ME00197B - New process for the preparation of trihydrate of magnesium salt of s-omeprasole - Google Patents

Abstract

The present invention relates to a novel process for the preparation of a novel form of the (-) - enantiomer of 5-rnetoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -nethyl] sulfinyl] -1H-benzimidazole, i. S-omeprazole. More specifically, it relates to a process for the preparation of S-omeprazole magnesium salt trihydrate. The invention further disclosed relates to novel intermediates used in this process. The present invention relates to a novel process for the preparation of a novel form of the (-) - enantiomer of 5-rnetoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -nethyl] sulfinyl] -1H-benzimidazole, i. S -omeprazole. More specifically, it relates to a process for the preparation of the magnesium salt trihydrate of S -omeprazole. The invention further disclosed relates to novel intermediates used in this process.

Description

This invention relates to a new process for obtaining a new form of (-)-enantiomer 5-methoxy-2-[[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzim[dazoia, ie S-omeprazole. In more detail, it refers to a new procedure for obtaining a new form of magnesium-S-omeprazole salt trihydrate and also refers to new intermediates used in the procedure and their preparation

EP 5129 describes the compound 5-meloxy-2-[f[(4-meth:Qxi-3,5-dimethyl-2-pyridinyl)methyl-1H-benzimidazole, which has the generic name omeprazoi and its therapeutically acceptable salt. Specific alkali salts of omeprazole are described in EP 124 495. Omeprazole is a proton pump inhibitor, i.e. an effective inhibitor of gastric acid secretion, so it is useful as an agent against stomach ulcers. In the most general sense, omeprazoic can be used for the prevention and treatment of diseases associated with stomach acid in mammals, and especially in humans.

Omeprazoic is a sulfoxide and a chiral compound, and the sulfur atom is a sterogenic center. Therefore, omeprazole is a racial mixture of its two individual enantiomers, the R- and S-enantiomers of omeprazole, which will be referred to here as R-omeprazole and S-omeprazole. The absolute configurations of the enantiomers of omeprazole were determined by X-ray study of the N-alkylated derivative (+)-enantiomer when not in the form of sofa. It was found that this (+)-enantiomer when not in the form of salt and the (-)-enantiomer when not in the form of salt, have - and S-configuration, respectively, and the (+)-enantiomer of the magnesium salt and the (-)-enantiomer of the magnesium salt were found to have the R- and S-configuration, respectively. The conditions for measuring the optical rotation of each of these enantiomers are described in WO 94/27988

Certain salts of certain enantiomers of omeprazole and their preparation are described in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties that provide an improved therapeutic profile, such as a lower degree of inter-individual variation.

WO 96/02535 describes a process for obtaining certain enantiomers of omeprazole and its salts, and WO 96/01623 describes suitable tablet dosage forms for, for example, magnesium salts of R- and S-omeprazole.

Figure 1 shows the powder X-ray diffractogram of magnesium-S-omeprazole salt trihydrate obtained according to the present invention.

Figure 2 shows an X-ray powder diffraction pattern of the potassium-S-omeprazole salt obtained and used in the present invention (see Examples 2 and 3).

Figure 3 shows the powder X-ray diffractogram of the magnesium-S-omeprazole salt dihydrate obtained and used in the present invention (see Example 5).

Figure 4 shows the X-ray diffractogram on the magnesium-S-omeprazole salt dihydrate powder, which is a polymorph of the dihydrate shown in Figure 3 (see example 6). This magnesium-S-omeprazole salt dihydrate is obtained and can be used in the preparation of magnesium-S-omeprazole salt dihydrate according to the present invention.

Figure 5 shows an X-ray diffractogram of a magnesium-S-omeprazole salt powder obtained according to Example A in WO 96/01623.

The r-magnesium-S-omeprazote salt was found to occur in a number of structurally different forms. Another object of the present invention is to obtain a substantially pure salt of magnesium-S-omeprazole trihydrate, also defined as trihydrate of the magnesium salt of S-bmeprazole, which will be referred to below as the compound according to the invention. This magnesium-S-omeprazole salt trihydrate can be obtained as a well-defined compound. The present invention also provides a process for making and a process for distinguishing magnesium-S-omeprazole salt trihydrate from other forms of magnesium-S-omeprazole salt.

More particularly, the present invention provides processes for obtaining magnesium-S-omeprazole salt trihydrate, comprising

Oxidations of 5-methoxy-2-[[[(4-methoxy-3, 5-dimethyl-2'pyridinyl)methyl]tto]-1H-benzimidazcl with an oxidizing agent and a chiral titanium complex, optionally in the presence of a base. Oxidation is carried out in an organic solvent, for example toluene or dichloromethane.

The crude product is converted to the corresponding potassium by treatment with a source of potassium, such as potassium hydroxide in methanol or potassium methylate in methanol, followed by isolation of the resulting salt.

The resulting potassium S-omeprazole salt is then converted to the corresponding magnesium salt by treatment with a source of magnesium, such as magnesium sulfate, in a lower alcohol, such as methanol. Optionally, the solution is filtered and precipitation is initiated by adding a non-solvent, such as acetone. The product is filtered, then optionally washed with water and further separated from the aqueous suspension, for example by squeezing or centrifugation and then dried to a constant mass. Alternatively, the potassium salt can be treated with a source of magnesium, such as magnesium sulfate in water, and any other conventional technique for transforming the potassium salt into the corresponding magnesium salt can be used to isolate the magnesium-S-omeprazole trihydrate salt, which is within scope of this invention.

The compound of the invention is advantageous because it is more stable than the corresponding magnesium salts of the compound in the prior art and therefore easier to handle and store. The compound of the invention is also easier to characterize because it exists in a well-defined state. Additionally, the compound of the invention is easier to synthesize in a reproducible manner and therefore easier to handle during full production.

The S-omeprazole magnesium salt trihydrate obtained according to the present invention is essentially free of R-omeprazole magnesium salt. The trihydrate, magnesium salt of S-omeprazole obtainable according to the present invention is also essentially free of other forms of the magnesium salt of S-omeprazole, such as the corresponding magnesium salt compounds described in the prior art and the dihydrates used in obtaining the trihydrate compounds according to the present invention.

The compound according to the invention is characterized by the positions and intensities of the main signals on the X-ray powder diffractogram, but can also be characterized by conventional FT-IR spectroscopy. These characteristics are not exhibited by any other form of magnesium salts of S-omeprazole and therefore, magnesium salt of S-omeprazole trihydrate is easily distinguished from any other crystalline form of magnesium salt of S-omeprazole described in the prior art. The compound according to the invention is characterized by being highly crystalline, i.e. has higher crystallinity than any other form of magnesium salt of S-omeprazof described in the prior art. The term 'any other form' refers to its anhydrides, hydrates, solvates and polymorphic or amorphous forms described in the state of the art. Examples of any other form of the magnesium salt of S-omeprazole include, but are not limited to, its anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates, alcoholates, such as methanolates and ethanolates and polymorphic or amorphous forms thereof.

A compound of the invention may also be characterized by its unit cell.

A further aspect of the presented invention, see examples 2 and 3, is the obtaining of a suitable intermediate used in obtaining the compound according to the invention, as well as the method of obtaining it. It was found that the potassium salt of S-omeprazole is a suitable intermediate, see examples 1, 4, 5 and 7, for obtaining compounds according to the invention, i.e. S-omeprazole magnesium salt trihydrate. The potassium salt of S-omeprazole can also be used as an active component of a pharmaceutical formulation used in the treatment of gastrointestinal diseases.

The compound of this invention, ie. with magnesium-S-omperazole trihydrate. obtained in accordance with the present invention, can be analyzed by the XRPD technique, which is well established.

The amount of water in the nrtagnesium-S-omeprazole trihydrate salt is determined by thermogravimetric analysis, a technique that is well known.

The compound of the present invention is an effective inhibitor of gastric acid secretion and is also useful as an anti-ulcer agent. In a broader sense, it can be used for the prevention and treatment of conditions related to stomach acid in mammals, especially humans, such as, for example, reflux esophagitis, gastritis, duodenitis, stomach ulcer and duodenal ulcer. Furthermore, it can be used for the treatment of other gastrointestinal disorders, where the effect of inhibiting stomach acid is desired, e.g. in patients under NSAID therapy, in patients with dyspepsia not caused by gastric ulcer, in patients with symptomatic gastroesophageal reflux disease, and in patients with gasphrynoma. The compound of this invention can also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, before and after surgery, to prevent aspiration of gastric acid, and in the prevention and treatment of stress ulcers. Further, a compound of the present invention can be used for the treatment of psoriasis, as well as for the treatment of Helicobacter infections and diseases associated therewith. The compound of the present invention can also be used for the treatment of inflammatory conditions in mammals, including humans.

Any suitable route of administration may be used to provide the patient with an effective dose of magnesium S-omeprazole trihydrate salt in accordance with the present invention. For example, oral or parenteral formulations and the like can be used. Dosage forms are capsules, tablets, dispersions, suspensions and the like.

Also provided is a pharmaceutical composition containing magnesium salt-S-omeprazole trihydrate according to this invention as an active ingredient, together with a pharmaceutically acceptable carrier, diluent or additive and optionally other therapeutic ingredients - Compositions containing other therapeutic ingredients are particularly interesting in the treatment of Helicobacter - ial infections. The present invention also provides the use of the magnesium-S-omeprazole trihydrate salt of the present invention in the manufacture of a medicament for use in the treatment of conditions associated with gastric acid and a method of treating conditions associated with gastric acid, the method comprising administering to a subject suffering from said condition a therapeutically effective amount magnesium-S-omeprazole trihydrate according to the present invention.

Compositions according to the invention include compositions suitable for oral or parenteral administration. The most preferred route of administration is the oral route. The compositions may be conventionally presented in unit dosage form, and obtained by any method known in the field of pharmacy.

When applying the invention, the most suitable method of administration as well as the amount of the therapeutic dose of magnesium-S-omeprazole trihydrate salt according to this invention in each individual case will depend on the nature and severity of the disease to be treated. The dose and frequency of dosing may also vary according to the age, body weight and response of each individual patient. Patients who have Zollonger-Ellison syndrome may have special requirements, such as the need for higher doses, than normal patients. Children and patients with liver diseases usually do better with doses that are slightly lower than average. Thus, in some conditions it may be necessary to use doses outside the range that will be specified below, for example, long-term treatments may require lower doses. These higher and lower doses are within the scope of the present invention. Daily doses may vary between 5 mg and 300 mg.

A typically suitable oral dosage form of a compound of the present invention falls within the range of 5 mg to 300 mg total daily dose, administered once as a single dose or in equally divided doses. The preferred dosage range is from 10 to 80 mg.

A compound of the present invention can be combined as an active component in an intimate mixture with a pharmaceutical carrier, according to conventional techniques, such as the oral formulation described in WO 96/01623 and EP 247 983, the disclosures of which are incorporated herein in their entirety by this reference.

You can also use combined preparations containing magnesium-S-omeprazole trihydrate salt and other active ingredients. Examples of such active ingredients include, but are not limited to, anti-bacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates, and prokinetic agents.

The following examples will further illustrate the preparation of compounds of the present invention, according to various preparation routes, including novel intermediates. These examples are not intended to limit the scope of this invention, as previously defined, or as will be disclosed by the patent claims that follow.

First 1

S-5-Methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt trihydrate (obtained using the compound prepared in Example 4, below)

Water (157 kg) is added to the wet crystals of the magnesium-S-omeprazole salt obtained according to Example 4 below. The mixture is heated to 38⁰C with stirring and left for 3 hours. The crystals are filtered and dried under vacuum. Yield 31.6 kg.

X-ray diffraction analysis was performed on a sample of the crystals obtained above according to standard procedures which can be found in, for example, Kitaigorodsky, AI (1973), Molecular Crystals and Molecules. Academic Press, New York; Bunn, C W (1948), Chemical Crystallography, Clarendon Press, London; or Kfug, H P. and A(exander L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York Analysis gave the diffractogram shown in Figure 1. The principal signals, with positions and relative intensities, were extracted from the diffractogram at Figure 1 and given below in Table 1. Relative intensities are less reliable, so instead of numerical values, the following definitions were used:

Some very weak signals found in the diffractogram are omitted from Table 1.

First 2

Kalijumova so S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinium)-methyl]sulfinyl]-1H-benzimidazola

A solution of 5-methoxy-2-[[(4-methoxy-3n5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (15.4 g, 46.8 mmol) in toluene (70 mL) was heated to 50⁰C, then water (0.05 ml, 2.8 mmol) and D-(-)-diethyltartrate (2.02 g, 982 mmol) were added. The reaction mixture is stirred for 20 min. stirs. Titanium(IV) isopropoxide (1.34 g, 4.68 mmol) was added, and the reaction mixture was stirred for 45 min. The mixture was cooled to 30°C, and diisopropylethylamine (0.91 g, 7.01 mmol) was added, followed by cumene hydroperoxide (9.52 g, 51.89 mmol). The resulting mixture is stirred for 3 hours at 30°C. Methanol (40 mL) was added followed by potassium hydroxide (3.05 g, 46.8 mmol) in methanol (30 mL). Seed crystals were added and the reaction mixture was stirred at 35°C overnight. The precipitated product was filtered, washed with methanol and toluene and dried under vacuum. Yield 9.74 g (54%).

First 3

Kalijumova so S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazola

To a solution of 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole in toluene (370 ml, 211.5 g/l) was added water (157.6 pl), so that the water content is 0.031 wt%, and then D-(-)-diethyltartrate (8.55 ml) is added. The solution is heated to 50°C, then for 20 min. stirs at this temperature. Titanium(IV) isopropoxide (7.15 ml) was added, and the reaction was left for 45 min. at 50°C. The temperature was lowered to 30°C, and diisopropylethylamine (6.2 ml) was added. Cumene hydroperoxide is added at a suitable rate, so that the temperature is maintained between 28 and 34°C. After 2 hours, the temperature was raised to 35°C, and potassium methoxide (24.55 g) in methanol (222 ml) was added. After 14 hours, the mixture is filtered, and the crystals are washed with methanol:toluene (240 ml, 1:1), then with methanol (120 ml) and dried. Yield 79 g (74%), ee >99.9%.

[a]D20=+28, 7° (c=1%, water); The content is 89% potassium salt of S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole (11% is methanol).

1H-NMR (200 MHz, DMSO-d6, δ, ppm): 2, 23 (s, 3H), 2, 24 (s, 3H), 3, 71 (s, 3H), 3, 75 (s, 3H), 4, 40 (d, 1H), 4, 78 (d, 1H), 6, 58 (dd, 1H), 7, 00 (d, 1H), 7, 35 (d, 1H), 8, 25 (s, 1H).

The products of Examples 2 and 3 were analyzed using X-ray powder diffraction, as described in Example 1, and gave the diffractogram shown in Figure 2 and given below in Table 2. Some additional signals of low intensity, which were found in the diffractogram in, were omitted. from Table 2.

First 4

Magnesium salt of S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2~pyridinyl)-methyl]sulfinyl]-1H-benzimidazole (prepared from the corresponding potassium salt)

Methanol (148 kg) was added to S-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridnyl)-methyl]sulfinyl]-1H-benzimidazole, potassium salt (71 kg, methanol content 13%). MgSO4 x 7H2O (40 kg) is added to this mixture with stirring. After 70 min. the mixture is filtered, and the filtrate is washed with methanol (46 kg). The solution is concentrated to a volume of 100 liters, then acetone (253 kg) is added, and the resulting garbage is left to stand for 4 hours. The settled product is filtered, then washed with acetone and water. The wet crystals are used directly, as described in Example 1.

First 5

Dihidrat magnesiaumove soli S-5-methoxy-2-[[(4-methoxy-3, 5'dimethyl'2-pyridinyl)-methyl]sulfinyl]- 1H-b enzimidazola

5.0 g of the wet product from Example 4 is taken, in which the dry substance content is approximately 74%, and dried overnight under vacuum at 35°C, yielding 3.58 g (2.68 mmol) of magnesium salt dihydrate S-5 -Methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, called obiik B.

The product was analyzed by X-ray powder diffraction, as described in Example 1, and the analysis gave the diffractogram shown in Figure 3 and given in Table 3, below. Some additional signals of low intensity, which were found in the diffractogram, are omitted from Table 3.

Conversion of magnesium-S-omeprazole salt dihydrate to trihydrate

This material is then transformed into the magnesium-S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl[-2-pyridinyl)-methyl]sulfinyl]-1H'bezimidazoIaf salt trihydrate using the procedure described for wet substance in Example 1.

First 6

S-5-Methoxy-2-[[(4-methoxy3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt dihydrate (prepared using the compound of Example 4)

A methanolic solution of the magnesium salt of S-5-methoxy-2-[[(4-methoxy-3, 5-dimethH-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazoia was prepared as described in Example 4. This solution of magnesium S-5niethoxy+2-[[(4-niethoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole salt (1.86 g) in 5 ml of methanol was concentrated by evaporation until nothing remained 1.58 ml of methanol Then a mixture of 1.6 ml of water and 6.32 ml of acetone is added The solution is left to crystallize for 26 hours at room temperature. The resulting crystals were filtered and dried at 40⁰C under reduced pressure, yielding 1.17 g of magnesium salt dihydrate S-5-methoxy-2-[[(4-methoxy-3,5H-methyl-2-pyridinyl}-methyl]sulfinyl]-1H -benzimidazole, called Form A.

This product was analyzed by X-ray powder diffraction, as described in Example 1, giving the diffractogram shown in Figure 4 and given in Table 4, below. Some additional signals of low intensity, which were found in the diffraction pattern, are omitted from Table 4.

First 7

S-5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt trihydrate (prepared from the corresponding potassium salt)

Dissolve 22.0 g (29.1 mmol) of the potassium salt of S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole in 40 ml water. The solution is seeded with 0.11 g (0.1 mmol) magnesium salt trihydrate S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H- benzimidazole: Over a period of 3 hours, 22 ml (69.6 mmol) of MgSO4 (aq) were added. The suspension is filtered, and the precipitate is stirred in water for approximately 30 min, then the crystals are filtered and dried (35°C, vacuum). Yield 9.15 g (11.6 mmol; 80%). The substance has a purity (HPLC): 99.8 surface %, Mg content: 3.40 mass% and ee.. 99.8%.

The product was analyzed using X-ray powder diffraction, and the results are consistent with Figure 1 and Table 1.

Reference primer A

Magnezijumova so S-5-methoxy-2-[[(4-methoxy-3t5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H-benzimidazola

(This procedure is in accordance with the procedure described in Example A in WO 96/01623).

Magnesium (0.11 g, 4.5 mmol) is dissolved and reacted with methanol (50 ml) at 40°C with a catalytic amount of methylene chloride. The reaction is carried out under nitrogen and is completed after five hours. At room temperature, a mixture of two enantiomers [90%(-)isotner and 10%(+)-isomer] S-5-methoxy-2-f[(4-methoxy-3-5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol). The mixture is stirred for 12 hours, after which a small amount of water (0.1 ml) is added to precipitate the inorganic magnesium salts. After 30 min of mixing, these inorganic salts are filtered, and the solution is concentrated on a rotary evaporator. The residue is now a concentrated methanolic solution of a mixture of enantiomers (ie, the title compound contaminated with the (+)-isomer), with an optical purity (or enantiomeric excess, (enantimeric execess, e.e.)) of 80%. This mixture is diluted with acetone (100 ml), and after 15 minutes of stirring at room temperature

a white precipitate is obtained. Additional 15 min. stirring followed by filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analysis of crystals and mother liquor was performed by chromalography on an analytical chiral column. The optical purity of the crystal was found to be 98.4 e. e.. and mother liquor 64, 4% ae. therefore, the optical purity (e.e.) increased from 80% to 98.4% simply by crystallizing the magnesium salt from a mixture of acetone and methanol. The product was crystalline, as shown by X-ray powder diffraction, and the magnesium content was 3.44%, as shown by atomic absorption spectroscopy. [α]D20=-131.5° (c=0.5%, methanol).

The product was analyzed by X-ray powder diffraction, as described in Example 1, and a diffractogram was obtained which is shown in Figure 5 and given in Table 5 below. Some additional very weak signals found in the diffractogram are omitted from Table 5

Claims (9)

1. The process for obtaining the magnesium salt of S-omeprazole trihydrate, which includes the following steps: a) mixing the potassium salt of S-omerazole with an organic solvent; b) converting the potassium salt of S-omeprazole into the corresponding magnesium salt of S-omeprazole by treating said potassium salt with a source of magnesium; c)    precipitation of the magnesium salt of S-omeprazole by adding a non-solvent; d)    isolation of the obtained magnesium salt of S-omeprazole; e) treating the obtained magnesium salt of S-omeprazole with water; and f) isolating and drying the thus obtained magnesium salt of S-omeprazole trihydrate. 2. The process according to claim 1, wherein said organic solvent used in step a) is methanol. 3. The process according to any one of claims 1-2, wherein said non-solvent used in step c) is acetone. 4. The method according to claim 1, in which steps a) to e) are replaced by one step: i) converting the potassium salt of S-omeprazole into the corresponding magnesium salt of S-omeprazole by treating said potassium salt with a source of magnesium in water. 5. A process according to any one of claims 1-4, wherein said magnesium source used in step b) of claims 1-3 or in step i) of claim 4 is magnesium sulfate. 6. A process for obtaining the potassium salt of S-omeprazole used in step a) in any of claims 1-5, which consists of the following steps: a) oxidation of 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole in S-omeprazole in an organic solvent; b) converting the crude S-omeprazole obtained in step a) into the corresponding potassium salt of S-omeprazole by treating said S-omeprazole with a source of potassium; c)    isolation obtaining the potassium salt of S-omeprazole. 7. The process according to claim 6, wherein said organic solvent used in step a) is toluene. 8. A process according to any one of claims 6-7, wherein said source of potassium used in step b) is methanolic potassium methoxide or methanolic potassium hydroxide. 9. The potassium salt of S-omeprazole prepared according to claim 6, characterized in that it has the following main signals in its X-ray powder diffractogram.