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Method for preparing halofuginone hydrobromide

A technology of permanenone hydrobromide and piperidone, which is applied in the field of preparation of permanenone hydrobromide, can solve the problems of three waste pollution process routes, complex reaction conditions, cumbersome synthesis steps, etc., and achieve cost reduction, good product purity, The effect of reducing the pollution of three wastes

Active Publication Date: 2013-09-04
CHONGQING WEIPENG PHARMA
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Problems solved by technology

[0029] The entire reaction process of this process route is relatively advanced, but in the process of synthesizing piperidine ring fragment compounds, expensive pyrrole and toxic reagent benzene are used. In addition, the key raw material 2-chloro-3-bromopropene is extremely unstable and needs to be prepared by itself , so there are certain obstacles in industrialization
[0030] The synthesis of piperidine ring fragment compounds is the key to the synthesis of hemosanone. All of the above methods have limitations to varying degrees. The main disadvantages are cumbersome synthesis steps, complicated reaction conditions, low overall yield, high production cost, and serious waste pollution and The process route is not suitable for industrialization and other issues

Method used

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  • Method for preparing halofuginone hydrobromide
  • Method for preparing halofuginone hydrobromide
  • Method for preparing halofuginone hydrobromide

Examples

Experimental program
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Embodiment 1

[0064] Preparation of Intermediate VIII

[0065] Add anhydrous potassium carbonate (13.71g, 0.99mol), anhydrous sodium iodide (14.90g, 0.99mol), acetonitrile 200mL, N-benzyl-3-piperidone (17.12g , 0.90mol), 2,3-dichloropropene (14.83g, 1.35mol), a reflux condenser was installed, heated and stirred to reflux for 13 hours. Cool, add 20 mL of water, recover acetonitrile by distillation, add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the ethyl acetate extracts, wash once with 50 mL of saturated saline, dry over anhydrous sodium sulfate, filter, and evaporate ethyl acetate The ester obtained 19.7 g of yellow viscous liquid, ie intermediate VIII, with a yield of 83%.

[0066] R f =0.6(petroleum ether:EtOAc=3:1); IR(KBr)v max : 2951, 1716, 1635, 1454, 1136, 885cm -1 ; 1 H NMR (400MHz, CDCl 3 ): δ1.97-2.04(m, 2H), 2.38-2.43(m, 1H), 2.45-2.57(m, 1H), 2.61-2.67(m, 1H), 2.84-2.86(m, 2H), 2.90 -2.95(m, 1H), 3.52(t, 1H, J=6.4Hz), 3.62(d, 1H, J=13.4Hz), 3.80(d, 1...

Embodiment 2

[0088] The preparation of embodiment 2 intermediate VIII

[0089] Add anhydrous sodium carbonate (10.49g, 0.099mol), acetonitrile 200mL, N-benzyl-3-piperidone (17.12g, 0.09mol), 2-chloro-3-bromopropene to a 500mL dry and clean reaction flask (22.66g, 0.135mol), a reflux condenser was installed, heated and stirred under reflux for 13 hours. Cool, add 20 mL of water, recover acetonitrile by distillation, add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the ethyl acetate extracts, wash once with 50 mL of saturated saline, dry over anhydrous sodium sulfate, filter, and evaporate ethyl acetate The ester obtained 21.7 g of yellow viscous liquid, ie intermediate VIII, with a yield of 87%.

[0090] R f =0.6(petroleum ether:EtOAc=3:1); IR(KBr)v max : 2951, 1716, 1635, 1454, 1136, 885cm -1 ; 1 H NMR (400MHz, CDCl 3 ): δ1.97-2.04(m, 2H), 2.38-2.43(m, 1H), 2.45-2.57(m, 1H), 2.61-2.67(m, 1H), 2.84-2.86(m, 2H), 2.90 -2.95(m, 1H), 3.52(t, 1H, J=6.4Hz), 3.62(d, 1H, J...

Embodiment 3

[0091] Example 3 Preparation of intermediate VIII with another structure, the structural formula is as follows:

[0092]

[0093] Add anhydrous sodium carbonate (10.49g, 0.099mol), anhydrous sodium bromide (10.18g, 0.099mol), acetonitrile 200mL, N-benzyl-3-piperidone (17.12g , 0.09mol), 2-butenyl chloride (crotyl chloride, 11.78g, 0.130mol), a reflux condenser was installed, and the reaction was heated and stirred under reflux for 13 hours. Cool, add 20 mL of water, recover acetonitrile by distillation, add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the ethyl acetate extracts, wash once with 50 mL of saturated saline, dry over anhydrous sodium sulfate, filter, and evaporate ethyl acetate The ester obtained 21.7 g of yellow viscous liquid, ie intermediate VIII, with a yield of 87%.

[0094] Rf = 0.7 (petroleum ether: EtOAc = 3: 1); 1H NMR (600MHz, CDCl3): δ0.89 (d, 3H, J = 6.0Hz, α), 1.11 (d, 3H, J = 6.0Hz, β ), 1.94-2.03(m, 2H, α+β), 2.23-2.39(m, 4H, ...

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Abstract

The invention discloses a method for preparing halofuginone hydrobromide, which comprises the following steps: by using N-benzyl-3-piperidone or hydrochloride thereof, organic or inorganic base, halide of alkali metal and beta, gamma-dihaloalkene or allyl haloalkane as initial raw materials, performing Steven rearrangement reaction to obtain an intermediate VIII; performing Von Braun reaction on the intermediate VIII to obtain an intermediate VII; performing reduction reaction on the intermediate VII to obtain an intermediate VI; obtaining an intermediate V after reaction of the intermediate VI and NBS (N-bromosuccinimide); obtaining an intermediate IV after the reaction of the intermediate V and a compound 7-bromine-6-chlorine-4(3H) quinazolinone; performing deprotection on the intermediate IV to obtain an intermediate III; performing backflow processing on the intermediate III in ethanol to obtain an intermediate II; and obtaining the halofuginone hydrobromide after the salt forming reaction of intermediate II. The invention develops an efficient and simple method for synthesizing the halofuginone hydrobromide. The total yield can reach over 50 percent, cost is greatly reduced and the product has high purity.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of fushenone hydrobromide. Background technique [0002] Changshanone (Halofuginone, WR237645) {7-Bromo-6-chloro-3-[(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4-(3H)-quinazolinone}, also known as bromochlorochangone, Haloquinone, halofuginone. It is a halogenated derivative of febrifugine, a quinazolinone alkaloid isolated from the medicinal plant Dichroa febrifuga in my country. [0003] [0004] U.S. Cyanamid Co. (American Cyanamid Co.) carried out the total synthesis of hemosanone hydrobromide in the 1960s (see literature U.S. Patent US3320124, US2775597), and it is now produced by the German Hearst Company under the trade name "Sudan" ( ). Hemosanone has strong insecticidal activity and has a strong inhibitory effect on various chicken coccidia. Adding 3ppm concentration of hemosanone to the feed can effectively control 6 kinds of chicken Eimeria, and...

Claims

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Application Information

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IPC IPC(8): C07D401/06
Inventor 颜伟伟张建李路邵劲松林松
Owner CHONGQING WEIPENG PHARMA
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