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Preparation method of trans-halofuginone hydrobromide and intermediate thereof

A technology of fushenone hydrobromide and intermediates, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of uneconomical reagents and media, easy decomposition of products, and decreased yield, and achieve simple and efficient preparation, easy Recycling and application, the effect of increasing the total yield

Inactive Publication Date: 2019-12-20
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the preparation method of fushenone hydrobromide has the disadvantages that the reagents and media used are not economical enough, and the post-treatment generally needs to undergo long-term high-temperature concentration, high energy consumption, and the product is prone to decomposition, resulting in a decrease in yield and other defects.

Method used

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  • Preparation method of trans-halofuginone hydrobromide and intermediate thereof
  • Preparation method of trans-halofuginone hydrobromide and intermediate thereof
  • Preparation method of trans-halofuginone hydrobromide and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation of embodiment 1 intermediate (III)

[0031]

[0032] Preparation example (1)

[0033] Take the compound of formula (V) (2,3-cis-2-bromoacetonyl-3-methoxyl-1-piperidine carboxylic acid allyl ester, 197.0 g, 0.589mol, 1.02eq) and the compound of formula (IV) (7-bromo-6-chloro-4(3H)-quinazolinone, 150.0g, 0.578 mol, 1.0eq), Na 2 CO 3 (64.3g, 0.607mol, 1.05eq) was added to 53% methanol aqueous solution (1.65 L) at room temperature, stirred and reacted at room temperature for 6 hours, concentrated under reduced pressure to recover methanol, added an equal volume of water to the concentrated solution, and stirred for 0.5 After one hour, filter and wash the filter cake successively with 15% methanol aqueous solution and water, and dry to obtain a white solid (267.1 g, yield 90.1%, purity 95.2%), which is intermediate (III);

[0034] MS(ESI): calcd for [C 21 h 23 BrClN 3 o 5 +H] + 512.06, 514.06, found 511.87, 513.93; calcd for [C 21 h 23 BrClN 3 o...

Embodiment 2

[0040] The preparation of embodiment 2 intermediate (II)

[0041]

[0042] Preparation example (1)

[0043] Add intermediate (III) (142.0g, 0.277mol) into 40% HBr aqueous solution (0.71L), heat to 100-102°C for 2 hours, then cool the reaction solution to 80°C, and add 40% HBr again Aqueous solution (0.14 L), and heated to 113 ~ 115 ° C for 2 hours, stop heating, the reaction solution was concentrated under reduced pressure and evaporated to dryness, then added ethanol (0.2 L) and diethyl ether (0.1 L), stirred for 1 hour, Filter, wash the filter cake with ethanol / ether (0.1L, V:V=1:1) mixture, and dry to obtain a solid (116.8g, yield 85.1%, purity 89.9%), which is intermediate (II);

[0044] TLC:R f =0.48 (developing agent CH 2 Cl 2 / MeOH / NH 3 h 2 O=160:20:1,V:V:V);

[0045] MS(ESI): calcd for [C 16 h 17 BrClN 3 o 3 +H] + 414.02, 416.02, found 413.92, 415.84; calcd for [C 16 h 17 BrClN 3 o 3 -OH] + 396.01, 398.01, found 395.87, 397.80;

[0046] 1 H NMR (4...

Embodiment 3

[0048] Suspend intermediate (III) (145.0g, 0.283mol) in 48% HBr aqueous solution (0.72L), heat to 100-102°C for 2 hours, then cool the reaction solution to 80°C, add 48% HBr again Aqueous HBr solution (0.14L), heated to 110-112°C for 2 hours, then stopped heating, concentrated the reaction solution at 75-80°C under reduced pressure, evaporated 0.81-0.82L of solvent, and added ethanol (0.2L) sequentially under stirring and diethyl ether (0.1L), and continued to stir for 1 hour, filtered, and the filter cake was washed with ethanol / diethyl ether (0.1L, V:V=1:1) and dried to obtain a solid (129.3g, yield 92.2%, purity 96.2 %), which is the intermediate (II). The preparation of embodiment 3 trans-hemosanone hydrobromide (I)

[0049]

[0050] Preparation example (1)

[0051] Disperse intermediate (II) (60g, 0.121mol) in 60% methanol aqueous solution (0.34L), raise the temperature to 70-72°C and stir until the reaction is complete (TLC detection), concentrate under reduced pres...

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Abstract

The invention relates to a preparation method of trans-halofuginone hydrobromide and an intermediate thereof, wherein the method comprises the following steps: (1) carrying out a reaction of a compound represented by the formula (V) with a compound represented by the formula (IV) in a methanol solution under the action of sodium carbonate to obtain an intermediate (III); (2) adding the intermediate (III) into an HBr aqueous solution, heating to 100-115 DEG C, carrying out a reaction for 2-3 h, cooling the reaction solution to 70-80 DEG C, adding the HBr aqueous solution, heating to 100-115 DEGC, and carrying out a reaction for 1-3 h to obtain an intermediate (II); and (3) dispersing the intermediate (II) in an alcoholic solution, heating to 70-85 DEG C, and carrying out a stirring reaction to obtain the compound represented by the formula (I).

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a preparation method of trans-hemosanone hydrobromide and an intermediate thereof. Background technique [0002] Halofuginone, also known as Halofuginone, belongs to quinazolinones, chemical name 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropane Base (acetonyl)]-4(3H)-quinazolinone has high coccidiocidal activity and is a broad-spectrum anticoccidial drug. The drug has the advantages of small dosage and no cross-resistance . There are two chiral centers at the 2,3-position on the piperidine ring of halofuginone, and there are two pairs of enantiomers, that is, a pair of trans-Halofuginone (trans-Halofuginone, commonly known as halofuginone, Halofuginone) And a pair of cis-Halofuginone (Isohalofuginone, i.e. Isohalofuingone), a total of four chiral structures, of which the biological activity of trans-Halofuginone is much higher than that of cis-Halofugin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06C07D491/048
CPCC07B2200/07C07D401/06C07D491/048
Inventor 江涛张海霖尹瑞娟刘璐钟滕江
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD