide drugs containing unnatural amino acid skeletons. These drugs are mostly used in antibacterial, anti-inflammatory, anti-convulsant, cell growth inhibitory and anti-tumor aspects. Many drugs have entered the clinical research stage. Therefore, how to efficiently synthesize optically pure α-unnatural amino aci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C271/22C07C269/04
Inventor 刘迎春孔令芳高源
Owner 北京欧凯纳斯生化科技有限公司
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