阅读说明：本技术 一种反式常山酮氢溴酸盐及其中间体的制备方法 (Preparation method of trans-halofuginone hydrobromide and intermediate thereof ) 是由 江涛 张海霖 尹瑞娟 刘璐 钟滕江 于 2019-10-21 设计创作，主要内容包括：本发明涉及一种反式常山酮氢溴酸盐及其中间体的制备方法,所述制备方法包括如下步骤：<Image he="380" wi="700" file="DDA0002241295950000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(1)式(V)化合物与式(IV)化合物,于甲醇溶液中,在碳酸钠作用下,反应得到中间体(III)；(2)将中间体(III)加入HBr水溶液中,加热至100～115℃反应2～3小时后,将反应液冷却至70～80℃,加入HBr水溶液,加热至100～115℃反应1-3小时后,得到中间体(II)；(3)将中间体(II)分散于醇溶液中,加热至70～85℃,搅拌反应即可得到式(I)化合物。(The invention relates to a preparation method of trans-halofuginone hydrobromide and an intermediate thereof, which comprises the following steps: (1) reacting the compound of the formula (V) with the compound of 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 ℃, reacting for 2-3 hours, cooling the reaction liquid to 70-80 ℃, adding the HBr aqueous solution, heating to 100-115 ℃, and reacting for 1-3 hours to obtain an intermediate (II); (3) dispersing the intermediate (II) in an alcohol solution, heating to 70-85 ℃, and stirring for reaction to obtain the compound of the formula (I).)

1. A preparation method of trans-halofuginone hydrobromide shown in formula (I) is characterized by comprising the following steps:

(1) reacting the compound of the formula (V) with the compound of 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 ℃, reacting for 2-3 hours, cooling the reaction liquid to 70-80 ℃, adding the HBr aqueous solution, heating to 100-115 ℃, and reacting for 1-3 hours to obtain an intermediate (II);

(3) dispersing the intermediate (II) in an alcohol solution, heating to 70-85 ℃, and stirring for reaction to obtain a compound of a formula (I);

two of the structures of the compound of the formula (V), the intermediate (III) and the intermediate (II)The key representation pointing into the paperAnd/or simultaneously pointing out of the plane of the paperTwo of the structures of the compound of formula (I)Keys, any one of which is directed into the pageThe other representation points out of the paper

2. The method according to claim 1, wherein the methanol solution in the step (1) is 50 to 60% methanol aqueous solution, preferably 53 to 58% methanol aqueous solution; the molar ratio of the compound of formula (V), the compound of formula (IV) and sodium carbonate is 1.0-1.1: 1.0: 1.0-1.1, preferably 1.02:1.0: 1.05.

3. Preparation process according to any one of claims 1-2, characterized in that the aqueous HBr solution in step (2) is preferably aqueous HBr having a concentration of 40% to 48%.

4. The production method according to any one of claims 1 to 3, wherein the aqueous alcohol solution in the step (3) is preferably an aqueous methanol solution, an aqueous ethanol solution and an aqueous isopropanol solution, and the concentration of the aqueous alcohol solution is 60% to 70%; more preferably, the concentration is 60% methanol aqueous solution, 70% ethanol aqueous solution, 66% isopropanol aqueous solution.

5. The process according to any one of claims 1 to 4, wherein, after the end of the reaction in step (1), it is preferably subjected to the following work-up operations: concentrating the reaction solution under reduced pressure to recover methanol, adding water with the same volume into the concentrated solution, stirring for 0.5 h, filtering, washing the filter cake with 15% methanol water solution and water in sequence, and drying.

6. The process according to any one of claims 1 to 5, wherein, after the end of the reaction in step (2), it is preferably subjected to the following work-up operations: concentrating the reaction solution under reduced pressure, evaporating to dryness, sequentially adding ethanol and diethyl ether (the volume ratio of ethanol to diethyl ether is 2:1), stirring for 1 hr, filtering, washing the filter cake with ethanol/diethyl ether (the volume ratio of ethanol to diethyl ether is 1:1), and drying.

7. The process according to any one of claims 1 to 6, wherein, after the end of the reaction in step (3), it is preferably subjected to the following work-up operations: concentrating the reaction solution under reduced pressure, evaporating 1/2-2/3 volume of solvent, cooling the concentrated solution to 10-15 ℃, filtering, washing the filter cake with an ethanol/diethyl ether mixed solution (the volume ratio of ethanol to diethyl ether is 3:2), and drying.

8. The production method according to any one of claims 1 to 7, characterized by comprising the steps of:

(1) at room temperature, adding Na₂CO₃(66.9g,0.631mol,1.05eq) and the compound of formula (IV) (7-bromo-6-chloro-4 (3H) -quinazolinone, 156.0g0.601mol,1.0eq), adding 58% methanol aqueous solution (1.72L), stirring for 1 hour at room temperature, adding compound (V) (2, 3-cis-2-bromoacetonyl-3-methoxy-1-allyl piperidine formate, 204.9g,0.613mol,1.02eq), stirring for reaction for 6 hours at room temperature, concentrating the reaction solution at 40-45 ℃ under reduced pressure, evaporating to remove 0.8-0.81L of solvent, adding water (0.52L) for dilution and stirring for 0.5 hour, filtering, washing the filter cake twice with 15% methanol aqueous solution (0.12L multiplied by 2) and once with water (0.1L), and drying to obtain white solid (302.3g, yield 98.1%, purity 99.1%), namely intermediate (III);

(2) suspending the intermediate (III) (145.0g,0.283mol) in 48% HBr aqueous solution (0.72L), heating to 100-102 ℃ for 2 hours, cooling the reaction solution to 80 ℃, adding 48% HBr aqueous solution (0.14L) again, heating to 110-112 ℃ for 2 hours, stopping heating, concentrating the reaction solution at 75-80 ℃ under reduced pressure, evaporating to remove 0.81-0.82L of solvent, adding ethanol (0.2L) and diethyl ether (0.1L) in sequence while stirring, stirring for 1 hour, filtering, washing the filter cake with ethanol/diethyl ether (0.1L, V: 1), and drying to obtain a solid (129.3g, yield 92.2%, purity 96.2%), namely intermediate (II);

(3) dispersing the intermediate (II) (60g,0.121mol) in 60% methanol water solution (0.34L), heating to 70-72 ℃, stirring until the reaction is finished (TLC detection), concentrating under reduced pressure, evaporating 1/2-2/3 volume of solvent, cooling the concentrated solution to 10-15 ℃, filtering, washing a filter cake with ethanol/ether mixed solution (0.1L, V: 3:2), and drying to obtain off-white solid (56.0g, yield 93.3%, purity 97.0%), namely the trans-halofuginone hydrobromide shown in the formula (I).

9. A process for producing an intermediate (II) for the production of trans-halofuginone hydrobromide, characterized by comprising the steps of:

and adding the intermediate (III) into an HBr aqueous solution, heating to 100-115 ℃, reacting for 2-3 hours, cooling the reaction liquid to 70-80 ℃, adding the HBr aqueous solution, heating to 100-115 ℃, and reacting for 1-3 hours to obtain an intermediate (II).

10. The process according to claim 9, characterized in that the aqueous HBr solution is preferably aqueous HBr having a concentration of between 40% and 48%; after the reaction is finished, the following post-treatment operations are preferably carried out: concentrating the reaction solution under reduced pressure, evaporating to dryness, sequentially adding ethanol and diethyl ether (the volume ratio of ethanol to diethyl ether is 2:1), stirring for 1 hr, filtering, washing the filter cake with ethanol/diethyl ether (the volume ratio of ethanol to diethyl ether is 1:1), and drying.

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of trans-halofuginone hydrobromide and an intermediate thereof.

Background

Halofuginone (Halofuginone) also called Halofuginone belongs to quinazolinone substances, has a chemical name of 7-bromo-6-chloro-3- [3- (3-hydroxy-2-piperidyl) -2-oxopropyl (acetonyl) ] -4(3H) -quinazolinone, has higher coccidiostatic activity, is a broad-spectrum anticoccidial drug, and has the advantages of small dosage, no cross drug resistance and the like. The piperidine ring of Halofuginone has two chiral centers at 2, 3-positions, and two pairs of enantiomers exist, namely a pair of trans-Halofuginone (so-called Halofuginone) and a pair of cis-Halofuginone (cis-Halofuginone, i.e. Halofuginone), wherein the biological activity of the trans-Halofuginone is far higher than that of the cis-Halofuginone.

Halofuginone antiparasitic agents sold as a commercial product are halofuginone hydrobromide, sold under the trade name Sudan (Stenolol), which was first synthesized and patented by the American Cyanamid company and then transferred to the company Hoechst-Roussel Agri-Vet, Germany for production and sale. In 1991, halofuginone hydrobromide (sudan, Stenorol) approved by FDA for the treatment of avian coccidiosis is shown in supporting documents as an enantiomeric mixture of a pair of trans halofuginone hydrobromides as the active ingredient.

The existing preparation method of halofuginone hydrobromide has the defects that the used reagent and medium are not economical enough, the post-treatment generally needs to be subjected to high-temperature concentration for a long time, the energy consumption is high, the product is easy to decompose, the yield is reduced, and the like. In order to overcome the defects in the prior art, the invention provides a method for efficiently preparing trans-halofuginone hydrobromide by using an easily obtained enantiomer mixture of cis-bromo piperidine fragments as a raw material, the whole process route is simple and convenient to operate, the reaction conditions are easy to realize, and the used solvent and reagents are cheap and easy to obtain, so that the method is very suitable for large-scale production.

Disclosure of Invention

The invention provides a preparation method of trans-halofuginone hydrobromide shown in formula (I), which is characterized by comprising the following steps:

(1) reacting the compound of the formula (V) with the compound of 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 ℃, reacting for 2-3 hours, cooling the reaction liquid to 70-80 ℃, adding the HBr aqueous solution, heating to 100-115 ℃, and reacting for 1-3 hours to obtain an intermediate (II);

(3) dispersing the intermediate (II) in an alcohol solution, heating to 70-85 ℃, and stirring for reaction to obtain a compound of a formula (I);

two of the structures of the compound of the formula (V), the intermediate (III) and the intermediate (II)The key representation pointing into the paperAnd/or simultaneously pointing out of the plane of the paperTwo of the structures of the compound of formula (I)Keys, any one of which is directed into the pageThe other representation points out of the paper

The methanol solution in the step (1) has the concentration of 50-60% and is preferably 53-58% methanol water solution; the molar ratio of the compound of formula (V), the compound of formula (IV) and sodium carbonate is 1.0-1.1: 1.0: 1.0-1.1, preferably 1.02:1.0: 1.05. After the reaction in step (1) is finished, the following post-treatment operations are preferably carried out: concentrating the reaction solution under reduced pressure to recover methanol, adding water with the same volume into the concentrated solution, stirring for 0.5 h, filtering, washing the filter cake with 15% methanol water solution and water in sequence, and drying.

The aqueous HBr solution in step (2) is preferably 40-48% aqueous HBr solution. After the reaction in step (2) is finished, the following post-treatment operations are preferably carried out: concentrating the reaction solution under reduced pressure, evaporating to dryness, sequentially adding ethanol and diethyl ether (the volume ratio of ethanol to diethyl ether is 2:1), stirring for 1 hr, filtering, washing the filter cake with ethanol/diethyl ether (the volume ratio of ethanol to diethyl ether is 1:1), and drying.

In the step (3), the alcohol aqueous solution is preferably selected from methanol aqueous solution, ethanol aqueous solution and isopropanol aqueous solution, and the concentration of the alcohol aqueous solution is 60-70%; more preferably, the concentration is 60% methanol aqueous solution, 70% ethanol aqueous solution, 66% isopropanol aqueous solution. After the reaction in step (3) is finished, the following post-treatment operations are preferably carried out: concentrating the reaction solution under reduced pressure, evaporating 1/2-2/3 volume of solvent, cooling the concentrated solution to 10-15 ℃, filtering, washing the filter cake with an ethanol/diethyl ether mixed solution (the volume ratio of ethanol to diethyl ether is 3:2), and drying.

In another embodiment of the present invention, a method for preparing trans-halofuginone hydrobromide represented by formula (I) is preferred, which comprises the steps of:

(1) at room temperature, adding Na₂CO₃(66.9g,0.631mol,1.05eq) and the compound of formula (IV) (7-bromo-6-chloro-4 (3H) -quinazolinone, 156.0g,0.601mol,1.0eq) were added to a 58% aqueous methanol solution (1.72L) and stirred at room temperature for 1 hour, then the compound of formula (V) (2, 3-cis-2-bromoacetonyl-3-methoxy-1-piperidinecarboxylic acid allyl ester, 204.9g,0.613mol,1.02eq) was added, the reaction mixture was stirred at room temperature for 6 hours, then concentrated at 40 to 45 ℃ under reduced pressure to remove 0.8 to 0.81L of the solvent, water (0.52L) was added under stirring and stirred for 0.5 hours, then the reaction mixture was filtered, the filter cake was washed twice with a 15% aqueous methanol solution (0.12L. times.2) and once with water (0.1L), and dried to give a white solid (302.3g, yield 98.1.1H), the purity is 99.1 percent), namely an intermediate (III);

(2) suspending the intermediate (III) (145.0g,0.283mol) in 48% HBr aqueous solution (0.72L), heating to 100-102 ℃ for 2 hours, cooling the reaction solution to 80 ℃, adding 48% HBr aqueous solution (0.14L) again, heating to 110-112 ℃ for 2 hours, stopping heating, concentrating the reaction solution at 75-80 ℃ under reduced pressure, evaporating to remove 0.81-0.82L of solvent, adding ethanol (0.2L) and diethyl ether (0.1L) in sequence while stirring, stirring for 1 hour, filtering, washing the filter cake with ethanol/diethyl ether (0.1L, V: 1), and drying to obtain a solid (129.3g, yield 92.2%, purity 96.2%), namely intermediate (II);

(3) dispersing the intermediate (II) (60g,0.121mol) in 60% methanol water solution (0.34L), heating to 70-72 ℃, stirring until the reaction is finished (TLC detection), concentrating under reduced pressure, evaporating 1/2-2/3 volume of solvent, cooling the concentrated solution to 10-15 ℃, filtering, washing a filter cake with ethanol/ether mixed solution (0.1L, V: 3:2), and drying to obtain off-white solid (56.0g, yield 93.3%, purity 97.0%), namely the trans-halofuginone hydrobromide shown in the formula (I).

Another embodiment of the present invention provides a method for preparing an intermediate (II) for the preparation of trans-halofuginone hydrobromide, characterized by comprising the steps of:

and adding the intermediate (III) into an HBr aqueous solution, heating to 100-115 ℃, reacting for 2-3 hours, cooling the reaction liquid to 70-80 ℃, adding the HBr aqueous solution, heating to 100-115 ℃, and reacting for 1-3 hours to obtain an intermediate (II). The aqueous HBr solution is preferably aqueous HBr solution with the concentration of 40-48 percent; after the reaction is finished, the following post-treatment operations are preferably carried out: concentrating the reaction solution under reduced pressure, evaporating to dryness, sequentially adding ethanol and diethyl ether (the volume ratio of ethanol to diethyl ether is 2:1), stirring for 1 hr, filtering, washing the filter cake with ethanol/diethyl ether (the volume ratio of ethanol to diethyl ether is 1:1), and drying.

The concentration of the alcohol-water solution (methanol, ethanol, isopropanol and the like) is volume percent, and the concentration of the HBr water solution is mass percent.

Compared with the prior art, the invention has the advantages that: the invention provides a simple and efficient process for preparing trans-halofuginone hydrobromide, which starts from a cis-bromo piperidine intermediate, adopts simple and convenient operation means and cheap reagents and reaction media, and prepares the trans-halofuginone hydrobromide with the purity higher than 97 percent by 3-step synthesis reaction and total yield higher than 82 percent. Compared with the prior literature reports, the step (1) is shortenedNa is cheap and easy to obtain in the synthesis reaction₂CO₃The method has the advantages that the method is used as alkali, the condition is mild, the byproducts are few, and the use amount of organic solvent is greatly reduced by using the mixed solution of methanol and water as solvent; adding a certain amount of hydrobromic acid aqueous solution midway to realize deprotection operation and generate a hemiketal ring; and (4) carrying out configuration conversion in the step (3) to obtain the trans-halofuginone hydrobromide with higher purity. The preparation method of the trans-halofuginone hydrobromide provided by the invention has the advantages that the total preparation yield is obviously improved, the reagent cost and energy consumption are greatly reduced, the reaction and post-treatment steps are simplified, the solvent system is easy to recycle and reuse, the process is more environment-friendly, the product purity is high, and the large-scale production is favorably realized.

Drawings

FIG. 1 is a drawing showing the preparation of trans-halofuginone hydrobromide salt (I) according to the present invention¹H NMR(500MHz,DMSO-d₆) A drawing;

FIG. 2 is a one-dimensional NOE (500MHz, DMSO-d) of trans-halofuginone hydrobromide (I) prepared in accordance with the present invention₆) A difference spectrum;

FIG. 3 is a drawing showing the preparation of trans-halofuginone hydrobromide salt (I) according to the present invention¹H NMR and one-dimensional NOE difference spectrum overlay chart;

FIG. 4 is a mass spectrum of trans-halofuginone hydrobromide (I) prepared according to the present invention;

FIG. 5 is an HPLC chart of trans-halofuginone hydrobromide (I) prepared according to the present invention.

Detailed Description

In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.

In the embodiment 1 of the invention, two structures of the compound of the formula (V), the intermediate (III) and the intermediate (II)The key representation pointing into the paperAnd/or simultaneously pointing out of the plane of the paperNamely, the compound of the formula (V), the intermediate (III) and the intermediate (II) are all 2, 3-cis mixtures; two of the structures of the compound of formula (I)Keys, any one of which is directed into the pageThe other representation points out of the paperI.e. the compound of formula (I) is a 2, 3-trans mixture.