CN113710655B

CN113710655B - Method for purifying haloperidol

Info

Publication number: CN113710655B
Application number: CN202080025740.4A
Authority: CN
Inventors: 陈小林; 杨易可; 占娅锋; 高鹏飞; 孙晔
Original assignee: Shanghai Xudong Haipu Pharmaceutical Co ltd
Current assignee: Shanghai Xudong Haipu Pharmaceutical Co ltd
Priority date: 2019-04-22
Filing date: 2020-01-13
Publication date: 2023-08-11
Anticipated expiration: 2040-01-13
Also published as: CN113710655A; WO2020215835A1; CN109970624B; CN109970624A

Abstract

The method for purifying haloperidol comprises the steps of dissolving the prepared haloperidol crude product in a hot DMSO solution, and filtering to remove dimeric impurities which are insoluble in DMSO, thus obtaining the haloperidol with qualified dimeric impurities. According to the purification method of haloperidol, the prepared crude haloperidol is added into a hot DMSO solution, so that dimeric impurities generated in synthesis are efficiently removed, and the content of the dimeric impurities of the obtained haloperidol is lower than 0.05w/w%.

Description

Method for purifying haloperidol

Technical Field

The invention relates to a method for preparing a butyryl benzene compound, in particular to a method for purifying haloperidol, which improves the purity of the product.

Background

Haloperidol is acute and chronic in all kinds of schizophrenia and mania. Intramuscular injection of the product can rapidly control agitation, hostile emotion and aggressive behavior, and can be used for treating brain organic mental disorder and senile mental disorder.

The synthetic process route is shown in the following formula I:

the second reaction step of the route is easy to produce a plurality of impurities, particularly dimeric impurities are difficult to remove, and active drug molecules with qualified purity cannot be obtained, as shown in the following formula II:

the conventional refining means is to remove the impurities by dissolving in an organic solvent and then recrystallizing.

Disclosure of Invention

The invention aims to provide a method for purifying haloperidol, which removes dimeric impurities generated in a haloperidol synthesis process, improves the purity of a product and prepares active drug molecules with qualified purity.

A method of purifying haloperidol comprising:

dissolving the prepared haloperidol crude product in a hot DMSO solution (for example, at the temperature of more than 50 ℃), and filtering to remove dimeric impurities which are insoluble in DMSO, thus obtaining the haloperidol with qualified dimeric impurities.

Another method for purifying haloperidol, comprising:

dissolving the prepared haloperidol crude product in a DMSO solution at 70-90 ℃ to separate out dimeric impurities from the DMSO solution, and removing the dimeric impurities which are insoluble in DMSO in a filtering mode;

then, after the filtrate is cooled, obtaining precipitated haloperidol;

and then adding absolute ethyl alcohol into the separated haloperidol, homogenizing (such as pulping) to remove DMSO solvent residues, and obtaining the haloperidol with the dimeric impurity content lower than 0.05w/w%.

According to the method for purifying haloperidol, provided by the invention, the temperature of the DMSO solution is preferably 80+/-0.5 ℃.

The technical scheme of the invention has the beneficial effects that:

according to the purification method of haloperidol, the prepared crude haloperidol is added into a hot DMSO solution, so that dimeric impurities generated in synthesis are efficiently removed, and the content of the dimeric impurities of the obtained haloperidol is lower than 0.05w/w%.

Compared with the prior art, the purification method provided by the invention is safe and efficient, has high product yield, and does not need to change the original purification process.

Detailed Description

The technical scheme of the present invention is described in detail below. The embodiments of the present invention are only for illustrating the technical scheme of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical scheme of the present invention, which is intended to be covered by the scope of the claims of the present invention.

EXAMPLE 1 preparation of haloperidol crude product (170826 batches, dimeric impurity content: 0.38 w/w%)

A500 mL reaction flask was charged with starting material III (10.01 g), intermediate (28.40 g), sodium carbonate (10.01 g), potassium iodide (3.92 g) and methyl isobutyl ketone (200 mL), heated to 130℃and stirred for reaction for 6 hours (HPLC detection starting material III < 5.0%), cooled to 50℃and stirred with water (100 mL) for 0.5h, the organic layer was separated, the organic layer continued to drop to 10-20℃for crystallization, filtered, the filter cake was washed with a small amount of methyl isobutyl ketone, and air-dried at 55℃to give 14.7g of the product with a yield of 82.7%.

EXAMPLE 2 preparation of haloperidol crude product (170808 batch, dimeric impurity content: 0.57 w/w%)

The reaction flask is added with a starting material III (20.1 g), an intermediate (57.0 g), potassium iodide (0.80 g), sodium carbonate (20.0 g) and methyl isobutyl ketone (600 mL), heated and stirred, reacted for 6 hours at 130 ℃ (the starting material III is less than 5.0 percent detected by HPLC), cooled to 50 ℃, added with water (200 mL) and stirred for 0.5 hour, an organic layer is separated, the organic layer is continuously cooled to 10 ℃ -20 ℃ for crystallization, filtered, a filter cake is washed by a small amount of methyl isobutyl ketone, and the filter cake is dried by blowing at 55 ℃ to obtain 30.0g of a product, and the yield is 84.1 percent.

EXAMPLE 3 purification of crude haloperidol

1.0g (batch 170821-2) of crude product, 10mL of absolute ethyl alcohol, stirring and heating to 70 ℃, dropwise adding 2mL of water after dissolving, cooling to 10-20 ℃, filtering, and drying by blowing at 55 ℃ to obtain 0.80g, wherein the yield is 80.0%.

In this example, the solvent was purified: the purity of ethanol/water, i.e. the haloperidol of the crude product is 89.37%, and after purification, 99.12% and the content of dimeric impurities is about 0.4w/w%, which indicates that the dimeric impurities are not significantly removed, and other impurities are significantly removed.

EXAMPLE 4 purification of crude haloperidol

3.0g (batch 170901-2) of crude product, 90mL of isopropanol, stirring and heating to 90 ℃, carrying out heat filtration after dissolving, cooling and crystallizing the filtrate, cooling to 5-10 ℃, stirring for 1-2 hours, filtering, and carrying out forced air drying on the filter cake at 55 ℃ to obtain 2.60g of product with 86.7 percent of yield.

In this example, the solvent was purified: after isopropanol is heated and dissolved, the yield is 86.7%, the content of dimeric impurities is about 0.3w/w%, and the removal effect is not obvious.

EXAMPLE 5 purification of crude haloperidol

400mL of absolute ethyl alcohol is added into a 500mL reaction bottle, stirring and heating are carried out, 70 ℃ is carried out, 20.05g (batch 170928-1) of crude product is added, after the crude product is dissolved, hot filtration, cooling crystallization, stirring for 1-2 hours at 10-20 ℃, filtration and filter cake washing are carried out by using a small amount of absolute ethyl alcohol, 16.52g of air blast drying is carried out at 55 ℃, and the yield is 82.39%.

In this example, the ethanol yield was 82.39%, the dimeric impurity content was about 0.35w/w%, and the removal effect was insignificant.

EXAMPLE 6 purification of crude haloperidol

Adding 50.00g of crude product (batch 171018-1) into a 2L reaction bottle, heating 300mL of DMSO to 80-90 ℃, stirring for 2h, hot filtering, cooling to room temperature, continuously stirring and crystallizing at 10-20 ℃ for 1-2 h, filtering to obtain a filter cake (the filter cake is directly subjected to the next step without drying), refluxing and pulping the filter cake with absolute ethyl alcohol (500 mL) for 2h, cooling to 10-20 ℃, filtering, washing the filter cake with a small amount of absolute ethyl alcohol, and air-blast drying the filter cake at 55 ℃ for 8h to obtain 43.00g of product with the yield of 86.0%

In this example, the solvent was purified: DMSO, total yield: 86%, the content of dimeric impurity is 0.04w/w%, and the removal effect is obviously improved.

Claims

1. A method for purifying haloperidol, which is characterized by comprising the following steps:

dissolving the prepared haloperidol crude product in a hot DMSO solution, and filtering to remove dimeric impurities which are insoluble in DMSO, thus obtaining haloperidol with qualified dimeric impurity content;

the dimerization impurity is shown in the following formula:

the haloperidol is synthesized by the following steps:

2. the method for purifying haloperidol according to claim 1, wherein the DMSO solution temperature is greater than 50 ℃.

3. The method for purifying haloperidol according to claim 1, wherein the DMSO solution has a temperature of 70-90 ℃.

4. The method for purifying haloperidol according to claim 1, wherein the DMSO solution has a temperature of 80.+ -. 0.5 ℃.

5. The method for purifying haloperidol according to claim 1, wherein the content of dimeric impurities is less than 0.05w/w%.

6. A method for purifying haloperidol, which is characterized by comprising the following steps:

then, after the filtrate is cooled, obtaining precipitated haloperidol;

then, absolute ethyl alcohol is added into the separated haloperidol, and the mixture is homogenized to remove DMSO solvent residues, so that haloperidol with dimeric impurity content lower than 0.05w/w% is obtained; the dimerization impurity is shown in the following formula:

the haloperidol is synthesized by the following steps:

7. the method for purifying haloperidol according to claim 6, wherein the DMSO solution has a temperature of 80.+ -. 0.5 ℃.