N alpha-Boc-N beta-Cbz-L-2,3 diaminopropionic acid derivative synthesis method

The technology of a diaminopropionic acid and a synthesis method is applied in the field of synthesis of Nα-Boc-Nβ-Cbz-L-2, 3-diaminopropionic acid derivatives, which can solve the problems of low yield and high cost, and achieve the goal of producing The effect of high yield, low cost and simple preparation method

Inactive Publication Date: 2006-11-22
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above methods, in the preparation of N α -Boc-protected 2,3-diaminopropionic acid derivatives often encounter low yields, or use expensive reagents such as bis[trifluoroacetoxy]-phenyliodine or azides Nitrogen phosphoric acid diphenyl ester (diphenyl phosphorazidate, DPPA), or L-serine, which is a relatively expensive amino acid, is used as a raw material.

Method used

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  • N alpha-Boc-N beta-Cbz-L-2,3 diaminopropionic acid derivative synthesis method
  • N alpha-Boc-N beta-Cbz-L-2,3 diaminopropionic acid derivative synthesis method
  • N alpha-Boc-N beta-Cbz-L-2,3 diaminopropionic acid derivative synthesis method

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Synthesis of Example 1 Compound 7

[0036] N-Boc-L-aspartic acid (25 mmol) was dissolved in 10 mL of ethyl acetate, and 200 mL of benzene was added. After heating to about 60°C, paraformaldehyde (50 mmol) and a catalytic amount of p-toluenesulfonic acid (1.5 mmol) were added. Install an oil-water separator, and after reflux for 2 hours, add 100 mL of ethyl acetate to the reaction solution, and then use 0.3M K 2 CO 3 (2.5mL), washed with saturated brine (2×10mL), anhydrous Na 2 SO 4 Let dry overnight. After filtration, the solvent was distilled off under reduced pressure to obtain 74.4 g of a slightly yellow solid (Compound 7), with a yield of 72%. m.p. = 132-134°C; [α] 20 D +153.1 (c=1, CH 3 OH); 1 HNMR (300MHz, CDCl 3 ): δ=1.49(s, 9H), 3.03-3.27(m, 2H), 4.31(s, 1H), 5.24(d, 2H, J=3), 5.45(br, 1H). 13 CNMR (75MHz, CDCl 3 ): δ=28.59, 34.70, 51.68, 78.84, 82.92, 152.24, 172.12, 175.26. MS: m / z=284 [M+K]+ .Anal.Calcd for C 10 h 15 NO 6 : C, 48.98; H, 6.17; N...

Embodiment 2

[0037] The synthesis of embodiment two compound 8

[0038] Compound 7 (10mmol) was dissolved in anhydrous THF (30mL), cooled in an ice-salt bath to below -15°C, after adding EtOCOCl (11mmol), N-methylmorpholine (NMM) (12mmol) was added, and a white precipitation. At this temperature, after stirring the mixture for 20 minutes, the NaN 3 (25mmol) aqueous solution (5mL) was added to the reaction solution, and stirring was continued at about -10°C for 1h. Stop the reaction, add a small amount of water to dissolve the insoluble matter, transfer it to a separatory funnel, extract once with ethyl acetate 150mL, wash with saturated brine (2×10mL), anhydrous Na 2 SO 4 Let dry overnight. After filtration, the solvent was evaporated under reduced pressure to obtain a slightly yellow liquid (note: compounds containing azide are explosive and cannot be evaporated to dryness). Transfer this crude product to a silica gel column, use petroleum ether / ethyl acetate (2:1, v / v) as eluent, co...

Embodiment 3

[0039] Synthesis of Embodiment Three Compound 9

[0040] Dissolve the compound 8 obtained in Example 2 in toluene (30 mL), install a spherical condenser, seal it with oil, and heat it to 75°C under stirring until no gas is generated (about 2h), evaporate the solvent under reduced pressure, and obtain a colorless thick product liquid compound 9. This compound was used immediately in the next reaction without further purification.

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Abstract

This invention relates method for synthesizing Nalpha-Boc protected ureido-alanine derivatives. Wherein: with p-toluenesulfonic acid as catalyst, conduct azeotropic dehydration of N-Boc-L-aspartate and paraformaldehyde in benzene or toluene to produce Nalpha-Boc-5-oxazolidinone; Nalpha-Boc-5-oxazolidinone reacts with ethyl chloroformate at -10--20Deg C for 20-30min under NaN3 effect to produce (S)-3-tertbutyloxycarbonyl-4-acetylazide-5-oxazolidinone which will produce corresponding isocyanate at 35-110Deg C through Curtius rearrangement, isocyanate and benzalcohol will produce (S)-3-tertbutyloxycarbonyl-4-benzyl oxylcarbony becan-5-oxazolidinone by alcoholysis, the obtained product conducts ring-opening by hydrolysis under basic condition to produce Nalpha-Boc-N beta-Cbz-L-2, 3-diaminopropionic acid derivant. This invention is characterized of simple process, and high yield.

Description

technical field [0001] The invention discloses a N α -Boc-N β -Cbz-L-2, the synthesis method of 3-diaminopropionic acid derivatives. Background technique [0002] L-2,3-Diaminopropionic acid is an unnatural amino acid, which widely exists in nature not only in the form of free amino acids, but also as an important component of peptides. Among these peptides, many have anti-tumor and anti-living activities, such as viomycin, capreomycin, tuberactinomycin and so on. Using L-2,3-diaminopropionic acid or its derivatives as key structural units to construct some peptide compounds has been proved to be effective enzyme inhibitors, metal chelators, and GPIIb / IIIa antagonists. [0003] At present, there are many reports on the synthesis of compound L-2,3-diaminopropionic acid. Commonly used methods are as follows: [0004] 1) Hoffman rearrangement of L-asparagine [0005] [0006] Reference: (1) Synthesis 1981, 266-227. A facile synthesis of N 2 -protectedL-2, 3-diaminopro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/04C07C229/26C07C231/02C07C237/06
Inventor 胡先明滕汉兵邱国福梁淑彩
Owner WUHAN UNIV
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