CN107325092B

CN107325092B - Novel preparation process of azithromycin

Info

Publication number: CN107325092B
Application number: CN201710665285.4A
Authority: CN
Inventors: 不公告发明人
Original assignee: Shandong Lu Ning Pharmaceutical Co ltd
Current assignee: Shandong Lu Ning Pharmaceutical Co ltd
Priority date: 2017-08-07
Filing date: 2017-08-07
Publication date: 2021-01-08
Anticipated expiration: 2037-08-07
Also published as: CN107325092A

Abstract

The invention relates to a preparation method of azilsartan, which is characterized in that 2-fluoro-3-bromonitrobenzene reacts with an intermediate 3 prepared by suzuki reaction, 2-position fluorine is substituted, then nitro reduction is carried out, the 2-position fluorine reacts with tetraethyl orthocarbonate to form a benzimidazole ring through cyclization, then the benzimidazole ring reacts with hydroxylamine hydrochloride, oxadiazole ring substituted on phenyl is synthesized under the action of CDI, finally, formic acid is formed with carbon dioxide under the catalysis of n-butyl lithium, and a product is obtained. The method has the advantages of easily obtained raw materials, simple process, high overall yield, less by-products and simple post-treatment, and is suitable for industrial production.

Description

Novel preparation process of azithromycin

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of azilsartan.

Background

Azilsartan (Azilsartan) is a novel antihypertensive drug developed by the pharmaceutical company wutian (Takeda) of japan, under the trade name Edabi, and belongs to the chemical drug class 3.1 as new as the patent protection period up to 2025. FDA approval was obtained in usa at 2 months 2011 and approved for marketing in japan at 28 days 1 month 2012. The compound is clinically applicable to hypertension resistance, can competitively and reversibly block the combination of angiotensin and AT1 receptor, plays a role in lowering blood pressure, is superior to valsartan and olmesartan in the aspect of hypertension resistance, and is clinically applied. The azithromycin sartan medoxomil serving as a prodrug of the azithromycin is hydrolyzed into the azithromycin by aromatic esterase in gastrointestinal tracts or blood plasma after oral administration, and has strong and lasting antihypertensive effect. The compound preparation is prepared by combining the azithromycin ester and the diuretic clinically.

According to the molecular structure of the azithromycin, molecular inverse synthesis analysis is adopted, and the key points are that the formation of imidazole rings and oxadiazole rings, the production method of functional groups and the introduction sequence are important to the influence of the whole process and aftertreatment.

The main synthetic routes of the azithromycin include the following steps:

1. in patent US5243054, azilsartan was first publicly developed and synthesized in 1993. The starting material is 2- [ N- (2 '-cyano [1, 1' -biphenyl ] -4-yl) methylamino ] -2-nitrobenzoic acid methyl ester, and the azilsartan is synthesized by five steps of reduction, cyclization, condensation, ring closure and hydrolysis, and the total yield is 9.57%. Patent US20050187269 discloses a synthesis method for preparing azilsartan medoxomil by carrying out esterification reaction on azilsartan and 4-chloromethyl-5-methyl-1, 3-dioxol-2-one.

The method has the disadvantages of complicated operation, low yield of multi-step reaction and complicated post-treatment, and is not favorable for industrial production.

2. The journal of Chinese pharmaceutical industry reports that 3-nitrophthalic acid-1-methyl ester is subjected to Curtius rearrangement, N-alkylation, tert-butyloxycarbonyl protection, Pd/C catalytic hydrogenation, ring closure, condensation, esterification, ring closure and hydrolysis for 9 steps to prepare a target compound, and the total yield is about 14%. The route needs to use sodium azide and has longer steps, and the industrial production has certain limitation.

Disclosure of Invention

The invention provides a novel synthesis process of azithromycin, which has the advantages of easily obtained raw materials, concise process, high overall yield, few byproducts, simple post-treatment and suitability for industrial production.

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

a synthetic method of azilsartan is characterized in that 2-fluoro-3-bromonitrobenzene reacts with an intermediate 3 prepared by suzuki reaction, 2-position fluorine is substituted, then nitro reduction is carried out, the 2-position fluorine reacts with tetraethyl orthocarbonate to form an imidazole ring through cyclization, then the imidazole ring reacts with hydroxylamine hydrochloride to synthesize oxadiazole ring substituted on phenyl under the action of CDI, and finally the oxadiazole ring reacts with carbon dioxide to form formic acid under the catalysis of n-butyl lithium to obtain a product, wherein the reaction route is as follows:

the first step solvent is glycol dimethyl ether, and the catalyst is Pd (dppf) Cl₂Or PdCl₂(PPh₃)₂(ii) a The mol ratio of the compound 4 to the compound 3 is 1-1.2: 1; the nitro reduction of compounds 5 to 6 can be carried out by tin chloride, iron powder, zinc powder, lithium aluminum hydride; the reaction solvent of the compound 6 to the compound 7 is acetic acid or formic acid; the compounds 7 to 10 are all heavy structures of different solventsCrystals are obtained and a higher yield is obtained.

The invention has the beneficial effects that:

1) easily obtained raw materials, simple process, short method route, mild reaction conditions, high overall yield and less by-products

2) Simple post-treatment, most of the products are recrystallized, convenient operation and suitability for industrial production

The specific implementation mode is as follows:

other objects, technical solutions and advantages of the present invention will be described in further detail with reference to the following examples.

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Example 1. synthesis of compound 3:

mixing compound 1(7.4g, 40mmol), compound 2(5.9g, 40mmol), Na₂CO₃(2M，80 mmol，)，Pd(dppf)Cl₂(2mmol) and 150mL of ethylene glycol dimethyl ether were sequentially added to a 500mL flask under nitrogen, refluxed for 2 hours, then extracted with ethyl acetate, sequentially washed with NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude product which was used in the next step without purification.

Example 2. synthesis of compound 5:

compound 4(9.0g, 41mmol), Na₂CO₃(8.7g, 82mmol), Compound 3(8.1g, crude) and 150mL of DMF were charged into a 250mL flask, reacted at 130 ℃ for 2h, cooled, concentrated, diluted with water, extracted with ethyl acetate, dried, and purified by column chromatography to give Compound 5(13g, yield, 80%)

Example 3. synthesis of compound 6:

SnCl₂(10g, 54mmol) was added to a solution of Compound 5(13g, 32mmol) in ethyl acetate (300mL) and refluxed for 17h, and after completion of the reaction was monitored, it was directly purified by concentration column chromatography to give Compound 6(10.5g, yield 87%)

Example 4. synthesis of compound 7:

compound 6(10.5g, 28mmol), tetraethyl orthocarbonate (9.64g, 50mmol) and acetic acid (5mL) were reacted at 80 ℃ with stirring for 4 hours, concentrated under reduced pressure, and the residue was recrystallized from 75% ethanol to give compound 7(11.0g, 91% yield)

Example 5. synthesis of compound 8:

triethylamine (15.5g, 153mmol) was added to 100mL DMSO dissolved hydroxylamine hydrochloride (10.6g, 153mmol), stirred at 75 ℃ for 20min, then compound 7(11.0g, 25.5mmol) was added followed by reaction for 7h, after completion of the reaction was cooled to room temperature, poured into ice water, stirred, filtered with suction, washed with water and recrystallized from isopropanol to give compound 8(8.4g, 71% yield).

Example 6 synthesis of compound 9:

compound 8(8.4g, 18.1mmol) was dissolved in 100mL of DMSO, CDI (3.74g, 22.9mmol), N-methylmorpholine (2.31g, 38.2mmol) were added in that order, the reaction was stirred at room temperature for 8 hours, after completion of the reaction, the reaction mixture was poured into ice water, extracted with ethyl acetate, dried, and concentrated to give a crude product, which was further recrystallized from acetone to give Compound 9(7.63g, 86% yield).

Example 7. synthesis of compound 10:

dissolving the compound 8(7.62g, 15.6mmol) in 120mL THF under nitrogen atmosphere, cooling to-70 deg.C, slowly adding n-butyl lithium (2.5M, 14mL) dropwise, after the dropwise addition is completed, blowing dry carbon dioxide gas at uniform speed until the reaction is completed, heating to room temperature, removing most of THF by rotary evaporation, adding 80mL dilute hydrochloric acid (1M), filtering, and recrystallizing the filter cake with ethanol to obtain the compound 10(5.1g, yield 71%)

It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A synthetic method of azilsartan is characterized in that 2-fluoro-3-bromonitrobenzene reacts with an intermediate 3 prepared from compounds 1 and 2, 2-position fluorine is substituted, then nitro reduction is carried out, the 2-position fluorine reacts with tetraethyl orthocarbonate to form an imidazole ring through cyclization, then the imidazole ring reacts with hydroxylamine hydrochloride to synthesize an oxadiazole ring substituted on phenyl under the action of CDI, and finally the oxadiazole ring reacts with carbon dioxide to form formic acid under the catalysis of n-butyl lithium to obtain a product, wherein the reaction route is as follows:

2. the method for synthesizing azilsartan according to claim 1, characterized in that: reacting the compound 1 with the compound 2 to obtain a compound 3, wherein the solvent is ethylene glycol dimethyl ether, and the catalyst is Pd (dppf) Cl₂Or PdCl₂(PPh₃)₂。

3. The method for synthesizing azilsartan according to claim 1, characterized in that: the molar ratio of the compound 4 to the compound 3 is 1-1.2: 1.

4. The method for synthesizing azilsartan according to claim 1, characterized in that: the nitro reduction of compounds 5 to 6 is carried out by tin chloride, iron powder, zinc powder or lithium aluminum hydride.

5. The method for synthesizing azilsartan according to claim 1, characterized in that: the reaction solvent of compound 6 to compound 7 is acetic acid or formic acid.