阅读说明：本技术 一种药物中间体氮杂螺环化合物的合成方法 (Synthetic method of drug intermediate azaspiro compound ) 是由 王羽 金琦浩 房忠雪 陆小琳 于 2020-12-04 设计创作，主要内容包括：本发明涉及药物中间体合成技术领域,尤其涉及一种药物中间体氮杂螺环化合物的合成方法,一种药物中间体氮杂螺环化合物的合成方法,包括以下步骤：S1、向反应釜中加入式(I)化合物和式(II)化合物,并向其中加入有机溶剂,由磁力棒搅拌混匀；S2、向S1的混合物中依次加入催化剂、氧化剂和助剂；S3、设定反应釜的反应温度和反应时间,反应完全后将产物自然冷却至室温,然后过滤。本发明通过在制备的原料中加入2-(4-异丁基苯基)丙酸作为助剂来使用,可以通过抑制环氧化酶,减少前列腺素的合成,产生镇痛、抗炎作用,并通过下丘脑体温调节中枢而起到相应的解热作用,对患者有镇痛消炎之效。(The invention relates to the technical field of synthesis of drug intermediates, in particular to a synthesis method of a drug intermediate azaspiro compound, which comprises the following steps: s1, adding the compound of the formula (I) and the compound of the formula (II) into a reaction kettle, adding an organic solvent into the reaction kettle, and uniformly stirring the mixture by a magnetic rod; s2, sequentially adding a catalyst, an oxidant and an auxiliary agent into the mixture of S1; s3, setting the reaction temperature and the reaction time of the reaction kettle, naturally cooling the product to room temperature after the reaction is completed, and then filtering. The 2- (4-isobutylphenyl) propionic acid is added into the prepared raw material to be used as an auxiliary agent, can reduce the synthesis of prostaglandin by inhibiting cyclooxygenase, has the functions of analgesia and anti-inflammation, plays a corresponding role of antipyresis by regulating the center of hypothalamus body temperature, and has the effects of analgesia and anti-inflammation for patients.)

1. A synthetic method of a drug intermediate aza spiro compound is characterized by comprising the following steps:

s1, adding the compound of the formula (I) and the compound of the formula (II) into a reaction kettle, adding an organic solvent into the reaction kettle, and uniformly stirring the mixture by a magnetic rod;

s2, sequentially adding a catalyst, an oxidant and an auxiliary agent into the mixture of S1;

s3, setting the reaction temperature and the reaction time of the reaction kettle, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing with saturated sodium carbonate aqueous solution, adding acetone for extraction for 2-3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through a 300-mesh 400-mesh silica gel column chromatography, and washing with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound in the formula (III);

wherein R is₁-R₃Each independently is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen;

the auxiliary agent is 2- (4-isobutylphenyl) propionic acid, and the organic solvent is ethylene glycol ether.

2. The method for synthesizing the azaspiro compound as the pharmaceutical intermediate of claim 1, wherein the molar ratio of the compound of formula (I) to the compound of formula (II) is 1 (1.4-2).

3. The method for synthesizing the azaspiro compound as the pharmaceutical intermediate of claim 1, wherein the catalyst is trifluoromethanesulfonyl catalyst.

4. The method for synthesizing a pharmaceutical intermediate azaspiro compound according to claim 1, wherein the oxidizing agent is potassium dichromate.

5. The method for synthesizing the drug intermediate azaspiro compound according to claim 1, wherein the molar ratio of the catalyst, the oxidant and the auxiliary agent is 2:1: 2.

6. The method for synthesizing a pharmaceutical intermediate azaspiro compound according to claim 1, wherein the temperature in S3 is set to 50-80 ℃ for 3-5 hours.

Technical Field

The invention relates to the technical field of synthesis of drug intermediates, in particular to a synthesis method of a drug intermediate aza spiro compound.

Background

The spiro molecular structure is widely existed in various natural products, medicines and functional material main bodies, and the spiro compound can also be used as a construction unit of various complexes. Particularly, the azaspirocyclohexadienone compounds with biological activity have attracted extensive attention of a plurality of researchers. However, in the medical field, when patients use the existing medicines prepared by the azaspiro compound, the yield of the product can be improved, but the medicine does not have great effect on the symptoms of the patients.

Therefore, we propose a synthesis method of azaspiro compound as a pharmaceutical intermediate to solve the above problems.

Disclosure of Invention

The invention aims to solve the defects in the prior art and provides a synthetic method of a drug intermediate azaspiro compound.

A synthetic method of a drug intermediate azaspiro compound comprises the following steps:

s1, adding the compound of the formula (I) and the compound of the formula (II) into a reaction kettle, adding an organic solvent into the reaction kettle, and uniformly stirring the mixture by a magnetic rod;

s2, sequentially adding a catalyst, an oxidant and an auxiliary agent into the mixture of S1;

s3, setting the reaction temperature and the reaction time of the reaction kettle, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing with saturated sodium carbonate aqueous solution, adding acetone for extraction for 2-3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through a 300-mesh 400-mesh silica gel column chromatography, and washing with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound in the formula (III);

wherein R is₁-R₃Each independently is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen;

the auxiliary agent is 2- (4-isobutylphenyl) propionic acid, and the organic solvent is ethylene glycol ether.

Preferably, the molar ratio of the compound of formula (I) to the compound of formula (II) is 1 (1.4-2).

Preferably, the catalyst is a trifluoromethanesulfonyl catalyst.

Preferably, the oxidizing agent is potassium dichromate.

Preferably, the molar ratio of the catalyst, the oxidant and the auxiliary agent is 2:1: 2.

Preferably, the temperature in S3 is set to be 50-80 ℃ and the set time is 3-5 hours.

The invention has the beneficial effects that:

the 2- (4-isobutylphenyl) propionic acid is added into the prepared raw material to be used as an auxiliary agent, can reduce the synthesis of prostaglandin by inhibiting cyclooxygenase, has the functions of analgesia and anti-inflammation, plays a corresponding role of antipyresis by regulating the center of hypothalamus body temperature, and has the effects of analgesia and anti-inflammation for patients.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples.

A synthetic method of a drug intermediate azaspiro compound comprises the following steps:

s1, adding the compound of the formula (I) and the compound of the formula (II) into a reaction kettle, adding an organic solvent ethylene glycol ether into the reaction kettle, and uniformly stirring the mixture by a magnetic rod;

s2, sequentially adding a trifluoromethanesulfonyl catalyst, potassium dichromate and 2- (4-isobutylphenyl) propionic acid into the mixture of S1;

s3, setting the reaction temperature of the reaction kettle to be 75 ℃ and the reaction time to be 3 hours, naturally cooling a product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing the filtrate by using a saturated sodium carbonate aqueous solution, adding acetone for extraction for 3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through a 300-mesh silica gel column chromatography, and washing the residue by using a mixed solution of ethyl acetate and dichloromethane in an equal volume ratio to obtain a compound in a formula (III);

wherein R is₁-R₃Each independently is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or halogen, the molar ratio of the compound of formula (I) to the compound of formula (II) being 1:1.4, and the molar ratio of catalyst, oxidant and auxiliary being 2:1: 2.

The first embodiment is as follows:

s1, adding 100mmol of the compound shown in the formula (I) and 140mmol of the compound shown in the formula (II) into the reaction kettle, adding an organic solvent ethylene glycol ether into the mixture, and stirring and uniformly mixing the mixture by a magnetic rod;

s2, sequentially adding a trifluoromethanesulfonyl catalyst, potassium dichromate and 2- (4-isobutylphenyl) propionic acid into the mixture of S1;

s3, setting the reaction temperature of the reaction kettle to be 75 ℃ and the reaction time to be 3 hours, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing the filtrate with saturated sodium carbonate aqueous solution, adding acetone for extraction for 3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through 300-mesh silica gel column chromatography, and washing the residue with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound shown in the formula (III).

Comparative example one:

s1, adding 100mmol of the compound shown in the formula (I) and 140mmol of the compound shown in the formula (II) into the reaction kettle, adding an organic solvent ethylene glycol ether into the mixture, and stirring and uniformly mixing the mixture by a magnetic rod;

s2, sequentially adding a trifluoromethanesulfonyl catalyst and potassium dichromate into the mixture of S1;

s3, setting the reaction temperature of the reaction kettle to be 75 ℃ and the reaction time to be 3 hours, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing the filtrate with saturated sodium carbonate aqueous solution, adding acetone for extraction for 3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through 300-mesh silica gel column chromatography, and washing the residue with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound shown in the formula (III).

Example two:

s1, adding 100mmol of the compound shown in the formula (I) and 140mmol of the compound shown in the formula (II) into the reaction kettle, adding an organic solvent ethylene glycol ether into the mixture, and stirring and uniformly mixing the mixture by a magnetic rod;

s2, sequentially adding a trifluoromethanesulfonyl catalyst, potassium dichromate and 2- (4-isobutylphenyl) propionic acid into the mixture of S1;

s3, setting the reaction temperature of the reaction kettle to be 75 ℃ and the reaction time to be 3 hours, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing the filtrate with saturated sodium carbonate aqueous solution, adding acetone for extraction for 3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through 300-mesh silica gel column chromatography, and washing the residue with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound shown in the formula (III).

Comparative example two:

s1, adding 100mmol of the compound shown in the formula (I) and 140mmol of the compound shown in the formula (II) into the reaction kettle, adding an organic solvent ethylene glycol ether into the mixture, and stirring and uniformly mixing the mixture by a magnetic rod;

s2, sequentially adding a trifluoromethanesulfonyl catalyst and potassium dichromate into the mixture of S1;

s3, setting the reaction temperature of the reaction kettle to be 75 ℃ and the reaction time to be 3 hours, naturally cooling the product to room temperature after the reaction is completed, then filtering, adjusting the pH value of the filtrate to be neutral, fully washing the filtrate with saturated sodium carbonate aqueous solution, adding acetone for extraction for 3 times, combining organic phases, carrying out reduced pressure distillation, passing the residue through 300-mesh silica gel column chromatography, and washing the residue with mixed solution of ethyl acetate and dichloromethane in equal volume ratio to obtain the compound shown in the formula (III).

According to the compound of formula (III) prepared in examples and comparative examples, the same patients were allowed to take the drugs prepared from the intermediate of the compound of formula (III) separately and observed the symptoms after three days, as shown in the following table:

from the above data, it can be seen that after patients take the medicine containing the compound of formula (III) prepared by the adjuvant 2- (4-isobutylphenyl) propionic acid, the inflammation and pain sensation is obviously reduced, and no pain is caused, while the rest patients still have pain sensation, therefore, the 2- (4-isobutylphenyl) propionic acid is added as the adjuvant to effectively produce the pain-relieving and inflammation-diminishing effects for the patients.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.