`Meese
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,858,650 B1
`Feb. 22, 2005
`
`US006858650B1
`
`(54) STABLE SALTS OF NOVEL DERIVATIVES
`OF 3,3-DIPHENYLPROPYLAMINES
`
`W0
`W0
`
`10/1998
`9843942
`11/1999
`9958478
`OTHER PUBLICATIONS
`
`(75)
`
`Inventor: Claus Meese, Monheim (DE)
`
`(73)
`
`Assignee: Schwarz Pharma AG (DE)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`(22)
`
`(86)
`
`(87)
`
`(30)
`
`Appl. No.:
`PCT Filed:
`
`PCT No.:
`
`10/130,214
`
`Nov. 15, 2000
`
`PCT/EP00/11309
`
`§ 371 (C)(1),
`(2), (4) Date: May 14, 2002
`
`PCT Pub. No.: W001/35957
`
`PCT Pub. Date: May 25, 2001
`
`Foreign Application Priority Data
`
`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
`..................... .. 514/530; 514/531; 514/534;
`(52) U.S. Cl.
`514/548; 514/551; 560/61; 560/122; 560/123;
`560/124; 560/138; 560/142; 560/250; 564/319
`(58) Field of Search ............................... .. 514/530, 531,
`514/534, 548, 551, 560/61, 122, 123, 124,
`138, 142, 250, 37, 18, 42, 140, 564/319
`
`(56)
`
`DE
`EP
`EP
`WO
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`........ .. 514/315
`11/1997 Johansson et al.
`5,686,464 A
`FOREIGN PATENT DOCUMENTS
`
`693 17 898 T2
`0 667 852 B1
`0 957 073 A1
`9411337
`
`10/1998
`4/1998
`11/1999
`5/1994
`
`....... .. C07C/217/62
`....... .. C07C/217/62
`........... .. C07C/1/00
`
`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 tolterodine 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
`
`invention concerns highly pure, crystalline,
`The present
`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-1-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 diagram 1
`(1), Liluflu (ii).
`tv) stand for:
`(iv):
`(1), (ii). (iii):
`Raney nickel/H2, (iii), Hegcll-CDC1,
`::,N,
`(iv),
`fullvaxic acid,
`(v), nydmchiuxiz: acids; R stands to: xsopzepyl (in)
`
`W
`/1
`8;?
`
`(.
`H
`
`H
`
`N
`
`..
`
`‘:d\
`
`
`
`.. .11).
`I
`(iv at V)
`(
`__.1 ?.2ae,2b
`R=i-Pr
`a:x=c.1-1,0.
`b:x=c1
`
`R-i.-Fr
`
`S
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0001
`
`
`
`U.S. Patent
`
`Feb. 22,2005
`
`US 6,858,650 B1
`
`Figure 1
`
`Reaction diagram 1
`
`(i),
`
`(ii), (iii),
`
`(iv),
`
`(v) stand for: (i), LiAlH4,
`
`(ii),
`
`Raney nickel/H2, (iii), Me2CH‘COCl, E‘.t3N,
`
`(iv),
`
`fumaric acid,
`
`(v), hydrochloric acids; R stands for isopropyl
`
`(iPr)
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0002
`
`
`
`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
`1.
`
`US 6,858,650 B1
`
`This application was filed under 35 U.S.C. 371, and is the
`U.S. National Stage of PCT/EP00/11309, filed 5 Nov. 2000.
`This patent application claims the benefit of priority
`under 35 U.S.C. §119 of German Patent Application No. 199
`55 190.1, filed 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
`
`10
`
`15
`
`20
`
`25
`
`HO
`
`O
`
`Formula A
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`in which R denotes C1-C5-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 transesterifica-
`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 purified 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
`
`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 final 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—C10-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.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0003
`
`
`
`US 6,858,650 B1
`
`3
`In accordance with a further design form of the invention
`R-configured compounds with general formula 2 are pro-
`vided
`
`Formula 2
`
`5
`
`
`
`in which R denotes C1-C5-alkyl, C3—C10-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.
`
`[(R)-3-(2-{1-[4-(1-
`Particular preference is for
`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]-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 fluorine, 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
`
`O ,x
`I X.
`
`in which R denotes C1-C6-alkyl, C3—C10-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
`
`H3C\O O 6
`o A
`
`A
`
`is split with a hydrogenation agent to form a compound of
`formula V
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0004
`
`
`
`O
`
`H3C
`
`\O
`
`OH
`
`)1‘;
`
`whereupon
`
`b) the compound of formula V so obtained is converted
`with agent, in order to give a compound of formula VI
`
`Formula VI
`
`HO
`
` OH
`
`“LA
`A
`
`which
`
`US 6,858,650 B1
`
`Formula V
`
`Formula I
`
`HO
`
`O
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`in which R denotes C1-C6-alkyl, C3—C10-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
`
`c) is converted with an acylation agent, in order to obtain
`of formula A
`
`R-configured compounds of the general formula 2 is
`described,
`
`45
`
`Formula A
`
`Formula 2
`
`HO
`
`0
`
`JR
`
`A
`/K
`
`in which R has the significance stated above, which d) is
`converted with a physiologically compatible inorganic or
`organic acid to form a compound of formula I
`
`50
`
`55
`
`60
`
`65
`
`HO
`
`
`
`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
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0005
`
`
`
`a) a compound of formula 3
`
`7
`
`US 6,858,650 B1
`
`Formula 3
`
`8
`
`Formula 1
`
`
`
`5
`
`10
`
`O
`
`NJK
`)\
`
`15 in which R has the significance stated above, which
`
`is split with a hydrogenation agent to form a compound of 20
`formula 5
`
`d) is converted with a physiologically compatible inor-
`ganic or organic acid to form a compound of formula
`2
`
`Formula 2
`
`Formula 5
`
`25
`
`30
`
`
`
`O
`
`H C
`3 \O
`
`OH
`
`i\NJ\
`)\
`
`35 in Which R denotes C1-C6-alkyl, C3—C10-cycloalkyl, unsub-
`stituted or substituted phenyl and X— is the acid residue of
`a physiologically compatible inorganic or organic acid.
`
`Advantageously in order to obtain compounds of general
`40 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-ma1ie acid, L-(_)-ma1ie acid, D-(+)-ma1ie acid,
`45 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,
`50 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.
`
`55
`
`60
`
`65
`
`R-(—)-4-benzyloxy-3-(3-diisopropylamino-1-phenyl-
`
`Particular advantageously, on the basis of the crystalline
`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 finally 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.
`
`whereupon
`
`b) the Compound of formula 5 50 (‘blamed 15 Converted
`with a reducing agent, in order to give a compound of
`formula 6
`
`Formula 6
`
`HO
`
`
`
`OH
`
`N
`
`L k
`K
`
`which
`
`c) is converted with an acylation agent, in order to obtain
`a compound of formula 1
`
`Depending on the acid chloride used, compounds of
`general formula 1 are obtained,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0006
`
`
`
`US 6,858,650 B1
`
`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
`
`o
`
`A A
`
`Formula 1
`
`
`
`in particular isopropyl,
`in which R denotes C1-C5-alkyl,
`C3—C1O-cycloalkyl or unsubstituted or substituted phenyl.
`
`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
`identifiable intermediate products is crucial.
`
`This is explained using reaction diagram 1 (see FIG. 1),
`in which the conversions with R-configured compounds are
`described, but without this being restrictive.
`In this:
`
`3=R-(—)-4-benzyloxy-3 -(3-diisopropylamino - 1 -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.
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`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0007
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`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0007
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`Compound of Formula V
`
`Compound of formula 6
`
`Formula V
`
`Formula 6
`
`..
`
`Compound of Formula 7
`
`10
`25
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`Formula VI 20
`
`.0
`
`40
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`Formula 3
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`1:0rmu1a5
`
`OH
`
`A K
`
`k
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`Compound of Formula VI
`
`
`
`0
`
`N/K
`)\
`
`Compound of Formula 5
`
`[(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-
`35 propyl]-d11sopropyl-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
`45 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
`50 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
`
`55
`
`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,
`65 ppm values stated) refer to the solvent resonances of CDCl3
`(77.10 ppm) 1H NMR data (CDCI3; 200 MHZ, ppm) refer to
`internal tetramethylsilane).
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`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 filtered off, washed with a
`little cold methanol and vacuum-dried. Yield: 41.8 g (60.6%
`of theoretical) colourless crystals, melting point 89.8° C.;
`[I]D2°=—30.7(c=1.0, ethanol).
`2. Preparation of R-(+)-[4-benzyloxy-3-(3-
`diisopropylamino-1-phenyl-propyl)-phenyl]-methanol (4)
`
`
`
`o
`NA
`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, filtered 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; [I]D2°=+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
`
`‘~
`
`LA
`A
`
`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 filtered. 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).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0009
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`Thin layer chromatography (DC, Rf given) was carried
`out on 5><10 cm E. Merck silica gel films (60F254), and the
`stains were revealed by fluorescence 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 specific 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
`Mol) 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 first extracted with 15
`litres and then again with 5 litres of dichloromethane. The
`organic phases are purified 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.
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`Patent Owner, UCB Pharma GmbH – Exhibit 2019 - 0009
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`US 6,858,650 B1
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`16
`
`Melting point 102.3° C.
`DC 1): 0.57
`(I 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-diisopropylamino-1-
`phenylpropyl)-4-hydroXymethylphenolisobutyrate ester (1)
`
`04
`
`A
`
`A solution of R-(+)-2-(3-diisopropylamino-1-
`phenylpropyl).-4-hydroxymethylphenol (6) (65.0. g, 190.3
`mmol) and tr1ethylam1ne (20.4 g, 201.7 mmol) in 750 ml
`dichloromethane has a solution of isobutyrate chloride (23.4
`g, 201.7 mmol) in 250 ml dichloromethane added under
`agitation and cooling. Following addition agitation takes
`place for a further 15 minutes at 0° C., then for 30 minutes
`at room temperature and then one after another washing with
`water (250 ml) and 5% aqueous sodium hydrogen carbonate
`solution. The organic phase is separated and concentrated on
`the rotary evaporator until dry. The ester R-(+)-2-(3-
`diisopropylamino-1-phenylpropyl)-4-
`hydroxymethylphenylisobutyrate ester
`is obtained as a
`colourless, viscous oil; yield: 77.1 g (98.4% of theoretical).
`DC (1): 0.26; [I]D22=+2.7 (c=1.0, ethanol).
`1°C-NMR (CDCI3): 19.01, 19.95, 20.59, 21.12, 34.28,
`36.89, 41.88, 42.32, 43.90, 48.78, 64.68, 122.57, 125:59,
`126.16, 126.86, 127.96, 128.54, 136.88, 138.82, 143.92,
`147.90, 175.96.
`6. Preparation of R-(+)-2-(3-Diisopropylamino-1-
`phenylpropyl)-4-hydroxymethyl-phenylisobutyrate ester
`hydrogen fumarate.
`
`
`
`A solution of 41.87 g (102 mmol) R-(+)-2-(3-
`diisopropylamino-1-phenylpropyl)-4-
`hydroxymethylphenylisobutyrate ester in 90 ml 2-butanone
`has fumaric acid (11.81 g, 102 mmol) added while heating.
`Following dissolution of the acid, cyclohexane (20-30 ml)
`is slowly added under agitation until the onset of turbidity.
`The colourless, homogenous deposit is initially left for 18
`hours at room temperature, and then for several hours at 0°
`C. The colourless crystals that have precipitated are sucked
`off, washed with a little cyclohexane/2-butanone (90:10,
`vol.-%)and dried in the vacuum at 30° C. 44.6 g (83.1% of
`theoretical) hydrogen furate salt of R-(+)-2-(3-
`diisopropylamino-1-phenylpropyl)-4-
`
`5
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`Patent Owner, UCB Pharma GmbH — Exhibit 2019 - 0010
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`15
`Melting point 143.7° C.; DSC 144.7° C.
`[I]D2°=—26.6 (c=0.93, ethanol).
`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-diisopropylamino-1-
`phenylpropyl)-4-hydrox