KR20040081236A - Purification method of crystal form i of torasemide - Google Patents

Abstract

PURPOSE: A purification method of crystal form I of torasemide is provided, thereby reducing the time for purifying the crystal form I of torasemide, and improving the purity and yield thereof. CONSTITUTION: The purification method of crystal form I of torasemide represented by the formula(1) comprises the steps of: reacting a compound of the formula(2) with phenylchloroformate to prepare a compound of the formula(4), and reacting the compound of the formula(4) with isopropylamine to prepare the crystal form I of torasemide of the formula(1); and dissolving the crystal form I of torasemide of the formula(1) in a mixed solvent of water and water-soluble aprotic solvent such as acetone at 60 to 70 deg. C, and cooling the solvent to 5 to 10 deg. C.

Description

Purification method of the torasemide variant I {PURIFICATION METHOD OF CRYSTAL FORM I OF TORASEMIDE}

The present invention relates to a method for purifying the stable variant I of torasemide, in particular, while maintaining the modified variant of torasemide from the synthesis of torasemide, which is stable in the pharmaceutical purification state, the rearrangement of the variants is not necessary. The present invention relates to a purification method of torasemide variant I that can be purified in high yield and high purity through a simple method that can be performed in a short time.

Torasemide having a structure of Formula 1, ie, (1-isopropyl-3-[(4-m-toluidino-3-pyridyl) -sulfonyl] -urea; hereafter referred to as 'toracemide' Abbreviation) is a compound with interesting pharmaceutical properties as set forth in Example 25 16 025 of the Federal Republic of Germany and Example 71 to US Pat. No. 4,018,929.

[Formula 1]

In particular, such torasemide has a strong diuretic effect when the water and sodium ions are discharged more strongly than potassium ions. Therefore, the present compounds are very interesting as diuretics. In addition, the torasemide compound is used for the treatment of edema caused by congestive heart failure or cirrhosis or renal dysfunction, and in particular, may be used for the treatment of hypertension with other antihypertensive drugs.

For this torasemide, US Pat. No. 4,018,929 describes a preparation method summarized by Scheme 1 below.

Scheme 1

Wherein X is a halogen element and R ₇ is C ₁ -C ₄ alkyl.

That is, referring to Scheme 1, the torasemide of Formula 1 is prepared by reacting a compound of Formula 2 with isopropyl isocyanate [(CH ₃ ) ₂ CHNCO], or the compound of Formula 2 is represented by general formula XC (= 0) After reacting with a compound having a structure of OR ₇ to prepare a compound of Formula 3, the compound of Formula 3 is reacted with isopropylamine [(CH ₃ ) ₂ CHNH ₂ ] to prepare.

In addition, in the above-described method for producing torasemide, the torasemide prepared through the above method is dissolved in an aqueous solution of sodium hydrogen carbonate or an alcoholic aqueous solution, the impurities are filtered, and then the torasemide is further removed. By impregnating with acetic acid or carbon dioxide, the process of purifying the torasemide of Chemical Formula 1 is carried out. After such purification, the final product is obtained in the form of white crystals having a melting point of 163-164 ° C.

On the other hand, when a substance can exist in more than one crystalline form, this property is defined as polymorphism, and these different crystalline forms are called polymorphs. Different polymorphs of a material have different crystal lattice energies, whereby the polymorphs in the solid state exhibit differences in physical properties such as shape, density, melting point, color, stability, solubility, granularity, etc. These affect the manufacturability, stability, solubility and bioavailability of the formulation in the drug, and consequently affect the action of the drug.

It is known in the reference that torasemide of formula (1) can also appear as a variant with two different crystal forms X-ray crystallographically; [References, Acta Cryst., 1978, pp. 2659-2662 and Acta Cryst., 1978. pp. 1304-1310. Both variants of this torasemide appeared at the same time when the torasemide solution in petroleum ether / ethanol was slowly evaporated. Prismatic variants, referred to below as variant I, are crystallized monolithically in space group P2 ₁ / C, and small leafy variants, referred to below as variant II, are monolithically crystallized in space group P2 / n.

However, when the torasemide of Formula 1 having such characteristics is prepared according to the method disclosed in the U.S. Patent, the torasemide of Formula 1 is prepared in the form of a mixture containing a large amount of variant II, and the torasemide It has been found that the variant obtained when purified by dipping with carbon dioxide is variant II which is mainly caused when recrystallized with another solvent. When the variant II of the torasemide is also stored in the form of a pure active substance, its form does not change, and in the case of all purification experiments, it is assumed that the variant II is also a stable variant. Surprisingly, when the torasemide of variant II is present in the granular form of the pharmaceutical tablet, the dissolution rate and crystallite size of the active substance change significantly with the injection of the pharmaceutical tablet into water, thereby transforming the variant II to variant I rather quickly. It has been recently discovered that it is arranged.

However, as described above, the crystal form of the active substance included in the pharmaceutical tablet and thus the dissolution rate of the tablet is one of the important factors that may affect the pharmaceutical action of administration, such a crystal in one pharmaceutical tablet Although it is clear that the form and thus the dissolution rate of the tablets should be kept constant, when preparing torasemide pharmaceutical tablets through the manufacturing method and purification method according to the prior art, it is unstable in the state of pharmaceutical tablets in water Due to the problems of the prior art, a method for preparing and purifying stable variant I of torasemide, which is not rearranged in a pharmaceutical refined state, in high yield and high purity is mainly included. This is urgently needed.

Of course, Korean Patent Publication No. 1993-9818 discloses a modified torasemide variant II by adding a catalytic amount of torasemide variant I to a suspension of the torasemide variant II obtained according to the above-described preparation method. A method for preparing torasemide variant I, which is rearranged by I, is disclosed, but this method undergoes a rearrangement process for torasemide II, which takes a long time of at least 3-6 hours. Moreover, the complexity of the reaction conditions such as the use of an acid or a base as a catalyst may be brought about, and the decomposition of the torasemide may be caused during the rearrangement, so that the yield and purity thereof may also be lowered. I have it.

Accordingly, there is an urgent need for a method for preparing and purifying the torasemide stable variant I by a simple method that requires a short time without rearranging the torasemide variant.

The present invention, in order to solve the problems of the prior art as described above, can be purified in a high yield, high purity within a short time through a simple method that does not require rearrangement of the modified torasemide stable in the pharmaceutical purification state To provide a method for purifying variant I of torasemide.

1 is a diagram showing an infrared absorption spectrum of torasemide (prior to purification) prepared according to Example 1,

2 is a diagram showing an infrared absorption spectrum of torasemide variant I (after purification) prepared according to Example 1,

3 is a diagram showing an infrared absorption spectrum of torasemide (prior to purification) prepared according to Example 2,

4 is a diagram showing an infrared absorption spectrum of torasemide modified I (after purification) prepared according to Example 2. FIG.

In order to achieve this object, the present invention comprises the steps of preparing the torasemide of Formula 1; And purifying the prepared torasemide in a mixed solvent of an aprotic solvent and a water-soluble aprotic solvent.

[Formula 1]

The purification method is a method of separating and purifying only variant I in high purity among torasemides prepared in the form of a mixture containing a large amount of variant II according to the manufacturing method according to the prior art. As is evident from the examples, by purifying the torasemide of Chemical Formula 1 in a mixed solvent of an aqueous aprotic solvent and water, it was found that only variant I of high purity can be isolated and purified, thereby completing the present invention. It is. That is, according to the purification method according to the present invention, a long time is required, and a short time is required without having to undergo rearrangement of the variant II requiring complicated reaction conditions such as addition of an acid or base catalyst. Through a simple process, it is possible to isolate and purify the high purity torasemide variant I.

In the purification method of the torasemide variant I according to the present invention, the step of preparing the torasemide of formula (1) proceeds according to the prior art, that is, the method disclosed in U.S. Patent No. 4,018,929 et al. Torasemide can be prepared, but in particular, as shown in Scheme 2 below, a compound of Formula 2 is reacted with phenylchloroformate [PhOC (= O) Cl] to prepare a compound of Formula 4. It is preferred to proceed by reacting the compound of Formula 4 with isopropylamine to prepare torasemide of Formula 1.

Scheme 2

As described above, in the case of preparing torasemide according to a conventional method such as U.S. Patent No. 4,018,929, since a large amount of Variant II is included in the final torasemide prepared, the present invention relates to such torasemide. When the purification process of the, the yield of the torasemide variant I is lowered, but the results of the present inventors, when preparing torasemide through the production method using the phenylchloroformate as described above, Almost all of the torasemide is obtained in the form of Variant I, and after preparing Variant I of torasemide in this manner, the above-mentioned variant I of torasemide is purified in high purity through the purification method according to the present invention. By refine | purifying, it becomes possible to obtain further with high yield and high purity of the modified body I of torasemide.

In addition, in the purification method of the torasemide variant I according to the present invention, as the water-soluble aprotic solvent, all common aprotic solvents such as acetonitrile, dimethyl sulfoxide, tetrahydrofuran, acetone can be used, in particular, Preference is given to using acetone. In addition, when using the acetone, the acetone is preferably mixed with water in a ratio of 2: 1 to 4: 1. In addition, the purifying step of the torasemide is preferably proceeded at a temperature of 0 to 85 ℃, more preferably the torasemide of Formula 1 of water and a water-soluble aprotic solvent at a temperature of 60 to 70 ℃ After dissolving in a mixed solvent, it is preferable to proceed with the purification step of the torasemide by cooling to a temperature of 5 to 10 ℃.

Under the above temperature, by using the mixed solvent of acetone and water mixed in the same ratio as above to purify the torasemide of Formula 1, decomposition of the torasemide in the purification process can be minimized, the torasemide modified It is possible to maximize the yield of I and at the same time obtain high purity torasemide variant I in a shorter time.

Hereinafter, the present invention will be described in more detail with reference to a preferred embodiment of the purification method of torasemide variant I according to the present invention. However, this is presented as an example, and accordingly, the scope of the present invention is not determined.

Example 1 Preparation and Purification of Torasemide Variant I

A mixture of 3.0 g of compound of formula 2, 60 mL of acetone, 1.90 mL of triethylamine and 1.72 mL of phenylchloroformate was stirred at reflux for about 30 minutes. After cooling to room temperature, the resultant was concentrated and 150 mL of purified water was added thereto, followed by stirring at room temperature. This was filtered to obtain 3.6 g of the compound of formula (4).

Next, a mixture of 3.6 g of the compound of Formula 4, 36 mL of 1,2-dimethoxyethane and 1.19 mL of isopropylamine was stirred at reflux for about 1 hour at room temperature. After cooling to room temperature, 300 mL of purified water was added thereto, followed by stirring. Acetic acid was added to the mixture, followed by acidification, followed by filtration to obtain 2.74 g of the torasemide compound of Chemical Formula 1.

In order to confirm the variant I, the melting point of the torasemide compound and the infrared spectroscopy were confirmed, and the infrared absorption spectrum of the torasemide obtained through the infrared spectroscopy is shown in FIG. 1.

Thereafter, a mixture of 2.74 g of the torasemide compound of Formula 1, 75 mL of acetone, and 25 mL of purified water obtained through the manufacturing process as described above was dissolved by heating to 60 to 70 ° C, and then cooled to room temperature. This mixture was filtered to obtain 2.04 g of torasemide variant I of formula (1).

In order to identify the variant I, the melting point, the infrared spectrometer, and X-ray were confirmed, and the infrared absorption spectrum of the torasemide variant I obtained through the infrared spectrometer is shown in FIG. 2. As a result of quantification according to the method of the American Pharmacopoeia, the content of the torasemide variant I was obtained at least 98.0%.

Example 2 Preparation and Purification of Torasemide Variant I

A mixture of 1.97 g of compound of formula 2, 6 mL of acetonitrile, 2.08 mL of triethamine and 0.7 g of isopropyl isocyanate was stirred at room temperature for about 3 hours. The mixture was adjusted to pH 4.0-5.0 with 5% aqueous hydrochloric acid solution and stirred. The mixture was filtered to give 1.92 g of torasemide compound of formula (1).

In order to confirm variant II, the melting point of the torasemide compound and the infrared spectroscopy were confirmed, and the infrared absorption spectrum of the torasemide obtained through the infrared spectroscopy is shown in FIG. 3.

Thereafter, a mixture of 1.92 g of the torasemide compound of Formula 1, 45 mL of acetone, and 15 mL of purified water obtained through the manufacturing process as described above was heated to melt at 60 to 70 ° C., and then cooled to room temperature. This mixture was filtrated to obtain 1.4 g of <Formula 3>.

In order to confirm the variant I, the melting point, the infrared spectrometer, and X-ray, and the infrared absorption spectrum of the torasemide variant I obtained through the infrared spectrometer are shown in FIG. 4. As a result of quantification according to the method of the American Pharmacopoeia, the content of the torasemide variant I was obtained at least 98.0%.

Melting points of the torasemide variant I obtained through Examples 1 and 2 are as shown in Table 1 below.

TABLE 1

Item Example 1 Example 2 Before refining 159.5-160.5 ℃ 160.5-161.7 ℃ After purification 160.0-162.0 ℃ 160.5-162.0 ℃

For reference, US Pat. No. 4,743,693 and US Reissue No. 34,580 disclose that the melting point of variant I of torasemide is 162 ° C. and that of variant II is 169 ° C. That is, referring to the melting point of the torasemide purified in Examples 1 and 2, it can be seen that the variant I of high purity is obtained according to the purification method according to the present invention.

In addition, Variant I of the torasemide prepared in Examples 1 and 2 was measured using a Bruker-AXS SMART CCD System with LT-3 diffractometer to measure the single crystal of Variant I of the torasemide, thereby providing a basic Crystallographic data were obtained and compared to the reference for variant I of torasemide (Acta cryst., 1978 pp. 1304-1310), demonstrating that the variants obtained through the purification method according to the present invention are identical. .

References to variant I of torasemide (Acta cryst., 1978 pp. 1304-1310) and crystallographic data (diffraction for single crystals) for variant I obtained through Examples 1 and 2 are given in Table 2 below. As shown.

TABLE 2

Parametric Determination Variant I (Reference) Example 1 Example 2 Measures conversion Measures conversion Space grid P 2 ₁ / c P 2 ₁ / c P 2 ₁ / c P 2 ₁ / c P 2 ₁ / c a (Å) 13.308 13.274 13.274 13.27 (2) 13.27 (2) b (Å) 8.233 8.234 8.234 8.244 (9) 8.244 (9) c (Å) 31.970 30.759 c '= 31.857 30.78 (4) c '= 31.822 (4) b (Å) 107.01 97.560 β '= 106.84 97.8 (1) β '= 106.6 (1) V (Å ^з ) 3345.5 3333 3332 3337 (7) 3336 (7)

As can be seen from Table 1, 2 and the attached Figures 1 to 4, according to the purification method of the torasemide variant I according to the present invention, a high purity of 98.0% or more through a simple method requiring only a short time Thus, it is possible to obtain a variant I of torasemide that is stable in a pharmaceutical refined state, and when applying the same production method using phenylchloroformate as in Example 1, the torasemide is synthesized from the process of synthesizing torasemide. It can be seen that is prepared almost in the form of variant I, by preparing the torasemide through this preparation method, and then purifying the variant I of the torasemide through the purification method of the present invention, It can be seen that variant I can be obtained with higher yield and higher purity.

As described above, according to the present invention, complex reaction conditions such as requiring a catalyst of an acid or a base are required, and can be carried out in a simple manner that can be performed in a short time without undergoing a rearrangement process of the transformant which takes a long time. It is possible to purify the stable variant I of the semid with high yield and high purity, and furthermore, by applying a two-step manufacturing process using phenylchloroformate for the preparation of the torasemide, the tora from the synthesis of torasemide Since the modified I of the semid can be maintained at a high yield, by applying the purification method of the present invention to the modified I again, the modified I of the torasemide can be further purified in high yield and high purity. .

Claims (6)

Preparing torasemide of Formula 1; And Purifying the torasemide variant I characterized in that it comprises the step of purifying in a mixed solvent of water-soluble aprotic solvent (aprotic solvent) and water. [Formula 1] The method of claim 1, wherein the preparing torasemide of Formula 1 is carried out by reacting a compound of Formula 2 with phenylchloroformate to prepare a compound of Formula 4, as shown in Scheme 2 below. A process for purifying toramidide variant I characterized by reacting the compound of formula 4 with isopropylamine to produce torasemide of formula 1. Scheme 2 3. The process of claim 1 or 2, wherein acetone is used as the water-soluble aprotic solvent. 4. The process of claim 3, wherein the acetone is mixed with water in a ratio of 2: 1 to 4: 1. 5. The process for purifying torasemide variant I according to claim 1, 2 or 4, characterized in that the purifying step of the torasemide proceeds at a temperature of 0 to 85 ° C. According to claim 5, The purifying step of the torasemide dissolves the torasemide of formula 1 in a mixed solvent of water and a water-soluble aprotic solvent at a temperature of 60 to 70 ℃, then cooled to a temperature of 5 to 10 ℃ The process of purifying torasemide variant I characterized by advancing.