KR101170940B1 - A process for preparing a crystalline pantoprazole sodium sesquihydrate - Google Patents

Abstract

The present invention comprises the steps of (a) dissolving pantoprazole in dichloromethane or chloroform; And (b) adding an aqueous sodium hydroxide solution to the solution obtained in step (a) to crystallize the same. Form 1 provides a method for preparing crystalline pantoprazole sodium sesquihydrate of Form-I.

In the preparation method of the present invention, Form-I crystalline pantoprazole sodium sesquihydrate can be prepared in a high yield without using a separate anti-solvent, and is also used as a solvent. Since the recovered dichloromethane or chloroform can be recovered and reused, the manufacturing cost can be greatly reduced, and environmental pollution due to the waste solvent can be reduced.

Crystalline Pantoprazole Sodium Sesquihydrate

Description

A process for preparing a crystalline pantoprazole sodium sesquihydrate

The present invention relates to a novel process for the preparation of crystalline pantoprazole sodium sesquihydrate of Form-I.

Pantoprazole sodium sesquihydrate is used in the treatment of antibiotics for the recurrence of gastroduodenal ulcers infected with Helicobacter pylori, gastric ulcer, duodenal ulcer, reflux esophagitis, etc., and is available in the form of tablets or injections. Pantoprazole sodium sesquihydrate has the structure of Formula 1, and various crystalline forms are known, including Form 1 (Form-I) and Form 2 (Form-II). Currently, pantoprazole sodium sesquihydrate, which is commercially available as a product, has a Form-I crystal form.

International Patent Publication No. WO91 / 19710 discloses a method for preparing a hydrate of pantoprazole sodium salt, but the obtained hydrate is in the form of a monohydrate rather than a sesquihydrate.

Journal of Medicinal Chemistry, 35, 1049-1057 (1992), dissolves pantoprazole in a mixed solvent of ethanol and dichloromethane (6: 1), adds an equivalent amount of 6N aqueous sodium hydroxide solution, and stirs at 20 ° C for 10 minutes. Diisopropyl ether was added as an anti-solvent until the solution became cloudy to obtain a method for obtaining pantoprazole sodium sesquihydrate crystal (Form-I).

In addition, U.S. Patent Publication No. 2004/0186139 discloses a solution of pantoprazole in a solvent at 20 to 50 ° C., followed by addition of an equivalent amount of 13.5 N aqueous sodium hydroxide solution, followed by the addition of an antisolvent, until the precipitate is formed, thereby producing a solution of -10 to It has been disclosed a method (yield: 7.2 to 89.9%) of obtaining pantoprazole sodium sesquihydrate crystals having a crystal form of Form 1 after cooling to 20 ° C. At this time, methanol, ethanol, normal-propanol, isopropanol, normal-butanol, secondary butanol, tert-butanol, tetrahydrofuran, acetonitrile, ethyl acetate, etc. are used, and as antisolvent, petroleum ether, hexane, normal-heptane, cyclo Hexane, cycloheptane, dichloromethane, chloroform, dimethyl ether, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether and the like are used.

However, the conventional manufacturing method is a manufacturing method through a solvent / anti-solvent system, and since at least two solvents (ie, a solvent and an antisolvent) must be used, a large amount of mixed solvent is required. In addition, there is a problem in that the use of, and to recover and reuse the used solvent and / or mixed solvent requires a separate fractional distillation equipment, if not equipped with the waste treatment as it is not manufactured There is a problem that increases and causes environmental pollution.

In addition, International Patent Publication Nos. 2004/056804 and US Patent Publication No. 2004/0177804 disclose various types of crystal forms, and disclose a method for preparing monohydrate, sesquihydrate, or solvate thereof. Regarding the preparation of double sesquihydrates, pantoprazole sodium sesquis may be recrystallized or suspended in a solvent of pantoprazole sodium salt (formula 5-7%) having a crystalline form of Form II as a starting material. Hydrate is prepared and 2-propanol, teprahydrofuran, acetonitrile, ethanol, water, secondary-butanol: dichloromethane (5: 4), dichloromethane, ethyl acetate, dimethyl carbonate, and the like are used as the solvent. Of these, when ethanol or the like is used as a solvent, heptane or ether-based solvents should be used as antisolvents for crystal formation. These antisolvents are flammable and explosive, which makes them difficult to apply to industrial sites. Do. In addition, the preparation method should be prepared by adjusting the crystalline form in the starting material step, to use as a starting material to prepare a crystalline pantoprazole sodium sesquihydrate of Form 1 using this preparation method The pantoprazole sodium salt having a crystalline form of Form 1 (Form-I) must be prepared separately.

In addition, International Patent Publication No. 2004/056804 and US Patent Publication No. 2004/0177804 disclose methods for preparing pantoprazole sodium sesquihydrate using pantoprazole as a starting material (Examples 61 to 61). 64), pantoprazole sodium sesquihydrate is prepared by a solvent / anti-solvent system, the Journal of Medicinal Chemistry, 35, 1049-1057 (1992) and US Patent Publication No. 2004 / Problems in the manufacturing method according to 0186139 are intact.

In addition, U.S. Patent Publication No. 2005/0096352 discloses azeotropic distillation at 30 ° C by adding pantoprazole to a 30% sodium methoxide methanol solution, stirring under reflux, cooling to 35 ° C, adding water and toluene, and at a temperature not exceeding 35 ° C under reduced pressure. distillation) to remove methanol, extraction with water and methyl ethyl ketone, extraction and concentration, and cooling to 20 ° C. to obtain pantoprazole sodium sesquihydrate crystals in 70.8% yield. Since the manufacturing method is complicated and shows a low yield (70.8%).

Furthermore, when the crystalline pantoprazole sodium sesquihydrate of Form-I is prepared according to the conventional preparation methods, the product may not crystallize [Journal of Medicinal Chemistry, 35, 1049-1057 (1992) or very high yield variations and very low yields (e.g., in the case of US 2004/0186139, yields in the examples range from 7.2% to 89.9%).

The inventors have developed a method for preparing crystalline pantoprazole sodium sesquihydrate of Form-I, which solves the problems of the prior art by using pantoprazole which is a readily available raw material as a starting material. As a result of studies, when using dichloromethane or chloroform as a solvent, high yields of crystalline pantoprazole sodium sesquihydrate of Form-I without the use of a separate anti-solvent It can be prepared, and can be used to recover and reuse the used solvent can not only significantly reduce the manufacturing cost, but also to significantly reduce the environmental pollution caused by the waste solvent was completed the present invention.

Accordingly, an object of the present invention is to provide a method for preparing crystalline pantoprazole sodium sesquihydrate of Form 1 (Form-I).

According to one aspect of the invention, (a) dissolving pantoprazole in dichloromethane or chloroform; And (b) adding an aqueous sodium hydroxide solution to the solution obtained in step (a) to crystallize. Form 1 provides a method for preparing crystalline pantoprazole sodium sesquihydrate of Form-I.

The preparation method of the present invention uses a readily available pantoprazole as a starting material, using dichloromethane or chloroform as a solvent, without using a separate anti-solvent (Form-I) Crystalline pantoprazole sodium sesquihydrate can be prepared in high yield. In particular, the dichloromethane or chloroform is a solvent used as an anti-solvent in a conventional solvent / anti-solvent system (US Patent Publication No. 2004/0186139), It is surprising that it can be used as a solvent in a single solvent system. In addition, the manufacturing method of the present invention can recover and reuse the dichloromethane or chloroform used as a solvent, not only can greatly reduce the manufacturing cost, but also greatly reduce the environmental pollution caused by waste solvent.

Dichloromethane or chloroform used as the solvent in step (a) is preferably used in a ratio of 5 to 100 ml per 1 g of pantoprazole, and considering the yield of the product, at least 15 ml per 1 g of pantoprazole. It is preferable to use the above (that is, 15-100 ml), and it is more preferable to use 15-45 ml. When the amount of solvent is small, stirring is not easy, and a warming process may be required to completely dissolve the solvent. In addition, the dichloromethane or chloroform may be used in excess of 100 ml per 1 g of pantoprazole. In this case, however, the reaction yield may not be significantly affected, and the manufacturing cost may be unnecessarily increased.

The aqueous sodium hydroxide solution used in the preparation method of the present invention is a solution prepared by dissolving solid sodium hydroxide in water, and the amount of water used is changed depending on the amount of pantoprazole and the amount of dichloromethane or chloroform used as a solvent. Can be. For example, when using 15 to 45 ml of dichloromethane or chloroform for 1 g of pantoprazole, water is used in an amount of 0.2 to 0.6 ml, more preferably about 0.2 ml per 1 g of pantoprazole. Can be. If the amount of water used is too high, the yield may be reduced or crystals may not be formed, and if it is too small, it may not be possible to dissolve the desired amount of sodium hydroxide. In addition, the amount of sodium hydroxide is preferably used in the range of stoichiometric equivalents to pantoprazole.

In the preparation method of the present invention, the crystallization step (step (b)) may be crystallized by adding ethanol after the crystallization is started (about 5-20 minutes). When ethanol is added during the crystallization step, ethanol acts as a phase-transfer between the sodium hydroxide solution and the pantoprazole solution, thereby facilitating mixing to form a more homogeneous and white product, Form. Crystalline pantoprazole sodium sesquihydrate of I) can be obtained. The amount of ethanol used may be changed depending on the amount of pantoprazole and the amount of dichloromethane or chloroform used as a solvent. For example, when using 15 to 45 ml of dichloromethane or chloroform for 1 g of pantoprazole, ethanol may be used in an amount of 0.1 to 0.5 ml, more preferably about 0.25 ml per 1 g of pantoprazole. Can be. When the amount of ethanol is increased, the yield is lowered or crystals are not produced.

In the manufacturing method of the present invention, since dichloromethane or chloroform used as a solvent can be recovered and reused in the manufacturing process, the manufacturing cost can be greatly reduced, and environmental pollution due to waste solvent can be greatly reduced. The recovery process of the solvent may be performed according to a conventional method, for example, when the solvent is carried out using a rotary evaporator may recover the solvent in a recovery rate of 90% or more. Even when the solvent thus recovered is reused and applied to the production method of the present invention, similar results can be obtained in terms of yield and crystal properties (see Example 30 below).

The preparation method of the present invention can carry out the reaction at room temperature and complete the reaction within a short reaction time (eg about 1 hour). In addition, the crystalline pantoprazole sodium sesquihydrate of Form-I prepared as described above may be obtained by drying in a conventional manner, for example, at about 45 ° C. under reduced pressure for about 7 to 10 hours. have. The crystalline pantoprazole sodium sesquihydrate thus obtained has a water content of 6.0 to 7.0% (Kalfisher, 500 mg).

The production method of the present invention has obtained the same result even in the mass synthesis of 500g scale, and thus the production method of the present invention is a production method suitable for mass production on an industrial scale.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are only for illustrating the present invention and the present invention is not limited thereto.

Example 1.

After dissolving 5 g (13.04 mmoles) of pantoprazole in 100 ml of dichloromethane, 521.6 mg (13.04 mmoles) of sodium hydroxide was added dropwise with 1 ml of water, followed by rapid stirring at 20 to 25 ° C. After about 5 minutes, crystallization started, and after 1 hour, the reaction solution was filtered, and the obtained crystals were washed with 50 ml of dichloromethane. The reaction mixture was dried for 8 hours at 45 ° C. under reduced pressure in a vacuum drying oven to give 5.36 g of crystalline pantoprazole sodium sesquihydrate of almost white Form-I.

Yield: 95%

Water content rate (Karl Fischer, 500mg): 6.56%

¹ H-NMR (DMSO-d ₆ ) ppm: 3.76 (3H, s), 3.89 (3H, s), 4.36 (1H, d), 4.62 (1H, d), 6.73 (1H, dd), 7.03 (1H , t), 7.08 (1H, d), 7.25 (1H, d), 7.45 (1H, d), 8.22 (1H, d)

Crystalline pantoprazole sodium sesquihydrate of Form 1 obtained above (Form-I) The XRD values are shown in Table 1.

2θ (°) century(%) 2θ (°) century(%) 5.334 100.00 25.329 3.14 7.394 2.24 26.323 2.28 10.626 0.44 27.098 3.93 11.524 1.26 27.869 3.01 12.482 0.42 28.741 1.58 13.018 1.45 29.494 2.42 13.405 1.59 30.886 0.77 14.531 2.66 31.998 1.11 15.326 1.06 32.601 1.84 15.909 2.21 33.667 1.52 16.643 4.98 34.123 0.67 17.616 2.04 34.760 1.38 17.969 1.59 35.608 0.60 18.360 1.05 37.706 2.61 20.064 4.24 38.532 0.61 20.608 4.75 41.460 0.57 21.272 1.43 41.776 0.78 22.231 5.28 43.523 1.49 22.832 3.36 44.029 1.26 23.353 1.59 45.411 0.27 24.042 2.81 46.040 0.40 24.493 3.14 47.980 0.44 24.966 1.57 49.233 0.61

From the moisture content it was confirmed that the product is sesquihydrate, and from the XRD value it was confirmed that the crystalline form of the product is Form 1 (Form-I).

Example 2-9.

The same procedure as in Example 1 was repeated except that the solvent and the amount of solvent were changed. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1. However, Examples 2 and 3 were heated to about 37 ± 2 ℃ to dissolve pantoprazole.

Solvent Solvent amount (ml) Yield (g, (%)) Moisture content (%) Example 2 Dichloromethane 25 4.65 (82) 6.54 Example 3 Dichloromethane 50 4.81 (85) 6.54 Example 4 Dichloromethane 75 5.11 (91) 6.56 Example 5 Dichloromethane 200 5.34 (95) 6.56 Example 6 Dichloromethane 300 5.32 (94) 6.56 Example 7 Dichloromethane 400 5.35 (95) 6.56 Example 8 Dichloromethane 500 5.30 (94) 6.58 Example 9 chloroform 100 5.32 (94) 6.29

Example 10.

After dissolving 5 g (13.04 mmoles) of pantoprazole in 100 ml of dichloromethane, 521.6 mg (13.04 mmoles) of sodium hydroxide was added dropwise with 2 ml of water, followed by rapid stirring at 20 to 25 ° C. After about 5 minutes, crystallization started, and after 1 hour, the reaction solution was filtered, and the obtained crystals were washed with 50 ml of dichloromethane. The reaction mixture was dried for 8 hours at 45 ° C. under reduced pressure in a vacuum drying oven to obtain 4.40 g of a nearly white crystalline pantoprazole sodium sesquihydrate of Form-I. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1.

Yield: 78%

Water content rate (Karlfisher, 500mg): 6.21%

Examples 11-19.

The same procedure as in Example 10 was repeated except that the type of solvent and the amount of water used were changed. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1.

Solvent Quantity (ml) Yield (g, (%)) Moisture content (%) Example 11 Dichloromethane One 5.36 (95) 6.30 Example 12 Dichloromethane 3 2.90 (51) 6.33 Example 13 Dichloromethane 5 Crystal not formed - Example 14 Dichloromethane 10 Crystal not formed - Example 15 chloroform One 5.33 (95) 6.23 Example 16 chloroform 2 4.30 (76) 6.21 Example 17 chloroform 3 2.70 (48) 6.25 Example 18 chloroform 5 Crystal not formed - Example 19 chloroform 10 Crystal not formed -

Example 20.

After dissolving 5 g (13.04 mmoles) of pantoprazole in 100 ml of dichloromethane, 521.6 mg (13.04 mmoles) of sodium hydroxide was added dropwise with 1 ml of water, followed by rapid stirring at 20 to 25 ° C. After about 5 minutes crystallization started, at which time 0.5 ml of ethanol was added. After 1 hour, the reaction solution was filtered, and the obtained crystals were washed with 50 ml of dichloromethane. The reaction mixture was dried in a vacuum drying oven at 45 ° C. for 8 hours under reduced pressure to obtain 4.81 g of white Form-I crystalline pantoprazole sodium sesquihydrate. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1.

Yield: 85%

Water content rate (Karlfisher, 500mg): 6.31%

Examples 21-29.

The same procedure as in Example 17 was repeated except for changing the type of solvent, the amount of use, and the amount of ethanol. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1.

menstruum Solvent amount (ml) Ethanol amount (ml) Yield (g, (%)) Moisture content (%) Example 21 Dichloromethane 200 0.5 5.38 (95) 6.30 Example 22 Dichloromethane 100 One 4.49 (80) 6.30 Example 23 Dichloromethane 200 One 5.26 (93) 6.32 Example 24 Dichloromethane 100 3 2.71 (48) 6.28 Example 25 Dichloromethane 200 3 3.20 (57) 6.27 Example 26 Dichloromethane 100 5 Crystal not formed - Example 27 Dichloromethane 200 5 0.73 (13) 6.33 Example 28 chloroform 100 0.5 4.71 (84) 6.27 Example 29 chloroform 200 0.5 5.21 (92) 6.32

Example 30.

500 ml of dichloromethane used in Example 8 was recovered using a rotary evaporator, and 450 ml (recovery rate: 90%) was recovered.

5 g (13.04 mmoles) of pantoprazole was dissolved in 200 ml of dichloromethane recovered above, 521.6 mg (13.04 mmoles) of sodium hydroxide was added dropwise with 1 ml of water, followed by rapid stirring at 20 to 25 ° C. After about 5 minutes crystallization started, at which time 0.5 ml of ethanol was added. After 1 hour, the reaction solution was filtered, and the obtained crystals were washed with 50 ml of dichloromethane recovered above. The reaction mixture was dried in a vacuum drying oven at 45 ° C. for 8 hours under reduced pressure to obtain 5.05 g of white Form-I crystalline pantoprazole sodium sesquihydrate. The ¹ H-NMR and XRD values of the obtained product were the same or equivalent to those of Example 1.

Yield: 90%

Water content rate (Karlfisher, 500mg): 6.30%

In the preparation method of the present invention, Form-I crystalline pantoprazole sodium ses using a dichloromethane or chloroform as a solvent for dissolving pantoprazole without using a separate anti-solvent. It is possible to prepare the hydrate in high yield, and also to recover and reuse the dichloromethane or chloroform used as the solvent, which can greatly reduce the manufacturing cost and reduce the environmental pollution caused by the waste solvent.

Claims (5)

(a) dissolving pantoprazole in dichloromethane or chloroform in a ratio of 5 to 100 ml per 1 g of pantoprazole; And (b) adding an aqueous sodium hydroxide solution prepared by dissolving sodium hydroxide in 0.2 to 0.6 ml of water per 1 g of pantoprazole to the solution obtained in step (a) to crystallize Method for producing a crystalline pantoprazole sodium sesquihydrate of Form 1 (Form-I) comprising a. delete The method according to claim 1, wherein the amount of dichloromethane or chloroform used is 15 to 45 ml per 1 g of pantoprazole. delete The method according to claim 1 or 3, wherein after crystallization is started in step (b), 0.1 to 0.5 ml of ethanol is added to 1 g of pantoprazole to crystallize.