阅读说明：本技术 一种他达拉非有关物质i的制备方法 (Preparation method of tadalafil-related substances I ) 是由 崔波 肖光林 黄超民 严紫薇 邓祥林 于 2019-12-04 设计创作，主要内容包括：本发明公开了一种他达拉非有关物质I的制备方法。该制备方法以他达拉非为起始原料,在有机溶剂中与过氧酸发生氧化反应,再经碱作用重排,柱层析纯化得到他达拉非有关物质I。<Image he="211" wi="700" file="DDA0002302307360000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of tadalafil related substances I, which comprises the steps of taking tadalafil as a starting raw material, carrying out oxidation reaction with peroxy acid in an organic solvent, carrying out rearrangement under the action of alkali, and carrying out column chromatography purification to obtain the tadalafil related substances I.)

1. the preparation of tadalafil related substance I comprises the following steps:

(1) reacting tadalafil with peroxy acid in organic solvents 1, quenching the reaction by using a reducing agent, and concentrating to obtain a compound shown as a formula II;

(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;

(3) and (3) purifying the crude product of the tadalafil related substance I obtained in the step (2) by column chromatography to obtain the tadalafil related substance I.

2. The preparation method according to claim 1, wherein the organic solvent 1 in the step (1) is or more selected from dichloromethane, chloroform, carbon tetrachloride and tetrahydrofuran, preferably dichloromethane.

3. The method according to claim 1, wherein the peroxy acid of step (1) is: peracetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid, or peroxysulfuric acid, preferably 3-chloroperoxybenzoic acid.

4. The production method according to claim 1, wherein the reducing agent in the step (1) is: sodium thiosulfate, sodium sulfite, or dimethyl sulfide.

5. The method according to claim 1, wherein the reaction temperature in the step (1) is: reaction at-30 to 40 ℃, preferably 15 to 30 ℃.

6. The method according to claim 1, wherein the reaction time in the step (1) is: 5 minutes to 1.5 hours.

7. The preparation method according to claim 1, wherein the organic solvent 2 in step (2) is or more selected from ethanol, isopropanol, n-butanol and methanol, preferably methanol.

8. The process according to claim 1, wherein the base used in step (2) is kinds or more selected from sodium ethoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, preferably sodium methoxide.

9. The production method according to claim 1, wherein the reaction temperature in the step (2): 30-85 ℃;

optionally, the reaction time of step (2) is: 10 minutes to 2 hours.

10. The preparation method according to claim 1, wherein the column chromatography purification method of step (3) is performed by eluting with single solvents or any two mixed solvents of ethyl acetate, petroleum ether, n-hexane, n-heptane, dichloromethane and methanol.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of tadalafil related substances I.

Background

Chemical name of Tadalafil (Tadalafil): (6R,12aR) -6- (1, 3-benzodioxol-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione, having the following structural formula:

tadalafil, an phosphodiesterase v (PDE-5) inhibitor, was marketed in the united states in 2003 under the trade name of celecoxib (Cialis), a drug used to treat male Erectile Dysfunction (ED) compared to other anti-ED drugs, tadalafil has a rapid onset of action and a longest duration of action, and is only of the four current anti-ED drugs unaffected by high fat diet and alcohol intake.

The tadalafil is collected in pharmacopoeia such as USP, EP, BP and the like, EP9.0 contains nine tadalafil-related substances A, B, C, D, E, F, G, H and I, only two documents reporting the preparation method of the tadalafil-related substance I at present, CN109796461A reports that the tadalafil is subjected to a method for obtaining the tadalafil-related substance I through the peroxidative rearrangement in an N-halogenated diimide, glacial acetic acid, tetrahydrofuran and water system, the reaction time of the method is relatively long, a large amount of sodium carbonate is used for neutralizing the glacial acetic acid in the post-treatment, the yield is low, and a paper (Qianpeng flying, "the synthesis of the tadalafil and the research of the related substances [ D ], Suzhou university, 2016) refers to a method for preparing the tadalafil-related substance I through the oxidation of D-tryptophan methyl ester hydrochloride, the total reaction is 4 steps, and the total yield is only 11.7%, so that synthesis methods which are simple and feasible are necessary to be developed, wherein the tadalafil-related substance I has the following structural formula:

disclosure of Invention

The invention provides a preparation method of tadalafil related substances I, which has the advantages of easily obtained raw materials, simple operation and high product purity, and provides a high-quality impurity reference substance for tadalafil quality research.

The invention provides a preparation method of tadalafil-related substances I, which comprises the following steps:

(1) reacting tadalafil with peroxy acid in organic solvents 1, quenching the reaction by using a reducing agent, and concentrating to obtain a compound shown as a formula II;

(2) dissolving the compound shown in the formula II obtained in the step (1) in an organic solvent 2 to react with alkali for rearrangement, and concentrating and extracting reaction liquid to obtain crude products of tadalafil related substances I;

(3) and (3) purifying the crude product of the tadalafil related substance I obtained in the step (2) to obtain the tadalafil related substance I.

In the above preparation method, wherein the reaction of steps (1) and (2) may be monitored by TLC.

In the above preparation method, the organic solvent 1 in step (1) is or more selected from dichloromethane, chloroform, carbon tetrachloride and tetrahydrofuran, preferably dichloromethane, the peroxy acid is peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid, or peroxysulfuric acid, preferably 3-chloroperoxybenzoic acid, and the reducing agent is sodium thiosulfate, sodium sulfite, or dimethyl sulfide.

In the preparation method, the reaction temperature of the reaction in the step (1) is-30-40 ℃, and the reaction is preferably 15-30 ℃; the reaction time is 5 minutes to 1.5 hours.

In the above preparation method, the organic solvent 2 in step (2) is or more selected from ethanol, isopropanol, n-butanol and methanol, preferably methanol, and the base is or more selected from sodium ethoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, preferably sodium methoxide.

In the preparation method, the reaction temperature of the reaction in the step (2) is 30-85 ℃, and the reaction time is 10 minutes-2 hours.

In the above preparation method, the purification in the step (3) is a column chromatography purification method, and elution is carried out using a single kinds of solvents or a mixed solvent among ethyl acetate, petroleum ether, n-hexane, n-heptane, methylene chloride, methanol and the like.

The invention has the advantages that brand-new methods for preparing tadalafil related substances I are provided, the raw materials are easy to obtain, the operation is simple, the product purity is high, and high-quality impurity reference substances are provided for tadalafil quality research.

The specific implementation mode is as follows:

for a better understanding of the contents of the invention, the invention is illustrated in below with reference to the following examples, which should not be construed as limiting the invention in any way.