(12; United States Patent
`Lenfers et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,774,236 B1
`Aug. 10, 2004
`
`US[][]6774236B1
`
`(54)
`
`I’R()Cl'lSS FOR THE I’RF.I’ARA'I‘I()N OF
`EN/\NTIOMERICAI.I5Y PURE
`CYCl,()AI.KAN()-INI)()I5 -AND AZ/\lNI)()l.
`-AND PYRIMIDO [1_.2A]
`INDOLCARBOCYCLIC ACIDS AND THEIR
`ACTIVATED DERIVATIVES
`
`(75)
`
`Inventors: Jan-Bernd Lenfers, Wuppertal (DE);
`Peter Fey, Wuppertal (DE); Paul Naab,
`Wu})pertal (DE); Kai Van Luak,
`Cologne (DE)
`
`(73) Assignee: Bayer Aktiengesellschaft, Leverkusen
`(DE)
`
`( 1‘) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.(.‘. t54{b) by 0 days.
`
`(21) Appl. No.: 09f307,980
`
`(22)
`
`Filed:
`
`May 10, [999
`
`Related U.S. Application Data
`
`5,527,809 A
`5,684,014 A
`5,714,494 A *
`
`(771996 Mi'I1|er—G|iemann et .11.
`ll;‘l9.97 Miiller et at.
`2719.98 Connell et al.
`
`514,-“Z63
`
`150R].-ll(jl\l PAT].-lN'l‘ DOCUMI;'N'I‘S
`
`IEP
`IE1’
`HI’
`HI’
`RP
`
`344519
`513533
`560163
`610698
`705861
`
`1171990
`11.71992
`971993
`871994
`471996
`
`OTHER PURI .I CATI ONS
`
`Connell et a]. (CA '126:3U5588, abstract of EP 764,647],
`1997.‘
`
`l\“lasaka7.u Miyakado. et al. Agr. Biol. Chem, 39(1),
`367—272; “Optical Resolution and Determination of Abso-
`lute Contigurations ol‘
`tr.—lsopropyl—4—substituted Pheny-
`lacetic Acids
`and
`Inseetieiclal Activities
`of Their
`5—Benzyl—3—furylmethyl l:'.sters” ( l 975).
`
`* cited by examiner
`
`Pririitrry Exoininci'—Sabiha Oazi
`(74) .4tt(Jrnc_}-‘, Agent, or F1'rm—Norris McLaughlin &
`Marcus PA
`
`(62) Division of application No. tJ8,:’829,5fi6, filed on Mai. 31,
`199?, now Pat. No. 5,952,498.
`
`(57)
`
`ABSTRACT
`
`(30)
`
`Foreign Application Priority Data
`
`Apr. 4, 1996
`
`(DE)
`
`[9613 549
`
`(51)
`
`Int. Cl.‘
`
`CtI7D 471,104; C[|7C 487704;
`C07C 69,’6'|(i; C07C 607612
`5447252; 56078; 5447248;
`(52) U.s. Cl.
`5447252; 54,684; 54..-“S5; 54186; 54/87; 5487427
`(58) Field of Search
`5(i0;’8; 5447252
`
`(56)
`
`References Cited
`U.S. PA'[‘l_-"NT l)()CUMl_-'N'[‘S
`
`-’l,97EJ,2lS A
`5,459,123!) A *
`
`1171990 Moltrs et al.
`If],-'199:_: Muller-
`Uliemann ct at.
`
`514.-“.397
`
`The invention relates lo a process and intermediates for the
`preparation of enantiomerically pure cycloalkanoindolecar-
`boxylic acids and azaindoleearboxylic acids and pyrirnido
`[1,2a]i11dolccarboxylic acids and their activated derivatives,
`characterized in that the lolyl acetic acid is lirst esterilied
`with a chiral alcohol, then diastereoselective substitution at
`(1-£.‘t1l'lJU[1 atoms is carried out and this product is haloge-
`nated in the tolyl group and then reacted with appropriate
`cycloalkanoindoles, cycloalkanoazaindoles or pyrimido[1,
`2a]indoles.
`It
`is possible by this method to prepare
`specifically,
`in high purity, the enantiomerically pure car-
`boxylic acids which are intermediates for valuable medica-
`nienls.
`
`2 Claims, No Drawings
`
`lufl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`1
`
`US 6,774,236 B1
`
`2
`
`G
`
`J
`
`PROCESS FOR THE PREPARATION OF
`ENANTIOMERICALLY PURE
`CYCl,()AI.KAN()-[NI}()L -AND A7./\lND()I.
`
`-AND PYRIMIDO [1,2A]
`INl)()I.CARB()CYCLIC ACIDS AND TH ICIR
`ACTIVATED DERIVATIVES
`
`This application is adivision ol'Ser. No. U8,=’829,5oo llled
`on Mar. 3'1, 199?‘, now Pat. No. 5,952,498, which claims
`priority to German Application 196 13 549.4 filed on Apr. 4,
`1996.
`
`The invention relates to a process for the preparation of
`enantiomerically pure cycloalkano—indolecarh0xylie acids
`and azaindolecarboxylic acids and pf,-'rimido['l,2a]
`indoleearboxylic acids and their activated derivatives, which
`represent important intermediates for the synthesis of anti-
`atherosclerotically active cycloalkanoindole derivatives and
`azaindole derivatives and pyrimido[l,2a]indole derivatives.
`It
`is known that enantiomerically pure eyeloa]kano—
`indoleearboxylic acids and azaindolecarboxylic acids and
`their activated derivatives can be separated into the corre-
`sponding enantiomers by diastereomerie separation by con-
`ventional methods, for example by chromatography or frac-
`tional crystallization.
`This process has a number of disadvantages: both the
`chromatographic diastereomeric separation and the frac-
`tional crystallization of the diastereomers are associated
`with high equipment requirements. In addition, in this case,
`generally 50% of the “wrong” diastcrcomcr arises, which
`can no longer be recycled to the original preparation process.
`This 50% loss of yield considerably impairs the eco-
`nomic elliciency of a (large) industrial-scale process, quite
`apart
`from the fact
`that 50% of “hy—produet” must be
`disposed of. Furthermore,
`the customary chiral auxiliary
`reagents. are generally very expensive even in small amounts
`and can then usually only be prepared via a complex
`synthetic pathway.
`It has now been found that enaotiomerieally pure
`cycloalkano—indoleearbexylic acids and az.aindoleearboxy—
`lie acids and pyrimido[l,2a]indole-earboxylic acids and
`their activated derivates of the general formula (1)
`
`(ll
`
`1* —
`C113
`\ Wm Q
`
`,-
`
`, _
`
`.1.
`
`DIV l
`hf/.,
`
`N/TALL
`/ N.\*J
`
`J, D, Li, G, L and M are identical or different and denote
`hydrogen, halogen,
`trifluorotnethyl, earboxyl,
`hydroxyl, linear or branched alkoxy or alkoxycarbonyl
`each having up to 6 carbon atoms, or linear or branched
`alkyl having up to 6 carbon atoms, which itself can be
`substituted by hydroxyl or by linear or branched alkoxy
`having up to 4 carbon atoms,
`in which
`
`including the double bond linking them,
`R1 and R2,
`together form a plienyl ring or pyridyl ring or a ring of
`the formula
`
`NR5
`
`where
`
`R5 denotes hydrogen or linear or branched alkyl having
`up to 4 carbon atoms,
`R3 and R4,
`including the double bond linking them,
`together form a phenyl ring or a 4- to 8-membered
`cyeloalkene or oxocycloalkene radical, where all the
`ring systems listed under RVR: and R3/“R4 are option-
`ally up to trisubstituted identically or differently by
`halogen, trilluoromethyl. carboxyl, hydroxyl, by linear
`or branched alkoxy or alkoxycarbonyl each having 11p
`to 6 carbon atoms, or by linear or branched alkyl having
`up to 6 carbon atoms, which itself can be substituted by
`hydroxyl or by linear or branched alkoxy having up to
`4 carbon atoms,
`'[' rcprcscnLs cycloalkyl having 4 to 12 carbon atoms, or
`represents linear or branched alkyl having up to 12
`carbon atoms,
`Q WPH3-WU‘-‘5 hYdT0XY1 OT *1“ <1‘3Ti‘-'3‘ inc‘; F“di‘3?11a
`and their salts are obtained
`by firstly converting compounds of the general formula [Ii],
`
`
`
`an
`
`1U
`
`15
`
`'
`
`30
`
`35
`
`4U
`
`45
`
`50
`
`in which
`
`A represents a radical of the formula
`
`R,
`
`_1
`
`R
`
`|
`
`|
`
`N
`l
`
`R,
`
`7
`R"
`
`55 in which
`R“ together with the oxygen atom represents a chiral
`alcohol radical, by means of conipounds of the general
`formula (111)
`
`5“
`
`65
`
`'l‘—'!.
`
`(III)
`
`in which
`T has the meaning specified and
`Z represents a typical leaving group, such as bromine,
`chlorine,
`iodine, mesyl,
`tosyl,
`or
`lrilluoromethylsulphonyl, preferably iodine or
`bromine,
`
`2 of 13
`
`PENN Ex. 2229
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`3
`n inert solvents in the presence of a base by diastcrcoselec—
`tive alkylation into the enantiomerically pure compounds of
`the general formula (IV)
`
`4
`The process according to the invention can be described
`by way of cxamplc by me following fmmula diagram:
`
`US 6,774,236 B1
`
`CII;
`
`
`
`in which
`T and R“ have the meaning specified,
`into the enanti0-
`then converting these, by halogenation,
`merically pure compounds of the general formula (V)
`
`_
`R.
`
`|
`CH2 \
`
`It
`.Ni/
`T
`
`C0°Rfi
`-
`
`W]
`
`_
`in which
`T and R“ have the meaning specified
`and
`
`R7 represents halogen, such as chlorine, bromine, iodine,
`preferably bromine, reacting these in a further step with
`compounds of the general formula (VI)
`
`UV]
`
`q Uglc
`"
`
`cn_. —-
`
`CO—Q
`
`
`
`(R, S)
`
`H_,{:
`
`(T
`
`
`
`"
`
`:1-
`
`3
`
`Cu-
`
`1m
`
`15
`
`En
`
`35
`
`30
`
`"'
`
`A—lI
`in which
`
`(VI)
`
`(1)-
`
`N
`
`x
`
`(in,
`
`..-|II||C
`formula (VI 1)
`
`R], R2, R3 and R" have the meaning specified,
`to give the enantiomerieally pure compounds of the general 35
`
`_
`
`1i,r:“'
`
`Fl‘: T
`CH2 \
`I
`x
`"
`Y
`T
`
`00 R’;
`'
`3
`
`(vni
`
`in whieli
`A, '1" and RC’ have the meaning specified,
`and,
`in the case of compounds of the general formula (I)
`where Q=OII, carrying out a hydrolysis, and in the case
`where Q=activating radical, starting from the enantiomeri—
`Cally pure acids reacting with activating reagents.
`These can be reacted in a further step with D— or
`L-plienylglyeinol to give com pounds of the general formula
`[VIIl)
`
`(VIII)
`
`4U
`
`45
`
`(‘[13
`\ ‘\
`/ _/
`5
`
`b
`( )
`
`_
`(‘H3
`
`
`
`-
`
`-
`
`A T
`|
`cu;
`
`,«
`
`m_NH
`
`OH
`
`.1.
`
`on
`
`65
`
`where these are in this case active compounds for medica-
`menls.
`
`3 "T13
`
`
`
`PENN EX. 2229
`CFAD V. UPENN
`lPR2015-01836
`
`

`
`US 6,774,236 B1
`
`5
`—eontinued
`
`6
`—eontinued
`
`1U
`
`15
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6!!
`
`65
`
`5
`
`on
`
`
`
`Surprisingly, the process according to the invention gives
`the wanted enantiomerically pure cycloalkano-
`indolecarboxylie acids and azaindo1e—earboxylie acids and
`pyrimido—indolecarboxylie acids and their activated deriva-
`tives without great equipment requirements in very good
`yields and high purity.
`Depending on the configuration of the radical R6 and
`stearie effects of the alkyl halide (II) used, the alkylation of
`the compound (11) proceeds in high yields. and in a simple
`manner diastereoselectively for the first
`time. The com-
`pounds {IV) arise with high diastereomerie excess and
`crystallize out oi‘ the reaction mixture directly, as a result of
`which even the simple crystallization of crude products
`gives the compounds of the formula (IV) in dia.-stcreomcri—
`Cally pure form.
`A further advantage of the process according to the
`invention is that, by suitable choice of the solvent and a base,
`the unwanted diaslereomer can be epimcrizcd to the desired
`diastereomer, which in turn crystallizes out directly. Thus,
`further (wanted) diastereomerieally pure product can he
`produced from the mother liquors by repeated epimerization
`and crystallization. Direct addition of the mother liquors to
`the alkylation step can optimize the entire process in the
`form of a cyclic process.
`
`4ufl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,774,236 B1
`
`7
`A further advantage of the process according to the
`invention is that the halogenated compounds of the general
`formula (V) surprisingly react with the compounds of the
`general formula (VI) without raeemization at
`the carbon
`atom in the 2 position to the carboxylie acid function, to give
`the compounds of the general formula (VII).
`A further advantage of the process according to the
`invention is the racemization-free reaction at
`the carbon
`atom at the 2 position to the carboxylic acid function of the
`compounds of the general formula (I) where Q=activated
`radical, preferably chlorine,
`to give the compounds of the
`general formula (VIII).
`Furthermore, it is a great advantage of the process accord-
`ing to the invention that the starting compounds are very
`readily accessible. They may be prepared in good yields
`from relatively simple building blocks with low equipment
`requirements. Furthermore,
`the process according to the
`invention enables amounts of known racemates of the com-
`
`1U
`
`15
`
`pounds of the general formula (I) present to be converted
`into the corresponding enantinmers. The process according -
`to the invention enables the preparation of the compounds
`according to the invention of the general formula [I] using
`few synthetic stages and in a considerably higher overall
`yield than by processes known from the prior art.
`R“,
`in the context of
`the above specified definition,
`represenLs a chiral alcohol radical, such as (+)- or (—)-
`menlhyl, [+)— or {—]—bornyl.
`(+)— or {—)—isobornyl or {—)—8—
`pheiiylrlienthyl. Preferably, R” represents (+)— or
`(—)—
`menthyl.
`Activating radicals (O), in the context of the invention,
`generally represent chloride, bromide, mesylate, tosylatc or
`trilluoride. Preference is given to chloride. Preferably, by the
`process according to the invention, compounds of the gen-
`eral formula (I) are prepared, in which
`A represents a radical of the formula
`
`30
`
`35
`
`8
`cyclohexene, cyeloheptene, cyelooetene,
`oxocyelope ntene, oxocyclohexene, oxoeyeloheptene
`or oxocyclooctene radical,
`where all ring systems, listed under RHR2 and R:‘fR"
`are optionally up to disubstitutcd identically or differ-
`ently by fluorine, chlorine, bromine, trifluoromcthyl,
`carhoxyl, hydroxyl, by linear or branched alkoxy or
`alkoxycarbonyl each having up to 4 carbon atoms, or
`by linear or branched alkyl having up to 4 carbon
`atoms, which itself can be substituted by hydroxyl or by
`linear or branched alkoxy having up to 3 carbon atoms,
`'I' represents cyclobutyl, eyclopentyl, cyclohexyl,
`cycloheptyl, cyclooctyl, or
`represents linear or
`brarichcd alkyl having up to 10 carbon atoms,
`0 represents hydroxyl or represents an activating radical,
`and their salts.
`Particularly preferably, compounds of the general formula
`(I) are prepared by the process according to the invention in
`which
`
`A represents a radical of the formula
`
`‘I
`
`R.
`
`I
`
`I
`
`,.
`
`1
`
`,2
`
`J
`
`,,
`
`DT
`K
`1:/N.
`
`|
`
`/
`
`G
`
`TI.
`,
`
`in which
`J, D, E, G, L and M are identical or different and denote
`hydrogen, fluorine, chlorine, bromine, trifluoromethyl,
`carboxyl, hydroxyl,
`linear or branched alkoxy or
`alkoxycarbonyl each having up to 3 carbon atoms, or
`denote linear or branched alkyl having up to 3 carbon
`atoms,
`
`including the double bond linking them,
`[ti and R2,
`together form a phenyl ring or pyridyl ring or a ring of
`the formula
`
`
`
`in which
`
`J, D, E, G, L and M are identical or different and denote
`hydrogen, fluorine, chlorine, bromine trifluoromelhyl,
`carboxyl, hydroxyl,
`linear or branched alkoxy or
`alkoxycarbonyl each having up to 4 carbon atoms, or
`linear or branched alkyl having up to 4 carbon atoms
`which itself can be substituted by hydroxyl or by linear
`or branched alkoxy having up to 3 carbon atoms, R1
`and R2,
`including the double bond linking them,
`together form a phenyl ring or pyridyl ring or a ring of
`the formula
`
`in which
`R5 denotes hydrogen or linear or branched alkyl having
`up to 3 carbon atoms,
`R3 and R", including the double bond linking them,
`together
`form a phenyl
`ring or
`a cyclopentene,
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`NR5
`
`in which
`
`R5 denotes hydrogen or methyl,
`R3 and R“,
`including the double bond linking them,
`together
`form a phenyl
`ring or
`a eyclopentene,
`cyclohexene, cycloheptene, cyelooctene,
`oxocyclopentene, oxocycloliexene, oxocycloheptene or
`oxocyclooctene radical,
`where all ring systems listed under Rlfl-12 and REE]-1" are
`optionally up to disubstituted identically or differ-
`ently by fluorine, chlorine, bromine, trilluoromethyl,
`carboxyl, hydroxyl, by linear or branched alkoxy or
`alkoxycarbonyl each having up to 3 carbon atoms or
`by linear or branched alkyl having up to 4 carbon
`atoms which itself can by substituted by hydroxyl,
`methoxy or ethoxy.
`T represents cyclopentyl, cyclohexyl, eyeloheptyl,
`cyclooctyl or linear or branched alkyl having up to 6
`carbon atoms,
`0 represents hydroxyl or an activating radical,
`and their salts.
`Very particularly preferably, the compounds of the gen-
`eral formula {I), in which
`
`5ofl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,774,236 B1
`
`9
`A represents a radical of the formula
`
`R3
`
`R“
`
`CH3
`
`\.
`
`X
`
`|
`
`i
`
`01
`
`T
`
`N
`
`CH3
`
`(Tl-I3
`
`N \
`
`X
`
`/ N
`
`on,
`
`in which
`
`R3 and R"=phenyl ring
`and having the radical *CH—'l'—(.‘OQ in the parapo—
`sition and O=chlorine, and their salts,
`are prepared by the above described process.
`Suitable solvents for the alkylation of the compound of
`the general formula (II) are customary organic solvents
`which do not change under the reaction conditions. 'lhcse
`preferably include ethers, such as diethyl ether, diisopropyl
`ether, tert—butyl methyl ether, dioxane, tetrahydrofuran, gly-
`col dimethyl ether, or hydrocarbons, such as benzene,
`toluene, xylene, hexane, cyclohexanc or mineral oil
`fractions, or halogenated hydrocarbons, such as
`diehloromethane,
`trichloro-metliane,
`tetrachlorolnethane,
`dichloroethylene,
`trichloroethylenc or chlorobenzene, or
`ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide,
`diInetliylformamide, N-inethylpyrrolidone, hexameth-
`ylphosphoric triamide, acetonitrile, acetone or nitromethane,
`methanol or ethanol. It is equally possible to use mixtures of
`the said solve-nLs. Preference is given to dimethylformamide.
`"the alkylation is carried out in the solvents listed above,
`if appropriate under a protective gas atmosphere, at
`tem-
`peratures of -20° (I. to +100” (1, preferably at -10° C. to
`+fi)° (2., at atmospheric pressure.
`Suitable bases for the diastereoseleclivc alkylation are the
`customary basic compounds. These include alkali metal
`hydrides, such as sodium hydride, alkyli metal amides such
`as sodium amide, alkali metal alkoxides, such as sodium
`methoxide, sodium ethoxide, potassium methoxide, potas-
`sium ethoxide or potassium tert-butoxide, or organic amines,
`such as trialkylamines, e.g. triethylamine, or organolithium
`compounds, such as butyllithium or phenyllithium. Prefer-
`ence is given to potassium tert-butoxide.
`In the diastereoselective alkylation, the base is used in an
`amount from '1 mol to '10 mol, preferably from 1.2 mol to 3
`mol, based on '1 mol of the compounds of the general
`formula (ll).
`Suitable solvents for the halogenation of the compound
`for the general formula (IV) are customary solvents which
`do not change under the reaction conditions. These prefer-
`ably include tetrachloromethane, ehlorobenzene,
`dichlorobenzene, acetonitrile, acetic acid, sulphuric acid,
`nitrobenzene, 'l,2—dichloroethane, dichloromcthanc, trichlo—
`romethane_
`
`For the halogenation, customary halogenating agents are
`suitable, such as bromine, chlorine, NBS, NCS,
`dichlorodimethylhydantoin, dibromndimethylhydantoin,
`trichlorisocyanuric acid, ehloramine-T.
`Suitable free-radical starters are,
`for example, AIBN,
`peroxides, such as dibenzoyl peroxide,
`t-hutyl
`
`10
`t—butyl peroxide, butyl
`hydroperoxide, dilauryl peroxide,
`perbenmate, di—t—butyl peroxalate, and photochemical meth-
`ods.
`
`in the solvents listed
`The halogenation is carried out
`above, if appropriate under a protective gas atmosphere, at
`ternperatures of 20° C.
`to 'l80° C.,
`if appropriate under
`pressure. Preferably, the halogenation is carried out at 70° C.
`to 130° C,
`In the halogenation, the halogenating agent is used at 0.8
`mol to 1.7 mol of active halogen, based on 1 mol of the
`compounds of the general formula (1).
`Suitable solvents for the alkylation of the compound of
`the general formula (VI) are customary organic solvents
`which do not change under the reaction conditions. These
`preferably include ethers, such as diethyl ether, diisopropyl
`ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, gly-
`col dimcthyl ether, or hydrocarbons, such as benzene,
`toluene, xylene, hexane, cyclohexanc or mineral oil
`fractions, or halogenated hydrocarbons, such as
`dichloromethane,
`triehloromethane,
`tetrachloromethane,
`dichloroethylene,
`trichloroethylene or chlorobcnzene, or
`ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide,
`dimethylformamide, N-methylpyrrolidone, hexamethyl-
`phosphoric triamide, acetonitrile, acetone or nitromethane. It
`is equally possible to use mixtures of the said solvents.
`I-‘reference is given to dimethylformamide,
`toluene and
`tetrahydrofurari.
`The alkylalion is carried out in the solvents listed above,
`if appropriate under a protective gas atmosphere, at
`tem-
`peratures of —20° C. to +l00° C., preferably at —10° C.
`to
`+30° C ., at atmospheric pressure.
`Suitable bases are generally inorganic or organic bases.
`These preferably include alkali metal hydroxides, such as
`sodium hydroxide or potassium hydroxide, alkaline earth
`metal hydroxides, such as barium hydroxide, alkali metal
`carbonates and alkali metal hydrogen carbonates, such as
`sodium carbonate, sodium hydrogen carbonate or potassium
`carbonate, alkaline earth metal carbonates, such as calcium
`carbonate, or alkali metal alkoxidcs or alkaline earth metal
`alkoxides, such as sodium methoxide or potassium
`methoxide, sodium ethoxide or potassium ethoxide or potas-
`sium tert-butoxide, or organic amines (trialkyl(C,—(f,,]
`amines], such as triethylamine, or heteroeylcles, such as
`l,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo
`[S,4,0]undcc—7—ene [DBU), pyridine, diaminopyridine,
`methylpiperdirie or rnorpholine. It is also possible to use
`alkali metals, such as sodium, or their hydrides, such as
`sodium hydride, as bases. Preference is given to sodium
`hydrogen carbonate, potassium carbonate and potassium
`terl—butoxide, DBU or DABCO.
`In the alkylation, the base is used in an amount of 1 mol
`to l0 mol, preferably of 1.2 mol to 3 mol, based on 1 mol
`of the compounds of the general formula (II).
`To eliminate the chiral radical R“ in the compounds of the
`general formula (VII),
`the customary organic carboxylic
`acids are suitable, such as acetic acid, formic acid, tril'luo-
`roacetic acid, methanesulphonic acid, or inorganic acids,
`such as hydrobromic acid, hydrochloric acid or sulphuric
`acid or mixtures of the said acids. Preference is given to
`acetic acid, formic acid, hydrobromic acid andfor sulphuric
`acid. Very particularpreferenceis given to the mixture acetic
`acidfsulphuric acid and also formic acidfhydrobromic acid
`and formic acidisulphuric acid.
`The acids or their mixtures are simultaneously employed
`as solvent and thus used in a great excess.
`The elimination proceeds in a temperature range from 0°
`C. to +150” C., preferably from 40° C. to 100° C.
`
`1U
`
`15
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`an
`
`65
`
`60fl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,774,236 B1
`
`in which
`
`12
`
`R° represents a chiral alcohol radical,
`are obtained
`
`by eslerifying compounds of the general formula (IX)
`
`(TH;
`
`
`
`(IX)
`
`5
`
`1U
`
`‘I5
`
`with chiral alcohols according to processes disclosed in the
`literature.
`
`The compounds of the general formula (IX) are known
`per se or can be prepared by customary methods.
`The enantiomerically pure compounds of the general
`formula (I) in which 0 represents tert—buIoxy are novel and
`can be prepared by first converting racemic carboxylic acids
`of the general formula (X)
`
`Hjc
`
`f_‘(_)1H
`_
`
`/ I
`I
`
`\ Y.1.
`
`(R5)
`
`in which
`
`EX)
`
`'I' has the meaning specified above, by reaction with (R)-
`or (S)—phenylethylamine in inert solvents and subse-
`quent crystallization of the phenethylammonium salts
`and subsequent hydrolysis of the salts, into the enan—
`tiomerically pure compounds of the general formula
`(X1)
`
`(XI)
`
`[I_1C
`
`/
`i
`,.
`~\ Y
`
`C0311
`
`in which
`
`T has the meaning specified above,
`converting these in a further step with isobutene, in inert
`solvents and in the presence of acids, into the enantiomeri-
`cally pure esters (XII)
`
`{XII}
`
`CH’ / I
`1
`‘\
`
`COEEBU
`
`"
`T
`
`in which
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`(11) an
`
`11
`It can generally be carried out at atmospheric pressure, but
`optionally alternatively at supcratmosphcric pressure or
`reduced pressure (e.g. 0.5 to 3 bar).
`After neutralization with bases in water or in one of the
`
`solvents listed above, in particular in a waterrtoluene, water!
`isopropanol, waterfnietlianol or waterr’ethanoI mixture, the
`acids are worked up by a customary method.
`Suitable bases for
`the neutralization are alkali metal
`
`hydroxides, such as sodium hydroxide or potassitlm hydrox-
`ide. Preference is given to sodium hydroxide.
`Suitable solvents for the activation of the compounds of
`the general
`formula (I) are customary organic solvents
`which do not change under the reaction conditions. Tliese
`preferably include ethers, such as diethyl ether, diisopropyl
`ether, tert—butyl methyl ether, dioxane, tetrahydrofiiran, gly-
`col dimethyl ether, or hydrocarbons, such as benzene,
`toluene, xylene, hexane, cyclohexane or mineral oil
`fractions, or halogenated hydrocarbons, such as
`dichloromethane,
`trichloromethane,
`tetraehloromethane,
`dichloroethylene,
`triehloroethylene or chlorobenzene, or
`ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide,
`dimethylformamide, acetonitrile, acetone or nitromethane. It
`is equally possible to use mixtures of the said solvents.
`Preference is given to dimethylformamide,
`toluene and
`dicliloronietliarie.
`
`For the activation, conventional activation agents are
`suitable. for example oxalyl chloride, phosphorus
`trichloride, phosphorus pentachloride, trichloroisc-cyanuric
`acid, thionyl chloride, phosphorus tribromide, phosphorus
`pentabromide, mesyl chloride,
`tnsyl chloride, phosgene,
`trilluorometlianesulpllonyl chloride, sulpliuryl cliloride.
`Preference is given to thionyl chloride, oxalyl chloride and
`phosgene.
`The activation is carried out in the solvents listed above,
`if appropriate under a protective gas atmosphere, at
`tem-
`peratures of -20“ (T. to 120° (7., optionally under pressure.
`Preferably, the activation is carried out at —20° C. to 80°.
`In the activation,
`the activation reagent
`is used in an
`amount of 1 mol to 10 mol, based on I molofthe compound
`of the general formula (I), or is optionally employed as
`solvent.
`
`The activation is optionally performed with the addition
`of bases, such as organic amines (trialkyl(C,—C,.,)arnines),
`such as triethylamine, or heterocycles, such as 1,4-
`diazabieye10[2,2,2]oetane (DABCO), 1,8—diazabicyclo[5,4,
`[l]undec—7—ene (UIIU), pyridine, diamirtopyridine, me1hylpi—
`peridine or morpholine.
`If appropriate,
`the activated
`derivatives can be prepared starting from earboxylie salts of
`alkali metals and alkaline earth metals by reaction with, e.g.,
`oxalyl chloride.
`The compounds of the general formula (II),
`
`
`
`'I' has the meaning specified above,
`65 then converting the esters (XII) by halogenation into the
`enantiomerically pure compounds of the general formula
`(XIII)
`
`7 of 13
`
`PENN EX. 2229
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`13
`
`_
`RI 2
`
`US 6,774,236 B1
`
`(XIII;
`
`on,
`
`14
`—continucd
`
`0
`
`\ /Y i
`
`4"
`
`..
`
`T
`
`O0-at-Bu
`
`"
`
`IC
`
`"?
`
`in which
`
`'1‘ has the meaning specified above
`and
`
`R7 represents a typical leaving group, such as chlorine,
`brolrtinc,
`iodine,
`to.~;ylate or
`1I1t:.~'.}'latt;, prclcralaly
`bromine,
`
`in a further step, by reaction with compound:-3 uftllc general
`formula (VI)
`
`1-‘\—H
`
`in which
`
`(V1)
`
`A has the meaning specified above,
`preparing the enantiomerically pure compounds ofthe gen-
`eral formula (I)
`
`(11
`
`:‘|\
`CH2
`
`T
`
`3
`
`_
`
`.1.
`
`in which
`
`A and '1' have the meaning specified above and
`Q represents tert—hutyl,
`and in the case of the (_‘()lT1p(ttll'I[lSIItrTl1C general formula (I)
`where Q=O1-1, carrying out a hydrolysis.
`Tert—butyl esters are generally saponilicd with acids, for
`example hydrochloric acid or trifluoroacetic acid,
`in the
`presence of one of the above specified solvents andfor water
`or their mixtures. preferably with dioxane or tetrahydrofu-
`ran.
`
`The compounds oi" the general lorrnula (X) are prepared
`from the corresponding esters disclosed in the literature by
`hydrolysis according to methods disclosed in the literature.
`
`(‘H3
`
`he nclh ylaminc2;.
`
`0II(1'ac)
`
`cu,
`
`O11
`
`b§.+
`
`1.-"X/\MP1.l_i 1
`
`2{R.fS)—2-Cyclopenty1—2-(4-methylplteuyll-acetic acid
`Me
`O
`
`011
`
`2.0 kg (7.2 mol) of tert—butyl 2(R.SJ—2—cyelopentyl-2—(4—
`methylphenyl}—acctate are dissolved in 4 l of dioxane in a 40
`l agitated vessel Iitted with an attached washing tower. After
`addition of 4.5 l of concentrated hydrochloric acid,
`the
`mixture is stirred at 50° C. to complete conversion (3 h). The
`reaction mixture is admixed with ice and adjusted to p11=12
`with concentrated sodium hydroxide solution. After addition
`of water to complete solution of the solids, the mixture is
`washed with acetic acid, the organic pliase is washed with
`dilute sodium hydroxide solution and the combined aqueous
`phases are adjusted to pI1=1, with cooling, with concen-
`trated hydrochloric acid. The mixture is washed twice with
`ethyl acetate, dried over sodium sulphate and concentrated.
`Yield: 1.27 kg; 81% of theory. Melting point: 92° C.
`1{,=0.20 (petroleum ether:ethy1aeetate=4:1)
`‘H—NMR
`(CDCI3, 200 MHZ, TMS): 5=U.‘)8 (tn, 1H); 1.20-1.71 (In,
`611); 1.82-2.05 (m, 111); 2.31 (5, 311); 2.52 (m, 111); 3.21 (d,
`1H); 7.10 (in, 2H); 7.21 (in, 2H]; 11.90 (br, 5, 1H) ppm.
`1:.XAMl’Ll:i 11
`
`(SJ—2—Cyt-lo pentyl-2-(4—u1etl:ylp]1en yl)—-acetic acid
`Me
`
`O
`
`0H
`
`1U
`
`15
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`61]
`
`65
`
`2.4 1 ol‘ T1117 and 129.7 g (1.28 rnol)oftriethylan1ine are
`added, with stirring, to a suspension of 560 g (2.57 mol) of
`
`80fl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,774,236 B1
`
`15
`in 4.8 1 of water. The
`the compound from Example I
`resulting solution is heated to 60° C., 155.4 g (1.28 mmol)
`ol‘ (S)-[—)-phenethylamine are added and the resulting sus-
`pension is stirred for 2 h at 60° C. The reaction mixture is
`cooled to 20° C., the precipitate is filtered 011 by suction,
`washed with 2.4 1 ol‘ wateri’Fill7 (2:1) and dried under
`reduced pressure.
`
`Yield: 360 g of phcncthylammonium salt; 41.3% of
`theory. 745 g (2.2 mol) of phertethylammonium salt are
`suspended in 3 1 of water, acidified (pll=1) with dilute
`hydrochloric acid (1:1) and stirred for 30 minutes. The oily
`suspension is washed 3 times, each time with I
`l of
`dichloromethane,
`the combined organic phases are now
`washed with water, dried over sodium sulphate and
`concentrated, the residue crystallixing out.
`Yield: 475 g; 37.3% of theory, based on raoemate of
`Example No. l ee: 96.3% (llPl_C) Melting point: 66° C.
`By crystallization of the phenethylarnrnonium salt from
`THF, as described above, the pure cnantiomcr is obtained:
`
`cc: >99.5% [HPl_C) Specific rotation:
`(etha11ol!c=0.85)
`The IIPLC method for determination of the cc value is as
`follows:
`
`[(1]L,2[:'=+59.55
`
`Column:
`Particle size:
`Packing:
`Mobile phase:
`Flow rate:
`[nlet pressure:
`
`Chiraeel OJ (Daicel)
`10;:
`250 x 2 mm (Cirom}
`n-hcplanc: I-propanol = 97:3
`(1.2 mL"min
`22 bar
`
`EXAMPI .E III
`
`Tell-l:Iut_vl [SJ-2-C _vclopcnty1-2-[4-melliylpiuznyl)-acetate
`M:
`
`O
`
`OtBtI
`
`6 ml ofconcentrated sulphuric acid are added to a solution
`of 465 g (2.13 mol) ofthe compound from Example II in 1.4
`lofdichloromethane, a temperature ol‘ approximately 10° C.
`being established. 550 ml (5 mol) of isobutene are oon-
`densed in a Dewar flask and added in one portion to the
`starting material solution. The reaction mixture is stirred
`over night. To complete the reaction, a further 6 ml of
`concentrated sulphuric acid and 500 ml of isobutene are
`added and stirred over night. After addition of 40 g of
`potassium carbonate, the mixture is stirred for 3 h. and then
`2 l of water are added, vigorous gas development initially
`occurring. The mixture is washed three times, each time with
`2 1 of dichloromethane, the combined organic phases are
`washed with 5 1 of sodium chloride solution, dried over
`sodium sulphate and concentrated to give an oil which
`slowly crystallizes.
`
`Yield: 480 g; 82% of theory Melting point: 45° C. Rf=0.90
`[toluene:ethy1 acetate=8:2)
`
`10
`
`15
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`16
`EXAMPLE IV
`
`Te rt—butyl (S)—2-(4-brornornethylphenyl)—2-eyclopentyl-acetate
`Br
`
`Otlin
`
`In it 10 1 flask, 480 g (1.75 mol) of the compound from
`Example II] are dissolved under reflux in 3.4 lo1tetrachlo—
`romethane and 70 g of a total amount of 311 g (1.75 mol) of
`NBS and 14 g (0.085 mol) ot‘AIBN are added. The reaction
`begins after refluxing for approximately 1 h; after it decays,
`further NBS is added in 50 g portions. After refluxing for 5
`h and subsequent standing over night at room temperature,
`for the work—up, the mixture is cooled to 0° C., the succin-
`imide is filtered off with suction and washed with 600 ml of
`tctrachloromcthanc. The combined filtrates are concentrated
`
`and residual solvent is removed under reduced pressure to
`constant weight.
`
`Crude yield: 570 g; approximately 100% o1" theory llPl.C':
`68.8% (15.5% starting material, 10.1 ‘.75; dibromo compound)
`The pure substance is obtained by column chromatography
`
`RJ,=0.42 (petroleum ether, ethyl acetate=20g‘l] III-NMR
`(CDCI3, 200 MHZ, TMS): 5=0.98 (m, 1H); 1.22-1.71 (1:11,
`6Il); 1.41] (s, 911); 1.90 (m, 111); 2.47 (m, 111); 3.16 (d, Ill);
`4.49 (s, 2H]; 7.32 (ni, 4H) ppm.
`
`EXAMPLE V
`
`(L)—rnerttl1yl 2-[4—to|y|J—acetate
`
`Me
`
`..nII:fi
`
`3.15 kg of p—tolylacetic acid and 9,45 l of toluene are
`introduced. 3.115 kg of l.-menthol and 21.4 ml of methane-
`sulphonic acid are added with stirring and cooling. The
`mixture is then heated to rellux temperature and the corre-
`sponding amount o1' water is separated o11' in the course of
`16 to 20 hours via a water separator. After cooling to room
`temperature,
`the mixture is stirred once with 4.41 1 of
`saturated sodium hydrogen carbonate solution and twice,
`each time with 4.41 1 of water. The organic phase is freed
`from solvent and gyes 5.725 kg of the wanted compound
`((}(T 99.9%, retention time 19.49 min).
`ll-l—NMR (ETIJCI3,
`ppm): 7.05-7.15 (4H, in); 4.55 (1H, t:-rd); 3.5 (2H, s); 2.8
`(3H, s}: 0.65 (3H, s).
`
`9ofl3
`
`PENN EX. 2229
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`US 6,774,236 B1
`
`1 7
`EXAMPLE VI
`
`t:LJ—menthy1 2-(S)—2-cyclopentyl -2-[4—toly1,'t—acetate
`we
`
`Me
`
`O
`
`5
`
`a~“\
`
`0.
`
`Me
`
`l\rle
`
`1,575 kg of potassium tert—butoxide are dissolved in 3.75
`1 of DM1’ at room temperatu