CN106854202B

CN106854202B - Novel method for preparing pranlukast high-purity asthma medicine

Info

Publication number: CN106854202B
Application number: CN201611102738.4A
Authority: CN
Inventors: 董来山; 刘忠平; 何长林; 王东健
Original assignee: Anhui Heryi Pharmaceutical Co ltd
Current assignee: Anhui Heryi Pharmaceutical Co ltd
Priority date: 2016-12-05
Filing date: 2016-12-05
Publication date: 2020-11-13
Anticipated expiration: 2036-12-05
Also published as: CN106854202A

Abstract

The invention discloses a novel method for preparing pranlukast high-purity asthma medicine, which relates to the technical field of medicine organic synthesis, and is characterized in that 8-amino-4-oxo-2-tetrazole-5-yl-4H-1 benzopyran hydrochloride is used as a reaction raw material, and is subjected to neutralization and salification reaction with an alkaline substance to generate an intermediate, and the obtained intermediate is subjected to amidation reaction with p-phenylbutoxy benzoyl chloride in a non-polar solvent to obtain the pranlukast. The whole process is simple, clean and easy to control, so that the purity of the obtained crude product can reach more than 99 percent, and the purity of the crude product can reach more than 99.9 percent after one-time purification.

Description

Novel method for preparing pranlukast high-purity asthma medicine

The technical field is as follows:

the invention relates to the technical field of medicine organic synthesis, in particular to a novel method for preparing pranlukast which is a high-purity asthma medicine.

Background art:

pranlukast is developed by the company Ribenxiaye, only selectively inhibits leukotriene receptors, hardly affects arachidonic acid metabolic enzyme, has no antagonism to acetylcholine, 5-hydroxytryptamine and the like, and has good treatment effect on special asthma and other types of bronchial asthma in clinical application.

At present, two methods for commercially producing pranlukast which are generally adopted at home and abroad are mainly adopted: the first method is that 3 '- (4- (4-phenylbutoxy) ammonium benzoate) -2' -hydroxyacetophenone (PBHA) is used as a raw material, and reacts with ethyl tetrachlorooxazolecarboxylate in a polar solvent in the presence of strong base to carry out ester ketone condensation reaction, and then the ring closure is carried out under an acidic condition to generate pranlukast; in the second method, pranlukast is prepared by amidation reaction of p-phenylbutoxybenzoyl chloride starting with 8-amino-4-oxo-2-tetrazol-5-yl-4H-1 benzopyran hydrochloride in the presence of an acid-binding agent.

The first method needs a large amount of polar solvent which is difficult to recycle and use and a large amount of strong base, a large amount of waste liquid, waste residue and waste water are generated in the production process, and the content of the obtained crude pranlukast product is very low due to the fact that the material is always in strong base and under the strong base closed-loop condition, and the crude pranlukast product can reach more than 99.5% after being purified for many times; the second method has the same problems as the above method, because AOTH contains hydrochloric acid, the hydrochloric acid needs to be neutralized by an acid-binding agent firstly in the reaction process to enable amino to be dissociated and to have amidation reaction with acyl chloride, hydrogen chloride continuously produced in the reaction process still needs to be removed in time by the acid-binding agent to enable the reaction to be continued, the purity of a crude product is only 80-85%, not only is multiple purification needed, but also the operation is complicated, and the cost is very high.

The invention content is as follows:

the technical problem to be solved by the invention is to provide a novel method for preparing high-purity pranlukast for asthma, which is simple to operate and generates less three wastes.

The technical problem to be solved by the invention is realized by adopting the following technical scheme:

a novel method for preparing pranlukast with high-purity asthma medicine is characterized in that 8-amino-4-oxo-2-tetrazole-5-yl-4H-1 benzopyran hydrochloride is used as a reaction raw material, neutralization and salification reaction are firstly carried out on the benzopyran hydrochloride and an alkaline substance to generate an intermediate, and the obtained intermediate and p-phenylbutoxy benzoyl chloride are subjected to amidation reaction in a non-polar solvent to obtain the pranlukast.

The alkaline substance is inorganic alkali or organic alkali.

The inorganic base is selected from one of sodium hydroxide and ammonia water.

The organic base is selected from one of pyridine and triethylamine.

The nonpolar solvent is selected from one of dichloromethane, dichloroethane, tetrahydrofuran, N-dimethylformamide and dimethyl sulfoxide.

Taking triethylamine as an example, the reaction route is as follows:

the reaction principle is as follows: the 8-amino-4-oxo-2-tetrazol-5-yl-4H-1 benzopyran hydrochloride reacts with triethylamine, on one hand, the triethylamine is utilized to neutralize the amino hydrochloride in the structure of the raw materials of the reaction, and the amino is liberated; on the other hand, the triethylamine is used for converting the tetrazole in the reaction raw material structure into triethylamine salt. When the obtained intermediate and p-phenylbutoxybenzoyl chloride are subjected to amidation reaction, ammonia chloride generated by the reaction can be timely neutralized with triethylamine to generate triethylamine hydrochloride, so that the effect of an acid-binding agent is achieved.

The invention has the beneficial effects that: the weak acid of the tetrazolyl in 8-amino-4-oxo-2-tetrazole-5-yl-4H-1-benzopyran hydrochloride (AOTH) is utilized, different from the salt formation of organic acid and amino in other inventions, triethylamine is used for forming the salt with the amino, the amino is dissociated, in the process of preparing pranlukast by reacting triethylamine salt of AOTH with acyl chloride, the generated ammonia chloride is timely neutralized with triethylamine to generate triethylamine hydrochloride, the triethylamine in molecules plays a role of an acid-binding agent, the whole process is simple, clean and easy to control, so that the purity of the obtained crude product can reach more than 99%, and the purity of the crude product can reach more than 99.9% after one-time purification.

The specific implementation mode is as follows:

in order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.

Example 1

80g of 8-amino-4-oxo-2-tetrazol-5-yl-4H-1 benzopyran hydrochloride is dissolved in 500ml of dichloromethane, 65g of triethylamine is dripped in, reflux reaction is carried out for 2H after the dripping is finished, the dichloromethane is recovered, the remainder is stirred for 30min at 0 ℃, and the intermediate compound, namely 93g of 8-amino-4-oxo-2-oxazole-5-yl-4H-1 benzopyran monotriethylamine salt is obtained after suction filtration.

Adding 67g of 8-amino-4-oxo-2-oxazole-5-yl-4H-1-benzopyran monotriethylamine salt and 60g of p-phenylbutoxybenzoyl chloride into a 1000ml reaction bottle filled with 700ml of dichloromethane, stirring, heating, refluxing for 6H, recovering the dichloromethane, adding 1200ml of 5% alkaline water into the residue, stirring, adding a small amount of activated carbon for decolorization, freezing and crystallizing to obtain pranlukast sodium salt, then adding 500ml of water into 500ml of ethanol, adjusting the pH to 6.8-7.2 with hydrochloric acid under stirring, filtering and washing with pure water for several times after repeated detection is not changed to obtain a white solid wet product, and drying to obtain 99g of product, wherein the purity is 99.92% by HPLC (high performance liquid chromatography).

Example 2

80g of 8-amino-4-oxo-2-tetrazol-5-yl-4H-1 benzopyran hydrochloride is dissolved in 500ml of dichloromethane, 50g of pyridine is dripped in the dichloromethane, reflux reaction is carried out for 2H after the dripping is finished, the dichloromethane is recovered, the remainder is stirred for 30min at the temperature of 0 ℃, and the intermediate 8-amino-4-oxo-2-oxazole-5-yl-4H-1 benzopyran monopyridine salt 86g is obtained after suction filtration.

62g of 8-amino-4-oxo-2-oxazole-5-yl-4H-1-benzopyran monopyridine salt and 60g of p-phenylbutoxybenzoyl chloride are put into a 1000ml reaction bottle filled with 700ml of dichloromethane, after stirring, heating and refluxing for 6H, the dichloromethane is recovered, 1200ml of 5% alkaline water is added into the residue, stirring is carried out, a small amount of activated carbon is added for decolorization, and freeze crystallization is carried out to obtain pranlukast sodium salt, then the obtained pranlukast sodium salt is put into 500ml of ethanol, 500ml of water is added, the pH value is adjusted to 6.8-7.2 by hydrochloric acid under stirring, filtration and pure water washing are carried out for a plurality of times after repeated detection is not changed, so as to obtain a white solid wet product, 97g of the product is obtained by drying, and the purity is 99.

The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims

1. A novel method for preparing pranlukast which is a high-purity asthma drug, is characterized in that: taking 8-amino-4-oxo-2-tetrazole-5-yl-4H-1 benzopyran hydrochloride as a reaction raw material, firstly carrying out neutralization and salification reaction with an alkaline substance to generate an intermediate, and carrying out amidation reaction on the obtained intermediate and p-phenylbutoxy benzoyl chloride in a non-polar solvent to obtain pranlukast;

the novel method for preparing the high-purity pranlukast for asthma comprises the following specific steps:

(1) dissolving 8-amino-4-oxo-2-tetrazol-5-yl-4H-1 benzopyran hydrochloride in dichloromethane, dropwise adding an alkaline substance, carrying out reflux reaction after dropwise adding, recovering dichloromethane, stirring the remainder at 0 ℃, and carrying out suction filtration to obtain an intermediate;

(2) putting the intermediate and p-phenylbutoxy benzoyl chloride into a reaction bottle filled with dichloromethane, stirring, heating for refluxing, recovering the dichloromethane, adding 5% alkaline water into the residue, stirring, adding a little activated carbon for decoloring, freezing and crystallizing to obtain pranlukast sodium salt, then putting the obtained pranlukast sodium salt into ethanol, adding water, adjusting the pH to 6.8-7.2 by hydrochloric acid under stirring, filtering after repeated detection is not changed, washing by pure water for several times to obtain a white solid wet product, drying to obtain a product, and detecting the purity by HPLC;

the alkaline substance is inorganic alkali or organic alkali; the inorganic base is selected from one of sodium hydroxide and ammonia water; the organic base is selected from one of pyridine and triethylamine.