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Synthesis method of double different protected amino acids

A synthesis method and amino acid technology are applied in the preparation of carbamate derivatives, chemical instruments and methods, preparation of organic compounds, etc., which can solve the problems of unsuitability for scale-up production, harsh and dangerous reaction conditions, etc., and achieve strong versatility and post-processing. Simple, high chiral purity effect

Inactive Publication Date: 2019-05-31
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a synthesis method of double differently protected amino acids, which mainly solves the technical problems of the existing synthesis methods such as harsh reaction conditions and danger, unsuitable for scale-up production, etc.

Method used

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  • Synthesis method of double different protected amino acids
  • Synthesis method of double different protected amino acids
  • Synthesis method of double different protected amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: N-fluorenylmethoxycarbonyl-N'-tert-butoxycarbonyl-homolysine

[0039]

[0040] Step 1.1:

[0041] Add 6-amino-1-hexanol (100.0 g, 0.97 mol) into a 2000 ml three-necked flask, then add acetone (600 mL) and water (600 mL); slowly add Boc 2 O (211.4 g, 0.97 mol) and triethylamine (107.7 g, 1.06 mol). After stirring at room temperature for 4 hours, the solvent was evaporated by a rotary evaporator, 1500 mL of ethyl acetate was added, the organic phase was separated, washed with water (1000 mL) and saturated brine (1000 mL), and dried over anhydrous sodium sulfate. The filtrate was spin-dried to obtain a colorless oil, compound 1 (1-Boc amino-5-pentanol, 197.1 g, yield 100%), which was directly used in the next reaction;

[0042] Step 1.2:

[0043] Compound 1 (197.1 g, 0.97 mol) was added to a 2000 ml three-necked flask, followed by dichloromethane (1000 mL), and methanesulfonyl chloride (116.2 g, 1.02 mol) and triethylamine (108.1 g, 1.07 mol). After the ...

Embodiment 2

[0052] Example 2: N-fluorenylmethoxycarbonyl-N'-tert-butoxycarbonyl-D-homolysine

[0053]

[0054] Step 2.1:

[0055] Add compound 4 (100 g, 0.33 mol) to a three-necked flask, adjust the pH to 8.0 with pure water (4 L) with 1 N NaOH, add D-acetylase (0.5 g, Sigma-Aldrich), and the reaction solution is heated at 38 °C Stir for 24 hours. After chiral HPLC detection, it was confirmed that the reaction was complete; the reaction solution was cooled to room temperature, filtered, the filtrate was adjusted to pH 7.2 with dilute hydrochloric acid, extracted with ethyl acetate (1500 mLх2), the aqueous phase was concentrated to 500 mL, and a solid precipitated. Filter and dry to obtain a white solid, compound 7 [(R)-2-amino-7-7-(Boc-amino)heptanoic acid, 37.5 g, yield 43%, ee:99%], directly used in the next step reaction;

[0056] Step 2.2:

[0057] Add compound 7 (37.5 g, 0.144 mol), acetone (300 mL), water (300 mL), and then potassium carbonate (23.8 g, 0.17 mol) and Fmoc-OSu ...

Embodiment 3

[0058] Embodiment 3: N-fluorenylmethoxycarbonyl-N'-benzyloxycarbonyl-homolysine

[0059]

[0060] Step 3.1:

[0061] Add 6-amino-1-hexanol (10.0 g, 97 mmol) to a 200 mL three-necked flask, then add acetone (60 mL) and water (60 mL); add Cbz-OSu (24.9 g, 0.1 mol) and Sodium (4.8 g, 0.12 mol). After stirring at room temperature for 4 hours, the solvent was evaporated by a rotary evaporator, 200 mL of ethyl acetate was added, the organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The filtrate was spin-dried to obtain a colorless oil, compound 9 (1-Cbz amino-5-pentanol, 22.3g, yield 100%), which was directly used in the next step;

[0062] Step 3.2 was the same as Step 1.2 of Example 1 to obtain compound 10 (1-Cbz-amino-5-iodopentane, yield 85%);

[0063] Step 3.3 was the same as Step 1.3 of Example 1 to obtain compound 11 [2-acetylamino-2-(7-Cbz-aminopentyl)diethyl malonate, yield 75%];

[0064] St...

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Abstract

The invention relates to a synthesis method of double different protected amino acids.The technical problems of harsh reaction conditions, inapplicability of production enlarging and the like in an existing synthesis method are mainly solved. According to the technical scheme, the synthesis method of double different protected amino acids comprises the following steps: one of Boc20, Alloc-Cl or Cbz-Osuis added to amino alcohol under the action of an alkaline reagent to obtain a compound 1; the compound 1 reacts with methanesulfonyl chloride or paratoluensulfonyl chloride to obtain an intermediate, then a halide is added into acetone, heating and refluxing are executed to obtain a compound 2; the compound 2 is condensed with diethyl acetamidomalonate under the action of an alkaline agent togenerate a compound 3; the compound 3 is dissolved in alcohol and water, an inorganic base is added, heating, hydrolyzing and decarboxylating are executed to obtain a compound 4; acetylase is added into deionized water to obtain a compound 5 through enzymolysis; amino acid protection is executed, wherein one of Fmoc-Osu, Cbz-OSu, Alloc-Cl or Boc20 is added into thecompound 5 under the action of an alkaline agent to generatea target compound A.

Description

technical field [0001] The invention relates to a synthesis method of amino acids, in particular to a synthesis method of double differently protected amino acids. Background technique [0002] Lysine-type basic amino acids, including lysine, ornithine, homolysine, 2,4-diaminopropionic acid, etc., have two amino groups and one carboxyl group in their molecules, and have very important biological properties . In drug research and peptide synthesis, it is necessary to use different protecting groups to distinguish the two amino groups in the molecule, among which the α-position fluorenylmethoxycarbonyl (Fmoc)-protection and the terminal-tert-butoxycarbonyl (Boc)-protection are the most important The form of N-fluorenylmethoxycarbonyl-N'-tert-butoxycarbonyl-like lysine. The commonly used method for synthesizing such double differently protected amino acids is to synthesize unprotected amino acids first, then use copper complexation-protect the terminal amino group-copper diss...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22C07C271/14C12P41/00C07C269/04C07C271/16
Inventor 葛胜祥袁伟芳徐红岩
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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