Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group

A technology for amino acids and derivatives, applied in the field of derivatives synthesis, can solve problems such as the preparation method of undiscovered hydroxyl and amino target chiral compounds, and achieve the effects of high yield, easy reaction, and easy purification

Inactive Publication Date: 2006-11-29
张文
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In summary, the prior art has not yet found target chiral compounds (including their corresponding intermediates) that can be simultaneously protected by hydroxyl and amino groups and their preparation methods in the present invention

Method used

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  • Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group
  • Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group
  • Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group

Examples

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Effect test

example 1

[0037] Example 1: Preparation of (S)-2-tert-butoxy-4-(9-fluorenylmethyloxy) carbonylaminobutyric acid (1a)

[0038] (1) Synthesis of (S)-2-hydroxy-4-aminobutyric acid methyl ester hydrochloride (3a) 5 . Mix 4g (33.58mmol) (S)-2-hydroxy-4-aminobutyric acid 2a, 7mL (95%, 93.35mmol) of thionyl chloride and 60mL methanol at 0°C for 15 minutes, then, at room temperature Continue to stir the reaction until the complete reaction of the raw material (TLC detection, CH 2 Cl 2 / MeOH / HOAc=2 / 2 / 1). Then, the solvent of this reaction mixture was removed by rotary evaporator. Next, after dissolving the obtained solid with a mixed solvent of methanol and carbon tetrachloride (1:1, v / v), the solvent was removed by a rotary evaporator, and the same operation was performed several times. Finally, 5.66 g of white solid product 3a was given (yield: 99.2%). TLC R f 0.50 (CH 2 Cl 2 / MeOH / HOAc, 2 / 2 / 1, v / v). 1 H-NMR (400MHz, D 2 O): δ4.33 (dd, 3 J H，H = 8.4Hz, 3 J H，H =4.0Hz, 1H, 2-H), ...

example 2

[0043] Example 2: Preparation of (R)-2-tert-butoxy-4-(9-fluorenylmethyloxy)carbonylaminobutyric acid (1b)

[0044] Preparation of 1b also adopts the synthetic route of 1a, and the data of each intermediate 3b, 4b, 5b and 6b and the final product 1b are characterized as follows:

[0045] (1) Synthesis of (R)-2-hydroxy-4-aminobutyric acid methyl ester hydrochloride (3b) 5 . white solid. Yield: 97.8%. TLC R f 0.50 (CH 2 Cl 2 / MeOH / HOAc, 2 / 2 / 1, v / v). 1 H-NMR (400MHz, D 2 O): δ4.32 (dd, 3 J H，H = 8.4Hz, 3 J H，H =4.0Hz, 1H, 2-H), 3.67(s, 3H, 1-OCH 3 ), 3.22(d, 3 J H，H = 1.2Hz, 1H, 2-OH), 3.04(m, 2H, 4-H), 2.07 & 1.90(m, 2H, 3-H). ESI Mass: C 5 h 12 ClNO 3 m / z, 169.15; found, 133.10 [M-HCl+H] + .

[0046] (2) Synthesis of (R)-methyl 2-hydroxy-4-(9-fluorenylmethyloxy)carbonylaminobutyrate (4b). white solid. Yield: 78.1%. TLC R f 0.30 (CH 2 Cl 2 / MeOH, 19 / 1, v / v). Analytical HPLC: t R =22.70min. 1 H-NMR (400MHz, DMSO-d 6 ): δ7.87(d, 3 J H，H =7.2Hz, 2H, Fl...

example 3

[0050] Example 3: Preparation of (S)-3-tert-butoxy-4-(9-fluorenylmethyloxy)carbonylaminobutyric acid (1c)

[0051] Using synthetic route II completely similar to synthetic route I, 1c can be prepared; the data of each intermediate 3c, 4c, 5c and 6c and the final product 1c are characterized as follows:

[0052] (1) Synthesis of (S)-3-hydroxy-4-aminobutyric acid methyl ester hydrochloride (3c). white solid. Yield: 98.0%. TLC R f 0.52 (CH 2 Cl 2 / MeOH / HOAc, 2 / 2 / 1, v / v). 1 H-NMR (400MHz, D 2 O): δ4.28(m, 1H, 3-H), 3.64(s, 3H, 1-OCH 3 ), 3.35(d, 3 J H，H = 1.6Hz, 1H, 2-OH), 3.10(m, 2H, 4-H), 2.28 & 2.11(m, 2H, 2-H). ESI Mass: C 5 h 12 ClNO 3 m / z, 169.15; found, 133.15 [M-HCl+H] + .

[0053] (2) Synthesis of (S)-methyl 3-hydroxy-4-(9-fluorenylmethyloxy)carbonylaminobutyrate (4c). white solid. Yield: 75.0%. TLC R f 0.32 (CH 2 Cl 2 / MeOH, 19 / 1, v / v). Analytical HPLC: t R =22.72min. 1 H-NMR (400MHz, DMSO-d 6 ): δ7.88(d, 3 J H，H =7.6Hz, 2H, Fluoren.-H), 7.69(...

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Abstract

A (S or R)-2(or 3)-tert-butyloxy-(3+n)-(9-fluorenyl methoxy) carbonylamino fatty-chain carboxylic acid with protected hydroxy and amino is prepared from (S or R)-2(or 3)-hydroxy-(3+n)-amino fatty-chain carboxylic acid through reaction on dichlorosulfoxide in solvent to generate the hydrochloride of relative methylester, reacting on FmocONSu in solvent to generate (S or R)-2(or 3)-hydroxy-(3+n)-(9- fluorenylmethoxy) carbonylamino fatty-chain methyl carboxylate, reacting on isobutene in solvent to generate (S or R)-2(or 3)-tert-butyloxy-(3+n)-(9-fluorenyl methoxy) carbonylamino fatty-chain methyl carboxylate, hydrolyzing, acidifying to generate (S or R)-2(or 3)-tert-butyloxy-(3+n)-amino fatty-chain carboxylic acid, and reacting of FmocONSu in solvent.

Description

technical field [0001] The present invention relates to the synthesis of derivatives of chiral non-alpha-amino acid compounds with amino and hydroxyl groups connected on the same aliphatic chain. The amino group of the compound is connected to the non-ring carbon atom or the carbon atom of the ring except the aromatic ring, the hydroxyl group is connected to the second and third carbon atoms on the aliphatic chain, and the carboxyl group is at the first position of the carbon chain. Optically pure chiral non-α-amino acid derivatives were prepared by protecting amino and hydroxyl groups. In particular, the invention is a method for preparing non-α-amino acid derivatives that can simultaneously protect hydroxyl and amino groups. Background technique [0002] In the synthesis of polypeptides, especially in the solid-phase synthesis of polypeptides, non-α-amino acids containing hydroxyl groups are often used, and usually the amino groups and hydroxyl groups are temporarily prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/04
Inventor 张文
Owner 张文
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