Preparation method of (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid and analogue thereof

A technology of methylheptanoic acid and its analogs, which is applied in the field of preparation of amino acid compounds, can solve problems such as unfavorable large-scale production, and achieve the effects of correct structure, easy operation and amplification, and mild reaction conditions

Active Publication Date: 2013-04-10
合肥华纳生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, some very expensive reagents are involved in the above methods, which is quite unfavorable for the large-scale production of Statine and Fmoc-Statine and their analogs in the future

Method used

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  • Preparation method of (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid and analogue thereof
  • Preparation method of (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid and analogue thereof
  • Preparation method of (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid and analogue thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The synthesis of embodiment 1 Fmoc-Statine and Statine (R=(CH 3 ) 2 CHCH 2 -isopropylmethylene)

[0028]Add 884 mg (2.5 mmol) of amino acid (a) (R is isopropyl methylene) protected by Fmoc at the nitrogen end, 10 mL of dichloromethane, 360 mg (2.5 mmol) of Meldrum's acid (b) and DMAP ( 4-Dimethylaminopyridine) 452 mg (3.7 mmol). After stirring and dissolving, slowly drop DIC 0.47mL (3.0mmol), react at room temperature for 3.5h, pour into 120mL 0°C cold ethyl acetate, and use cold 5% NaHSO 4 Aqueous solution (3×30 mL), cold water (3×30 mL) and washed with saturated brine 30 mL. Ethyl acetate organic layer with anhydrous MgSO 4 Dry for 6h. After filtration, the filtrate was concentrated to about 30 mL by rotary evaporation, heated to reflux in ethyl acetate on a water bath for 1 h, and the solvent was distilled off under reduced pressure to obtain a crude product of light red gum d.

[0029] Then add 10 mL of dichloromethane and 1 mL of acetic acid, and slowly add ...

Embodiment 2

[0032] The synthesis of embodiment 2 Fmoc-Statine (R=(CH 3 ) 2 CHCH 2 -isopropylmethylene)

[0033] 22.1 g (62.5 mmol) of a, 250 mL of dichloromethane, 9.0 g (62.5 mmol) of b and 13.0 g (106.3 mmol) of DMAP were added to a round bottom flask. After stirring and dissolving, slowly drop DIC 13.6mL (87.5mmol), react at room temperature for 3.5h, pour into 1500mL 4°C cold ethyl acetate, and use cold 5% NaHSO 4 Aqueous solution (3×500 mL), cold water (3×500 mL) and washed with saturated brine 250 mL. Anhydrous MgSO for organic layer 4 Dry for 6h. After filtration, the filtrate was concentrated to about 500 mL by rotary evaporation, heated to reflux in ethyl acetate on a water bath for 3 h, and the solvent was evaporated under reduced pressure to obtain a crude product of light red gum d.

[0034] Then add 250 mL of dichloromethane and 20 mL of acetic acid, and slowly add NaBH under cooling in an ice-water bath at 4°C. 4 3.6g (93.8mmol), kept stirring at 0°C for 3.5h. The re...

Embodiment 3

[0036] Example 3 Synthesis of Fmoc-Statine analogs and Statine analogs (R=Benzyl benzyl)

[0037] Add a (R is benzyl) 9.69g (25mmol), dichloromethane 100mL, b 3.6mg (25mmol) and DMAP5.5g (45mmol) in a round bottom flask. After stirring and dissolving, slowly drop DIC 4.3mL (27.5mmol), react at room temperature for 3.5h, pour into 1200mL 4°C cold ethyl acetate, and use cold 5% NaHSO 4 Aqueous solution (3×300 mL), cold water (3×300 mL) and washed with saturated brine 300 mL. Anhydrous MgSO for organic layer 4 Dry for 6h. After filtration, the filtrate was concentrated to about 200 mL by rotary evaporation, heated to reflux in ethyl acetate on a water bath for 1 h, and the solvent was distilled off under reduced pressure to obtain a crude product of light red gum d.

[0038] Then add 100 mL of dichloromethane and 11.4 mL of acetic acid, and slowly add NaBH under cooling in an ice-water bath at 0°C. 4 1.9g (50mmol), kept stirring at 0°C for 3.5h. The reaction solution was pou...

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Abstract

The invention provides a preparation method of (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid (Statine) and an analogue thereof. The method adopts four-step reaction, firstly amino acid a with an amino end protected by Fmoc and Meldrum's acid b react to generate compound c under the condition that DMAP and a carboxyl activating agent are existed; the compound c generates Tetramic acid compoundd by ring closure reaction; the compound d is reduced into 4-hydroxy-ketopyrrolidine derivative e under the condition that acetic acid is existed; and the compound e generates Statine analogue with the amino end protected by Fmoc by reflux in dilute hydrochloric acid. The Statine analogue with the amino end protected by Fmoc can be transformed into Statine and the analogue thereof by conventionalorganic synthesis methods. The invention can utilize available raw material to obtain Statine and the analogue thereof with extremely high optical purity by four conventional organic chemistry methods. The yield of the four-step reaction is 45-70%. The structure of the obtained compound is determined to be correct by HNMR, mass spectrum rotational analysis.

Description

technical field [0001] The invention relates to a preparation method of amino acid compounds, in particular to a preparation method of (3S, 4S)-4-amino-3-hydroxyl-6-methylheptanoic acid and analogues thereof. Background technique [0002] The chemical name of Statine is (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, which is an important unnatural amino acid, and its structural formula is as follows: [0003] [0004] In 1970, Umezawa isolated a polypeptide, Pepstatin, from natural products, which is an inhibitor of aspartic proteases (such as renin, pepsin, and cathepsin D) and has anti-inflammatory activity. Kinetic studies have shown that its physiological activity is closely related to the action of Statine and enzymes. Further research shows that: Statine can simulate the tetrahedral hydrolysis transition state of the active site of aspartic protease substrate, so as to achieve the purpose of effectively combining with the enzyme and not being easily cleaved by t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/22C07C229/34C07C227/20C07C227/22
Inventor 许峰刘迎春高源
Owner 合肥华纳生物医药科技有限公司
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