(12) United States Patent
`US 7,411,070 B2
`(10) Patent N0.:
`Cotton et al.
`(45) Date of Patent:
`*Aug. 12, 2008
`
`USOO7411070B2
`
`(54) FORM OF S-OMEPRAZOLE
`
`(75)
`
`Inventors: Hanna Cotton, Sédertalje (SE); Anders
`Kronstrom, Sodcrtaljc (SE); Anders
`Mattson, Sodertalje (SE); Eva VIiiller,
`Sodertalje (SE)
`
`
`
`(73) Assignee: AstraZenecaAB, Sodertalje (S3)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl.No.: 10/672,936
`
`(22)
`
`Filed:
`
`Sep. 25, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2005/0075369 A1
`
`Apr. 7, 2005
`
`Related US. Application Data
`
`(60) Continuation of application No. 10/076,711, filed on
`Feb. 14, 2002, now Pat. No. 6,677,455, which is a
`division of application No. 09/077,719, filed as appli-
`cation No. PCT/SE98/00974 on May 25, 1998, now
`Pat. No. 6,369,085.
`
`(30)
`
`Foreign Application Priority Data
`
`May 30, 1997
`
`(SE)
`
`.................................... 9702065
`
`(51)
`
`Int. Cl.
`(2006.01)
`C07D 401/12
`(2006.01)
`A61K 31/4439
`(52) US. Cl.
`.................................... 546/273.7; 514/338
`(58) Field of Classification Search ................. 514/338;
`546/2737
`
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`............ 424/263
`3/1981 Junggren et al.
`4,255,431 A
`4/1988 Brandstrom ................ 514/338
`4,738,974 A *
`11/1988 Lovgren et a1.
`424/468
`4,786,505 A
`
`.................. 562/571
`6/1996 Nore et al.
`5,530,160 A
`10/1997 Tiers et al.
`.................. 252/582
`5,676,884 A
`5,690,960 A * 11/1997 Bengtsson et a1.
`514/338
`5,693,818 A
`12/1997 Vion Unge ........
`514/338
`5,714,504 A
`2/1998 Lindberg et a1.
`.....
`514/338
`5,817,338 A
`10/1998 Bergstrand et a1.
`424/468
`.....
`5,877,192 A
`3/1999 Lindberg et a1.
`514/338
`.
`5,900,424 A
`5/1999 Kallstrom et a1.
`514/338
`6,369,085 B1
`4/2002 Cotton et a1.
`............... 514/338
`1/2004 Kronstrom et a1.
`6,677,455 B2
`6/2004 Kronstrom et a1.
`6,747,155 B2
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`CN
`DE
`EP
`EP
`
`1136564
`4 035 455
`0005129
`0124495
`
`11/1996
`5/1992
`10/1979
`11/1984
`
`EP
`EP
`IN
`W0
`W0
`W0
`W0
`
`0247983
`WO 95/01977
`1344/DEL/98
`9427988
`9501977
`9601623
`9602535
`
`*
`
`12/1987
`1/1995
`5/1998
`12/1994
`1/1995
`1/1996
`2/1996
`
`OTHER PUBLICATIONS
`
`Japanese Chemical Society, Experimental Chemical Seminar. vol.
`18. p. 55 (translation), 1958*
`An Introduction to Crystal Chemistry by Evans Cambridge At the
`Univ. Press, 1914*
`Erlandsson, P. Et a1., “Resolution of the enantiomers of omeprazole
`and some of its analogues by liquid chromatography on a
`trisphenylcarbamoyl cellulose-based stationary phase”, Journal of
`Chromatography, 532 (1990) 305-319.
`von Unge, S. et al. “Stereochemical assignment ofthe enantiomers of
`omeprazole from X-ray analysis of a fenchyloxylmethyl derivative of
`(+)-(R)-0meprazole", Tetrahedron Asymmetry, v01. 8, N0. 12, pp.
`1967-1970 (1997).
`An Introduction to Crystal ChemistIy by Evans Cambridge at the
`Univ. Press, 1964.
`Opposition filed by Ranbaxy Laboratories Limited against Indian
`Patent Application No. 1344/DEL/98.
`Opposition filed by Torrent Pharmaceuticals Limited against Indian
`Patent Application No. 1344/DEL/98.
`X-ray powder diffraction pattern of Mg-salt 0f S-omeprazole
`trihydrate depicted by Torrent obtained by method ofWO 94/27988.
`NDA 21-153/S-020 for Nexium® (esomeprazole magnesium)
`Delayed Release Capsule.
`NDA 21-153/21-154 entitled “Medical Review(s)”.
`Statement with Exhibits A-C on Behalfofthe Applicant, AstraZeneca
`AB, t0 the Opposition filed by Ranbaxy Laboratories Limited against
`Indian Patent Application No. 1344/DEL/98.
`the Applicant,
`Statement with Exhibits A-D on Behalf of
`Astraleneca AB, t0 the Opposition filed by Torrent Pharmaceuticals
`Limited against Indian Patent Application No. 1344/DEL/98.
`Decision of the Pre-grant Opposition filed by Ranbaxy Laboratories
`Limited against Indian Patent Application No. 1344/DEL/98.
`Decision of the Pre-grant Opposition filed by Torrent Pharmaceuti-
`cals Limited against Indian Patent Application No. 1344/DEL/98.
`Notice of Allegation, dated Nov. 13, 2007, pursuant to the Patented
`Medicines (Notice ofComp]iance) Regulations with respect to Cana-
`dian Letters Patent No. 2,290,963.
`
`* cited by examiner
`
`Primary ExamineriCharanjit S Aulakh
`(74) Attorney, Agent, or Firm7White & Case LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a novel form of the (—)-
`enantiomer of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-
`pyridinyl)-methyl]sulfinyl]-1H-benzimidazole,
`i.e. S-ome-
`prazole. More specifically, it relates to a novel form of the
`magnesium salt of the S-enantiomer of omeprazole trihy-
`drate. The present invention also relates to processes for pre-
`paring 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.
`
`4 Claims, 5 Drawing Sheets
`
`DRL EXHIBIT 1024 PAGE 1
`
`DRL EXHIBIT 1024 PAGE 1
`
`

`

`US. Patent
`
`Aug. 12, 2008
`
`Sheet 1 of5
`
`US 7,411,070 B2
`
`Ln
`m
`
`QJ\-
`
`S
`‘1’
`Q fim
`El
`N
`
`Ln
`N
`
`Q
`N
`
`QN
`
`Ln
`
`[\I
`
`.\
`*3
`
`Q
`a
`'\
`
`\-
`8.5
`QN
`N
`
`Q
`Q
`Ln
`
`Q
`
`DRL EXHIBIT 1024 PAGE 2
`
`DRL EXHIBIT 1024 PAGE 2
`
`

`

`US. Patent
`
`Aug. 12, 2008
`
`Sheet 2 of5
`
`US 7,411,070 B2
`
`[27']402-Thez‘a—Scale
`
`30
`
`20
`
`[0
`
`
`
`
`
`
`500
`
`2000
`
`Lin([0uns)
`
`7500
`
`1000
`
`DRL EXHIBIT 1024 PAGE 3
`
`DRL EXHIBIT 1024 PAGE 3
`
`

`

`US. Patent
`
`Aug. 12, 2008
`
`Sheet 3 of5
`
`US 7,411,070 B2
`
`Ln
`m.
`
`i’
`E’.U)
`I
`
`Q E
`m gl\
`
`lN
`
`QN
`
`LnN
`
`Q'\
`
`Ln
`
`51-17
`
`-\
`
`*‘é’:,§
`
`E
`S
`\l
`
`8
`Q
`N
`
`Q
`Q
`L-Q
`
`(3
`Q
`S
`
`g
`In
`
`Q
`
`DRL EXHIBIT 1024 PAGE 4
`
`DRL EXHIBIT 1024 PAGE 4
`
`

`

`US. Patent
`
`Aug. 12, 2008
`
`Sheet 4 of5
`
`US 7,411,070 B2
`
`’2
`
`30352—Theta-Scale
`
`25
`
`20
`
`75
`
`70
`
` Lin(Cunfs)
`
`500'
`
`I000
`
`DRL EXHIBIT 1024 PAGE 5
`
`DRL EXHIBIT 1024 PAGE 5
`
`

`

`US. Patent
`
`Aug. 12, 2008
`
`Sheet 5 of5
`
`US 7,411,070 B2
`
`in
`m
`
`30 2-Them-Scale
`
`25
`
`20
`
`mN
`
`.5-
`{x
`43::
`
`5
`
`2%
`:21—
`—:=::;:I
`
`
`kr
`
`:
`
`_\
`U]
`
`Ln
`
`8
`|\
`
`8
`\0
`
`a 838 a
`Ln
`xtsrn
`N
`‘4
`
`Q
`2
`
`a
`
`DRL EXHIBIT 1024 PAGE 6
`
`DRL EXHIBIT 1024 PAGE 6
`
`

`

`US 7,411,070 B2
`
`1
`FORM OF S-OMEPRAZOLE
`
`This application is a continuation of US. patent applica-
`tion Ser. No. 10/076,711, filed Feb. 14, 2002, now US. Pat.
`No. 6,667,455 whichis a diVis'onal ofU.S. patent application
`Ser. No. 09/077,719, filed Jul. 8, 1998, now US. Pat. No.
`6,369,085, which was the National Stage of International
`Application No. PCT/SE98/00974, filed May 25, 1998.
`FIELD OF THE INVENTION
`
`
`
`The present invention relates to a novel form of the (—)—
`enantiomer of 5 -methoxy-2 - [[(4 -methoxy-3 , 5-dimethyl -2-
`pyridinyl)-methyl]sulfinyl]-1H-benzimidazole,
`i.e. S-ome-
`prazole. More specifically, it relates to a novel form of the
`magnesium salt of the S-enantiomer of omeprazole trihy-
`drate. The present invention also relates to processes for pre-
`paring 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 their preparation.
`
`PRIOR ART
`
`BACKGROUND OF THE INVENTION AND
`
`The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
`2-pyridinyl)methyl]sulfinyl]-1H-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
`especially in man.
`Omeprazole is a sulfoxide and a chiral compound, wherein
`the sulfur atom being the stereogenic center. Thus, omepra-
`zole is a racemic mixture of its two single enantiomers, the R
`and S-enantiomer of omeprazole, herein referred to as
`R-omeprazole and S-omeprazole. The absolute configura-
`tions ofthe 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 ofthe magnesium salt and the (—)-enantiomer
`of the magnesium salt were also found to have R 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 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 ofthe
`single enantiomers of 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
`
`FIG. 1 shows a X-ray powder diffractogram of the magne-
`sium salt of S-omeprazole trihydrate prepared according to
`the present invention.
`FIG. 2 shows a X-ray powder diffractogram of the potas-
`sium salt of S-omeprazole prepared and used in the present
`application (See examples 2 and 3)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`60
`
`65
`
`2
`FIG. 3 shows a X-ray powder diffractogram of a magne-
`sium salt of S-omeprazole dihydrate prepared and used in the
`present application (See example 5)
`FIG. 4 shows a X-ray powder diffractogram ofa magne-
`sium salt of S-omeprazole dihydrate which is a polymorph of
`
`the dihydrate shown in FIG. 3 (See Example 6). This magne-
`sium 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 invention.
`FIG. 5 shows X-ray powder diffractogram of the magne-
`sium salt of S-omeprazole prepared according to example A
`in WO 96/01623.
`
`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
`substantially pure magnesium salt of S-omeprazole trihy-
`drate, hereinafter referred to as the compound of the inven-
`tion. This trihydrate can be obtained as a well defined com-
`pound. 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-omeprazole.
`The compound of the invention is advantageous because it
`is more stable than the corresponding magnesium salt com-
`pounds 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 repro-
`ducible 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-omeprazole trihydrate obtained according to the present
`invention is also substantially free from other forms of mag-
`nesium salts of S-omeprazole, such as the corresponding
`magnesium salt compounds described in prior art, and dihy-
`drates 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 major peaks in the X-ray
`powder diffractogram, but may also be characterized by con-
`ventional FT—IR spectroscopy. These characteristics are not
`exhibited by any other form of magnesium salt of S—omepra—
`zole and accordingly, the magnesium salt of S—omeprazole
`trihydrate is easily distinguishable from any other crystal
`form of the magnesium salt of S-omeprazole disclosed in
`prior art. The compound of the invention is characterized by
`being 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 amor-
`phous forms thereof disclosed in the prior art. Examples of
`any other forms ofmagnesium salt of S-omeprazole includes,
`but are not limited to, anhydrates, monohydrates, dihydrates,
`sesquihydrates, trihydrates, alcoholates, such as methano-
`lates and ethanolates, and polymorphs or amorphous forms
`thereof.
`
`The compound of the invention may also be characterized
`by its unit cell.
`In a further aspect, the present invention provides pro-
`cesses for the preparation of the magnesium salt of S-ome-
`prazole trihydrate which comprises;
`
`DRL EXHIBIT 1024 PAGE 7
`
`DRL EXHIBIT 1024 PAGE 7
`
`

`

`US 7,411,070 B2
`
`3
`a) treating a magnesium salt of S-omeprazole of any form,
`for example prepared according is 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 tempera-
`ture is meant a temperature which induces the transfor-
`mation of starting material to product without decom-
`posing any of these compounds. Examples of such
`suitable temperatures include, but are not limited to,
`room temperature and above. By a suitable time is meant
`a time that results in high conversion of the starting
`material into product without causing any decomposi-
`tion of either compounds, i.e. results in a good yield.
`This suitable time will vary depending on the tempera-
`ture 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 cru—
`
`cial and Will depend on the process conditions used. The
`magnesium salt of S-omeprazole trihydrate is thereafter
`separated from the aqueous slurry, for example by fil-
`tration or centrifugation and thereafter dried to constant
`weight; or
`b) oxidizing 5 -methoxy-2- [[(4 -methoxy-3, 5-dimethyl-2-
`pyridinyl)methyl]thio]-1H-benzimidazole, with an oxi-
`dizing agent and a chiral titanium complex, optionally in
`the presence of a base. The oxidation is carried out in an
`organic
`solvent,
`for example toluene or dichlo-
`romethane.
`
`The crude product is converted to the corresponding potas-
`sium salt by treatment with a potassium source, such as
`methanolic potassium hydroxide or methanolic potassium
`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 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 corresponding mag-
`nesium 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 ofthe 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 potassium salt of S-omeprazole may also
`be used as an active component of a pharmaceutical formu-
`lation to bc uscd in thc trcatmcnt of gastrointestinal discascs.
`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 is
`known per se.
`The amount of water in the magnesium salt of S-omepra-
`zole trihydrate is determined by thermogravimetric analysis,
`a technique which is known per se.
`The compound ofthe 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 treat-
`me it of gastric-acid related conditions in mammals and espe-
`cia ly in man, including e.g. reflux esophagitis, gastritis,
`duodenitis, gastric ulcer and duodenal ulcer. Furthermore, it
`may be used for treatment of other gastrointestinal disorders
`
`
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`60
`
`65
`
`4
`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 ofthe inven-
`tion may also be used in patients in intensive care situations,
`in patients with acute upper gastrointestinal bleeding, pre-
`and po stoperatively to prevent aspiration ofgastric 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 dis-
`
`eases related to these. The compound of the invention may
`also be used for treatment of inflammatory conditions in
`mammals, including man.
`Any suitable route of administration may be employed for
`providing the patient with an effective dosage of the magne-
`sium salt of S-omeprazole trihydrate, according to the inven-
`tion. For example, peroral or parental formulations and the
`like may be employed. Dosage forms include capsules, tab-
`lcts, dispcrsions, suspcnsions and thc like.
`It is further provided a pharmaceutical composition corn-
`prising the magnesium salt of S-omeprazole trihydrate
`according to the invention, as active ingredient, in association
`with a pharrnaceutically acceptable carrier, diluent or excipi—
`ent and optionally other therapeutic ingredients. Composi-
`tions comprising other therapeutic ingredients are especially
`of 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 effec-
`tive amount ofthe magnesium salt of S-omeprazole trihydrate
`according to the invention.
`The compositions of the invention include compositions
`suitable for peroral or parental administration. The most pre-
`ferred route is the oral route. The compositions may be con-
`veniently presented in unit dosage forms, and prepared by any
`methods known in the art of pharmacy.
`1n 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 disease to be treated. The dose, and dose
`frcqucncy, may also vary according to thc agc, body wcight,
`and response of the individual patient. Special requirements
`may be needed for patients having Zollinger-Ellison syn-
`drome, 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 use
`doses outside the ranges stated below, for example long term
`treatments may request lower do sage. Such higher and lower
`doses are within the scope ofthe 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 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 pharmaceuti-
`cal carrier according to conventional techniques, such as the
`oral formulations described in WO 96/01623 and EP 247 983,
`the disclosures of which are hereby incorporated as a whole
`by reference.
`
`DRL EXHIBIT 1024 PAGE 8
`
`DRL EXHIBIT 1024 PAGE 8
`
`

`

`US 7,411,070 B2
`
`5
`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
`are not limited to anti-bacterial compounds, non-steroidal
`anti-inflammatory agents, antacid agents, alginates and pro-
`kinetic agents.
`The examples which follow will further illustrate the
`preparation of the compound of the 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-pyridi-
`nyl)-methyl]sulfinyl]-1H-benzimidazole Magnesium
`Salt Trihydratc
`
`Water (157 kg) was added to the wet crystals of the mag-
`nesium 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.
`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 gave the diffractogram depicted in
`FIG. 1. The main peaks, with positions and relative intensi-
`ties, have been extracted from the diffractogram in FIG. 1 and
`is given below in table 1. The relative intensities are less
`reliable and instead of numerical values the following defini-
`tions are used.
`
`% 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 diffracto-
`gram have been omitted from table 1.
`
`TABLE 1
`
`Positions and intensities of the maj or peaks in the XRP-diffractogram
`ofthe maonesium salt of S-omeprazole trihydrate.
`
`d-value/A
`2.67
`2.79
`3.27
`3.52
`3.82
`3.96
`4.14
`5.2
`5.6
`6.7
`6.9
`
`Relative Intensity
`
`waBBBfiwr/IBBB
`
`6
`
`
`TABLE 1-continued
`
`Positions and intensities of the major peaks in the XRP-diffractogram
`of the magnesium salt of S-omeprazole trihydrate.
`
`d-value/A
`8.3
`16.6
`
`Relative Intensity
`w
`vs
`
`Example 2
`
`S-5 -methoxy-2-[[(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`nyl)mcthyl]sulfinyl]-1H-bcnzimidazolc Potassium
`Salt
`
`A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`pyridinyl)methyl]thio]—1H—benzimidazole
`(15.4
`g,
`46.8
`mmol) 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 mmol)
`were added. The reaction mixture was stirred for 20 minutes.
`
`Titanium(IV)isopropoxide (1.34 g, 4.68 mmol) was added
`and the reaction mixture was stirred for 45 minutes. The
`mixture was cooled to 30° C. and diisopropylethylamine
`(0.91 g, 7.01 mmol) was added followed by cumene hydrop-
`eroxide (9.52 g, 51.89 mmol). 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 mmol) in
`methanol (30 ml). Seed crystals were added and the reaction
`mixture was stirred at 35° C. overnight. The precipitated
`product was filtered off, washed with methanol and toluene
`and dried in vacuo. Yield: 9.74 g (54%).
`
`Example 3
`
`S-5 -methoxy-2-[[(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`nyl)-mcthyl] sulfinyl] - 1 H-bcnzimidazolc Potassium
`Salt
`
`Water (157.6 111) 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 g/l) with a water
`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(lV)
`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 hydrop-
`eroxide was added at an appropriate speed to maintain the
`temperature from 28° C. to 34° C. The temperature was raised
`to 35° C. after 2 hours and 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%.
`[0L]DZO:+28.7° (c:1%, water); Assay: 89% is S-5-meth-
`oxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]
`sulfinyl]-1H-benzimidazole potassium salt (11% is metha-
`nol).
`1H-NMR (200 MHZ, DMSO-d6, 6 ppm): 2.23 (s, 311), 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 from Examples 2 and 3 were analysed using
`X-ray powder diffraction as described in Example 1 and gave
`the diffractogram depicted in FIG. 2 and given below in Table
`
`5
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`60
`
`65
`
`DRL EXHIBIT 1024 PAGE 9
`
`DRL EXHIBIT 1024 PAGE 9
`
`

`

`US 7,411,070 B2
`
`7
`2. Some additional very weak peaks found in the diffracto-
`gram have been omitted from Table 2.
`
`TABLE 2
`
`8
`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.
`
`Positions and intensities of the major peaks in the XRP-diffractograrn
`ofthe potassium salt of S-omeprazole.
`Relative
`intensity
`4m
`
`d-Value/A
`13.6
`10.6
`7.8
`6.8
`6.5
`6.2
`6.1
`5.8
`5.4
`5.3
`5.2
`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
`3.52
`3.42
`3.38
`3.34
`3.28
`3.20
`3.12
`3.06
`3.03
`2.97
`2.93
`2.89
`2.85
`2.76
`2.71
`2.66
`2.58
`2.57
`2.56
`2.52
`2.47
`2.45
`2.43
`2.40
`2.38
`2.31
`
`giggiggs22;;sasgssssasassaaaassssgas22233223masaaai
`
`10
`
`15
`
`20
`
`25
`
`40
`
`45
`
`Example 5
`
`S-5 -methoxy-2-[[(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`nyl)-methylj sulfinylj -1H-benzimidazole Magnesium
`Salt Dihydrate
`
`5 .0 g ofthe moist product from Example 4 with an approxi-
`mate dry content of 74%, was dried in vacuum at 350 C. over
`night to yield 3.58 g (2.68 mmol) of S-5-methoxy-2-[[(4-
`mcthoxy-3 ,5 -dimcthyl-2-pyridinyl)-mcthyl] sulfinyl] -1 H-
`benzimidazole magnesium salt dihydrate, named Form B.
`The product was analyzed using X-ray powder diffraction
`as described in Example 1, and the analyze gave the diffrac-
`togram depicted in FIG. 3 and given below in Table 3. Some
`additional peaks with low intensities found in the diffracto-
`gram have been omitted from Table 3.
`
`TABLE 3
`
`POSitions and intensities of the major peaks in the XRP-diffractogram
`of the magnesium salt of Seomeprazole dihydrate, Form B.
`
`d-value/A
`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
`
`Relative Intensity
`
`fiEEWEMEEEEWEwmeEE
`
`Conversion of Magnesium Salt of S-omeprazole Dehydrate
`to Trihydrate
`This material was subsequently processed to S-5-methoxy-
`2-[[(4-methoxy-3,5-dimethyl-2-pyridiny1)-methy1]sulfinyl]—
`1H-benzimidazole magnesium salt trihydrate according to
`the procedure described for the moist substance in Example 1 .
`
`Examplc 6
`
`S-5 -methoxy-2-[[(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`nyl)-methyl] sulfinyl] -1H-benzimidazole Magnesium
`Salt Dihydrate
`
`A methanolic solution of S-5-methoxy-2-[[(4-methoxy-3,
`5 -dimethyl-2 -pyridinyl)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-dim-
`ethyl-2 -pyridinyl)methyl] sulfinyl] - 1 H-benzimidazole mag-
`nesium salt (1.86 g) in 5 ml methanol was concentrated by
`evaporation until 1.58 ml methanol remained. Then, a mix-
`ture of 1.6 ml water and 6.32 ml aceton was added. The
`
`60
`
`65
`
`solution was allowed to crystallize during 26 h at room tem-
`perature. The resulting crystals were filtered off and dried at
`
`a1 = 1.54060 A
`
`Example 4
`
`S-5 -methoxy-2-[ [(4-methoxy-3 ,5 -dimethyl-2-pyridi -
`ny1)-methyl]sulfinyl]—1H-benzimidazole Magnesium
`Salt
`
`Methanol (148 kg) was added to S-5-methoxy-2-[[(4-
`methoxy-3, 5 -dimethyl -2 -pyridinyl)methyl] sulfinyl] - 1 H-
`benzimidazole potassium salt
`(71 kg, methanol
`con-
`tent:13%). MgSO4x7H20 (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 concentrated to a volume of 100 liter, acetone (253 kg)
`
`DRLEXHIBIT 1024 PAGE 10
`
`DRLEXHIBIT 1024 PAGE 10
`
`

`

`US 7,411,070 B2
`
`9
`40° C. under reduced pressure giving 1.17 g of S-5-methoxy-
`2-[ [(4-methoxy-3 ,5 -dimethyl-2 -pyridinyl)methyl] sulfinyl] -
`1H-benzimidazole magnesium salt dihydrate. named formA.
`The product was analyzed using X-ray powder diffration as
`described in Example 1 and gave the diffractogram depicted
`in FIG. 4 and given below in Table 4. Some additional peaks
`with low intensities found in the diffractogram have been
`omitted from Table 4.
`
`TABLE 4
`
`Positions and intensities of the 111aon peaks in the XRP-diffractogram
`ofthe magnesium salt ofS-omepramle dihydrate Form A.
`
`d-Value/A
`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
`
`Relative Intensity
`
`mamammamm
`
`vs
`s
`vs
`
`Example 7
`
`S-5 -methoxy-2-[ [(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`ny1)-methyl]sulfinyl]—1H-benzimidazole Magnesium
`Salt Trihydrate
`
`22.0 g (29,1 mmol) of S-5-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2 -pyridinyl) methyl] sulfinyl] -1 H-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 -pyridinyl)-methyl] sulfinyl] - 1 H-
`benzimidazole magnesium salt
`trihydrate. 22 mL (69,6
`mmol) of MgSO4 (aq) was added under a 3 11 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).
`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 FIG. 1 and Table 1.
`
`Reference Example A
`
`S-5 -methoxy-2-[ [(4-methoxy-3 ,5 -dimethyl-2-pyridi-
`ny1)-methyl]sulfinyl]—1H-benzimidazole Magnesium
`Salt
`
`(The method used is in accordance with the method
`described in Example A in WO 96/01623)
`Magnesium (0.1 pg, 4.5 mmol) was dissolved and reacted
`with methanol (50 ml) at 400 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]
`
`1 0
`of 5 -methoxy-2 - [[(4 -methoxy-3 , 5 -dimethyl -2 -pyridinyl)me-
`thyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was
`added to the magnesium methoxide solution. The mixture
`was stirred for 12 hours whereupon a small amount of water
`(0.1 ml) was added in order to precipitate inorganic magne-
`sium 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 an optical purity
`(enantiomeric excess, e.e.) of 80%. This mixture was diluted
`with acetone (100 ml) 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
`(5 0%) ofthe title compound as white crystals. Chiral analyses
`of the crystals and mother liquor were performed by chroma-
`tography on an analytical chiral column. The optical purity of
`the crystals and mother liquor was found to be 98.4 e.e. and
`64.4% e.e., respectively. Thus, the optical purity (e.e.) has
`been enhanced from 80% to 98.4% simply by crystallizing
`the Mg-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
`absorption spectroscopy. [a]DZO:—131.5° (c:0.5%, metha-
`nol).
`The product was analyzed using X-ray powder diffraction
`as described in Example 1 and gave the diffractogram
`depicted in FIG. 5 and given below in Table 5. Some addi-
`tional very weak peaks found in the diffractograms have been
`omitted from Table 5.
`
`TABLE 5
`
`Positions and intensities of the major peaks
`in the XRP-diffractogram shown in FIG. 5.
`
`d-value/A
`2.90
`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.