Piperidine derivative, and preparation method and application thereof in preparation of halofuginone

A kind of derivative, piperidine technology, applied in the synthesis field of alkaloid halofuginone hydrobromide, can solve the problems of affecting the final yield, increasing the difficulty of industrialization, increasing the cost of equipment and the like

Active Publication Date: 2013-12-25
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] In addition, Ogasawara, K et al. (Ogasawara, K Or g Lett, 2000, 2(20), 3193-3195.), Li Shuoliang, Zang Shengli. (Research on the synthesis of hemosanone intermediates [D]. Lanzhou: Lanzhou University. 2003. ), CN1583729A, JP2000007673A and other synthetic methods mostly have low total yields, which affect the final yield and are not easy for industrialization
[0013] In a word, according to the current literature and patents, some special conditions are

Method used

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  • Piperidine derivative, and preparation method and application thereof in preparation of halofuginone
  • Piperidine derivative, and preparation method and application thereof in preparation of halofuginone
  • Piperidine derivative, and preparation method and application thereof in preparation of halofuginone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] (1) Preparation of Cbz-protected 5-aminopental (Ⅱ)

[0056]

[0057] Weigh 14.52g (0.1mol) of 5-aminovaleryl (I), 16.8mL (0.12mol) of triethylamine, put them together in a 500mL three-necked flask, add 60mL of dichloromethane solvent; 17.92 g (0.105 mol) of benzyl chloroformate dissolved in 20 mL of dichloromethane was added dropwise thereto, and the reaction was stirred at room temperature (25° C.) for 10 hours. Stop the reaction, transfer the reaction solution into a separatory funnel, add 80mL of water, mix well, let stand to separate layers, wash the organic layer with saturated ammonium chloride aqueous solution (80mL×2), dry the organic phase with anhydrous magnesium sulfate, and evaporate under reduced pressure. The organic phase was dried to obtain 27.64 g of Cbz-protected 5-aminovaleryl (II), with a yield of 99%.

[0058] (2) Preparation of benzyl N-formate-2,3-epoxypiperidine (Ⅳ)

[0059]

[0060] Weigh 27.93g (0.1mol) of Cbz-protected 5-aminovaleryl (II...

Embodiment 2

[0076] (1) Preparation of 4-(4-oxo-3H-quinazolin-3 base)-3-oxo-butanoic acid ethyl ester (VII-2)

[0077]

[0078] Add 7.3g (0.05mol) of 3H-quinazolin-4-one (Ⅴ-2), 8.28g (0.06mol) of potassium carbonate, and 60mL of DMF into a 250ml round bottom flask. Stir the reaction at room temperature for half an hour, add 10.45 g (0.05 mol) of ethyl bromoacetoacetate, and react at 70° C. for 8 hours under a nitrogen atmosphere. Stop the reaction, evaporate the solvent, then extract with 70mL ethyl acetate, and wash with saturated sodium chloride solution (60mL×3). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent by a rotary evaporator. The intermediate 4-(4-oxo-3H-quinazolin-3 base)-3-oxo-butanoic acid was separated by silica gel column chromatography (mobile phase dichloromethane:methanol=100:1-2, volume ratio) Ethyl ester (VII-2) 13.18g, yield 96.2%. The structural characterization data are as follows:

[0079...

Embodiment 3

[0089] (1) Preparation of 4-(7-bromo-4-carbonyl-3H-quinazolin-3 base)-3-oxo-butanoic acid ethyl ester (VII-3)

[0090]

[0091] Add 11.25g (0.05mol) of 7-bromo-3H-quinazolin-4-one (Ⅴ-3), 8.28g (0.06mol) of potassium carbonate, and 65mL of DMF into a 250ml round bottom flask. Stir the reaction at room temperature for half an hour, add 10.45 g (0.05 mol) of ethyl bromoacetoacetate, and react at 70° C. for 8 hours under a nitrogen atmosphere. Stop the reaction, evaporate the solvent, then extract with 80×2mL ethyl acetate, and wash with saturated sodium chloride solution (60mL×3). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the solvent by a rotary evaporator. The intermediate 4-(7-bromo-4-carbonyl-3H-quinazolin-3 base)-3- Oxo-butyric acid ethyl ester (VII-3) 16.9 g, yield 95.8%. The structural characterization data are as follows:

[0092] 1 H NMR (500MHz, TMS, CD 3Cl)δ8.36(s,1H),7.90(s,1H),7.73-7.71(m,1H),7....

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Abstract

The invention discloses a piperidine derivative represented by a formula (VIII), and a preparation method and an application thereof in preparation of halofuginone. Under an alkaline condition and under catalysis of HMPA (hexamethylphosphoramide), cuprous iodide, TMEDA (tetramethylethylenediamine) and the like, a 1,3 dicarbonyl compound which easily generates stable negative ions is adopted to highly selectively undergo a reaction with an epoxy compound to synthesize the compound (VIII) with high yields. Compared with other process routes of synthesis of halofuginone, a process route provided by the invention comprises that the piperidine derivative (VIII) undergoes a one-step reaction to simultaneously complete decarboxylation and removal of a Cbz protecting group, more effectively shortens synthetic steps of the process route, and thereby greatly improving the yield of halofuginone hydrobromide; and moreover, the whole process route is simple and feasible in operation, has mild reaction conditions, has the adopted catalysts which are low in cost and are easy to get, and quite easily realizes the large-scale industrialized production.

Description

(1) Technical field [0001] The present invention relates to a synthesis method or process of the alkaloid hiruzenone hydrobromide, in particular to a preparation method of a piperidine derivative and its application in the preparation of hiruzenone hydrobromide, the method can be used to synthesize hydrogen bromide with a high yield Hemoshenone, and the whole process route is simple and easy to operate, and the reaction conditions are mild; the catalyst used is cheap and easy to obtain; it is very easy to realize large-scale industrial production. (2) Background technology [0002] Hydrogen bromide is a natural alkaloid of quinazolones obtained from a plant Changshan (Dichroa fabrifuga), which is a new type of broad-spectrum anticoccidial drug (Zhang, De-Fu, et al.Parasitology Research, 2012, 111(2), 695-701; Li Anxing, postdoctoral research report of Sun Yat-sen University; Guler Yavas, et al. Medicine, 2009, 91, 73-84.), treatment of chronic graft fibrosis-versus-host dis...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D491/056
CPCY02P20/55
Inventor 王宇光朱冰春朱勍
Owner ZHEJIANG UNIV OF TECH
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