`Meese
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,858,650 B1
`Feb. 22, 2005
`
`US006858650B1
`
`(54) STABLE SALTS OF NOVEL DERIVATIVES
`0F 3,3-DIPHENYLPROPYLAMINES
`
`WO
`W0
`
`10/1998
`9843942
`11/1999
`9958478
`OTHER PUBLICATIONS
`
`(75) Inventor: Claus Meese, Monheim (DE)
`
`Assignee: Schwarz Pharma AG (DE)
`
`(73)
`(*)
`
`(21)
`(22)
`(86)
`
`(87)
`
`Notice:
`
`Appl. No.:
`
`PCT Filed:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`10/130,214
`Nov. 15, 2000
`
`PCT No.:
`
`PCT/EP00/11309
`
`§ 371 (6X1),
`(2), (4) Date: May 14, 2002
`PCT Pub. No.: WO01/35957
`
`PCT Pub. Date: May 25, 2001
`Foreign Application Priority Data
`
`(30)
`Nov. 16, 1999
`
`(DE) ....................................... .. 199 55 190
`
`(51) Int. Cl.7 ...................... .. A01N 37/08; A01N 37/12;
`A01N 37/44; A61K 31/215; A61N 31/24
`(52) US. Cl. ..................... .. 514/530; 514/531; 514/534;
`514/548; 514/551; 560/61; 560/122; 560/123;
`560/124; 560/138; 560/142; 560/250; 564/319
`Field of Search ............................... .. 514/530, 531,
`514/534, 548, 551; 560/61, 122, 123, 124,
`138, 142, 250, 37, 18, 42, 140; 564/319
`
`(58)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,686,464 A
`
`11/1997 Johansson et al. ........ .. 514/315
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`EP
`EP
`WO
`
`693 17 898 T2
`0 667 852 B1
`0 957 073 A1
`9411337
`
`10/1998
`4/1998
`11/1999
`5/1994
`
`....... .. CO7C/217/62
`
`....... .. CO7C/217/62
`
`........... .. CO7C/1/OO
`
`Nilvebrant et al, “Antimuscarinic Potency and Bladder
`Selectivity of PNU—200577, a Major Metabolite of Toltero
`dine” Pharmacology and Toxicology. vol. 81, pp. 169—172
`(1997).*
`L. Palmer, L. Andersson, T. Andersson, U. Stenberg: Deter
`mination of tolteroa'ine and the 5—hydroxymethly metabolite
`in plasma, serum and urine using gas chromatography—
`mass spectrometry; Journal of Pharmaceutical and Bio
`medicalAnalysis; Jan. 20, 1997; pp. 155—165.
`
`* cited by examiner
`Primary Examiner—Richard L. Raymond
`Assistant Examiner—Zachary C. Tucker
`(74) Attorney, Agent, or Firm—Peter F. Corless; Christine
`C. O’Day; Edwards & Angell, LLP
`(57)
`ABSTRACT
`
`The present invention concerns highly pure, crystalline,
`stable compounds of novel derivatives of 3,3
`diphenylpropylamines in the form of their salts, a method for
`the manufacture and highly pure, stable intermediate prod
`ucts.
`
`The method is in particular characterized by regio- and
`chemoselectivity and high yield. Salts of phenolic
`monoesters of 3,3-diphenylpropylamines are provided, that
`are particularly Well-suited for use in pharmaceutical for
`mulations. Preferred compounds are R-(+)-2-(3-diisopropy
`lamino-1-phenyl-propyl)-4-hydroxymethylphenylisobu
`tyrate
`ester
`hydrogen fumarate
`and R-(+)-2-(3
`diisopropylamino-l-phenylpropyl)-4
`hydrochloride
`hydroxymethylphenylisobutyrate
`ester
`hydrate. Furthermore, stable, crystalline intermediate prod
`ucts that are essential for obtaining the abovementioned salts
`are provided. A preferred intermediate product is R-(—)-3
`(3-diisopropylamino-phenyl-propyl)-4-hydroxy-benZoic
`acid methyl ester.
`
`24 Claims, 1 Drawing Sheet
`
`Reaction :11! rain 1
`
`(11, (ii). (iii), (iv), (v) stand for: (l), Lumu, (ii),
`Raney nickel/Hz, (iii), HegCH-CQCI, no‘, (iv), fumazic and,
`(v), hydrochloric acids; 8 stands to: isopzepyl (in)
`
`(iv a: v)
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 1
`
`
`
`U.S. Patent
`
`Feb. 22,2005
`
`US 6,858,650 B1
`
`Figure 1
`
`Reaction diagram 1
`
`(i) ,
`
`(ii) , (iii) , (iv) ,
`
`(v) stand for: (i) , LiAlHq, (ii) ,
`
`Raney nickel/H2, (iii) , Me2CH_cOC]-' Et3N, (iv) , fumaric acid,
`
`(v) , hydrochloric acids; R stands for isopropyl (iPr)
`
`Li
`A a
`
`HO
`
`I-go
`Ck
`
`Ho
`
`(iii)
`
`(iv or v)
`
`H _
`
`-———> 1 '———> 2a or 21)
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 2
`
`
`
`US 6,858,650 B1
`
`1
`STABLE SALTS OF NOVEL DERIVATIVES
`OF 3,3-DIPHENYLPROPYLAMINES
`
`2
`general formula H-X, in Which “X represents the respective
`acid residue, into their respective salt With general formula
`I.
`
`This application Was ?led under 35 U.S.C. 371, and is the
`US. National Stage of PCT/EP00/11309, ?led 5 Nov. 2000.
`This patent application claims the bene?t of priority
`under 35 U.S.C. §119 of German Patent Application No. 199
`55 190.1, ?led Nov. 16, 1999. German Patent Application
`No. 199 55 190.1 is incorporated herein in its entirety by
`reference.
`The present invention concerns highly pure, crystalline,
`stable compounds of novel derivatives of 3,3
`diphenylpropylamines in the form of their salts, a method for
`manufacturing these and highly pure, stable, intermediate
`products.
`From document PCT/EP99/03212 novel derivatives of
`3,3-diphenylproprylamines are knoWn.
`These are valuable prodrugn for the treatment of urinary
`incontinence and other spasmodic complaints, Which over
`come the disadvantage of the active substances available to
`date, namely inadequate absorption of the active substance
`by biological membranes or the unfavourale metabolism of
`these.
`Furthermore these novel prodrugs have improved phar
`macokinetic characteristics compared With OXybutynin and
`Tolterodin.
`Preferred compounds from the group of these novel
`derivatives of 3,3-diphenylpropylarines are esters of ali
`phatic or aromatic carboXylic acids With the general formula
`A referred to beloW
`
`Formula A
`
`HO
`
`R
`
`O
`
`)1
`,k
`A
`
`10
`
`15
`
`35
`
`40
`
`HO
`
`O
`
`Formula I
`
`The problem for the present invention is therefore to
`provide highly pure, crystalline, stable compounds of novel
`derivatives of 3,3-diphenylpropylamines in the form of their
`salts, that avoid the stated disadvantages and are Well suited
`to use in pharmaceutical-technical formulations and can be
`processed into these.
`A further problem for the present invention is to provide
`a method for manufacturing such highly pure, crystalline,
`stable compounds in the form of their salts, as Well as highly
`pure, stable intermediate products.
`The ?nal problem for the invention is to provide a method
`for manufacturing the abovementioned compounds With
`Which a high yield of the products of the process and the
`respective intermediate products can be obtained chemo- or
`regioselectively.
`This problem is solved in that highly pure, crystalline,
`stable compounds of the 3,3-diphenylpropylamines in the
`form of their salts With general formula I are provided,
`
`HO
`
`O
`
`Formula I
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, sub
`stituted or unsubstituted phenyl and X- is the acid residue of
`a physiologically compatible inorganic or organic acid.
`In accordance With a design of the invention the salts of
`general formula I can contain the respective acid residue X“
`of the acids mentioned beloW:
`hydrochloric acid, hydrobromic acid, phosphoric acid,
`sulphuric acid, nitric acid, acetic acid, propionic acid,
`palmitic acid, stearic acid, maleic acid, fumaric acid,
`oXalic acid, succinic acid, DL-malic acid, L-(—)-malic
`acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric
`acid, D-(—)-tartaric acid, citric acid, L-aspartic acid,
`L-(+)-ascorbic acid, D-(+)-glucuronic acid,
`2-oXopropionic acid (pyruvic acid), furan-2-carboXylic
`acid (mucic acid), benZoic acid, 4-hydroXybenZoic
`acid, salicyclic acid, vanillic acid, 4-hydroXycinammic
`acid, gallic acid, hippuric acid (N-benZoyl-glycine),
`aceturic acid (N-aectylglycine), phloretinic acid (3-(4
`hydroXyphenyl)-propionic acid), phthalic acid, meth
`anesulfonic acid or orotic acid.
`
`in Which R denotes C1—C6-alkyl, C3—C10-cycloalkyl or
`unsubstituted or substituted phenyl. These can occur in their
`optical isomers form as racemic mixtures and in the form of
`their individual enantiomers.
`Compounds With the structure of formula A do, hoWever,
`have loW solubility in Water. This restricts their oral bio
`availability.
`Finally, monoesters of the structure, as shoWn in formula
`A, have a tendency toWards intermolecular transesteri?ca
`tion. During long periods of storage, therefore, as the content
`of the compounds With the structure of general formula A
`drops an increase in diesters and free diol can be detected.
`Basically salts of the compounds of general formula Acan
`be obtained if solutions of the compounds of formulaA(base
`component) are puri?ed With solutions of acids in suitable
`solvents, but the salts obtained in the form of solid matter
`can prove to be altogether amorphous and/or hygroscopic
`and cannot be directly crystalliZed from the normal solvents
`either. Such salts have inadequate chemical stability to be
`galenically processed as valuable pharmaceutically active
`substances.
`Surprisingly, it has noW been found that the abovemen
`tioned disadvantages can be avoided if compounds With the
`structure of general formula A, once they have been pre
`pared under a special reaction process, are converted With a
`physiologically compatible inorganic or organic acid With
`
`45
`
`55
`
`65
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 3
`
`
`
`US 6,858,650 B1
`
`3
`In accordance With a further design form of the invention
`R-con?gured compounds With general formula 2 are pro
`vided
`
`Formula 2
`
`15
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, sub
`stituted or unsubstituted phenyl and X“ is the acid residue of
`a physiologically compatible inorganic or organic acid.
`In accordance With an advantageous design form of the
`invention the compounds in the form of their salts of general
`formula 2 can contain the respective acid residue X“ of the
`acids mentioned beloW:
`hydrochloric acid, hydrobromic acid, phosphoric acid,
`sulphuric acid, nitric acid, acetic acid, propionic acid,
`palmitic acid, stearic acid, maleic acid, fumaric acid,
`oxalic acid, succinic acid, DL-malic acid, L-(—)-malic
`acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric
`acid, D-(—)-tartaric acid, citric acid, L-aspartic acid,
`L-(+)-ascorbic acid, D-(+)-glucuronic acid,
`2-oxopropionic acid (pyruvic acid), furan-2-carboxylic
`acid (mucic acid), benZoic acid, 4-hydroxybenZoic
`acid, salicyclic acid, vanillic acid, 4-hydroxycinammic
`acid, gallic acid, hippuric acid (N-benZoyl-glycine),
`aceturic acid (N-aectylglycine), phloretinic acid (3-(4
`hydroxyphenyl)-propionic acid), phthalic acid, meth
`anesulfonic acid or orotic acid.
`Preferred compounds of the present invention are the salts
`R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenylisobutyrate ester hydrogen fuma
`rate and
`R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenylisobutyrate ester hydrochloride
`hydrate.
`Furthermore, compounds are preferred in Which R stands
`for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-(1
`cyclo-propyl-methanoyloxy)-phenyl, 4-(1-cyclobutyl
`methanoyloxy)-phenyl, 4-(1-cyclohexyl-methanoyloxy)
`phenyl or 4-(2,2-dimethyl-propanoyloxy)-phenyl and X
`denotes chloride.
`Particular preference is for [(R)-3-(2-{1-[4-(1
`cyclopropyl-methanoyloxy)-phenyl]-methanoyloxy}-5
`hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl
`ammonium chloride, [(R)-3-(2-{1-[4-(1-cyclobutyl
`methanoyloxy)-phenyl]-methanoyloxy}-5-hydroxymethyl
`phenyl)-3-phenyl-propyl]-diisopropyl-ammonium chloride,
`[(R)-3-(2-{1-[4-(1-cyclohexyl-methanoyloxy)-phenyl]
`methanoyloxy}-5-hydroxymethyl-phenyl)-3-phenyl
`propyl]-diisopropyl-ammonium chloride, [(R)-3-(2-{1-[4
`(2,2-dimethyl-propanoyloxy)-phenyl]-methanoyloxy}-5
`hydroxymethyl-phenyl)-3-phenyl-propyl]-diisopropyl
`ammonium chloride, {(R)-3-[2-(1-cyclopropyl
`methanoyloxy)-5-hydroxymethyl-phenyl]-3-phenyl
`propyl}-diisopropyl-ammonium chloride, {(R)-3-[2-(1
`cyclobutyl-methanoyloxy)-5-hydroxymethyl-phenyl]-3
`phenyl-propyl}-diisopropyl-ammonium chloride, {(R)-3-[2
`(1-cyclopentyl-methanoyloxy)-5-hydroxymethyl-phenyl]
`
`4
`3-phenyl-propyl}-diisopropyl-ammonium chloride and
`{(R)-3-[2-(1-cyclohexyl-methanoyloxy)-5-hydroxymethyl
`phenyl]-3-phenyl-propyl}-diisopropyl-ammonium chloride.
`In the compounds of the present invention the expression
`“alkyl” preferably stands for a straight-chain or branched
`chain hydrogen group With betWeen 1 and 6 C-atoms.
`Special preference is for methyl, ethyl, propyl, isopropyl,
`butyl, isobutyl, pentyl and hexyl. The expression
`“cycloalkyl” designates cyclical hydrogen groups, that have
`betWeen 3 and 10 hydrogen atoms, that may also contain
`suitable substitutes in place of the hydrogen atoms.
`The expression “phenyl” designates a —C6H5-group that
`may be substituted or unsubstituted. Suitable substitutes can
`be, for example, alkyl, alkoxy, halogen, nitro and amine. The
`expression “alkoxy” has, With respect to the alkyl
`component, the same meaning as already given above for
`“alkyl”. Suitable halogens are ?uorine, chlorine, bromine
`and iodine atoms
`The present invention also includes methods for manu
`facturing the compounds in accordance With the invention of
`general formula I as Well as valuable intermediate products.
`The method is characterised by chemo- and regioselec
`tivity.
`
`Compounds of General Formula I
`
`Formula I
`
`kkggoi R a
`
`A X.
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, sub
`stituted or unsubstituted phenyl and X- is the acid residue of
`a physiologically compatible inorganic or organic acid, are
`that
`
`a) a compound of formula III
`
`Formula III
`
`A
`
`is split With a hydrogenation agent to form a compound of
`formula V
`
`25
`
`35
`
`40
`
`45
`
`55
`
`65
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 4
`
`
`
`US 6,858,650 B1
`
`O
`
`H3C \O
`
`Formula V
`
`Formula I
`
`HO
`
`O
`
`OH
`
`)5
`
`10
`
`15
`
`whereupon
`
`b) the compound of formula V so obtained is converted
`With agent, in order to give a compound of formula VI
`
`25
`
`Formula VI
`
`35
`
`40
`
`45
`
`55
`
`Which
`
`c) is converted With an acylation agent, in order to obtain
`of formula A
`
`HO
`
`Formula A
`
`O Oi,
`A
`A
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, unsub
`stituted or substituted phenyl and X- is the acid residue of
`a physiologically compatible inorganic or organic acid.
`
`In accordance With the invention, for the manufacture of
`the compounds of general formula I hydrochloric acid,
`hydrobromic acid, phosphoric acid, sulphuric acid, nitric
`acid, acetic acid, propionic acid, palmitic acid, stearic acid,
`maleic acid, fumaric acid, oXalic acid, succinic acid,
`DL-malic acid, L-(—)-malic acid, D-(+)-malic acid,
`DL-tartaric acid, L-(+)-tartaric acid, D-(—)-tartaric acid, cit
`ric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)
`glucuronic acid, 2-oXopropionic acid (pyruvic acid), furan
`2-carboXylic acid (mucic acid), benZoic acid,
`4-hydroXybenZoic acid, salicyclic acid, vanillic acid,
`4-hydroXycinammic acid, gallic acid, hippuric acid
`(N-benZoyl-glycine), aceturic acid (N-aectylglycine), phlo
`retinic acid (3-(4-hydroXyphenyl)-propionic acid), phthalic
`acid, methanesulfonic acid or orotic acid are used.
`
`In accordance With an advantageous further development
`of the invention a method for the manufacture of
`R-con?gured compounds of the general formula 2 is
`described,
`
`HO
`
`Formula 2
`
`in Which R has the signi?cance stated above, Which d) is
`converted With a physiologically compatible inorganic or
`organic acid to form a compound of formula I
`
`65
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, sub
`stituted or unsubstituted phenyl and X“ is the acid residue of
`a physiologically compatible inorganic or organic acid, in
`that
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 5
`
`
`
`7
`a) a compound of formula 3
`
`US 6,858,650 B1
`
`Formula 3
`
`HO
`
`O
`
`Formula 1
`
`1O
`
`A
`A
`
`is split With a hydrogenation agent to form a compound of
`formula 5
`
`Formula 5
`
`25
`
`Lk
`A
`
`in Which R has the signi?cance stated above, Which
`
`d) is converted With a physiologically compatible inor
`ganic or organic acid to form a compound of formula
`2
`
`Formula 2
`
`35
`
`in Which R denotes C1—C6-alkyl, C3—C1O-cycloalkyl, unsub
`stituted or substituted phenyl and X- is the acid residue of
`a physiologically compatible inorganic or organic acid.
`
`Whereupon
`
`40
`
`b) the compound of formula 5 so obtained is converted
`With a reducing agent, in order to give a compound of
`formula 6
`
`45
`
`Formula 6
`
`OH
`
`55
`
`65
`
`Which
`
`c) is converted With an acylation agent, in order to obtain
`a compound of formula 1
`
`Advantageously in order to obtain compounds of general
`formula 2, in accordance With the method hydrochloric acid,
`hydrobromic acid, phosphoric acid, sulphuric acid, nitric
`acid, acetic acid, propionic acid, palmitic acid, stearic acid,
`maleic acid, fumaric acid, oXalic acid, succinic acid,
`DL-malic acid, L-(—)-malic acid, D-(+)-malic acid,
`DL-tartaric acid, L-(+)-tartaric acid, D-(—)-tartaric acid, cit
`ric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)
`-glucuronic acid, 2-oXopropionic acid (pyruvic acid), furan
`2-carboXylic acid (mucic acid), benZoic acid,
`4-hydroXybenZoic acid, salicyclic acid, vanillic acid,
`4-hydroXycinammic acid, gallic acid, hippuric acid
`(N-benZoyl-glycine), aceturic acid (N-aectylglycine), phlo
`retinic acid (3-(4-hydroXyphenyl)-propionic acid), phthalic
`acid, methanesulfonic acid or orotic acid are used.
`Particular advantageously, on the basis of the crystalline
`R-(—)-4-benZyloXy-3-(3-diisopropylamino-1-phenyl
`propyl)benZoic acid methyl ester, the highly pure, crystalline
`intermediate product R-(—)-3-(3-diisopropylamino-phenyl
`propyl)-4-hydroXy-benZoic acid methyl ester is prepared,
`Which is reduced to R-(+)-2-(3-diisopropylamino-1
`phenylpropyl)-4-hydroXymethylphenol, is ?nally acylated
`in a suitable manner and is then converted With a physi
`ologically compatible inorganic or organic acid under spon
`taneous crystalliZation to the respective highly pure,
`crystalline, stable salt.
`Depending on the acid chloride used, compounds of
`general formula 1 are obtained,
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 6
`
`
`
`US 6,858,650 B1
`
`HO
`
`Formula 1
`
`10
`
`O Oi,
`LA
`A
`
`in Which R denotes C1—C6-alkyl, in particular isopropyl,
`C3—C1O-cycloalkyl or unsubstituted or substituted phenyl.
`
`15
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`In order to obtain the compounds in accordance With the
`invention in the form of their salts the special reaction
`process via particular intermediate stages and individually
`identi?able intermediate products is crucial.
`This is explained using reaction diagram 1 (see FIG. 1),
`in Which the conversions With R-con?gured compounds are
`described, but Without this being restrictive.
`
`25
`
`In this:
`3=R-(—)-4-benZyloxy-3-(3-diisopropylamino-l-phenyl
`propyl)-benZoic acid-methyl ester
`4=R-(+)-[4-benZyloxy-3-(3-diisopropylamino-1-phenyl
`propyl)-phenyl]-methanol
`5=R-(—)-3-(3-diisopropylamino-phenyl-propyl)-4
`hydroxy-benZoic acid methyl ester
`6=R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenol
`1=R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenyl-isobutyrate ester
`2a=R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenyl-isobutyrate ester hydrogen
`fumarate
`2b=R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenyl-isobutyrate ester hydrochloride
`hydrate
`In accordance With the reaction process explained in the
`embodiment the preliminary stage 3 (R-(—)-4-benZyloxy-3
`(3-diisopropylamino-1-phenyl-propyl)-benZoic acid
`methylester) is prepared in crystalline, pure form.
`Using normal methods—such as BBr3, AlCl3—but pref
`erably by means of hydrogen gas via Raney nickel in
`methanol as the solvent at room temperature (RT), prelimi
`nary stage 3 is split into 5 (R-(—)-3-(3-diisopropylamino
`phenyl-propyl)-4-hydroxy-benZoic acid methylester. This
`develops in highly pure, crystalline form (melting point
`143.7° C.).
`Finally, using a suitable reducing agent—such as NaBH4/
`EtOH—preferably LiAlH4 5 is reduced into an inert solvent
`at loW temperature (—78° C. to +10° C.) and the compound
`6 (R-(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenol) is obtained. The compound 6 is
`obtained in a highly pure state and can be crystallised from
`a suitable solvent such as ethyl acetate. The colourless,
`compact grained material has a melting point of 102.3° C.
`
`35
`
`40
`
`45
`
`55
`
`65
`
`10
`This is surprising in that the compound 6 in the state of the
`art is described as an amorphous solid.
`Compound 6 is noW acylated With very good yield and
`regio- and chemoselectivity, into a phenolic ester. This
`reaction is performed at RT or loW temperatures With an
`equivalent acid chloride in the presence of a base in a
`suitable solvent. Suitable solvents are ethyl acetate,
`dichloromethane, tetrahydrofurane, acetonitrile or toluene.
`The reaction is preferably performed With isobutyrylchlo
`ride as the acid chloride and triethylamine as the base at the
`abovementioned temperatures. The 1 (R-(+)-2-(3
`diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenylisobutyrate ester) then obtained,
`occurs With such purity that With solutions of the fumaric
`acid in suitable solvents spontaneous crystallisation starts
`With the formation of the hydrogen fumarate salt 2a.
`This salt has a high melting point of 103° C., is stable at
`RT, is non-hygroscopic and does not contain crystallose
`agents. It can be recrystallised as often as desired.
`If instead of fumaric acid anhydrous hydrochloric acid is
`used—for example as an etheric solution—salt formation
`also takes place With the crystalline product 2b (R-(+)-2-(3
`diisopropylamino-1-phenylpropyl)-4
`hydroxymethylphenyl-isobutyrate ester hydrochloride
`hydrate being obtained.
`FolloWing a further recrystallisation the product 2b has a
`melting point range of 97—106° C.
`Finally the product 2b can particularly advantageously be
`obtained by the folloWing variants of the inverse reaction
`process, starting With the compound 6 of reaction diagram 1.
`The product 2b can thus be obtained Without the addition of
`an external acid-intercepting base, as explained in the fol
`loWing.
`Solutions of 6 (R-(+)-2-(3-diisopropylamino-1
`phenylpropyl)-4-hydroxymethylphenol) are dripped into
`solutions of isobutyrate chloride, so that under suitable
`polarity conditions the anhydrous product 2b rapidly crys
`tallises out. 2b is very hygroscopic.
`If the abovementioned reaction is carried out in a humid
`solvent, that contains at least one mole equivalent of Water,
`a stable and crystalline, hydrate-containing product 2b is
`obtained, that has the abovementioned melting characteris
`tics.
`The compounds in accordance With the invention of
`general formulae 1 and 2 are suited to bulk material.
`Of particular advantage are the highly pure compounds of
`general formulas III, V, VI, 3, 5, 6 and 7 Which can be
`obtained.
`Compound of Formula III
`
`Formula III
`
`A
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 7
`
`
`
`Compound of Formula V
`
`Compound of formula 6
`
`11
`
`12
`
`US 6,858,650 B1
`
`Formula V
`
`Formula 6
`
`OH
`
`A
`
`Compound of Formula VI
`
`Formula VI
`
`Sir A
`
`Compound of Formula 3
`
`35
`
`Formula 3
`
`~
`
`013
`
`N
`
`Compound of Formula 5
`
`Formula 5
`
`40
`
`45
`
`55
`
`65
`
`%
`0%
`OYQ/ O
`
`Y J\\\\/ g+
`
`Formula 7
`
`O
`
`1O
`
`15
`
`3O
`
`Compound of Formula 7
`
`O
`
`
`
`W O
`
`O
`
`O
`
`[(R)-3-(2-{1-[4-(2,2-dimethyl-propanoyloXy)-phenyl]
`methane-oyloXy}-5-{1-[4-(2,2-dimethyl-propanoyloXy)
`phenyl]-methane-oyloXymethyl}-phenyl)-3-phenyl
`propyl]-diisopropyl-ammonium-chloride.
`The abovementioned compounds III, V, VI, 3, 5, 6 and 7
`are particularly suited to use in each case as a highly pure,
`crystalline, stable intermediate product in the manufacture
`of pharmaceutically useful compounds.
`Of particular advantage are compounds for use as an
`intermediate product in the manufacture of R-(+)-2-(3
`diisopropylamino-1-phenylpropyl)-4
`hydroXymethylphenylisobutyrate ester hydrogen fumarate
`and R -(+)-2-(3-diisopropylamino-1-phenylpropyl)-4
`hydroXymethylphenylisobutyrate ester hydrochloride
`hydrate.
`Finally, the method can be carried out in a particularly
`advantageous Way by converting a compound of general
`formula 6 (see reaction diagram 1) With an equivalent
`isobutyryl chloride in the presence of triethylamine using
`one of the respective solvents ethylacetate,
`dichloromethane, tetrahydrofurane, acetonitrile or toluene
`regio- and chemoselectively into R-(+)-2-(3
`diisopropylamino-1-phenylpropyl)-4
`hydroXymethylphenylisobutyrate ester.
`In accordance With the invention R-(+)-2-(3
`diisopropylamino-1-phenylpropyl)-4
`hydroXymethylphenylisobutyrate ester is particularly suited
`to conversion With fumaric acid or hydrochloric acid With
`the formation of the respective salt.
`The folloWing embodiments explain the invention.
`Experimental
`I. General
`All compounds have been fully characterised by 1H and
`13C NMR-spectroscopy (Bruker DPX 200). The stated
`chemical displacements in the 13C-NMR-spectra (50 MHZ,
`ppm values stated) refer to the solvent resonances of CDCl3
`(77.10 ppm) 1H NMR data (CDCI3; 200 MHZ, ppm) refer to
`internal tetramethylsilane).
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 8
`
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`
`US 6,858,650 B1
`
`13
`Thin layer chromatography (DC, Rf given) Was carried
`out on 5><10 cm E. Merck silica gel ?lms (60F254), and the
`stains Were revealed by ?uorescence erasure or by spraying
`With alkaline potassium permanganate solution.
`Absorbent systems Were: (1), n-heXane/acetone/
`triethylamine (70/20/10, v/v-%); (2), toluene/acetone/
`methanol/acetic acid (70/5/20/5, v/v-%).
`The optical rotations Were measured at a Wavelength of
`589.3 nm (sodium D-line), at room temperature using etha
`nol as a solvent (apparatus: Perkin Elmer Polarimeter Type
`241), melting points (in ° C.) are uncorrected and Were
`determined on the Mettler FP apparatus, or by differential
`thermoanalysis (DSC) on the Perkin Elmer Model DSC7,
`using “Pyris” evaluation softWare.
`UV/VIS measurements Were carried out on the spectro
`photometer. model Lambda 7 (Perkin-Elmer) With a layer
`thickness of 1 cm. The speci?c absorption stated is for a 1%
`solution (A1 %1 Cm)
`IR spectra Were recorded on a Perkin-Elmer FTIR spec
`trometer Series 1610 (resolution 4 cm_1).
`Gas chromatography mass spectrometry (GC-MS, m/Z
`values and relative intensity With reference to the base ion
`(%) Was carried out With a Finnigan TSQ 700 Triple Mass
`Spectrometer in positive (P-CI) or negative (N-CI) chemical
`ioniZation measurement mode With methane or ammonium
`as a reactant gas or via electron impact ionisation. HydroXy
`compounds Were measured as trimethylsilylether
`derivatives.
`Coupled liquid chromatography-mass spectrometry (LC
`MS): Waters Integrity System, Thermabeam Mass Detector
`(EI, 70 eV), m/Z-values and relative intensity (%) are given
`over a quantity range of 50—500 a.m.u.
`II. Embodiments
`The Arabic numerals in brackets (3), (4), (5), (6) refer to
`the identical designations in reaction diagram 1.
`1. Preparation of R-(—)-4-benZyloXy-3-(3
`diisopropylamino-1-phenyl-propyl)-benZoic acid methyl
`ester (3)
`
`A
`A
`
`A solution of R-(—)-4-benZyloXy-3-(3-diisopropylamino
`1-phenyl-propyl)-benZoic acid hydrochloride (2.30 kg, 4.77
`M01) in 26.4 litres of methanol and 0.25 litre of concentrated
`sulphuric acid is heated for 16 hours With recycling. Then a
`third of the solvent is distilled off, cooled and under agitation
`miXed With 5 kg ice and 2.5 litres 25% aqueous sodium
`carbonate solution. The deposit is ?rst eXtracted With 15
`litres and then again With 5 litres of dichloromethane. The
`organic phases are puri?ed and concentrated on the rotary
`evaporator until dry. 1.99 kg (90.7% of theoretical) dark
`yelloW oil With a purity of approximately 90% (DC, NMR)
`are obtained.
`DC (1): 0.58
`13C-NMR (CDCl3): 20.55, 20.65, 36.83, 41.84, 43.63,
`51.82, 70.12, 111.09, 122.46, 125.28, 127.49, 128.02,
`128.35, 128.50, 129.22,129.49, 133.20, 136.39, 144.51,
`159.87, 167.09.
`
`10
`
`15
`
`20
`
`25
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`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`14
`Recrystallisation 69.0 oily raW material is dissolved in 150
`ml boiling methanol. FolloWing the addition of 15 ml
`distilled Water it is left at 0° C., Whereupon colourless
`crystals precipitate. These are ?ltered off, Washed With a
`little cold methanol and vacuum-dried. Yield: 41.8 g (60.6%
`of theoretical) colourless crystals, melting point 898° C.;
`[I1D2O=—30.7(c=1.0, ethanol).
`2. Preparation of R-(+)-[4-benZyloXy-3-(3
`diisopropylamino-1-phenyl-propyl)-phenyl]-methanol (4)
`
`A
`
`RaW product (3) (28 g) is dissolved in 230 ml pure
`diethylether and under agitation is dripped into a suspension
`of 1.8 g lithium-aluminium hydride in diethylether (140 ml).
`After 18 hours of agitation at room temperature, 4.7 ml of
`Water are added in drop form. The organic phase is separated
`off, dried With anhydrous sodium sulphate, ?ltered and
`concentrated on the rotary evaporator until dry. 26 g (98.9%
`of theoretical) R-(+)-[4-benZyloXy-3-(3-diisopropylamino
`1-phenyl-propyl)-phenyl]-methanol (4) are obtained as a
`colourless oil.
`DC (2): 0.32; [I1D20=+6.3 (c=1.0, ethanol).
`13C-NMR (CDCl3): 20.53, 20.61, 36.87, 41.65, 44.14,
`48.82, 65.12, 70.09, 111.80, 125.77, 125.97, 126.94, 127.55,
`128.08, 128.37, 128.44, 133.27, 134.05, 134.27, 137.21,
`144.84.
`3. Preparation of R-(—)-3-(3-diisopropylamino-phenyl
`propyl)-4-hydroXy-benZoic acid methyl ester (5)
`
`OH
`
`To an agitated suspension of 5 g Raney nickel (Washed
`With Water, then With methanol) in 200 ml methanol, 10 g
`(21.8 mmol) R-(—)-4-benZyloXy-3-(3-diisopropylamino-1
`phenyl-propyl)-benZoic acid methyl ester (3) are added.
`FolloWing brief heating, in order to dissolve all (3)
`completely, the apparatus is placed under a hydrogen gas
`atmosphere. After three hours of agitation at normal pressure
`and room temperature, the thin layer chromatography dem
`onstrates complete conversion. The deposit is rinsed With
`nitrogen gas and folloWing addition of some active charcoal
`is ?ltered. FolloWing concentration of the methanolic solu
`tion on the rotary evaporator 6.0 g (75% of theoretical)
`R-(—)-3-(3-diisopropylaminophenyl-propyl)-4-hydroXy
`benZoic acid methyl ester (5) remains in the form of colour
`less crystals With a purity of 99.6% (HPLC).
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1001 - Page 9
`
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`
`US 6,858,650 B1
`
`15
`Melting point 143.7° C.; DSC 144.7° C.
`
`13c-NMR (CDC13): 18.74, 19.21, 19.62, 33.12, 39.68,
`42.36, 48.64, 51.42, 117.99, 120.32, 126.23,127.81, 128.85,
`129.39, 130.26, 132.21, 144.06, 162.43, 167.35.
`4. Preparation of R-(+)-2-(3-diisopropylarnino-1
`phenylpropyl)-4-hydroXyrnethylphenol (6)
`
`16
`
`Melting point 102.3° C.
`DC 1); 0.57
`LI D2 =+21.3 (c=1.0, ethanol).
`C-NMR (CDC13): 19.58, 19.96, 33.30, 39.52, 42.10,
`48.00, 65.40, 118.58, 126.31, 126.57, 127.16, 127.54,
`128.57, 132.63, 132.83, 144.55, 155.52.
`5. Preparation of R-(+)-2-(3-diisopropylarnino-1
`phenylpropyl)-4-hydroXyrnethylphenolisobutyrate ester (1)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`65
`
`a) Starting from the intermediate stage (4), R-(+)-[4
`benZyloXy-3-(3-diisopropylarnino-1-phenyl-propyl)
`phenyl]-rnethanol
`R-(+)-[4-benZyloXy-3-(3-diisopropylarnino-1-phenyl
`propyl)-phenyl]-rnethanol (19.7 g, 45.7 rnrnol) are dissolved
`in 220 ml methanol and Raney nickel (5 g). The apparatus
`is rinsed With hydrogen gas and the deposit is agitated for
`tWo days at room temperature. FolloWing the addition of a
`further 5 g Raney nickel, agitation for a further tWo days at
`room temperature takes place under a hydrogen gas
`atmosphere, folloWed by ?ltration off from the catalyser and
`concentration until dry on the rotary evaporator. The oily,
`pale yelloW residue is dissolved in 100 ml diethylether,
`Washed tWice With 100 ml Water each time, dried via sodiurn
`sulphate, ?ltered and concentrated until dry. 14.1 g (90.4%
`of theoretical) R-(+)-2-(3-diisopropylarnino-1
`phenylpropyl)-4-hydroXyrnethylphenol are obtained in the
`form of a crearn-coloured, arnorphous. solid. For recrystal
`lisation see under c).
`b) Starting from the intermediate stage (5); R-(—)-3-(3
`diisopropylarnino-phenyl-propyl)-4-hydroXy-benZoic acid
`methyl ester
`A solution of 370 mg (1.0 rnrnol) R-(—)-3-(3
`diisopropylarnino-phenyl-propyl)-4-hydroXy-benZoic acid
`methyl ester in 20 ml anhydrous tetrahydrofurane is sloWly
`and at room temperature dropped into an agitated mixture of
`dried tetrahydrofurane (10 ml) and a 1M solution of lithium
`alurniniurn hydride in tetrahydrofurane (3 ml) (under a
`nitrogen protective gas atmosphere). Excess hydride is
`decomposed by the dropped addition of a saturated sodium
`carbonate solution. FolloWing separation of the organic
`phase this is concentrated on the rotary evaporator and then
`dried in the high-vacuurn. 274 mg (74% of theoretical) pale
`yelloW oil is obtained, that sloWly so