阅读说明：本技术 一种普拉洛芬杂质的制备方法 (Preparation method of pranoprofen impurity ) 是由 陈容 汪国松 徐杨 徐朗 杨尚志 于 2021-07-28 设计创作，主要内容包括：本发明提供一种普拉洛芬杂质的制备方法,包括以下步骤：A)将化合物1和双氧水在溶剂中加热至回流,进行反应,得到化合物2；B)将化合物2、甲醇和混酸混合,进行酯化反应,得到具有式I结构的普拉洛芬杂质粗品；C)将所述具有式I结构的普拉洛芬杂质粗品进行重结晶,得到具有式I结构的普拉洛芬杂质。本发明以(RS)-2-(10H-9-噁-1-氮杂蒽-6-基)丙酸(1)为起始物,经过两步合成反应步骤得到普拉洛芬杂质粗品,粗品经过重结晶纯化得到终产物普拉洛芬杂质((RS)-2-(9-噁-10-酮-1-氮杂蒽-6-基)丙酸甲酯),产物经质谱和核磁检测,检测数据结果与杂质结构信息相符合,并且具有较高的纯度和收率。(The invention provides a preparation method of pranoprofen impurity, which comprises the following steps: A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2; B) mixing the compound 2, methanol and mixed acid, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I; C) and recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I. The method takes (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) as an initial material, a pranoprofen impurity crude product is obtained through two steps of synthetic reaction steps, the crude product is recrystallized and purified to obtain a final product of the pranoprofen impurity ((RS) -2- (9-oxa-10-one-1-azaanthracene-6-yl) methyl propionate), and the product is subjected to mass spectrum and nuclear magnetic detection, so that the detection data result accords with the impurity structure information, and the purity and the yield are high.)

1. A preparation method of pranoprofen impurity comprises the following steps:

A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2;

B) mixing the compound 2, methanol and mixed acid, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I;

C) recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I;

2. the preparation method according to claim 1, wherein the molar ratio of the compound 1 to hydrogen peroxide is 1: (3-10).

3. The method according to claim 1, wherein the reflux reaction is carried out for 24 to 48 hours.

4. The method according to claim 1, wherein after the reaction in step a), water and ethyl acetate are added, an organic phase is obtained by extraction, and compound 2 is obtained by concentration.

5. The method according to claim 1, wherein the molar ratio of compound 2 to methanol is 1: (4-10).

6. The production method according to claim 1, wherein the mixed acid is a mixed acid of p-toluenesulfonic acid and hydrochloric acid, a mixed acid of p-toluenesulfonic acid and trifluoroacetic acid, or a mixed acid of hydrochloric acid and acetic acid.

7. The preparation method according to claim 1, wherein the molar ratio of the mixed acid to the compound 2 is 1: (2-5).

8. The preparation method according to claim 1, wherein the temperature of the reaction in the step B) is 50-60 ℃; the reaction time is 3-5 hours.

9. The preparation method according to claim 1, wherein after the reaction in step B), water and dichloromethane are added, an organic phase is obtained by extraction, and the organic phase is concentrated to obtain a crude pranoprofen impurity product having a structure shown in formula I.

10. The preparation method according to claim 1, wherein the solvent used for recrystallization comprises one or more of ethanol, isopropanol, ethyl acetate and n-heptane.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a pranoprofen impurity.

Background

Pranoprofen, chemically named 2-5H- [1] benzopyran [2,3-b ] pyridin-7-yl propionic acid, has significant analgesic, anti-inflammatory, antipyretic and antirheumatic effects.

Pranoprofen propionic acid derivatives are nonsteroidal anti-inflammatory analgesics, and can inhibit biosynthesis of prostaglandin to exert antipyretic, analgesic and anti-inflammatory effects. The inhibition effect of pranoprofen on rabbit fever is stronger than that of indomethacin, ibuprofen and aspirin, and almost no influence is caused on normal body temperature; in the experiment that Lipopolysaccharide (LPS) causes fever of rabbits, syrup is used for oral administration, and the antipyretic effect is dose-dependent. In addition, animal experiments also show that pranoprofen has stronger analgesic effect than ibuprofen and aspirin.

Pranoprofen impurity can be prepared according to the following route:

in the second step of reaction, impurities shown as formula I are generated, and the research on the impurities is important for producing the high-purity pranoprofen product.

Disclosure of Invention

The invention provides a preparation method of pranoprofen impurity, which can prepare the pranoprofen impurity shown in the formula I, and has high purity and high yield.

The invention provides a preparation method of pranoprofen impurity, which comprises the following steps:

A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2;

B) mixing the compound 2, methanol and mixed acid, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I;

C) recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I;

preferably, the molar ratio of the compound 1 to hydrogen peroxide is 1: (3-10).

Preferably, the time of the reflux reaction is 24-48 hours.

Preferably, after the reaction in the step a) is finished, water and ethyl acetate are added, an organic phase is obtained by extraction, and the compound 2 is obtained after concentration.

Preferably, the molar ratio of the compound 2 to the methanol is 1: (4-10).

Preferably, the mixed acid is a mixed acid of p-toluenesulfonic acid and hydrochloric acid, a mixed acid of p-toluenesulfonic acid and trifluoroacetic acid, or a mixed acid of hydrochloric acid and acetic acid.

Preferably, the molar ratio of the mixed acid to the compound 2 is 1: (2-5).

Preferably, the reaction temperature in the step B) is 50-60 ℃; the reaction time is 3-5 hours.

Preferably, after the reaction in the step B) is completed, water and dichloromethane are added, an organic phase is obtained by extraction, and a pranoprofen impurity crude product having a structure shown in formula I is obtained by concentration.

Preferably, the solvent used for recrystallization comprises one or more of ethanol, isopropanol, ethyl acetate and n-heptane.

The invention provides a preparation method of a pranoprofen impurity, which comprises the following steps: A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2; B) mixing the compound 2, methanol and mixed acid, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I; C) and recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I. According to the invention, (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) is used as an initial material, a pranoprofen impurity crude product is obtained through two steps of synthetic reaction steps, the crude product is recrystallized and purified to obtain a final product, namely, the pranoprofen impurity ((RS) -2- (9-oxa-10-one-1-azaanthracene-6-yl) methyl propionate), the product is subjected to mass spectrum and nuclear magnetic detection, and the detection data result conforms to the structure information of the impurity II and has higher purity and yield.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.

FIG. 1 is a mass spectrum of the product of example 1 of the present invention;

FIG. 2 is a nuclear magnetic hydrogen spectrum of the product of example 1 of the present invention;

FIG. 3 is a nuclear magnetic carbon spectrum of the product of example 1 of the present invention.

Detailed Description

The invention provides a preparation method of a pranoprofen impurity, which comprises the following steps:

A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2;

B) mixing the compound 2, methanol and a sulfonic acid catalyst, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I;

C) recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I;

the preparation route of the invention is shown as formula II:

the method preferably comprises the steps of mixing a compound 1((RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid) with a solvent, stirring to dissolve the compound 1, adding hydrogen peroxide, heating to reflux, and carrying out an oxidation reaction for 24-48 hours to form a carbonyl group. And then cooling to 0-10 ℃, adding water and ethyl acetate, continuously stirring for 0.5-2 hours at room temperature, standing, separating liquid, reserving an organic phase, and concentrating the organic phase to dryness to obtain a compound 2 which can be directly used for the next reaction.

In the present invention, the solvent for dissolving the compound 1 is preferably one or more of ethanol, propanol, isopropanol and n-butanol; the molar ratio of the hydrogen peroxide to the compound 1 is preferably (3-10): 1, more preferably (5-8): 1, most preferably (5-6): 1.

the time of the oxidation reaction is preferably 24 to 48 hours, such as 24 hours, 28 hours, 30 hours, 32 hours, 34 hours, 36 hours, 38 hours, 40 hours, 42 hours, 44 hours, 46 hours or 48 hours, and is preferably a range value in which any of the above values is an upper limit or a lower limit.

In the present invention, the water and ethyl acetate act as extractants.

In the present invention, the concentration method is not particularly required, and a concentration method commonly used by those skilled in the art may be adopted, and specifically, in the embodiment of the present invention, a rotary evaporator may be used for rotary evaporation concentration.

After the compound 2 is obtained, preferably, the compound 2 is dissolved in methanol, then mixed acid is added to carry out esterification reaction, after the esterification reaction is finished, water and ethyl acetate are added, stirring is continued for 0.5-2 hours at room temperature, standing and liquid separation are carried out, an organic phase is left, and then the organic phase is concentrated to be dry, so that an impurity crude product is obtained.

In the present invention, the molar ratio of the compound 2 to methanol is preferably 1: (3-10), more preferably 1: (5-8); the mixed acid is preferably a mixed acid of p-toluenesulfonic acid and hydrochloric acid, a mixed acid of p-toluenesulfonic acid and trifluoroacetic acid or a mixed acid of hydrochloric acid and acetic acid; the molar ratio of the mixed acid to the compound 2 is 1: (2-5), more preferably 1: (3-4).

The temperature of the esterification reaction is preferably 50-60 ℃, such as 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃ and 60 ℃, and is preferably a range value taking any value as an upper limit or a lower limit; the esterification time is preferably 3-5 hours, and more preferably 3-4 hours; the esterification reaction is preferably carried out under stirring, and the stirring rate is not particularly limited in the present invention.

In the present invention, the water and ethyl acetate act as extractants.

In the present invention, the concentration method is not particularly required, and a concentration method commonly used by those skilled in the art may be adopted, and specifically, in the embodiment of the present invention, a rotary evaporator may be used for rotary evaporation concentration.

After the crude impurity is obtained, the crude impurity is preferably dissolved by using a solvent, and the pranoprofen impurity with the structure of the formula I is obtained after recrystallization, filtration and drying.

In the invention, the solvent is preferably one or more of ethanol, isopropanol, ethyl acetate and n-heptane. The number of the recrystallization is preferably 1.

In the invention, the drying temperature is preferably 50-60 ℃; the drying time is preferably 12-24 hours.

The invention provides a preparation method of a pranoprofen impurity, which comprises the following steps: A) heating the compound 1 and hydrogen peroxide in a solvent to reflux, and reacting to obtain a compound 2; B) mixing the compound 2, methanol and mixed acid, and carrying out esterification reaction to obtain a pranoprofen impurity crude product with a structure shown in a formula I; C) and recrystallizing the pranoprofen impurity crude product with the structure shown in the formula I to obtain the pranoprofen impurity with the structure shown in the formula I. According to the invention, (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) is used as an initial material, a pranoprofen impurity crude product is obtained through two steps of synthetic reaction steps, the crude product is recrystallized and purified to obtain a final product, namely, the pranoprofen impurity ((RS) -2- (9-oxa-10-one-1-azaanthracene-6-yl) methyl propionate), the product is subjected to mass spectrum and nuclear magnetic detection, and the detection data result conforms to the structure information of the impurity II and has higher purity and yield.

In order to further illustrate the present invention, the following examples are provided to describe the preparation method of pranoprofen impurity provided by the present invention in detail, but should not be construed as limiting the scope of the present invention.

Example 1

Adding 10 g of (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) into a 500 ml reaction bottle, adding 150 ml of ethanol, stirring to dissolve the materials, then adding 50 ml of hydrogen peroxide, heating to reflux for reaction for 24 hours, cooling to 0-10 ℃, adding water and ethyl acetate, continuously stirring for 0.5 hour at room temperature, standing, separating, reserving an organic phase, concentrating the organic phase to dryness, and obtaining a compound 2 concentrate which is directly used for the next reaction.

Dissolving the compound 2 concentrate in 10 times of methanol, adding 10 g of mixed acid of p-toluenesulfonic acid and 10 g of hydrochloric acid, stirring and reacting for about 5 hours at 50 ℃, cooling to room temperature, adding water and dichloromethane, continuously stirring for 0.5 hour at room temperature, standing, separating liquid, taking an organic phase, and concentrating the organic phase to dryness to obtain a pranoprofen impurity II crude product.

Dissolving the pranoprofen impurity II crude product with 6 times of ethanol as a solvent, recrystallizing, filtering, and drying to obtain an impurity II fine product.

The structure of the pranoprofen impurity II is confirmed,

pranoprofen impurity II having molecular formula C₁₆H₁₃NO₄And the molecular weight is 283.28.

Mass ESI + showed (fig. 1) that the molecular ion peak of the compound was 284.1(M +1), indicating that the molecular weight of the compound was about 283.2, which corresponds to the molecular weight of pranoprofen impurity II.

The nuclear magnetic hydrogen spectrum shows (figure 2), the compound has 8 groups of nuclear magnetic hydrogen signals, 13 hydrogens in total, and the chemical shifts (delta, ppm) are respectively 8.72-8.76 (2H, Ar-H), 8.22-8.23 (1H, Ar-H), 7.76-7.77 (1H, Ar-H), 7.60-7.62 (1H, Ar-H), 7.44-7.48 (1H, Ar-H), 3.90-3.92 (1H, CHCH)₃)，3.67～3.69(3H，CO₂CH₃)，1.59～1.69(3H，CHCH₃) The number of 13 hydrogens contained in the formula of pranoprofen impurity II is consistent, and the comparison of each group of hydrogen signals one by one is also consistent with the structural information of the compound.

The nuclear magnetic carbon spectrum (figure 3) shows that the compound has 16 nuclear magnetic carbon signals, the chemical shifts (delta, ppm) are 177.46, 174.30, 160.33, 154.89, 154.24, 137.39, 137.21, 135.11, 125.35, 121.41, 121.12, 118.95, 116.70, 52.26, 44.79 and 18.45 respectively, the nuclear magnetic carbon spectrum corresponds to the number of 16 carbons contained in the pranoprofen impurity II molecular formula, and the structural information of the compound is also matched by comparing the carbon signals one by one.

The above information was combined to conclude that the synthesized compound was pranoprofen impurity II, and the chemical structure is shown in fig. 1.

Example 2

Adding 10 g of (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) into a 500 ml reaction bottle, adding 150 ml of ethanol, stirring to dissolve the materials, then adding 60 ml of hydrogen peroxide, heating to reflux for reaction for 24 hours, cooling to 0-10 ℃, adding water and ethyl acetate, continuously stirring for 0.5 hour at room temperature, standing, separating, reserving an organic phase, concentrating the organic phase to dryness, and obtaining a compound 2 concentrate which is directly used for the next reaction.

Dissolving the compound 2 concentrate in 10 times of methanol, adding mixed acid of 11 g of p-toluenesulfonic acid and 10 g of hydrochloric acid, stirring and reacting for about 5 hours at 50 ℃, cooling to room temperature, adding water and dichloromethane, continuously stirring for 0.5 hour at room temperature, standing, separating liquid, taking an organic phase, and concentrating the organic phase to dryness to obtain a pranoprofen impurity II crude product.

Dissolving the pranoprofen impurity II crude product with 6 times of ethanol as a solvent, recrystallizing, filtering, and drying to obtain an impurity II fine product.

Example 3

Adding 10 g of (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) into a 500 ml reaction bottle, adding 150 ml of ethanol, stirring to dissolve the materials, then adding 70 ml of hydrogen peroxide, heating to reflux for reaction for 24 hours, cooling to 0-10 ℃, adding water and ethyl acetate, continuously stirring for 0.5 hour at room temperature, standing, separating, reserving an organic phase, concentrating the organic phase to dryness, and obtaining a compound 2 concentrate which is directly used for the next reaction.

Dissolving the compound 2 concentrate in 10 times of methanol, adding 10 g of mixed acid of acetic acid and 10 g of hydrochloric acid, stirring and reacting for about 5 hours at 50 ℃, cooling to room temperature, adding water and dichloromethane, continuously stirring for 0.5 hour at room temperature, standing, separating liquid, reserving an organic phase, and concentrating the organic phase to dryness to obtain the pranoprofen impurity II crude product.

Dissolving the pranoprofen impurity II crude product with 6 times of ethanol as a solvent, recrystallizing, filtering, and drying to obtain an impurity II fine product.

Example 4

Adding 10 g of (RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propionic acid (1) into a 500 ml reaction bottle, adding 150 ml of ethanol, stirring to dissolve the materials, then adding 60 ml of hydrogen peroxide, heating to reflux for reaction for 24 hours, cooling to 0-10 ℃, adding water and ethyl acetate, continuously stirring for 0.5 hour at room temperature, standing, separating, reserving an organic phase, concentrating the organic phase to dryness, and obtaining a compound 2 concentrate which is directly used for the next reaction.

Dissolving the compound 2 concentrate in 10 times of methanol, adding mixed acid of 11 g of p-toluenesulfonic acid and 10 g of trifluoroacetic acid, stirring and reacting for about 5 hours at 60 ℃, cooling to room temperature, adding water and dichloromethane, continuing stirring for 0.5 hour at room temperature, standing, separating liquid, taking an organic phase, and concentrating the organic phase to dryness to obtain a crude pranoprofen impurity II.

Dissolving the pranoprofen impurity II crude product with 6 times of ethanol as a solvent, recrystallizing, filtering, and drying to obtain an impurity II fine product.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.