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`H
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`
`1
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`1
`
`USOOS714504A
`
`United States Patent
`
`[191
`
`[11] Patent Number:
`
`5,714,504
`
`Lindberg et al.
`
`[45] Date of Patent:
`
`Feb. 3, 1998
`
`[54] COMPOSITIONS
`
`[75]
`
`Inventors: Per Lennart Lindberg. Molndalg
`Sverker Von Unge. Fj'ziris. both of
`Sweden
`
`[73] Assignee: Astra Aktiebolag. Sodeitalje. Sweden
`
`[21] Appl. No.: 376,512
`
`[22] Filed:
`
`Jan. 23, 1995
`
`Related US. Application Data
`
`[63] Continuation-impart of Ser. No. 256,174, filed as PCT/
`SE94/00509, May 27, 1994.
`
`[30]
`
`Foreign Application Priority Data
`
`May 28, 1993
`
`[SE]
`
`Sweden .................................. 9301830
`
`Int. Cl.6 ......................... C07D 401/12; A61K 31/44
`[51]
`[52] us. Cl. ......................................... 514/338; 546/273.7
`[58] Field of Search .......................... 546/273.7; 514/338
`
`[56]
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`0005129
`0124495
`4035455
`4035455
`
`European Fat. 011'.
`4/1981
`l/1987 European Fat. 011'.
`11/1990 Germany .
`5/1992 Germany .
`
`.
`.
`
`OTHER PUBLICATIONS
`
`Frlandsson et al.. J. Chromatography. vol.532. pp. 305—319
`(1990).
`Cairns. et a1. “Enantioselective HPLC detu'mination .
`Journal of Chromatography 8.666 (1995) 323—328.
`
`. ”
`
`.
`
`Yamada et a1. “Synthesis and isomerization of optical
`active .
`.
`. " Chem. Pharm. Bull. 42(8) (1994) 1679—1681.
`K. Miwa et a1. Jpn. Pharmacol. Ther. “Proton pump inhibitor
`in rats. mice and dogs” 18 (1990) 165—187 (n'ansl).
`l-I. Katsuki et a1. “Determination of R(+)—and S(—)—Lanso-
`prazole” Pharmaceutical Research 13(4) (1996) 611—615.
`M. Tanaka et a1. “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.
`. . ” Reprint from Acta
`A. Brandslrom “Chemical reactions .
`Chemica Scandinavica 43 (1989) 536—611.
`K. Sigrist—Nelson et a1. “Ro 18—5364. a potent inhibitor of
`the gastric (H+ +K*)—ATPase” Eur. J. Bioch. 166 (1987)
`453.
`Polomorncoll et al. CA 117;90292. 1992.
`
`Primary Examiner—Jane Fan
`Attorney, Agent, or Finn—White & Case
`[57]
`ABSTRACT
`
`The novel optically pure compounds Na‘“. Mg”. If. K“.
`Ca2+ and N‘*(R)4 salts of (+)v5—meihoxy—2—[[(4-methoxy-3.
`5-dimethyl-2—pyridinyl)methyl] sulfinylj- lH-benzimidazole
`or
`(—)-5—methoxy-2-[[(4-methoxy-3.5-dimethyl-2-
`pyridinyl)methyl]su1.finyl]-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 tile compounds.
`
`10 Claims, No Drawings
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 1
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 1
`
`

`

`1
`COMPOSITIONS
`
`5 .714,504
`
`2
`
`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 and their 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—pyridiny1)methyl]sulfinyl]-lH-benzirnidazole. having the
`generic name omeprazole. and therapeutically acceptable
`alkaline salts thereof are described in US. Pat. No. 4.255.
`431 to Iunggren et al.. EP 5129 and EP 124 495. respec-
`tively. Omeprazole and its 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 etha
`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 diflicult to handle in large scale production.
`Thae is no example in the known prior art of any isolated
`or charactu'ized salt of optically pure omeprazole. i.e. of
`single enantiomas 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
`interiudividual variation. The present invention provides
`such compounds. which are novel salts of single enanti—
`omers of omeprazole.
`A preferred embodiment of the present invention provides
`pure crystalline enantiomeric salts of omeprazole and meth-
`ods for the preparation thereof.
`A more preferred embodiment of the present invention is
`directed to an optically pure crystalline enantiomeric mag—
`nesium salt of omeprazole and method for the preparation
`thereof.
`
`10
`
`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 enantiomu of omeprazole magnesium salt or
`analogues thereof which includes steps of stirring a crude
`
`65
`
`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 compounds of 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 treatment of 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
`where gastric antisecretory effect is desirable e.g. in patients
`on NSAID therapy. in patients with gastrinomas. and in
`patients with acute upper gastrointestinal bleeding. They
`may also 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“. LP.
`1C. Ca2+ and N‘TR)4 salts of the single enantiomers of
`omeprazole. where R is an alkyl with 1—4 carbon atoms. is.
`Na+. Mg“. LP. K”. Ca2+ and N"'(R)4 salts of (+)—5-
`methoxy-Z- [ [(4-methoxy—3 .5 -dimet.hyl-2-pyridinyl)methyl]
`sulfinyl]—1H-benzirnidazole and (—)-5-methoxy~2—[[(4-
`methoxy-3 ,5 —dimethyl-2-pyridinyl)methyl] sulfinyl]- 1 H-
`benzirnidazole. where R is an alkyl with 1—4 carbon atoms.
`
`Particularly preferred salts according to the invention are
`the Na+. Ca2+ and Mg2+ salts. i.e (+)—5-methoxy—2-[[(4—
`methoxy—3 ,5-dimethyl—2-pyridiny1)methyl] su lfinyl]- 1H-
`benzirnidazole sodium salt. (—)—5-methoxy-2—[[(4—methoxy-
`3 .5-dimethyl-2—pyridinyl)methyl ] sulfiny1]- 1H-
`benzirnidazole sodium salt. (+)—5-methoxy-2—[[(4—methoxy-
`3 .5—dimethyl-2—pyridinyl)methyl ] sulfi nyl]-1H-
`benzimidazole magnesium salt.
`(—)-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)methyl] sulfinyl]— 1H—
`benzimidazole calcium salt and (—)—5—methoxy-2-[ [(4-
`methoxy—3 .5—dimethyl-2-pyridinyl)methle sulfinyl]- 1H-
`benzimidazole calcium salt.
`
`Most preferred salts according to the invention are the
`optically pure Na+ salts of omeprazole according to com-
`pounds Ia and lb
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 2
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 2
`
`

`

`5,714,504
`
`OCH:
`
`(Ia. Ib)
`
`OCH:
`
`M
`
`CH3
`
`(”1)
`
`Hac \ CH3
`I
`
`/
`
`N
`
`O
`/
`ll
`CH2_S —<
`
`N
`
`OCH:
`
`I
`
`E N
`
`at
`
`Ia (+)-enantiomer
`lb (—)-enantiorner
`
`10
`
`15
`
`and the optically pure magnesium salts of omeprazole
`according to compounds 11a and Ill)
`
`CH3
`
`(113,111?)
`
`20
`
`N
`0
`I
`ll
`Cl-Ig—S—<
`
`OCH;
`
`|
`
`E M
`
`82+
`
`nae
`
`I
`
`OCH;
`
`\
`
`/
`
`N
`
`Ila (+)-enanticmer
`lIb (—)-enantiomer
`
`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 means of the 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.
`Because it 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
`enantiomeiic 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 III.
`which is an immediate used in the specific method of
`preparation.
`
`N
`0
`/
`ll
`CH2—S—<
`
`I
`
`/
`
`N
`
`if
`CH2
`
`OCH;
`
`\? i)“
`C—CH
`0/
`
`Preparation
`The optically pure compounds of 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)methyl]sulfinyl]-1—[acyloxymethyl]-1H-
`benzirnidazole. formula IV
`
`OCH3
`
`(IV)
`
`0cm
`
`N
`
`N|C
`
`I
`
`H;
`
`ch \ CH3
`I
`
`/
`
`N
`
`0
`/
`||
`CH;—S—<
`
`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
`diastercomer in an alkaline solution. The formed single
`enantiomers of omeprazole are then isolated by neutralizing
`aqueous solutions 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
`chromatography or 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 dimethylformarnide. The react-
`ing base may be OH" or Rlo- where R1 can be any alkyl 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 NaOR2 wherein R2
`is an alkyl group containing 1-4 carbon atoms. or with
`NaNl-I2. In addition, alkaline salts wherein the cation is Li+
`or K“r may be prepared using lithium or potassium salts of
`the above mentioned bases. 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 Mg2+ salts of the invention.
`optically pure enantiomeric Na+ salts may be treated with an
`aqueous solution of an inorganic magnesium salt such as
`MgClz. whereupon the Mg2+ salts are precipitated. The
`optimlly pure Mg2+ salts may also be prepared by treating
`single enantiomers of omeprazole with a base. such as
`
`25
`
`30
`
`35
`
`4s
`
`50
`
`55
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 3
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 3
`
`

`

`5,714,504
`
`5
`
`Mg(OR3)2. wherein R3 is an alkyl group containing 1—4
`carbon atoms. in a non-aqueous solvent such as alcohol
`(only for alcoholates). e.g. ROI-I. or in an ether such as
`tetrahydrofuran. In an analogous way. also alkaline salts
`wherein the cation is Ca2+ can be prepared using an aqueous
`solufion of an inorganic calcium salt such as CaClg.
`Alkaline salts of the single enantiomers of the invention
`are. as mentioned above. beside the sodium salts
`(compounds Ia and Ib) and the magnesium salts (compounds
`11a and 11b). exemplified by their salts with Li)". K’". Ca2+ and
`Wm)... where R is an alkyl with 1—4 C-atoms.
`For clinical use the single enanfiomers. 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 amount of active
`compound is between 0.1—95 % by weight of the preparation.
`between 02—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 anothm' suitable
`carrier. stabilizing substances such as alkaline compounds
`e.g. carbonates. hydroxides and oxides of sodium.
`potassium. calcium. magnesium and the like 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
`remains in the stomach. The enteric 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 among tablets 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 entaic-coated as described
`above.
`Hard gelatine capsules may contain granules or eaterie-
`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. parafiin 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.
`
`6
`liquid preparation for oral administration may be pre-
`pared in the form of syrups or suspensions. e.g. solufions 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-
`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 phannaoeutically 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
`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 gentn'al. 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-
`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-Z—pyridinyl)methyl]sulfinyl]-1H-
`benzimidazole Sodium Salt
`
`100 mg (0.3 mmol) of (-)-5-methoxy—2-[[(4—methoxy—3.
`S-dimethyl-2-pyridinyl)methyl] sulfinyl]- lH—benzimidazole
`(contaminated with 3% of the (+)-isomer) was dissolved in
`1 ml of 2-butanone with stirring. 60 pl of an aqueous
`solufion 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 was stirred at ambient temperature
`over night. The formed precipitate was filtered off and
`washed with ether. There was obtained 51 mg (46%) of the
`title compound as whim crystals m.p. (decomposition)
`246°—248° C. The optical purity (e.e.) which was analyzed
`by chiral column chromatography was 299.8%. [a]02°=+
`423° (concentration. t:0.5%. water).
`NMR data are given below.
`
`EXAMPLE 2
`
`10
`
`15
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Preparation of (—-)—5-methoxy-2-[[(4-methoxy-3.5-
`dimethyl-Z-py1idinyl)methyl]sulfinyl]-1H-
`benzimidazole Sodium Salt
`
`65
`
`100 mg-(O.3 mmol) of (+)-5-methoxy—2—[[(4—methoxy-3.
`5—dimethy1-2-pyridinyl)—methyl]sulfinyl]- 1H-
`benzimidazole (contaminated with 3% of the (—)-isomer)
`was dissolved in 1 ml of 2-butanone with stirring. 60 pl of
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 4
`
`

`

`7
`
`5,714,504
`
`8
`
`TABLE 1
`
`1 E
`
`
`
`x. Solvmt NMR data 5 ppm
`1. masoa6 2.20 (s, 311). 2.22 (s, 311), 3.69 (s. 311), 3.72 (s, 31-1),
`500 MHz 4.37 (ct 1H). 4.75 (a 111). 6.54 (dd, 111), 6.96 (a 111)
`7.30 (d, 11-1), 8.21 (s, 111).
`2. mvrsoa.s 2.20 (s, 311), 2.22 (s, 311), 3.69 (s, 311), 3.72 (5, 31-1),
`500 MHz 4.33 (d, 1H), 4.73 (d. 1H), 6.54 (dd, 111), 6.96 (CL 111),
`7.31 (ct 1H), 3.21 (s, 111).i
`
`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.
`5-dimethy1—2-pyridinyl)-methyl]sulfinyIJ—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 m1) at 40° C. with a catalytic amount of
`methylene chloride. The reaction was run under niU'ogen 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-Z—
`pyridinyl)methyl]sulfiny1]—lH-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 (+)—isoma). with
`an optical purity (enantiommic 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 mintues and thereafter
`filtration afiorded 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 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. [01] D20:
`—131.5° (30.5%. methanol).
`
`EXAMPLE 7
`
`Enhancement of the Optical Purity by Preparing the
`Magnesium Salt of (+)-5—methoxy—2-[[4-methoxy-3.
`5-dimethyl-2-pyridinyl)-methyl]sulfinyl]—1H-
`benzimidazole in Nonaqueous Solution Followed
`by Crystallization of Said Salt
`
`an aqueous solution of 5.0M sodium hydroxide and 2 m1 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 was stirred
`at ambient temperature over night. The formed precipitate
`was filtered 011" and washed with ether. Thae 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
`a99.8%. [01D2°=—44.1° (c=0.5%. water).
`NMR data are given below.
`
`EXAMPLE 3
`
`Preparation of (+)-5-methoxy-2-[[(4-methoxy-3.5-
`dimethyl-2—py1idinyl)methyl] sulfinyll- 1H-
`benzimidazole Magnesium Salt
`
`2.9 ml of a 0.1M solution of NaOI-I was added to 0.10 g
`(0.29 mmol) (+)-5-methoxy-2—[[(4—methoxy-3.5-dimethyl—
`2-pyridiny1)methyl]sulfiny1]—ll-I-benzirnidazole. 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) MgCl2 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.
`[or]D2°=+101.2° (c=1%.
`methanol). The Mg content of the sample was found to be
`3.0%. shown by atomic absorption spectroscopy.
`
`EXAMPLE 4
`
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`
`Preparation of (+)—5—methoxy—2-[[(4—methoxy—3.5-
`dimethyl-Z-pyridinyl)rnethy1]sulfiny1]— 1H—
`benzimidazole Magnesium Salt
`
`(—)-5-methoxy-2-[[(4-methoxy-3.5—dimethy1-2-
`pyridinyl)methyl]sulfinyl]—1H—benzirnidazole sodium salt
`(0.500 g. 1.36 mmol) was dis solved in water (10 ml). To this
`mixture 10 ml of an aqueous solution of MgClle-IZO (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 (cc) of the product was 99.8% which was the same as
`the optical purity of the starting material. The optical purity
`was determined by chromatography on an analytical chiral
`column. [u]D2°=+129.9° (c=l%. methanol).
`
`EXAMPLES
`
`Preparation of (-)—5-methoxy-2-[[(4—methoxy-3.5-
`dimethyl-2-pyridinyl)met.hy1] sulfinyl]— 1H—
`benzimidazole Magnesium Salt
`
`(+)-5-methoxy-2-[[(4-methoxy-3.S-dimethyl-Z-
`pyridinyl)methyl]-sulfinyl]—lH-benzimidazole sodium salt
`(0.165 g. 0.45 mmol) was dissolved in water (3 m1). To this
`mixture 2 ml of an aqueous solution of MgClszZO (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. [or],_,2°=—128.2° (c=l%. methanol).
`
`45
`
`50
`
`55
`
`Magnesium (0.11 g. 4.5 mmol) was dissolved and reacted
`with methanol (50 ml) at 40° C. with a catalytic amount of
`methylene chloride. The reaction was run under ninogen 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]sulfinyll-lH-benzimidazole (2.84 g. 8.2
`
`65
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1025 PAGE 5
`
`

`

`5,714,504
`
`9
`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 ofl’ 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.e.) of 80%. This mixture was diluted 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 compound as 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. The optical
`purity of the two crystal fractions was 98.8% e.e. and 99.5%
`e.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 difl‘iaction and the magnesium content of the
`same fraction was 3.49% as shown by atomic absorption
`spectroscopy. [alpm=+135.6° (@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.
`
`EXAMPLES
`
`Preparation of 6—methoxy-2—[[(4—mel:hoxy—3.5-
`dimethyl—Z-pyridinyl)methyl] -(R/S )-sulfinyl]- 1— [(R)—
`mandeloyloxymethyl]- lH-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)-(—)-ma.ndelic
`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)methyl] -sul.finyl]- l-
`[chloromethyl]- lH-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
`MgSO4 and then evaporated. The crude material was pini-
`fied by recrystallization from 100 m1 aoetonilrile. giving 8.1
`g of the title compound (38%) as a diastereomeric mixture.
`NMR data are given below.
`
`EXAMPLE 9
`
`Separation of the More Hydrophilie Diastereomer
`of 6—methoxy-2—[[(4-methoxy-3.5-dimethyl—2—
`pyridinyl)methyl]{R/S)—sulfinyl]— 1 [(R)
`mandeloyloxymethyll- IH-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 ml hot acetoniIIile 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 compounds were eluted with
`a mixture of aqueous 0.1M ammoniumacetate and aoetoni—
`
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`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. diying over Na2SO4 and evaporation of the
`solvent on a rotavapor (at the end of the evaporation the
`removal of acetonilrile 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
`syrup.
`NMR data are given below.
`
`EXAMPLE 10
`
`Preparation of 6—methoxy-2-[[(4-methoxy-3.5-
`dimethyl-Z—pyridinyl)methyII-(RlS)-sulfinyl]— H (S )-
`mandeloyloxymethyll—1H—benzimidazole
`
`The product was obtained from 8.1 g (202 mmol) sodium
`hydroxide in 100 ml water. 34.4 g (101 mmol) tetrabuty-
`[ammonium 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.S—dimethyl-Z-pyridinyl)
`methyl]-sulfinyl]-l-[chloromethyl]-lH-benzimidazole
`using the same procedure as in Example 8. Recrystallization
`from 100 ml acetonitrile yielded 21.3 g, Le. 41% of the title
`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-d.imethyl-2—
`pyridinyl)methyl]—(RlS)—sulfinyl]—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-Z-pyridinyl)methyl}—(R/S)—sulfinyl]-1-[(S)-
`mandeloloxymethyl]-lH-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-35—
`dimethyl-Z-pyridinyl)methyl]—sul.finyl]— 1H-
`benzimidazole
`
`0.2