CN111410626B

CN111410626B - Preparation method of silodosin alpha-crystal form

Info

Publication number: CN111410626B
Application number: CN201910006237.3A
Authority: CN
Inventors: 李文华; 王松; 西亮; 魏帅
Original assignee: Shanghai Huilun Pharmaceutical Co ltd
Current assignee: Shanghai Huilun Hubei Pharmaceutical Co ltd; Shanghai Huilun Pharmaceutical Co ltd
Priority date: 2019-01-04
Filing date: 2019-01-04
Publication date: 2022-11-04
Anticipated expiration: 2039-01-04
Also published as: CN111410626A

Abstract

The invention provides a preparation method of a silodosin alpha-crystal form, which comprises the following steps: dissolving silodosin in a solvent, and cooling and crystallizing to obtain the silodosin crystal; the solvent comprises a good solvent and a poor solvent, the good solvent comprises a ketone solvent, and the poor solvent comprises an ether solvent and/or an alkane solvent. The preparation method provided by the invention is simple to operate, the obtained product is high in yield, the solvent residue is low, and the drying time can be obviously reduced.

Description

Preparation method of silodosin alpha-crystal form

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a silodosin alpha-crystal form.

Background

Silodosin, also known as Silodosin, is an alpha-form of a drug developed by kumquat industries co ₁ -adrenoceptor antagonists useful in the treatment of dysuria.

Silodosin is chemically known as 1- (3-hydroxypropyl) -5- [ (2R) -2- ({ 2- [2- (2, 2-trifluoroethoxy) phenoxy ] ethyl } amino) propyl ] -2, 3-dihydro-1H-indole-7-carboxamide and has the following structural formula:

three crystalline forms (alpha-, beta-and gamma-forms) of silodosin and methods for their preparation are disclosed in patent CN 03824796.8. The alpha-crystal form preparation method disclosed by the patent is to heat and dissolve silodosin in ethyl acetate and then cool the silodosin, but researches show that the residual solvent amount of the alpha-crystal form silodosin complex ethyl acetate prepared by the method still reaches 1.5% -2.5% even if the alpha-crystal form silodosin complex ethyl acetate is dried for 16 hours, and the residual ethyl acetate amount is still very high (0.5% -1.5%) even if higher drying temperature (70-80 ℃) is adopted and the drying time is further prolonged, so that the medicinal requirement cannot be met. Therefore, there is a need in the art for a method for preparing crystalline silodosin alpha-form with reduced solvent residue.

Disclosure of Invention

The invention aims to solve the problem that solvent residues are easy to exceed the standard in the existing preparation process of the silodosin alpha-crystal form, and further provides a novel preparation method of the silodosin alpha-crystal form. The preparation method comprises the steps of dissolving silodosin in a solvent, and cooling and crystallizing, wherein the solvent comprises a good solvent and a poor solvent. The method is simple to operate, and the obtained product is high in yield, high in purity, low in solvent residue and high in application and market popularization prospects.

The invention provides a preparation method of a silodosin alpha-crystal form shown in a formula I, which comprises the following steps:

dissolving silodosin in a solvent, and cooling and crystallizing;

the solvent comprises a good solvent and a poor solvent, the good solvent comprises a ketone solvent, and the poor solvent comprises an ether solvent and/or an alkane solvent.

In the present invention, the ketone solvent is preferably one or more of methyl ethyl ketone, acetone, cyclohexanone, methyl butanone, and methyl isobutyl ketone, and more preferably one or more of methyl ethyl ketone, acetone, cyclohexanone, and methyl isobutyl ketone. When the ketone solvent of the present invention is a mixture of a plurality of ketones, the volume ratio of each ketone is not particularly limited as long as the experimental purpose can be achieved, and for example, the mixture may be equal in volume.

In the present invention, the ether solvent is preferably one or more of diethyl ether, dipropyl ether, dibutyl ether, isopropyl ether and methyl tert-butyl ether, more preferably methyl tert-butyl ether and/or isopropyl ether. When the ether solvent of the present invention is a mixture of a plurality of ether substances, the volume ratio of the various ether substances is not particularly limited as long as the experimental purpose can be achieved.

In the invention, the alkane solvent is C ₄ -C ₁₀ An alkane solvent, preferably C ₅ -C ₈ The alkane solvent is preferably one or more selected from n-hexane, cyclohexane, n-heptane and n-octane, and more preferably n-hexane and/or n-heptane. If the alkane solvent is a mixture of a plurality of alkanes, the volume ratio of the alkanes is not particularly limited as long as the experimental purpose can be achieved.

In the present invention, the volume ratio of the good solvent to the poor solvent is 1.

In the present invention, the mass-to-volume ratio of silodosin to good solvent is preferably 1 to 10g/ml, more preferably 1 to 5g/ml.

In the invention, the mass volume ratio of the silodosin to the poor solvent is 1 to 20g/ml, preferably 1.

In the present invention, the method for dissolving silodosin in the solvent may be a conventional dissolving method in the art, such as dissolving by heating, and the heating temperature may be 30 to 80 ℃, and more preferably 40 to 70 ℃.

The cooling method in the present invention may be a cooling method that is conventional in the art, and the cooling temperature is 20 ℃ or less, preferably 10 ℃ or less, and more preferably 5 ℃ or less.

In the invention, when the silodosin alpha-crystal form is prepared, crystal seeds of the alpha-crystal form and the beta-crystal form can be optionally added or not added for inducing crystallization.

The preparation method of the silodosin alpha-crystal form can also comprise the operations of filtering and drying after crystallization. The filtration may be a filtration operation conventional in the art, such as vacuum filtration and the like. The drying may be a drying operation conventional in the art, such as vacuum drying, etc., and the drying temperature is preferably 20 to 80 ℃, more preferably 40 to 70 ℃.

In the present invention, the term room temperature may be defined as room temperature as is conventional in the art, and unless otherwise specified, generally means an ambient temperature of 25 ℃.

The preparation method of the silodosin alpha-crystal form adopts the good solvent and the poor solvent as the crystallization solvents, is simple to operate, has high product yield, high purity and less solvent residue, can obviously reduce the drying time, and has high application and market popularization prospects.

Drawings

Fig. 1 is an X-ray diffraction pattern of silodosin in the form of a-crystal prepared in example 1.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.

The X-ray diffraction analysis instrument of the invention has the following types: d/max-2550VB/PCX ray powder polycrystal diffractometer; experimental conditions current 330 μ a, ka1=1.54060, ka2=1.54433, ka2/Ka1 ratio =0.5, ka =1.54184.

Other reagents or samples used in the experiment are prepared by self-made or commercial products or are prepared by methods reported in the prior literature.

Example 1: preparation and determination of alpha-crystal silodosin

Adding 20.0 g of silodosin into a mixed solvent of 60ml of good solvent acetone and 80ml of poor solvent methyl tert-butyl ether, heating to 50 ℃ for dissolution, adding a small amount of alpha-crystal form seed crystal for induced crystallization, dropwise adding 160ml of methyl tert-butyl ether, cooling to 0-5 ℃ for crystallization, filtering, collecting crystals, and performing vacuum drying for 8 hours to obtain 19.43 g of alpha-crystal form silodosin, wherein the yield is 97.15%, the HPLC purity is 99.72%, the acetone residue is 0.035%, and the methyl tert-butyl ether residue is not detected.

The obtained crystal is subjected to X-ray diffraction pattern measurement, the characteristic peaks are shown in figure 1, the 2 theta angles of the main peaks are respectively 5.380, 5.920, 9.679, 10.940, 12.040, 16.260, 19.500 and 19.779, and the data are consistent with the X-ray diffraction pattern data of the alpha-crystal form silodosin reported in the literature.

Example 2

Adding 20.0 g of silodosin into a mixed solvent of 40ml of good solvent acetone and 160ml of poor solvent methyl tert-butyl ether, heating to 60 ℃ for dissolution, cooling to below 10 ℃ for crystallization, filtering, collecting crystals, and drying for 6 hours to obtain 18.94 g of alpha-crystal silodosin with the X-ray diffraction pattern shown in figure 1, wherein the yield is 94.7%, the HPLC purity is 99.67%, and the acetone residue is 0.039%; methyl tert-butyl ether residue was not detected.

The crystalline silodosin α -form was prepared by selecting different crystallization solvents and crystallization conditions according to the preparation methods of the above examples 1 or 2, and the experimental conditions and results were as follows:

note: in example 10, induction was performed by adding beta seeds.

Comparative example 1

Adding 130 g of silodosin into 1300ml of ethyl acetate, heating to 50 ℃ for dissolution, then cooling for crystallization, filtering and collecting crystals, and carrying out vacuum drying at 50 ℃ for 16 hours to obtain 120.2 g of alpha-crystal silodosin with the yield of 92.5%. HPLC purity 96.81%, ethyl acetate residue 1.5554%.

Comparative example 2

Adding 20g of silodosin into 100ml of ethyl acetate, heating to 50 ℃ for dissolving, dropwise adding 200ml of n-heptane, cooling to 0-5 ℃ after dropwise adding, crystallizing, filtering, collecting crystals, and drying at 50 ℃ for 18 hours to obtain 18.79 g of alpha-crystal silodosin with the yield of 93.95%. HPLC purity 97.83%, ethyl acetate residual 1.23%, n-heptane residual 0.086%.

Claims

1. A process for preparing silodosin α -form, comprising the steps of:

heating and dissolving silodosin in a solvent, and cooling and crystallizing;

the solvent comprises a good solvent and a poor solvent, the good solvent is acetone, and the poor solvent is methyl tert-butyl ether or isopropyl ether;

the volume ratio of the good solvent to the poor solvent is 1-8;

the heating temperature is 40-70 ℃.

2. The preparation method according to claim 1, wherein the mass-to-volume ratio of silodosin to good solvent is 1;

the mass volume ratio of the silodosin to the poor solvent is 1.

3. The method for preparing silodosin α -form according to claim 1, wherein the mass/volume ratio of silodosin to good solvent is 1; the mass volume ratio of the silodosin to the poor solvent is 1.

4. The process for preparing crystalline silodosin α -form of claim 1, wherein the volume ratio of the good solvent to the poor solvent is 1.

5. The process for preparing crystalline silodosin α -form according to claim 1, wherein after dissolving by heating, silodosin seed crystals are added for crystallization.