|
`
`United States Patent
`Lindbergetal.
`
`115
`
`[11] Patent Number:
`
`[45] Date of Patent:
`
`5,714,504
`Feb. 3, 1998
`
`[54] COMPOSITIONS
`
`[75]
`
`Inventors: Per Lennart Lindberg. Molndal;
`Sverker Von Unge, Fjaras, both of
`Sweden
`
`[73] Assignee: Astra Aktiebolag, Sodertalje, Sweden
`
`[21] Appl. No.: 376,512
`
`[22] Filed:
`
`Jan. 23, 1995
`
`Related U.S. Application Data
`
`{63] Continuation-in-part of Ser. No. 256,174, filed as PCT/
`SE94/00509, May 27, 1994.
`
`[30]
`
`Foreign Application Priority Data
`
`May 28,1993
`
`[SE]
`
`Sweden .....csccsssressrsseeseees 9301830
`
`Int. CLS once CO7D 401/12; A61K 31/44
`[51]
`[52] WS. CU. cceccccscceseescccseesscerener sense 514/338; 546/273.7
`[58] Field of Search ..........cce 546/273.7; 514/338
`
`[56]
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`0005129
`0124495
`4035455
`4035455
`
`European Pat. Off. .
`4/1981
`1/1987 European Pat. Off. .
`11/1990 Germany .
`5/1992 Germany.
`
`OTHER PUBLICATIONS
`
`Erlandssonet al., J. Chromatography. vol.532, pp. 305-319
`(1990).
`Cairns, et al. “Enantioselective HPLC determination...”
`Journal of Chromatography 8,666 (1995) 323-328.
`
`Yamada et al. “Synthesis and isomerization of optical
`active...” Chem. Pharm. Bull. 42(8) (1994) 1679-1681.
`K. Miwaet al. Jpn. Pharmacol. Ther. “Proton pump inhibitor
`in rats, mice and dogs” 18 (1990) 165-187 (transl).
`H. Katsuki et al. “Determination of R(+)—-and S(-}+Lanso-
`prazole” Pharmaceutical Research 13(4) (1996) 611-615.
`M. Tanaka et al. “Direct determination of pantoprazole
`enantiomers...” Anal. Chem. 68 (1996) 1513-1516.
`P. Lindberg et al. “Omeprazole: The first proton pump
`inhibitor” Medicinal Res. Rev. 10 (1990) 2-50.
`P. Lindberg et al. “The mechanism of action of...
`omeprazole” Journal of Medicinal Chemistry 29 (1986)
`1327.
`A. Brandstrom “Chemical reactions...” Reprint from Acta
`Chemica Scandinavica 43 (1989) 536-611.
`K. Sigrist—Nelsonet al. “Ro 18-5364, a potentinhibitor of
`the gastric (H* +K*)-ATPase” Eur. J. Bioch. 166 (1987)
`453.
`Polomomcoll et al. CA 117;90292, 1992.
`
`Primary Examiner—Jane Fan
`Attomey, Agent, or Firm—White & Case
`[57]
`ABSTRACT
`
`The novel optically pure compounds Na*, Mg?*, Li*, K*,
`Ca** and N*(R), salts of (+)-5-methoxy-2-[[(4-methoxy-3,
`§-dimethy1-2-pyridinyl)methy1]|sulfinyl|- 1H-benzimidazole
`or
`(—)-5-methoxy-2-[[(4-methoxy-3,5-dimethy1-2-
`pyridinyl )methy]}sulfinyl]-1H-benzimidazole.
`in particular
`sodium and magnesium salt form thereof, where R is an
`alkyl with 1-4 carbon atoms, processes for the preparation
`thereof and pharmaceutical preparations containing the
`compounds as active ingredients, as well as the use of the
`compounds in pharmaceutical preparations and intermedi-
`ates obtained by preparing the compounds.
`
`10 Claims, No Drawings
`
`DRL EXHIBIT 1025 PAGE 1
`
`DRL EXHIBIT 1025 PAGE 1
`
`

`

`5,714,504
`
`1
`COMPOSITIONS
`
`This application is a continuation-in-part of application
`Ser. No. 08/256,174, filed as PCT/SE94/00509, May 27,
`1994,
`
`FIELD OF THE INVENTION
`
`The present invention is directed to new compounds of
`high optical purity and crystalline salts thereof, their use in
`medicine. a process for their preparation andtheir use in the
`manufacture of pharmaceutical preparation. The invention
`also relates to novel intermediates in the preparation of the
`compounds of the invention.
`
`BACKGROUND OF THE INVENTION
`
`The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
`2-pyridinyl)methyl|sulfinyl|-1H-benzimidazole, having the
`generic name omeprazole, and therapeutically acceptable
`alkaline salts thereof are described in U.S. Pat. No. 4.255,
`431 to Junggren et al., EP 5129 and EP 124 495, respec-
`tively. Omeprazoleandits alkaline salts are effective gastric
`acid secretion inhibitors, and are useful as antiulcer agents.
`The compounds, being sulfoxides, have an asymmetric
`center in the sulfur atom, i.e. exist as two optical isomers
`(enantiomers).
`The separation of the enantiomers of omeprazole in
`analytical scale is described in e.g. J. Chromatography, 532
`(1990), 305-19 and in a preparative scale in DE 4035455.
`The latter has been done by using a diastereomeric ether
`which is separated and thereafter hydrolysed in an acidic
`solution. Under the acidic conditions needed for hydrolysis
`of the attached group, omeprazole is quite sensitive and the
`acid has to be quickly neutralized with a base to avoid
`degradation of the acid-sensitive compound. In the above
`mentioned application (DE 4035455) this is done by adding
`the reaction mixture containing concentrated sulfuric acid to
`a concentrated solution of NaOH.This is disadvantageous
`because them is a great risk of locally reaching pH values
`between 1-6, which would be devastating for the substance.
`Moreover,
`instantaneous neutralization will create heat
`which will be difficult to handle in large scale production.
`There is no example in the knownpriorart of anyisolated
`or characterized salt of optically pure omeprazole, i.e. of
`single enantiomers of omeprazole or of any isolated or
`characterized salt of any optically pure omeprazole ana-
`logue.
`
`SUMMARY OF THE INVENTION
`
`It is desirable to obtain compounds with improved phar-
`. Macokinetic and metabolic properties which will give an
`improved therapeutic profile such as a lower degree of
`interindividual variation. The present invention provides
`such compounds, which are novel salts of single enanti-
`omers of omeprazole.
`Apreferred embodimentof the present invention provides
`pure crystalline enantiomeric salts of omeprazole and meth-
`ods for the preparation thereof.
`A more preferred embodimentof the present invention is
`directed to an optically pure crystalline enantiomeric mag-
`nesium salt of omeprazole and method for the preparation
`thereof.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`A nonaqueous process according to the present invention
`is directed to the preparation of crystalline forms of an
`optically pure enantiomer of omeprazole magnesium salt or
`analogues thereof which includes steps of stirring a crude
`
`65
`
`2
`preparation of the omeprazole enantiomer under nitrogen
`into a methanolic magnesium methoxide solution, precipi-
`tating inorganic magnesium salt with addition of a small
`amount of water, removing any precipitated inorganic mag-
`nesium salts, concentrating the residual methanolic solution,
`precipitating the omeprazole enantiomer by adding acetone
`to the residual solution, and filtering off the optically pure
`enantiomer crystals of magnesium omeprazole or analogues
`thereof.
`
`The present invention in a further aspect provides a novel
`method for preparing the novel compoundsof the invention
`in large scale. This novel method can also be used in large
`scale to obtain single enantiomers of omeprazole in neutral
`form.
`
`The compounds according to the invention may be used
`for inhibiting gastric acid secretion in mammals and man.In
`a more general sense, the compounds of the invention may
`be used for the treatmentof gastric acid-related diseases and
`gastrointestinal
`inflammatory diseases in mammals and
`man, such as gastric ulcer, duodenal ulcer, reflux
`esophagitis, and gastritis. Furthermore, the compounds may
`be used for treatment of other gastrointestinal disorders
`wheregastric antisecretory effect is desirable e.g. in patients
`on NSAID therapy, in patients with gastrinomas, and in
`patients with acute upper gastrointestinal bleeding. They
`mayalso be used in patients in intensive care situations, and
`pre- and postoperatively to prevent acid aspiration and stress
`ulceration. The compound of the invention may also be used
`for treatment or prophylaxis of inflammatory conditions in
`mammals, including man, especially those involving lysozy-
`mal enzymes. Conditions that may be specifically mentioned
`for treatment are rheumatoid arthritis and gout. The com-
`pound of the invention may also be useful in the treatment
`of psoriasis as well as in the treatment of Helicobacter
`infections.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The present invention refers to the new Nat, Mg**, Lit,
`K", Ca?" and N*(R), salts of the single enantiomers of
`omeprazole, where R is an alkyl with 1-4 carbon atoms.i.e.
`Na*, Mg’*, Li*, K*, Ca?* and N*(R), salts of (4)-5-
`methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]
`sulfinyl]-1H-benzimidazole and (—)-5-methoxy-2-[[(4-
`methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-
`benzimidazole, where R is an alkyl with 1-4 carbon atoms.
`
`Particularly preferred salts according to the invention are
`the Na‘, Ca** and Mg?" salts, i.e (+)-5-methoxy-2-[[(4-
`methoxy-3,5-dimethy]-2-pyridinyl)methyl] sulfiny]]-1H-
`benzimidazole sodium salt, (—)-5-methoxy-2-{[(4-methoxy-
`3,5-dimethyl-2-pyridinyl)methy]]sulfinyl]-1H-
`benzimidazole sodium salt, (+)-5-methoxy-2-{[(4-methoxy-
`3,5-dimethy1-2-pyridinyl)methy] |sulfinyl]-1H-
`benzimidazole magnesium salt,
`(—)-S-methoxy-2-[[(4-
`methoxy-3 ,5-dimethyl-2-pyridinyl)methyl |sulfinyl]-1H-
`benzimidazole magnesium salt, (+)-5-methoxy-2-[[(4-
`methoxy-3 .5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-
`benzimidazole calcium salt and (—)-5-methoxy-2-[[(4-
`methoxy-3,5-dimethy1-2-pyridinyl)methyl|sulfinyl]-1H-
`benzimidazole calcium salt.
`
`Most preferred salts according to the invention are the
`optically pure Na* salts of omeprazole according to com-
`poundsIa and Ib
`
`DRL EXHIBIT 1025 PAGE 2
`
`DRL EXHIBIT 1025 PAGE 2
`
`

`

`OCH;
`
`zs
`
`N
`
`CH;
`
`(m1)
`
`oN
`Oo
`ih
`Il
`cH—s
`
`|
`
`'
`CH
`
`0
`
`OCH;
`
`“ppC—CH
`
`5,714,504
`
`Ia, Ib)
`
`HC.
`
`a
`
`10
`
`30
`
`OCH;
`
`OCH3
`HC. — CH3
`|
`
`o
`z
`i}
`f
`N cus |
`
`N N
`
`at
`
`Ia (+)-enantiomer
`Tb (--enantiomer
`
`and the optically pure magnesium salts of omeprazole
`according to compounds Ila and IIb
`
`HC,
`
`|
`
`OCH,
`we
`2
`
`N
`
`(ila,IIb)
`
`OCHs
`
`2
`
`CH,
`
`y
`o
`i
`tH}
`Cl)—S + |
`N
`2+
`
`Ms
`Tia (+)-enantiomer
`Ub (—-)-enantiomer
`
`Preparation
`The optically pure compoundsof the invention, i.e. the
`single enantiomers, are prepared by separating the two
`stereoisomers of a diastereomeric mixture of the following
`type, 5- or 6-methoxy-2-[[(4-methoxy-3.5-dimethyl-2-
`pyridinyl)methy1|sulfinyl]-1-{acyloxymethyl]-1H-
`benzimidazole, formula IV
`
`OCH3
`we CH;
`
`z
`
`N
`
`oN
`ll
`h
`cu—s —€
`
`qv)
`
`OCH;
`
`|
`
`H,
`
`N\C
`
`HC.
`
`|
`
`“OAcyl
`wherein the methoxy substituent in the benzimidazole moi-
`ety is in position 5 or 6, and wherein the Acyl radical is as
`defined below, followed by a solvolysis of each separated
`diastereomer in an alkaline solution. The formed single
`enantiomers of omeprazoleare then isolated by neutralizing
`aqueoussolutions of the salts of the single enantiomers of
`omeprazole with a neutralizing agent which can be an acid
`or an ester such as methyl formate.
`The Acyl moiety in the diastereomeric ester may be a
`chiral acyl group such as mandeloyl, and the asymmetric
`center in the chiral acyl group can have either R or S
`configuration.
`The diastereomeric esters can be separated either by
`chromatographyor fractional crystallization.
`The solvolysis usually takes place together with a base in
`a protic solvent such as alcohols or water, but the acyl group
`may also be hydrolyzed off by a base in an aprotic solvent
`such as dimethylsulfoxide or dimethylformamide. The react-
`ing base may be OH” or R'O” where R’ can be anyalkyl or
`aryl group.
`To obtain the optically pure Na*salts of the invention, i.e.
`the single enantiomers of omeprazole Na’salts, the resulting
`compound is treated with a base, such as NaOH, in an
`aqueous or nonaqueous medium, or with NaOR?wherein R?
`is an alkyl group containing 14 carbon atoms, or with
`NaNH,.In addition, alkaline salts wherein the cation is Li*
`or K* may be prepared using lithium or potassium salts of
`the above mentionedbases. In order to obtain the crystalline
`form of the Na™ salt, addition of NaOH in a non-aqueous
`medium such as a mixture of 2-butanone and toluene, is
`preferred.
`To obtain the optically pure Mg”* salts of the invention.
`optically pure enantiomeric Na* salts may be treated with an
`aqueous solution of an inorganic magnesium salt such as
`MgCl,, whereupon the Mg** salts are precipitated. The
`optically pure Mg?" salts may also be prepared by treating
`single enantiomers of omeprazole with a base, such as
`
`With the expression “optically pure Na" salts of omepra-
`zole” is meant the (+)-enantiomer of omeprazole Na-salt
`essentially free of the (—)-enantiomer of omeprazole Na-salt
`and the (—)-enantiomer essentially free of the (+)-
`enantiomer, respectively. Single enantiomers of omeprazole
`have hitherto only been obtained as syrups and not as
`crystalline products. The salts defined by the present inven-
`tion are easy to obtain by meansofthe novel specific method
`according to one aspect of the invention of preparing the
`single enantiomers of omeprazole. In contrast to the neutral
`forms the salts can be obtained as crystalline products.
`Becauseit is possible to purify optically impure or partially
`pure salts of the enantiomers of omeprazole by
`crystallization, they can be obtained in very high optical
`purity, namely 299.8% enantiomeric excess (e.e.) even
`from an optically contaminated preparation. Moreover, the
`optically pure salts are stable resisting racemization both in
`neutral pH and basic pH, which is surprising since the
`known deprotonation at the carbon atom between the pyri-
`dine ring and the chiral sulfur atom was expected to cause
`racemization under alkaline conditions. This high stability
`against racemization makes it possible to use a single
`enantiomeric salt of the invention in therapy.
`
`The specific method of preparation of the single enanti-
`omers of omeprazole is a further aspect of the invention as
`mentioned above and it can be used to obtain the single
`enantiomers of omeprazole in neutral form as well as the
`salts thereof.
`
`Yet a further aspect of the invention is the compound Ii.
`which is an intermediate used in the specific method of
`preparation.
`
`50
`
`35
`
`65
`
`DRL EXHIBIT 1025 PAGE 3
`
`DRL EXHIBIT 1025 PAGE 3
`
`

`

`5,714,504
`
`5
`Mg(OR*),, wherein R® is an alkyl group containing 14
`carbon atoms, in a non-aqueous solvent such as alcohol
`(only for alcoholates). e.g. ROH, or in an ether such as
`tetrahydrofuran. In an analogous way, also alkaline salts
`wherein the cation is Ca** can be prepared, using an aqueous
`solution of an inorganic calcium salt such as CaCl.
`Alkaline salts of the single enantiomers of the invention
`are, as mentioned above, beside the sodium salts
`(compoundsIa and Ib) and the magnesium salts (compounds
`Hla and IIb), exemplified by their salts with Lit, K*, Ca** and
`N*(R),, where R is an alkyl with 1-4 C-atoms.
`For clinical use the single enantiomers, i.e. the optically
`pure compounds, of the invention are formulated into phar-
`maceutical formulations for oral, rectal, parenteral or other
`modes of administrations. The pharmaceutical formulations
`contain the single enantiomers of the invention normally in
`combination with a pharmaceutically acceptable carrier. The
`carrier may be in form of a solid, semi-solid or liquid
`diluent, or capsule. These pharmaceutical preparations are a
`further object of the invention. Usually the amountofactive
`compoundis between 0.1-95% by weight of the preparation,
`between 0.2-20% by weight in preparations for parenteral
`use and between 1-50% by weight in preparations for oral
`administration.
`In the preparation of pharmaceutical formulations in form
`of dosage units for oral administration the optically pure
`compound may be mixed with a solid, powdered carrier.
`such as lactose, saccharose, sorbitol, mannitol, starch,
`amylopectin. cellulose derivates, gelatin or another suitable
`carrier, stabilizing substances such as alkaline compounds
`e.g. carbonates, hydroxides and oxides of sodium,
`potassium, calcium, magnesium andthelike as well as with
`lubricating agents such as magnesium stearate, calcium
`stearate, sodium stearyl fumarate and polyethyleneglycol
`waxes. The mixture is then processed into granules or
`pressed into tablets. Granules and tablets may be coated with
`an enteric coating which protects the active compound from
`acid catalyzed degradation as long as the dosage form
`Temains in the stomach. Theenteric coating is chosen among
`pharmaceutically acceptable enteric-coating materials e.g.
`beeswax, shellac or anionic film-forming polymers and the
`like, if preferred in combination with a suitable plasticizer.
`To the coating various dyes may be added in order to
`distinguish amongtablets or granules with different amounts
`of the active compound present.
`Soft gelatine capsules may be prepared with capsules
`containing a mixture of the active compound, vegetable oil,
`fat, or other suitable vehicle for soft gelatine capsules. Soft
`gelatine capsules may also be enteric-coated as described
`above.
`Hard gelatine capsules may contain granules or enteric-
`coated granules of the active compound. Hard gelatine
`capsules may also contain the active compound in combi-
`nation with a solid powdered carrier such as lactose,
`saccharose, sorbitol, mannitol, potato starch, amylopectin,
`cellulose derivates or gelatin. The capsules may be enteric-
`coated as described above.
`Dosage units for rectal administration may be prepared in
`the form of suppositories which contain the active substance
`mixed with a neutral fat base, or they may be prepared in the
`form of a gelatine rectal capsule which contains the active
`substance in a mixture with a vegetable oil, paraffin oil or
`other suitable vehicle for gelatine rectal capsules, or they
`may be prepared in the form of a ready-made micro enema,
`or they may be prepared in the form of a dry micro enema
`formulation to be reconstituted in a suitable solvent just
`prior to administration.
`
`5
`
`15
`
`6
`Liquid preparation for oral administration may be pre-
`paredin the form of syrups or suspensions, e.g. solutions or
`suspensions containing from 0.2% to 20% by weight of the
`active ingredient and the remainder consisting of sugar or
`sugar alcohols and a mixture of ethanol, water, glycerol,
`propylene glycol and/or polyethylene glycol. If desired, such
`liquid preparations may contain coloring agents, flavoring
`agents, saccharine and carboxymethyl cellulose or other
`thickening agents. Liquid preparations for oral administra-
`10 tion may also be prepared in the form of dry powder to be
`reconstituted with a suitable solvent prior to use.
`Solutions for parenteral administrations may be prepared
`as solutions of the optically pure compounds of the inven-
`tion in pharmaceutically acceptable solvents, preferably in a
`concentration from 0.1 to 10% by weight. These solutions
`may also contain stabilizing agents and/or buffering agents
`and may be manufactured in different unit dose ampoules or
`vials. Solutions for parenteral administration may also be
`prepared as dry preparations to be reconstituted with a
`20 suitable solvent extemporaneously before use.
`The typical daily dose of the active compound will
`depend on various factors such as for example the individual
`requirement of each patient, the route of administration and
`the disease. In general, oral and parenteral dosages will be
`in the range of 5 to 500 mg per day of active substance.
`The invention is illustrated by the following examples
`using preferred procedures for the preparation of optically
`pure sodium salts and magnesium salts.
`The processes described below for optically pure enan-
`30 tiomeric sodium salts of omeprazole result in change of
`directions from (—) to (+) optical rotation and, vice versa,
`from (+) to (—) optical rotation when preparing the sodium
`salt from the neutral form of omeprazole and again, when
`preparing the magnesium salt from the sodium salt of
`omeprazole.
`
`EXAMPLE 1
`
`Preparation of (+)-5-methoxy-2-[[(4-methoxy-3.5-
`dimethyl-2-pyridinyl)methy]|sulfinyl|-1H-
`benzimidazole Sodium Salt
`
`100 mg (0.3 mmol) of (—)-5-methoxy-2-[[(4-methoxy-3,
`§-dimethyl-2-pyridinyl)methy!] sulfinyl]-1H-benzimidazole
`(contaminated with 3% of the (+)-isomer) was dissolved in
`1 ml of 2-butanone with stirring. 60 pl of an aqueous
`solution of 5.0M sodium hydroxide and 2 ml of toluene were
`added. The resultant mixture was non-homogeneous. In
`orderto obtain a clear solution, more 2-butanone was added
`(ca 1 ml) and the mixture wasstirred at ambient temperature
`over night. The formed precipitate was filtered off and
`washed with ether. There was obtained 51 mg (46%) ofthe
`title compound as whim crystals m.p. (decomposition)
`246°-248° C. The optical purity (e.c.) which was analyzed
`by chiral column chromatography was 299.8%. [a]p7°=+
`42,8° (concentration, c=0.5%, water).
`NMR data are given below.
`
`EXAMPLE 2
`
`Preparation of (—)-5-methoxy-2-[[(4-methoxy-3,5-
`dimethy1-2-pyridinyl)methy]|sulfinyl]-1H-
`benzimidazole Sodium Salt
`
`65
`
`100 mg-(0.3 mmol) of (+}5-methoxy-2-[[(4-methoxy-3,
`§-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-
`benzimidazole (contaminated with 3% of the (—)-isomer)
`was dissolved in 1 ml of 2-butanone with stirring. 60 pl of
`
`DRL EXHIBIT 1025 PAGE 4
`
`DRL EXHIBIT 1025 PAGE 4
`
`

`

`5,714,504
`
`7
`an aqueoussolution of 5.0M sodium hydroxide and 2 ml of
`toluene were added. The resultant mixture was non-
`homogeneous. In order to obtain a clear solution, more
`2-butanone was added (ca 1 ml) and the mixture wasstirred
`at ambient temperature over night. The formed precipitate
`wasfiltered off and washed with ether. There was obtained
`56 mg (51%) of the title compound as white crystals mp.
`(decomposition) 247°-249° C. The optical purity (e.e.)
`which was analyzed by chiral column chromatography was
`299.8%. [a]p°=44.1° (c=0.5%, water).
`NMR data are given below.
`
`EXAMPLE 3
`
`Preparation of (+)-5-methoxy-2-[[(4-methoxy-3.5-
`dimethyl-2-pyridinyl)methy]]sulfinyl|-1H-
`benzimidazole Magnesium Salt
`
`2,9 ml of a 0.1M solution of NaOH was added to 0.10 g
`(0.29 mmol) (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-
`2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. To this
`mixture 2 ml methylene chloride was added, and after
`mixing in a separatory funnel the aqueous solution was
`separated off. A solution of 14 mg (0.145 mmol) MgCl, in
`water was added dropwise. The formed precipitate was
`isolated by centrifugation, and 52 mg (50%) of the product
`was isolated as an amorphous powder. The optical purity
`(e.e.) was 98%, and thus the same as the starting material.
`The optical purity was determined by chromatography on an
`analytical chiral column.
`[0]p7°=+101.2° (c=1%,
`methanol). The Mg content of the sample was found to be
`3.0%. shown by atomic absorption spectroscopy.
`
`EXAMPLE 4
`
`10
`
`20
`
`25
`
`30
`
`35
`
`Preparation of (+)-5-methoxy-2-[[(4-methoxy-3.5-
`dimethyl-2-pyridinyl)methyl)sulfinyl]-1H-
`benzimidazole Magnesium Salt
`(—)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`pyridinyl)methy]]sulfiny]]-1H-benzimidazole sodium salt
`(0.500 g. 1.36 mmol) wasdissolved in water (10 ml). Tothis
`mixture 10 ml of an aqueous solution of MgCl,xH,0 (138
`mg. 0.68 mmol) was added dropwise and the formed pre-
`cipitate was isolated by centrifugation. There was obtained
`418 mg (86%)of the product as a white powder. The optical
`purity (ce) of the product was 99.8% which was the sameas
`the optical purity of the starting material. The optical purity
`was determined by chromatography on ananalytical chiral
`column.[0(])7°=+129.9° (c=1%. methanol).
`
`EXAMPLE 5
`
`Preparation of (—)-5-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2-pyridinylmethyl|sulfinyl]-1H-
`benzimidazole Magnesium Salt
`
`(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
`pyridinyl)methy!]-sulfinyl]-1H-benzimidazole sodium salt
`(0.165 g. 0.45 mmol) wasdissolved in water (3 ml). To this
`mixture 2 ml of an aqueoussolution of MgCl,xH,O (46 mg,
`0.23 mmol) was added dropwise and the formed precipitate
`was isolated by centrifugation. There was obtained 85 mg
`(51%) of the product as a white powder. The optical purity
`(ee) of the product was 99.9% which was the same or better
`as the optical purity of the starting material. The optical
`purity was determined by chromatography on an analytical
`chiral column. [c])7=-128.2° (c=1%. methanol).
`
`45
`
`50
`
`35
`
`65
`
`8
`
`TABLE 1
`
`Ex. Solvent
`
`NMR data 5 ppm
`
`1. DMSO-d, 2.20 (s, 3HD, 2.22 (s, 3H), 3.6 (s, 3H), 3.72 (s, 3H),
`500 MHz 4.37 (d, 1H), 4.75 (d, 1H), 6.54 (dd, 1H), 6.96 (d, 1H)
`7.30 (d, 1H), 8.21 (s, 1H).
`2. DMSO-d, 2.20 (s, 3H), 2.22 (6, 3H), 3.69 (6, 3H), 3.72 (s, 3ED,
`§00 MHz 4.38 (d, 1H), 4.73 G, 1H), 6.54 (dd, 1H), 6.96 (d, 1H),
`7.31 (d, 1H), 8.21 (s, 1K).
`
`A preferred method for preparing optically pure omepra-
`zole enantiomer crystal salts of magnesium is described in
`Examples 6 and 7.
`
`EXAMPLE 6
`
`Enhancement of the Optical Purity by Preparing the
`Magnesium Salt of (-)-5-methoxy-2-[[4-methoxy-3,
`§-dimethyl-2-pyridinyl)-methyl|sulfiny!]-1H-
`benzimidazole in Nonaqueous Solution Followed
`by Crystallization of Said Salt
`Magnesium (0.11 g. 4.5 mmol) was dissolved and reacted
`with methanol (50 ml) at 40° C.with a catalytic amountof
`methylene chloride. The reaction was run under nitrogen and
`wasfinished 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-
`pytidinyl)methyl]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 magnesium salts. After 30 minutes stirring, these
`inorganic salts were filtered off and the solution was con-
`centrated on a rotavapor. The residue was now a concen-
`trated methanolic solution of the enantiomeric mixture(i.e.
`the title compound contaminated with the (+)-isomer), with
`an optical purity (enantiomeric excess, e.c.) 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 mintues and thereafter
`filtration afforded 1.3 g (50%) ofthe title compoundas white
`crystals. Chiral analyses of the crystals and mother liquor
`were performed by chromatography 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 shownby atomic absorption spectroscopy.[ol] p=
`—131.5° (c=0.5%, methanol).
`
`EXAMPLE 7
`
`Enhancement of the Optical Purity by Preparing the
`Magnesium Salt of (+)-5-methoxy-2-[[4-methoxy-3,
`5-dimethyl-2-pyridinyl)-methy]]sulfinyl]-1H-
`benzimidazole in Nonaqueous Solution Followed
`by Crystallization of Said Salt
`Magnesium (0.11 g. 4.5 mmol) was dissolved and reacted
`with methanol (50 ml) at 40° C. with a catalytic amountof
`methylene chloride. The reaction was run under nitrogen and
`wasfinished 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)methy!]sulfinyl]-1H-benzimidazole (2.84 g, 8.2
`
`DRL EXHIBIT 1025 PAGE 5
`
`DRL EXHIBIT 1025 PAGE 5
`
`

`

`5,714,504
`
`9
`Tomol) 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 magnesium salts. After 30 minutesstirring, these
`inorganic salts were filtered off and the solution was con-
`centrated on a rotavapor. The residue was now a concen-
`trated methanolic solution of the enantiomeric mixture(i.e.
`the title compound contaminated with the (—)-isomer), with
`an optical purity (e.¢.) of 80%. This mixture wasdiluted with
`acetone (100 ml) and after stirring at room temperature for
`one hour, a white precipitate was obtained. Additonal stir-
`ring for 30 minutes and thereafter filtration afforded 0.35 g
`of the title compoundas white crystals. Additional stirring of
`the mother liquor for 24 hours at room temperature afforded
`another 1.0 g (total yield=52%). Chiral analyses of the
`crystals and the second mother liquor were performed by
`chromatography on an analytical chiral column. Theoptical
`purity of the two crystal fractions was 98.8% e.e. and 99.5%
`c.e., respectively. The optical purity of the mother liquor was
`found to be 57% e.e. Thus, the optical purity (e.e.) has been
`enhanced from 80% to approximately 99% simply by crys-
`tallizing the Mg-salt from a mixture of acetone and metha-
`nol. The first precipitation was crystalline as shown by
`powder X-ray diffraction and the magnesium content of the
`same fraction was 3.49% as shown by atomic absorption
`spectroscopy.[0t])7°=+135.6° (c=0.5%, methanol).
`The crystalline salt according to Example 6 is most
`preferred.
`Preparation of the synthetic intermediates according to the
`invention is described in the following examples.
`
`EXAMPLE 8
`
`Preparation of 6-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2-pyridinyl)methy1]-(R/S)-sulfimyl)-1-[CR)-
`mandeloyloxymethyl}- 1H-benzimidazole
`
`A solution of 3.4 g sodium hydroxide in 40 ml water was
`added to a mixture of 14.4 g (42 mmol) tetrabutylammonium
`hydrogen sulfate and 6.4 g (42 mmol) (R}(—)-mandelic
`acid. The mixture was extracted with 400 ml chloroform.
`After separation, the organic extract was heated to reflux
`with 16.6 g (42 mmol) of the racemate of 6-methoxy-2-[[
`(4-methoxy-3.5-dimethyl-2-pyridinyl)methy1]-sulfinyl]-1-
`[chloromethy1]-1H-benzimidazole. Evaporation of the sol-
`vent was followed by dilution with 100 ml dichloromethane
`and 700 ml ethyl acetate. The mixture was washed with
`3x200 ml water and the organic solution was dried over
`MgSO, and then evaporated. The crude material was puri-
`fied by recrystallization from 100 ml acetonitrile, giving 8.1
`g of the title compound (38%) as a diastereomeric mixture.
`NMR data are given below.
`
`EXAMPLE 9
`
`Separation of the More Hydrophilic Diastereomer
`of 6-methoxy-2-[[(4-methoxy-3 ,5-dimethyl-2-
`pyridinyl)methy1]}-(R/S)-sulfinyl]-1[(R)
`mandeloyloxymethyl]- 1H-benzimidazole
`
`The diastereomers of the title compound in Example 8
`were separated using reversed phase chromatography
`(HPLC). Approximately 300 mg of the diastereomeric mix-
`ture was dissolved in 10 mi hot acetonitrile which was
`diluted with 10 ml of a mixture of aqueous 0.1M ammo-
`niumacetate and acetonitrile (70/30). The solution was
`injected to the column and the compoundswere eluted with
`a mixture of aqueous 0.1M ammoniumacetate and acetoni-
`
`15
`
`20
`
`25
`
`a5
`
`45
`
`55
`
`65
`
`10
`trile (70/30). The more hydrophilic isomer was easier to
`obtain pure than the less hydrophilic one. The work up
`procedure for the fraction which contained pure isomer was
`as follows; extraction with dichloromethane, washing the
`organic solution with aqueous 5% sodium hydrogen carbon-
`ate solution, drying over Na,SO, and evaporation of the
`solvent on a rotavapor (at the end of the evaporation the
`removal of acetonitrile was facilitated by adding more
`dichloromethane). Using 1.2 g of the diastereomeric mixture
`with the above mentioned technique, the more hydrophilic
`isomer, 410 mg, was obtained in a pure state as a colorless
`symup.
`NMR data are given below.
`
`EXAMPLE 10
`
`Preparation of 6-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1-{(S)-
`mandeloyloxymethyl|-1H-benzimidazole
`
`The product was obtained from 8.1 g (202 mmol) sodium
`hydroxide in 100 ml water, 34.4 g (101 mmol)tetrabuty-
`lammonium hydrogen sulfate, 15.4 g (101 mmol) (S)-(+)-
`mandelic acid and 39.9 g (101 mmol) of the racemate of
`6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)
`methy1)-sulfinyl]-1-[chloromethy1]-1H-benzimidazole
`using the same procedure as in Example 8. Recrystallization
`from 100 ml acetonitrile yielded 21.3 g, ie. 41% of thetitle
`compound as a diastereomeric mixture.
`NMR data are given below.
`
`EXAMPLE 11
`
`Separation of the More Hydrophilic Diastereomer
`of 6-methoxy-2-[[(4-methoxy-3,5-dimethy]-2-
`pyridinyl)methyl}-(R/S)-sulfiny!J-1-[(S)-
`mandeloyloxymethyl]-1H-benzimidazole
`
`The diastereomers of the title compound in Example 10
`were separated using reversed phase chromatography
`(HPLC) in the same way as in Example 7, but using the
`diasteromeric mixture of 6-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2-pyridinyl)methyl}-(R/S)-sulfinyl]-1-[(S)-
`mandeloloxymethyl]-1H-benzimidazole instead of the (R)-
`mandelic ester used in Example 9. Using 2.1 g of the
`diastereomeric mixture, the more hydrophilic isomer, 760
`mg, was obtained in a pure state as a colorless syrup.
`NMR data are given below.
`
`EXAMPLE 12
`
`Preparation of (—)-5-methoxy-2-[[(4-methoxy-3,5-
`dimethyl-2-pyridinyl)methy]]-sulfinyl|- 1H-
`benzimidazole
`
`0.23 g (0.45 mmol) of the more hydrophilic diastereomer
`of 6-methoxy-2-[{(4-methoxy-3,5-dimethyl-2-pyridinyl)
`methyl! ]sulfinyl]-1-[(R)-mandeloyloxymethyl]-1H-
`benzimidazole was dissolved in 15 ml methanol. A solution
`of 36 mg (0.9 mmol) sodium hydroxide in 0.45 ml water was
`added, and after 10 minutes the mixture was evaporated on
`a rotavapor. The residue was partitioned between 15 ml
`water and 15 ml dichloromethane. The organic solution was
`extracted with 15 ml water and to the combined aqueous
`solut