PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`wo 98/54171
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`C07D 401/12, A61K 31/44
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`3 December 1998 (03.12.98)
`
`(21) International Application Number:
`
`PCT/SE98/00974
`
`(22) International Filing Date:
`
`25 May 1998 (25.05.98)
`
`(30) Priority Data:
`9702065-5
`
`30 May 1997 (30.05.97)
`
`SE
`
`(71) Applicant (for all designated States except US): ASTRA
`AKTIEBOLAG [SE/SE]; S-151 85 SMertiilje (SE).
`
`(72) Inventors; and
`COTTON, Hanna
`(75) Inventors/Applicants (for US only):
`[SE/SE]; Astra Production Chemicals AB, S-151 85
`SMertiilje (SE). KRONSTROM, Anders [SE/SE]; Astra
`Production Chemicals AB, S-151 85 SOdertiilje (SE).
`MATTSON, Anders [SE/SE]; Astra Production Chemicals
`AB, S-151 85 Sodertalje (SE). MOLLER, Eva [SE/SE];
`Astra Production Chemicals AB, S-151 85 SOdertiilje (SE).
`
`(74) Agent: ASTRA AKTIEBOLAG; Patent Dept., S-151 85
`SMertalje (SE).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: NOVEL FORM OF SOMEPRAZOLE
`
`(57) Abstract
`
`The present invention relates to a novel form of the (-)-enantiomer of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl)(cid:173)
`methyl]sulfinyl]-1!!-benzimidazole, i.e S-omeprazole. More specifically, it relates to a novel form of the magnesium salt of the S-enantiomer
`of omeprazole trihydrate. The present invention also relates to processes for preparing such a form of the magnesium salt of S-omeprazole
`and pharmaceutical compositions containing it. Furthermore, the present invention also relates to new intermediates used in the process.
`
`

`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`cz
`DE
`DK
`EE
`
`Albania
`Annenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Ci'>te d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Gennany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The fanner Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Narn
`Yugoslavia
`Zimbabwe
`
`

`
`wo 98/54171
`
`PCT /SE98/0097 4
`
`NOVEL FORM OF S-OMEPRAZOLE
`
`Field of the Invention
`
`The present invention relates to a novel form of the (-)-enantiomer of 5-methoxy-2-[[(4-
`
`5 methoxy-3,5-dimethyl-2-pyridinyl)-methyijsulfinyl]-1 H-benzimidazole, i.e. S-omeprazole.
`
`More specifically, it relates to a novel form of the magnesium salt of the S-enantiomer of
`
`omeprazole trihydrate. The present invention also relates to processes for preparing such a
`
`form of the magnesium salt of S-omeprazole and pharmaceutical compositions containing
`
`it. Furthermore, the present invention also relates to intermediates used in the process, and
`
`10
`
`their preparation.
`
`Background of the invention and prior art
`
`The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyijsulfinyl]-1H-
`
`15
`
`benzimidazole, having the generic name omeprazole, and therapeutically acceptable salts
`
`thereof, are described in EP 5129. The specific alkaline salts of omeprazole are disclosed in
`
`EP 124 495. Omeprazole is a proton pump inhibitor, i.e. effective in inhibiting gastric acid
`
`secretion, and is useful as an antiulcer agent. In a more general sense, omeprazole may be
`
`used for prevention and treatment of gastric-acid related diseases in mammals and
`
`20
`
`especially in man.
`
`Omeprazole is a sulfoxide and a chiral compound, wherein the sulfur atom being the
`
`stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers,
`
`the Rand S-enantiomer of omeprazole, herein referred to as R-omeprazole and S-
`
`25
`
`omeprazole. The absolute configurations of the enantiomers of omeprazole have been
`
`determined by an X -ray study of an N-alkylated derivative of the ( + )-enantiomer in non-salt
`form. The ( + )-enantiomer of the non-salt form and the (-)-enantiomer of the non-salt form
`were found to have R and S configuration, respectively, and the ( + )-enantiomer of the
`
`magnesium salt and the (-)-enantiomer of the magnesium salt were also found to haveR
`
`

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`PCT /SE98/0097 4
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`2
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`and S configuration, respectively. The conditions for the optical rotation measurement for
`
`each of these enantiomers are described in WO 94/27988.
`
`Certain salts of single enantiomers of omeprazole and their preparation are disclosed in
`
`5 WO 94/27988. These compounds have improved pharmacokinetic and metabolic
`
`properties which will give an improved therapeutic profile such as a lower degree of
`
`interindividual variation.
`
`WO 96/02535 discloses a process for the preparation of the single enantiomers of
`
`10
`
`omeprazole and salts thereof, and WO 96/01623 discloses a suitable tableted dosage forms
`
`of for instance magnesium salts of R-and S-omeprazole.
`
`Brief description of the drawings
`
`15
`
`Figure 1 shows a X-ray powder diffractogram of the magnesium salt ofS-omeprazole
`
`trihydrate prepared according to the present invention.
`
`Figure 2 shows a X-ray powder diffractogram of the potassium salt of S-omeprazole
`
`prepared and used in the present application (See examples 2 and 3)
`
`Figure 3 shows a X-ray powder diffractogram of a magnesium salt ofS-omeprazole
`
`20
`
`dihydrate prepared and used in the present application (See example 5)
`
`Figure 4 shows a X-ray powder diffractogram of a magnesium salt of S-omeprazole
`
`dihydrate which is a polymorph of the dihydrate shown in Figure 3 (See Example 6). This
`
`magnesium salt of S-omeprazole dihydrate has been prepared and can be used in the
`
`preparation of the magnesium salt of S-omeprazole trihydrate according to the present
`
`25
`
`invention.
`
`Figure 5 shows X-ray powder diffractogram of the magnesium salt of S-omeprazole
`
`prepared according to example A in WO 96/01623 .
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`

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`PCT /SE98/0097 4
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`3
`
`Description of the Invention
`
`It has surprisingly been found that the magnesium salt of S-omeprazole occurs in a number
`
`of structurally different forms. It is an object of the present invention to provide a
`
`s
`
`substantially pure magnesium salt of S-omeprazole trihydrate, hereinafter referred to as the
`
`compound of the invention. This trihydrate can be obtained as a well defined compound.
`
`The present invention also provides a process to obtain and a method of differentiating the
`
`magnesium salt of S-omeprazole trihydrate from other forms of magnesium salts of S(cid:173)
`
`omeprazole.
`
`10
`
`The compound of the invention is advantageous because it is more stable than the
`
`corresponding magnesium salt compounds in prior art and is 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
`
`1s
`
`reproducible manner and thereby easier to handle in a full scale production.
`
`The magnesium salt of S-omeprazole trihydrate obtained according to the present invention
`
`is substantially free from magnesium salts of R-omeprazole. The magnesium salt of S(cid:173)
`
`omeprazole trihydrate obtained according to the present invention is also substantially free
`
`20
`
`from other forms of magnesium salts of S-omeprazole, such as the corresponding
`
`magnesium salt compounds described in prior art, and dihydrates used in the preparation of
`
`the trihydrate compound according to the present invention.
`
`The compound of the invention is characterized by the positions and intensities of the
`
`25 major peaks in the X-ray powder diffractogram, but may also be characterized by
`
`conventional Ff-IR spectroscopy. These characteristics are not exhibited by any other form
`
`of magnesium salt of S-omeprazole and accordingly, the magnesium salt of S-omeprazole
`
`trihydrate is easily distinguishable from any other crystal form of the magnesium salt ofS(cid:173)
`
`omeprazole disclosed in prior art. The compound of the invention is characterized by being
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`

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`wo 98/54171
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`PCT /SE98/0097 4
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`4
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`highly crystalline, i.e. having a higher crystallinity than any other form of magnesium salt
`
`of S-omeprazole disclosed in the prior art. With the expression "any other form" is meant
`
`anhydrates, hydrates, solvates, and polymorphs or amorphous forms thereof disclosed in
`
`the prior art. Examples of any other forms of magnesium salt of S-omeprazole includes, but
`
`5
`
`are not limited to, anhydrates, monohydrates, dihydrates, sesquihydrates, trihydrates,
`
`alcoholates, such as methanolates and ethanolates, and polymorphs or amorphous forms
`
`thereof.
`
`The compound of the invention may also be characterized by its unit cell.
`
`10
`
`In a further aspect, the present invention provides processes for the preparation of the
`
`magnesium salt of S-omeprazole trihydrate which comprises;
`
`a) treating a magnesium salt of S-omeprazole of any form, for example prepared according
`
`15
`
`to procedures known in the art such as Example A in WO 96/01623 which is incorporated
`
`herein by reference, with water at a suitable temperature for a suitable time. By a suitable
`
`temperature is meant a temperature which induces the transformation of starting material to
`
`product without decomposing any of these compounds. Examples of such suitable
`
`temperatures include, but are not limited to, room temperature and above. By a suitable
`
`20
`
`time is meant a time that results in high conversion of the starting material into product
`
`without causing any decomposition of either compounds, i.e. results in a good yield. This
`
`suitable time will vary depending on the temperature used in a way well known to people
`
`in the art. The higher the temperature, the shorter time is needed to give the desired
`
`conversion. The amount of water is not crucial and will depend on the process conditions
`
`25
`
`used. The magnesium salt of S-omeprazole trihydrate is thereafter separated from the
`
`aqueous slurry, for example by filtration or centrifugation and thereafter dried to constant
`
`weight; or
`
`b) oxidizing 5-methoxy-2-[[( 4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-IH-
`
`30
`
`benzimidazole, with an oxidizing agent and a chiral titanium complex, optionally in the
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`PCT /SE98/0097 4
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`5
`
`presence of a base. The oxidation is carried out in an organic solvent, for example toluene
`
`or dichloromethane.
`
`The crude product is converted to the corresponding potassium salt by treatment with a
`
`potassium source, such as methanolic potassium hydroxide or methanolic potassium
`
`s methylate, followed by isolation of the formed salt.
`
`The resulting potassium salt of S-omeprazole is thereafter converted to the corresponding
`
`magnesium salt by treatment with a magnesium source, such as magnesium sulfate in a
`
`lower alcohol, such as methanol. The solution is optionally filtered and the precipitation is
`
`10
`
`initialized by addition of a non-solvent such as acetone. The product is filtered off and
`
`optionally washed with water and further processed as is described in a) above.
`
`Alternatively, the potassium salt may be treated with a magnesium source, such as
`
`magnesium sulfate in water, and isolation of the magnesium salt of S-omeprazole
`
`trihydrate, or any other conventional technique for transforming a potassium salt to the
`
`15
`
`corresponding magnesium salt can be used and is within the scope of the present invention.
`
`Yet a further aspect of the present invention is to provide a suitable intermediate used in
`
`the preparation of the compound of the invention, as well as a process for its preparation.
`
`The potassium salt of S-omeprazole is found to be such a suitable intermediate. The
`
`20
`
`potassium salt of S-omeprazole may also be used as an active component of a
`
`pharmaceutical formulation to be used in the treatment of gastrointestinal diseases.
`
`The compound of the invention, i.e. the magnesium salt of S-omeprazole trihydrate ,
`
`prepared according to the present invention may be analyzed by XRPD, a technique which
`
`25
`
`is known per se.
`
`The amount of water in the magnesium salt of S-omeprazole trihydrate is determined by
`
`thermogravimetric analysis, a technique which is known per se.
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`PCT/SE98/00974
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`6
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`The compound of the invention is effective as a gastric acid secretion inhibitor, and is
`
`useful as an antiulcer agent. In a more general sense, it can be used for prevention and
`
`treatment of gastric-acid related conditions in mammals and especially in man, including
`
`e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore,
`
`s
`
`it may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory
`
`effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia,
`
`in patients with symptomatic gastro-esophageal reflux disease, and in patients with
`
`gastrinomas. The compound of the invention may also be used in patients in intensive care
`
`situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to
`
`10
`
`prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, the
`
`compound of the invention may be useful in the treatment of psoriasis as well as in the
`
`treatment of Helicobacter infections and diseases related to these. The compound of the
`
`invention may also be used for treatment of inflammatory conditions in mammals,
`
`including man.
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`15
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`20
`
`Any suitable route of administration may be employed for providing the patient with an
`
`effective dosage of the magnesium salt of S-omeprazole trihydrate, according to the
`
`invention. For example, peroral or parental formulations and the like may be employed.
`
`Dosage forms include capsules, tablets, dispersions, suspensions and the like.
`
`It is further provided a pharmaceutical composition comprising the magnesium salt of S(cid:173)
`
`omeprazole trihydrate according to the invention, as active ingredient, in association with a
`
`pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic
`
`ingredients. Compositions comprising other therapeutic ingredients are especially of
`
`25
`
`interest in the treatment of Helicobacter infections. The invention also provides the use of
`
`the magnesium salt of S-omeprazole trihydrate of the invention in the manufacture of a
`
`medicament for use in the treatment of a gastric-acid related condition and a method of
`
`treating a gastric-acid related condition which method comprises administering to a subject
`
`suffering from said condition a therapeutically effective amount of the magnesium salt of
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`30
`
`S-omeprazole trihydrate according to the invention.
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`

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`wo 98/54171
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`7
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`The compositions of the invention include compositions suitable for peroral or parental
`
`administration. The most preferred route is the oral route. The compositions may be
`
`conveniently presented in unit dosage forms, and prepared by any methods known in the art
`
`s
`
`of pharmacy.
`
`In the practice of the invention, the most suitable route of administration as well as the
`
`magnitude of a therapeutic dose of the magnesium salt of S-omeprazole trihydrate
`
`according to the invention in any given case will depend on the nature and severity of the
`
`10
`
`disease to be treated. The dose, and dose frequency, may also vary according to the age,
`
`body weight, and response of the individual patient. Special requirements may be needed
`
`for patients having Zollinger-Ellison syndrome, such as a need for higher doses than the
`
`average patient. Children and patients with liver diseases generally will benefit from doses
`
`that are somewhat lower than the average. Thus, in some conditions it may be necessary to
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`15
`
`use doses outside the ranges stated below, for example long term treatments may request
`
`lower dosage. Such higher and lower doses are within the scope of the present invention.
`
`Such daily doses may vary between 5 mg to 300 mg.
`
`In general, a suitable oral dosage form of the compound of the invention may cover a dose
`
`20
`
`range from 5 mg to 300 mg total daily dose, administered in one single dose or equally
`
`divided doses. A preferred dosage range is from 10 mg to 80 mg.
`
`The compound of the invention may be combined as the active component in intimate
`
`admixture with a pharmaceutical carrier according to conventional techniques, such as the
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`25
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`oral formulations described in WO 96/01623 and EP 247 983, the disclosures of which are
`
`hereby incorporated as a whole by reference.
`
`Combination preparations comprising the magnesium salt of S-omeprazole trihydrate and
`
`other active ingredients may also be used. Examples of such active ingredients include, but
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`are not limited to anti-bacterial compounds, non-steroidal anti-inflammatory agents,
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`antacid agents, alginates and prokinetic agents.
`
`The examples which follow will further illustrate the preparation of the compound of the
`
`5
`
`invention, according to different process routes and including new intermediates. These
`
`examples are not intended to limit the scope of the invention as defined hereinabove or as
`
`claimed below.
`
`Examples
`
`Example 1
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sul.finyl]-JH(cid:173)
`
`benzimidazole magnesium salt trihydrate
`
`10
`
`15
`
`Water (157 kg) was added to the wet crystals of the magnesium salt of S-omeprazole,
`
`prepared according to Example 4, below. The mixture was heated to 38°C with stirring and
`
`left for 3 hours. The crystals were filtered off and dried in vacuo. Yield: 31.6 kg
`
`20 X-ray powder diffraction analysis was performed on a sample of the crystals prepared
`
`above according to standard methods, which can be found in e.g. Kitaigorodsky, A. I.
`
`(1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C. W.
`
`(1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander,
`
`L. E. (1974), X-Ray Diffraction Procedures, John Wiley and Sons, New York. The analysis
`
`25
`
`gave the diffractogram depicted in Figure 1. The main peaks, with positions and relative
`
`intensities, have been extracted from the diffractogram in Figure 1 and is given below in
`
`table 1. The relative intensities are less reliable and instead of numerical values the
`
`following definitions are used.
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`% Relative Intensity
`
`Definition
`
`25-100
`
`10-25
`
`3-10
`
`1-3
`
`<1
`
`vs (very strong)
`
`s (strong)
`
`m (medium)
`
`w(weak)
`
`vw (very weak)
`
`Some additional very weak peaks found in the diffractogram have been omitted from table
`
`1.
`
`Table 1. Positions and intensities of the major peaks in the XRP-diffractogram of
`
`the magnesium salt of S-omeprazole trihydrate.
`
`d-value I A Relative Intensity
`
`5
`
`10
`
`2.67
`
`2.79
`
`3.27
`
`3.52
`
`3.82
`
`3.96
`
`4.14
`
`5.2
`
`5.6
`
`6.7
`
`6.9
`
`8.3
`
`16.6
`
`m
`
`m
`
`m
`
`s
`
`s
`
`vs
`
`m
`
`m
`
`m
`
`vs
`
`s
`
`w
`
`vs
`
`

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`wo 98/54171
`
`Example 2
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`PCT /SE98/0097 4
`
`10
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-JH(cid:173)
`
`benzimidazole potassium salt
`
`5
`
`A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H(cid:173)
`
`benzimidazole (15.4 g, 46.8 rnmol) in toluene (70 ml) was heated to 50°C and water (0.05
`
`ml, 2,8 mmol) and D-(-)-diethyl tartrate (2.02 g, 9.82 rnmol) were added. The reaction
`
`mixture was stirred for 20 minutes. Titanium(IV)isopropoxide ( 1.34 g, 4.68 rnmol) was
`
`1 o
`
`added and the reaction mixture was stirred for 45 minutes. The mixture was cooled to 30°C
`
`and diisopropylethylamine (0.91 g, 7.01 rnmol) was added followed by cumene
`
`hydroperoxide (9 .52 g, 51.89 rnmol). The resultant mixture was stirred at 30°C for 3 hours.
`
`Methanol (40 ml) was added followed by potassium hydroxide (3.05 g, 46.8 rnmol) in
`
`methanol (30 ml). Seed crystals were added and the reaction mixture was stirred at 35°C
`
`ts
`
`overnight. The precipitated product was filtered off, washed with methanol and toluene and
`
`dried in vacuo. Yield: 9.74 g (54%).
`
`Example 3
`
`20
`
`S-5-methoxy-2-[[ ( 4-methoxy-3,5-dimethyl-2-pyridinyl )-methyl]sulfinyl ]-1 H(cid:173)
`
`benzimidazole potassium salt
`
`Water (157.6!11) was added to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]thio]-1H-benzimidazole in toluene (370 ml; 211.5 gil) with a water
`
`25
`
`content of 0.031% (w/w), followed by addition of D-(-)-diethyl tartrate (8.55 ml). The
`
`solution was heated to 50°C and stirred at this temperature for 20 minutes.
`
`Titanium(IV)isopropoxide (7 .15 ml) was added and reaction was left at 50°C for 45
`
`minutes. The temperature was lowered to 30°C and diisopropylethylamine (6.2 ml) was
`
`added. Cumene hydroperoxide was added at an appropriate speed to maintain the
`temperature from 28°C to 34 oc. The temperature was raised to 35°C after 2 hours and
`
`30
`
`

`
`wo 98/54171
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`PCT /SE98/0097 4
`
`11
`
`potassium methoxide (24.55 g) in methanol (222 ml) was added. The mixture was filtered
`
`after 14 hours and the crystals were washed with methanol: toluene (240 ml; 1:1) and
`
`methanol (120 ml) and dried. Yield: 79 g (74%), ee > 99.9%.
`20
`
`[a]o
`
`= +28.7° (c = 1%, water); Assay: 89% is S-5-methoxy-2-[[(4-methoxy-3,5-
`
`s
`
`dimethyl-2-pyridinyl)-methyl]sulfinyl]-IH-benzimidazole potassium salt (11% is
`
`methanol).
`
`1H-NMR (200 MHz, DMSO-d6, 8 ppm): 2.23 (s, 3H), 2.24 (s, 3H), 3.71 (s, 3H), 3.75 (s,
`
`3H), 4.40 (d, lH), 4.78 (d, lH), 6.58 (dd, lH), 7.00 (d, 1H), 7.35 (d, 1H), 8.25 (s, 1H).
`
`10
`
`The products from Examples 2 and 3 were analysed using X-ray powder diffraction as
`
`described in Example 1 and gave the diffractogram depicted in Figure 2 and given below in
`
`Table 2. Some additional very weak peaks found in the diffractogram have been omitted
`
`from Table 2.
`
`1s
`
`Table 2. Positions and intensities of the major peaks in the XRP-diffractogram of the
`
`potassium salt of S-omeprazole.
`
`

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`wo 98/54171
`
`PCT /SE98/0097 4
`
`12
`
`d-value/A
`
`Relative
`
`d-value/
`
`Relative
`
`intensity
`
`(A)
`
`intensity
`
`13.6
`
`10.6
`
`7.8
`
`6.8
`
`6.5
`
`6.2
`
`6.1
`
`5.8
`
`5.4
`
`5.3
`
`5.2
`
`vs
`
`vw
`
`m
`
`m
`
`m
`
`w
`
`m
`
`s
`
`m
`
`w
`
`w
`
`vw
`
`3.52
`
`3.42
`
`3.38
`
`3.34
`
`13.28
`
`3.20
`
`13.12
`
`3.06
`
`13.03
`
`2.97
`
`2.93
`
`2.89
`
`m
`
`w
`
`w
`
`m
`
`w
`
`m
`
`w
`
`w
`
`w
`
`w
`
`vw
`
`w
`
`a1 = 1.54060 A
`
`5.0
`
`4.75
`
`4.71
`
`4.52
`
`4.42
`
`4.32
`
`4.27
`
`3.98
`
`3.92
`
`3.89
`
`3.87
`
`3.81
`
`3.74
`
`3.60
`
`3.55
`
`m
`
`w
`
`w
`
`w
`
`w
`
`m
`
`2.85
`
`2.76
`
`2.71
`
`12.66
`
`2.58
`
`2.57
`
`vw
`
`12.56
`
`w
`
`w
`
`w
`
`w
`
`m
`
`m
`
`m
`
`2.52
`
`2.47
`
`2.45
`
`2.43
`
`12.40
`
`12.38
`
`12.31
`
`m
`
`w
`
`vw
`
`vw
`
`w
`
`w
`
`w
`
`vw
`
`vw
`
`vw
`
`vw
`
`vw
`
`vw
`
`vw
`
`

`
`wo 98/54171
`
`Example 4
`
`PCT/SE98/00974
`
`13
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sul.finyl]-JH(cid:173)
`
`benzimidazole magnesium salt
`
`5
`
`Methanol (148 kg) was added to S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)(cid:173)
`
`methyl]sulfinyl]-1H-benzimidazole potassium salt (71 kg, methanol content= 13%).
`
`MgS04 x 7 H20 (40 kg) was added to the mixture while stirring. After 70 minutes the
`
`mixture was filtered and the filtrate was washed with methanol ( 46 kg). The solution was
`
`10
`
`concentrated to a volume of 100 liter, acetone (253 kg) was added and the resulting
`
`mixture was left for 4 hours. The precipitated product was filtered off, washed with acetone
`
`and water. The wet crystals were immediately used as is described in Example 1.
`
`Example 5
`
`15
`
`20
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sul.finyl]-JH(cid:173)
`
`benzimidazole magnesium salt dihydrate
`
`5.0 g of the moist product from Example 4 with an approximate dry content of 74%, was
`dried in vacuum at 35 oc over night to yield 3.58 g (2.68 mmol) of S-5-methoxy-2-[[(4-
`methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt
`
`dihydrate, named Form B.
`
`The product was analyzed using X-ray powder diffraction as described in Example 1, and
`
`2s
`
`the analyze gave the diffractogram depicted in Figure 3 and given below in Table 3. Some
`
`additional peaks with low intensities found in the diffractogram have been omitted from
`
`Table 3.
`
`

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`wo 98/54171
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`PCT/SE98/00974
`
`14
`
`Table 3. Positions and intensities of the major peaks in the XRP-diffractogram of the
`
`magnesium salt of S-omeprazole dihydrate, Form B.
`
`d-value/ A
`
`Relative Intensity
`
`4.19
`
`4.45
`
`4.68
`
`4.79
`
`4.91
`
`4.98
`
`5.1
`
`5.4
`
`5.5
`
`5.6
`
`5.8
`
`6.3
`
`6.7
`
`7.9
`
`8.1
`
`11.0
`
`11.8
`
`14.9
`
`m
`
`m
`
`m
`
`s
`
`s
`
`s
`
`m
`
`s
`
`m
`
`m
`
`m
`
`m
`
`s
`
`m
`
`s
`
`m
`
`m
`
`vs
`
`s Convertion of magnesium salt of S-omeprazole dihydrate to trihydrate
`
`This material was subsequently processed to S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium salt trihydrate according to the
`
`procedure described for the moist substance in Example 1.
`
`

`
`wo 98/54171
`
`Example 6
`
`PCT /SE98/0097 4
`
`15
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sul.finyl]-JH(cid:173)
`
`benzimidazole magnesium salt dihydrate
`
`5
`
`A methanolic solution of S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)(cid:173)
`
`methyl]sulfinyl]-1H-benzimidazole magnesium salt was prepared as is described in
`
`Example 4. Such a solution of S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)(cid:173)
`
`methyl]sulfinyl]-lH-benzimidazole magnesium salt (1.86g) in 5 ml methanol was
`
`to
`
`concentrated by evaporation until 1.58 ml methanol remained. Then, a mixture of 1.6 ml
`
`water and 6.32 ml aceton was added. The solution was allowed to crystallize during 26 h at
`
`room temperature. The resulting crystals were filtered off and dried at 40 °C under reduced
`
`pressure giving 1.17 g of S-5-methoxy-2-[[( 4-methoxy-3 ,5-dimethyl-2-pyridinyl)(cid:173)
`
`methyl]sulfinyl]-1H-benzimidazole magnesium salt dihydrate, named form A.
`
`15
`
`The product was analyzed using X -ray powder diffration as described in Example 1 and
`
`gave the diffractogram depicted in Figure 4 and given below in Table 4. Some additional
`
`peaks with low intensities found in the diffractogram have been omitted from Table 4.
`
`20
`
`Table 4. Positions and intensities of the major peaks in the XRP-diffractogram of the
`
`magnesium salt of S-omeprazole dihydrate, Form A.
`
`

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`wo 98/54171
`
`PCT /SE98/0097 4
`
`16
`
`d-value/ A
`
`0
`
`Relative Intensity
`
`3.04
`
`3.14
`
`3.18
`
`4.05
`
`4.19
`
`4.32
`
`4.54
`
`4.69
`
`5.2
`
`5.3
`
`5.8
`
`6.2
`
`6.6
`
`15.5
`
`Example 7
`
`s
`
`s
`
`m
`
`s
`
`s
`
`m
`
`s
`
`vs
`
`s
`
`s
`
`s
`
`vs
`
`s
`
`vs
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sul.finyl]-JH-
`
`s
`
`benzimidazole magnesium salt trihydrate
`
`22,0 g (29,1 mmol) of S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)
`
`methyl]sulfinyl]-lH-benzimidazole potassium salt was dissolved in 40 mL of water. The
`
`solution was seeded with 0,11 g (0,1 mmol) S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`
`IO
`
`pyridinyl)-methyl]sulfinyl]-lH-benzimidazole magnesium salt trihydrate. 22 mL (69,6
`
`mmol) of MgS04 (aq) was added under a 3 h period. The slurry was filtered off and the
`
`precipitate was elutriated in water for approximately 30 minutes and the crystals were
`
`filtered off and dried (35 °C, vacuum).
`
`

`
`wo 98/54171
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`PCT/SE98/00974
`
`17
`
`Yield: 9,15 g (11,6 mmol; 80%). The substance had a purity (HPLC):99,8 area%, Mg
`
`content: 3,40 % (w/w) and ee: 99,8%.
`
`The product was analyzed using X-ray powder diffraction and the result complies with
`
`5
`
`Figure 1 and Table 1.
`
`Reference Example A
`
`S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]suljinyl]-JH-
`
`Io
`
`benzimidazole magnesium salt
`
`(The method used is in accordance with the method described in Example A in WO
`
`96/01623)
`
`15 Magnesium (0.1lg, 4.5 rnrnol) was dissolved and reacted with methanol (50 rnl) at 40°C
`
`with a catalytic amount of methylene chloride. The reaction was run under nitrogen and
`
`was finished after five hours. At room temperature a mixture of the two enantiomers
`
`[90%(-)-isomer and 10%( +)-isomer] of 5-methoxy-2-[[ ( 4-methoxy-3,5-dimethyl-2-
`
`pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 rnrnol) was added to the
`
`20 magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small
`
`amount of water (0.1 rnl) was added in order to precipitate inorganic magnesium salts.
`
`After 30 minutes stirring, these inorganic salts were filtered off and the solution was
`
`concentrated on a rotavapor. The residue was now a concentrated methanolic solution of
`
`the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with
`
`2s
`
`an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone
`
`(100 rnl) and after stirring at room temperature for 15 minutes, a white precipitate was
`
`obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 _g (50%) of
`
`the title compound as white crystals. Chiral analyses of the crystals and mother liquor were
`
`performed by chromatography on an analytical chiral column. The optical purity of the
`
`30
`
`crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the
`
`

`
`wo 98/54171
`
`PCT /SE98/0097 4
`
`18
`
`optical purity (e.e.) has been enhanced from 80% to 98.4% simply by crystallizing the Mg(cid:173)
`
`salt from a mixture of acetone and methanol. The product was crystalline as shown by
`
`powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic
`20
`absorption spectroscopy. [a]o
`
`=-131.5° (c=0.5%, methanol).
`
`5
`
`The product was analyzed using X-ray powder diffraction as described in Example 1 and
`
`gave the diffractogram depicted in Figure 5 and given below in Table 5. Some additional
`
`very weak peaks found in the diffractograms have been omitted from Table 5.
`
`

`
`wo 98/54171
`
`PCT /SE98/0097 4
`
`19
`
`Table 5. Positions and intensities of the major peaks in the XRP-diffractogram shown in
`
`Figure 5.
`
`d-value I A Relative Intensity
`2.90
`
`s
`
`3.41
`
`3.90
`
`4.13
`
`4.79
`
`5.00
`
`5.4
`
`5.7
`
`6.3
`
`6.8
`
`7.8
`
`8.4
`
`10.8
`
`12.2
`
`15.1
`
`s
`
`s
`
`s
`
`vs
`
`vs
`
`vs
`
`s
`
`s
`
`s
`
`s
`
`vs
`
`s
`
`s
`
`vs
`
`5
`
`

`
`wo 98/54171
`
`Claims.
`
`PCT /SE98/0097 4
`
`20
`
`1. The magnesium salt of S-omeprazole trihydrate.
`
`5
`
`2. The magnesium salt of S-omeprazole trihydrate according to claim 1, characterized by
`
`being highly crystalline.
`
`3. The magnesium salt of S-omeprazole trihydrate according to claim 1, characterized by
`
`the following major peaks in its X-ray powder diffractogram.
`
`10
`
`d-value I A j Relative Intensity
`2.67
`m
`
`2.79
`
`3.27
`
`3.52
`
`3.82
`
`3.96
`
`4.14
`
`5.2
`
`5.6
`
`6.7
`
`6.9
`
`8.3
`
`16.6
`
`m
`
`m
`
`s
`
`s
`
`vs
`
`m
`
`m
`
`m
`
`vs
`
`s
`
`w
`
`vs
`
`4. A process for the preparation of the magnesium salt of S-omeprazole trihydrate
`
`according to any of claims 1-3 which comprises treating a magnesium salt of S-omeprazole
`
`of any other form with water.
`
`15
`
`

`
`wo 98/54171
`
`PCT /SE98/0097 4
`
`21
`
`5