CN112759570B - Method for synthesizing simvastatin impurity D - Google Patents

Abstract

The invention provides a method for synthesizing simvastatin impurity D, which comprises the following steps: taking simvastatin which is a raw material medicine and is easy to obtain as an initial raw material, firstly opening a ring of lactone, then protecting two hydroxyl groups in a molecule by using acetonide, condensing an obtained intermediate with the simvastatin which is a raw material medicine of another molecule, and finally removing the acetone which is a protecting group by using hydrochloric acid to obtain a simvastatin impurity D. The method provided by the invention takes the cheap and easily available raw material medicine simvastatin as an initial raw material, obtains a final target product through four-step reaction, has a simple and economic whole reaction route and very strong practical value, can be used for preparing a large amount of simvastatin, is used for guiding production, and also fills the blank of no report about the compound synthesis method at present.

Description

Method for synthesizing simvastatin impurity D

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing simvastatin impurity D.

Background

Simvastatin was extracted from aspergillus terreus, was first developed by the merck pharmaceutical factory and began to enter medical use in 1992. The drug is named in the basic drug list of the world health organization, belongs to one of essential drugs of the basic medical system, and therefore, the quality of the drug needs to be strictly controlled. Simvastatin impurity D (structural formula I below) is an inevitable impurity in the production of simvastatin, and it is shown in the reaction solution to be 0.24% based on data of US 2004/19225. Therefore, the workload of extracting simvastatin impurity D from the reaction liquid for preparing simvastatin is large and the operation is complex. However, no synthesis method of simvastatin impurity D has been reported. Therefore, the synthesis method of the simvastatin impurity D is provided, and has important significance for preparing impurity standard products and controlling the quality of simvastatin.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a method for synthesizing simvastatin impurity D, which can conveniently obtain a large amount of simvastatin impurity D, avoid the huge workload of extracting impurities from production samples, and provide important technical support for production and drug declaration.

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

the invention provides a method for synthesizing simvastatin impurity D, which takes simvastatin as an initial raw material, firstly, lactone is subjected to ring opening, then two hydroxyls in a molecule are protected by an acetonide, an obtained intermediate is condensed with another molecule of raw material medicine simvastatin, and finally, acetone on a protecting group is removed by hydrochloric acid to obtain the simvastatin impurity D.

Further, the method comprises the following steps:

step one, simvastatin, calcium hydroxide, tetrahydrofuran (THF) and water are mixed and react; then filtering the reaction product to obtain filtrate, and removing partial THF by spinning; finally, adjusting the pH value, extracting, drying and spin-drying to obtain an intermediate product 2;

step two, completely dissolving the intermediate product 2 in 2, 2-dimethoxypropane, then adding p-toluenesulfonic acid, stirring at room temperature, finally adding Ethyl Acetate (EA), washing with water, drying an organic phase, spin-drying, and separating by column chromatography to obtain an intermediate product 3;

step three, carrying out condensation reaction on the intermediate product 3 and simvastatin in Dichloromethane (DCM) to obtain an intermediate product 4;

step four, adding the intermediate product 4 and hydrochloric acid into a container containing tetrahydrofuran respectively, and reacting at room temperature; and after the reaction is completed, adding water and DCM, separating an organic phase, washing the organic phase once with water, drying, spin-drying the solvent, and performing column chromatography separation to obtain simvastatin impurity D.

Further, the ratio of simvastatin, calcium hydroxide, tetrahydrofuran and water in step one is 1mol.

Further, the reaction time in the first step is 40 to 80 minutes, preferably 60 minutes.

Further, in the step one, the pH value of the filtrate is adjusted to 2.5-4 by acid; preferably, the pH is adjusted to 3.

Further, the extractant used in the extraction in the first step is EA.

Further, the molar ratio of the intermediate product 2 to the p-toluenesulfonic acid is (8-12): 1, preferably 10.

Further, the stirring time in the second step is 20-40 minutes; preferably 30 minutes.

Further, the molar ratio of intermediate 3 to simvastatin was 1: (0.8-1.2); preferably 1.

Further, in the third step, 1, 3-dicyclohexyl carbodiimide (DCC) and 4-Dimethylaminopyridine (DMAP) are added into a reaction substrate for reaction for 40-80 minutes; preferably, the reaction time is 60 minutes.

Further, the molar ratio of DCC, DMAP to intermediate 3 was 0.239:0.0196:0.199.

further, the reaction time in the fourth step is 3 to 6 hours, preferably 4 hours.

Further, the concentration of hydrochloric acid in the fourth step is 1N; the addition ratio of intermediate 4, hydrochloric acid, tetrahydrofuran was 0.5g:1.5ml:100ml.

By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:

the method for synthesizing simvastatin impurity D provided by the invention takes cheap and easily available raw material simvastatin as an initial raw material, and obtains a final target product through four-step reaction.

Drawings

FIG. 1 is a HNMR map of simvastatin impurity D synthesized in one example of the present invention;

FIG. 2 is an ESI-MS spectrum of simvastatin impurity D synthesized in one example of the present invention.

Detailed Description

The invention provides a method for synthesizing simvastatin impurity D, which comprises the steps of taking easily-obtained raw material simvastatin as an initial raw material, firstly opening a lactone ring, then protecting two hydroxyl groups in a molecule by using acetonide, condensing an obtained intermediate with the other molecular raw material simvastatin, and finally removing protective group acetone by using hydrochloric acid to obtain a target product; the method specifically comprises the following steps:

step one, simvastatin, calcium hydroxide, THF and water are mixed and react; then filtering the reaction product to obtain filtrate, and removing partial THF by spinning; finally, adjusting the pH value, extracting, drying and spin-drying to obtain an intermediate product 2;

step two, completely dissolving the intermediate product 2 in 2, 2-dimethoxypropane, then adding p-toluenesulfonic acid, stirring at room temperature, finally adding EA, washing with water, drying an organic phase, spin-drying, and performing column chromatography separation to obtain an intermediate product 3;

step three, carrying out condensation reaction on the intermediate product 3 and simvastatin in DCM to obtain an intermediate product 4;

step four, adding the intermediate product 4 and hydrochloric acid into a container containing tetrahydrofuran respectively, and reacting at room temperature; and after the reaction is completed, adding water and DCM, separating an organic phase, washing the organic phase once with water, drying, spin-drying the solvent, and performing column chromatography separation to obtain simvastatin impurity D.

In a preferred embodiment of the invention, the ratio of simvastatin, calcium hydroxide, tetrahydrofuran and water in step one is 1mol.

In a preferred embodiment of the present invention, the reaction time in step one is 40 to 80 minutes, more preferably 60 minutes.

In a preferred embodiment of the invention, the pH of the filtrate is adjusted to 2.5-4 in step one with an acid; more preferably, the pH is adjusted to 3.

In a preferred embodiment of the invention, the extractant employed in the extraction in step one is EA.

In a preferred embodiment of the present invention, the molar ratio of intermediate 2 to p-toluenesulfonic acid is (8-12) to 1, more preferably 10.

In a preferred embodiment of the present invention, the stirring time in the second step is 20 to 40 minutes; more preferably 30 minutes.

In a preferred embodiment of the invention, the molar ratio of intermediate 3 to simvastatin is 1:

(0.8-1.2); more preferably 1.

In a preferred embodiment of the invention, in step three, DCC and DMAP are added into the reaction substrate for reaction, and the reaction time is 40-80 minutes; more preferably, the reaction time is 60 minutes.

In a preferred embodiment of the invention, the molar ratio of DCC, DMAP to intermediate 3 is 0.239:0.0196:0.199.

in a preferred embodiment of the present invention, the reaction time in step four is 3 to 6 hours, more preferably 4 hours.

In a preferred embodiment of the present invention, the concentration of hydrochloric acid in step four is 1N; the addition ratio of intermediate 4, hydrochloric acid, tetrahydrofuran was 0.5g:1.5ml:100ml.

The present invention will be described in detail and specifically with reference to the following examples and drawings so as to provide a better understanding of the invention, but the following examples do not limit the scope of the invention.

In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.

Example 1

This example provides a method for synthesizing simvastatin impurity D, comprising the steps of:

step one, simvastatin (418.5mg, 1mmol), calcium hydroxide (74mg, 1mmol), THF (6 ml) and water (0.6 ml) are sequentially added into a 50ml three-necked bottle, reacted for 1 hour at room temperature, filtered, part of THF is removed from the filtrate, then acid is added to adjust ph =3, EA is used for extraction, and dried to obtain 376mg of intermediate 2, yield: and 90 percent.

Step two, sequentially adding the intermediate product 2 (208mg, 0.5mmol) and 2, 2-dimethoxypropane (0.25 ml) into a three-neck flask, stirring for 5min until the intermediate product is completely dissolved, then adding p-toluenesulfonic acid (5mg, 0.05mmol), stirring for 0.5 h at room temperature, adding EA, washing twice, drying an organic phase, spin-drying, and separating by column chromatography to obtain 106mg of an intermediate product 3, wherein the yield is as follows: and 47 percent.

Step three, adding the intermediate 3 (95mg, 0.199mmol), simvastatin (91.7mg, 0.219mmol), DCM (2 ml), DCC (49mg, 0.239mmol) and DMAP (2.4mg, 0.0196mmol) into a three-necked flask in sequence, reacting for 1 hour at room temperature, filtering, and separating 129mg of intermediate 4 by spin-dry column chromatography, wherein the yield is as follows: 70 percent.

Step four, sequentially adding the intermediate product 4 (0.5 g), 1NHCl (1.5 ml) and tetrahydrofuran (100 ml) into a three-necked bottle, reacting for 4 hours at room temperature, adding water and DCM after the reaction is completed, separating an organic phase, washing the organic phase once with water, drying, spin-drying the solvent, and separating by column chromatography to obtain 325mg of simvastatin impurity D, wherein the yield is as follows: 70% of the total content of the components, and HNMR and ESI-MS spectrograms of the components are respectively shown in figures 1-2.

The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims (9)

1. A method for synthesizing simvastatin impurity D is characterized in that simvastatin is used as an initial raw material, lactone is subjected to ring opening, two hydroxyls in a molecule are protected by an acetonide, an obtained intermediate is condensed with another molecule of raw material simvastatin, and finally, protective group acetone is removed by hydrochloric acid to obtain the simvastatin impurity D;

the method specifically comprises the following steps:

step one, simvastatin, calcium hydroxide, THF and water are mixed and react; then filtering the reaction product to obtain filtrate, and removing partial THF by spinning; finally, adjusting the pH value, extracting, drying and spin-drying to obtain an intermediate product 2;

step two, completely dissolving the intermediate product 2 in 2, 2-dimethoxypropane, then adding p-toluenesulfonic acid, stirring at room temperature, finally adding EA, washing with water, drying an organic phase, spin-drying, and performing column chromatography separation to obtain an intermediate product 3;

step three, carrying out condensation reaction on the intermediate product 3 and simvastatin in DCM to obtain an intermediate product 4;

step four, adding the intermediate product 4 and hydrochloric acid into a container containing tetrahydrofuran respectively, and reacting at room temperature; and after the reaction is completed, adding water and DCM, separating an organic phase, washing the organic phase once with water, drying, spin-drying the solvent, and performing column chromatography separation to obtain the simvastatin impurity D.

2. The method of claim 1, wherein the reaction time in step one is 40 to 80 minutes.

3. The method of claim 1, wherein the pH of the filtrate in step one is adjusted to 2.5-4 with an acid.

4. The process of claim 1, wherein the extractant used in the extraction in step one is EA.

5. The process of claim 1, wherein the molar ratio of intermediate 2 to p-toluenesulfonic acid is (8-12): 1.

6. the method of claim 1, wherein the molar ratio of intermediate 3 to simvastatin is 1: (0.8-1.2).

7. The method of claim 1, wherein DCC and DMAP are added to the reaction substrate in step three and the reaction is carried out for 40 to 80 minutes.

8. The method of claim 7, wherein the molar ratio of DCC, DMAP to intermediate 3 is 0.239:0.0196:0.199.

9. the method of claim 1, wherein the hydrochloric acid has a concentration of 1N in step four; the adding proportion of the intermediate product 4, hydrochloric acid and tetrahydrofuran is 0.5g:1.5ml:100ml.

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