Ulllted States Patent
`
`|19|
`
`|11| Patent Number:
`
`5,952,498
`
`Lenfers ct al.
`
`|4s] Date of Patent:
`
`*Scp. 14, 1999
`
`USO0S952498A
`
`|54] PROCESS FOR THE PRICI-’ARA'["l()N 01"
`[EN/\NTI()MERlCA[.LY PURE
`CYCl,U/\l.KAN()-IN[)()I, -ANI) AZ/\INI)()l.
`-AND PYRIMIDO [l,2A]
`INDOIEARWXCYCLIC ACIDS AND 'I‘HI;II{
`ACTIVATED DERIVATIVES
`
`[75]
`
`Inventors: Jan-Bernd Lenfc-rs; PL“tl![' Fe ; Paul
`Naab, all of Wuppcrtal; Kai Van Larak,
`Kfiitln, all of Germany
`
`[73] Assigncc: Bayer Akticngescllschaft, IJJVCl'kUSCl'],
`Germany
`
`[ *] Notice:
`
`This patent issucd on El contimtcd pros-
`cculion application filed undcr 37 CFR
`l.53(t'_l_]. and is subject to the twenty year
`patent
`tcrm provisions of 35 U.S_C‘.
`l54(a)(2).
`
`|5(i|
`
`References Cited
`:
`I
`LIS‘ PATHNT DOCUMENTS
`......................... .. 514.5311
`ll,-‘I990 Mohrs cl al.
`4,97"'U_.2l5
`
`.
`6,-"1996; Mtt1Ier—-Gliemann et al
`:El4,-""303
`5,527,809
`ll,’l‘)‘)".-" Muller et al.
`......................... ..
`:>l4,’2‘.J2
`:a,6.‘ii4,(li4
`150R].-ll(jl\l PI\l"l_iN'l' DOCUMILNTS
`
`344519
`513533
`560163
`610698
`705831
`
`ll,’l99(]
`ll,’l‘)‘)2
`911993
`8,9994
`4;"199t‘3
`
`European Pat. Off.
`Iiuropeau Pat. Off.
`European Pat. Off.
`European Pal. Ofi‘.
`European Pal. Off.
`
`.
`.
`.
`.
`.
`
`Prirrtttry Exarttinw Jose‘ G. Dccs
`Assistant I?xmm'nrJ.r—Sahihn N. Qazi
`An‘0rm'y, Agent, or Firm—Sprung Kramcr Schacfcr &
`Tlfisctlc
`
`|57|
`
`ABS'I‘RAC'l"
`
`lg” App]‘ No_: II3;g29’555
`M
`_
`l—-l
`F1159?
`30
`F
`
`l
`
`I,
`
`Man 31: 1997
`I
`It D m
`I
`A " __ u
`Um gm
`1
`r M y
`3
`pp (A U"
`APR 4.- 1995
`[DH]
`U*‘T'T“1")' ----------------------- -- 196 13 549
`[51]
`Int. Cl.“ ...................... C07D 471104; com 487/04;
`Cojc 60,610, Ctnc 601617
`'
`'
`’
`'
`'
`’
`'
`'
`‘
`.......................... .. 544,t'252‘ 544E749‘ S46E84‘
`54w85; 540980; 540"r87; 5489400; 548E410;
`548,427; 51 4f2(i7; S|4;‘202
`[53] Field of Search ................................... .. 5443249, 252;
`514267. 292, 312; 546f84—8't'; 548E427
`
`[52] U.S. CI.
`
`'l'hc invcntion rclatcs to a proccss and intermediates for thc
`preparation of cnantiorncrically purc cycloalkanoindolccar—
`hoxyltc acids and azaindolccarboxylic acids and pyrtmtdo
`[1 ,2a]indolt-Lcarhoxylic acids and their activated derivatives,
`characterized In lhal the lolyl accltc acid 15-‘.
`lirst cstertfictl
`with a chiral alcohol, lhcn cliastcrcosclcctivc substitution at
`0.—carbon atoms is carried out and this product is haloge-
`'?“‘_‘i‘]_‘"‘”“". ‘”]'>" {‘%"““I"1“f‘;1"“""‘,‘,“:*‘fj“"1 W“ “1’F?“’Pl"‘i‘“
`<.y<._0.tlkano1nL0_les, cycoa kanoazmn 016:: or pyr1m1( o[l,
`"*a]1t1dolcs
`It
`15 possible by this method to prepare
`:5 ccl tca
`, 1n
`lg
`uI1 y,
`t: cnan lomcnca
`urc car-
`'
`-
`T 11
`-
`h- h
`-1
`th
`I‘
`1
`H
`hloxylic acids which zijrc intcrmcdiatcs for valual9lcpmcdica—
`mom;
`i
`i
`
`'
`
`10 Claims, N0 Drawings
`
`1 of 17
`
`PENN EX. 2213
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,952,498
`
`1
`PROCESS FOR THE PREPARATION OI"
`ENA N'I‘I()M ERI CAI J .Y PU RE
`CYCI,()AI.-KANO-INI)()L -AND A7.AINI)()I.
`-ANI) I’YRIMIl)() [l,2A]
`INl)()LCARI}()XCYCIiIC ACIDS AND THEIR
`ACTIVATED DERIVATIVES
`
`2
`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
`
`5
`
`1U
`
`I5
`
`The invention relates to a process for the preparation of
`enantiomerically pure cycloalkano-indolecarboxylic acids
`and azaindolecarboxylic acids and pyrimido[1,2a]
`indoleearboxylic acids and their activated derivatives, wl1icl1
`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 cycloalkano—
`indolecarboxylic acids and azaindole-carhoxylic acids and
`their activated derivatives can be separated into the corre-
`sponding enantiomers by diastereomeric separation by con-
`ventional methods, for example by chromatography or l'rac-
`tional crystallization.
`This proccss has a number of disadvantages: both the '
`chromatographic diastereorneric separation and the frac-
`tional crystallization of the diastereorners are associated
`with high equipment requirements. In addition, in this case,
`generally 50% of the “wrong" diastereomer arises, which
`can no longer be recycled to the original preparation process.
`This 50% loss of yield considerably impairs the coo-
`nomic efliciency of a (large) industrial—scale process, quite
`apart
`from the fact
`that 50% of “by-product” must be
`disposed of.
`liurthermore,
`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.
`II has now been found that enantiomerie-ally pure
`eyeloaIkano—indolecarboxylic acids and az.aindoleearboxy—
`lic acids and pyrimido[l,2a]indole—carboxylie acids and
`their activated derivates of the general formula (I)
`
`30
`
`35
`
`including the double bond linking them,
`R‘ and R2,
`together form a phenyl ring or pyridyl ring or a ring of
`the formula
`
`where
`
`R5 denotes hydrogen or linear or branched alkyl having
`up to 4 carbon atoms,
`R3 and R",
`including the double bond linking them,
`together form a phenyl ring or a 4- to 8—membered
`cycloalkenc or oxocycloalkcnc radical, where all the
`ring systems listed under RUR2 and RRIR" are option-
`ally up to trisubstituted identically or differently by
`halogen, trilluoromethyl, carboxyl, hydroxyl, by linear
`or branched alkoxy or alkoxycarbonyl each having up
`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,
`
`T represents cycloalkyl having 4 to 12 carbon atoms, or
`represents linear or branched alkyl having up to 12
`carbon atoms,
`0 represents hydroxyl or an activating radical,
`and their salts are obtained
`
`by firstly converting compounds of the general formula
`('1),
`
`(U)
`
`
`
`in which
`
`R“ together with the oxygen atom represents a chiral
`alcohol radical, by means of compounds of the general
`fon'nu]a (III)
`
`'l'-V.
`
`in which
`
`(III)
`
`'I' has the meaning specified and
`Z represents a typical
`leaving group, such as bromine,
`chlorine,
`iodine, mesyl,
`tosyl,
`or
`trifluoromethylsulphonyl, preferably iodine or
`bromine,
`in inert solvents in the presence of a base by diastereose-
`lective alkylation into the enantiomerically pure compounds
`of the general formula (IV)
`
`T _cI1__
`
`T
`
`in which
`
`A represents a radical of the formula
`
`or
`
`J, D, l:'., G, L and M are identical or different and denote
`hydrogen. halogen,
`trirluoromethyl, carhoxyl,
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`201']?
`
`PENN EX. 2213
`
`CFAD V. UPENN
`IPR20l5-01836
`
`

`
`CII3
`
`i
`
`/
`
`‘\
`/W,/coop,“_
`
`T
`
`in which
`T and R6 have the meaning specified,
`then converting these, by halogertation, into the enat1tio—
`merically pure compounds of the general formula (V)
`
`{W
`
`6
`
`tlz"-
`L113
`
`;
`
`_
`
`\ .Y°'°'3R
`
`T
`
`_
`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)
`A-It
`in which
`
`(VI)
`
`R1, R2, R3 and R" have the meaning specified,
`to give the enantiomerically pure compounds of the
`general formula (VII)
`
`5
`
`1U
`
`15
`
`en
`
`35
`
`3n
`
`3
`
`5,952,498
`
`(WJ
`
`4
`
`CO;R
`
`6
`
`‘
`
`T
`e‘11~4O
`\ ‘Y
`
`,
`
`.1.
`
`.
`.
`in which
`
`A, '1' and R“ have the meaning speeilied,
`and, in the ease of (T0mp0t.Il'l[l,S of the general formula (I)
`where Q=OII. carrying o1It a hydrolysis, and in the
`case where Q=activating radical. starting from the
`enanliomerically pure acids. reacting with activating
`
`reagents.
`further step with D— or
`These can be reacted in a
`I,—pheny]g]yeinoI to give compounds ofthe general formula
`VIII)
`(
`
`(VIII)
`
`A
`
`'
`
`.1.
`
`where these are in this case active compounds for medica-
`rnenls.
`
`The process according to the invention can be described
`by way of example by the following formula diagram:
`
`lI_1C
`
`H3C.'
`
`Iir
`
`C.‘()—()
`
`(.‘H_;
`
`(R-8:
`
`n,r;
`
`
`
` H
`
`CH3
`
`of
`
`CH3
`
`Cr 13
`
`\I \
`
`/
`
`U‘)
`
`/ 1x‘
`
`(‘.113
`
`3uf17
`
`PENN EX. 2213
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,952,498
`
`—contin1.1cd
`
`C[l_x
`
`4 of 17
`
`PENN EX. 2213
`CFAD V. UPENN
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`

`
`5,952,498
`
`—continued
`
`
`
`menthyl, (+)- or (—)—|Jornyl, (+)- or (—]—i.-sobomyl or (—)—8—
`Surprisingly, the process according to the invention gives the
`wanted enantiomerically pure cycloalkano-indolecarboxylic 30 phenylmenthyl. Preferably, R9 represents (+)- or
`i[—)-
`acids and azaindole—carboxylie acids and pyrimido—
`m¢m|]y[_
`indoleearboxylie acids and their activated derivatives with-
`Acljvaijng radicals (Q), in [116 c(_)[1[cX[ of mg jnvgnrjgn’
`0111 21'93-1 0511' lpmcm 1'¢Q11i1'°mC1'1t5 £11 VCFY 2.005] Yl"~3ld5 and
`generally represent chloride, bromide, mesylate, tosylate or
`high P‘-Hit?’
`_
`trillate. Preference is given to chloride.
`Depending on the configuration of the radical R" and 35
`preferably, by the process according to the 1-nvcmion’
`Slcarlc cficcls of the alkyl h‘11_1dc,(H) u,3'cd’ the a],k3"la“_0n of
`compounds ofthe general forrnula (I) are prepared, in which
`the compound (II) proceeds in high yields and in a simple
`.
`.
`manner diastereoselectively for the first
`time. The com—
`A represenls 3 radical of The formula
`pounds (IV) arise with high diastereomeric excess and
`crystallize out of the reaction mixture directly, as a result of m
`which even the simple crystallization of crude products '
`gives the compounds of the formula (IV) in diastcrcomcri—
`eally pure form.
`A further advantage of the process according to the
`invention is that, by suitable choice ofthe solvent and a base,
`the unwanted diastereomer can be epimerized to the desired 35
`diastereomer, which in turn crystallizes out directly. Thus,
`further (wanted) diastereomerically pure product can be
`produced from the mother liquors by repeated cpimerization
`and crystallization. Direct addition of the mother liquors to
`the alkylation step can optimize the entire process in the 40
`form of a cyclic process.
`A funher 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 45
`n'll.0I'I'I ll] l.hC 2p0Slll0I'1 l0 ll"IC C«'.ll'l')C|XyllC acid function, l0 glVC
`1'13 C0TT1P0U“d-‘i 0f the gflnwil fmmulii (VII)
`A fU1'lh°1' «'ld"'«'lUlaQC' of ill‘? DTGCCSS a0C01'(liT1g 10 lhc
`invention is the racemi7.ation—free reaction at
`the carbon
`atom at the 2 position to the carboxylic acid function ol‘ the 50
`compounds 0t the gcnclial tomulla (I) whcrc O=aC[‘V?lcd
`radical, preferably chlorine, to give the compounds ot the
`general forinula‘(\‘/III).
`‘
`Furthermore, ll is a great advantage ol the process accord-
`ing to the invention that the starting compounds are very 55
`readily accessible.
`'lI'iey 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-
`
`N
`|
`
`l
`
`J
`
`r,\/
`n_
`ls
`13/xi
`
`R”
`
`R4
`
`l
`
`l
`
`R‘
`
`R;
`
`"T
`
`1
`
`N/*4
`TL
`/ , J
`N’\M
`
`in which
`J, I), I.-‘, G, Land M are identical or diilierent and denote
`hydrogen, fium-inc, chlm-inc, In-ominc ti-jflum-omcthyl,
`garboxyl’ hydfgxyls lingaf of branchgd alkgxy gr
`alkoxycarbonyl each having up to 4 carbon atoms, or
`linear or branched alkyl having up to 4 carbon atoms
`w[-,i;_~[-111,,-;;1f;_—m] 13¢ §ub§[i[u[g_;db3r hyglfoxyl 0; by 11.1531;
`or bfanchgd alkoxy having up to 3 carbon atoms’
`R‘ and R2,
`including the double bond linking them,
`mgclher form a phcnvl ring or pyridyl ring or a ring of
`the formula
`'
`
`__‘
`NR‘
`
`pounds of the general formula (1) present to be converted an
`into the corresponding enantiomers_ 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.
`R6,
`in the context of
`the above specified detinition,
`represents a chiral alcohol radical, such as (+)- or (—)-
`
`65
`
`0
`
`_
`_
`"1 whlch
`Rs ‘1“v"01¢-*9 h}’dT"g*=T1 UT “T133? OT branchfld 3116'] hiwlng
`“P K‘ 3 Carllfln 3l0m5'i,
`R3 and R",
`including the double bond linking them,
`together forrn a phenyl
`ring or
`a eyclopeutene,
`
`5 of 17
`
`PENN EX. 2213
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`

`
`5,952,498
`
`9
`eyclohexene, cyclohepterie, cyelooctene,
`oxocyclopentene, oxocyclohcxene, oxocycloheptc ne or
`oi-zocyclooctene radical,
`where all ring systems, listed under Rlfk: and RJER4 are
`optionally up to clisubstitilted identically or differently 5
`by fluormc’ Chlorine’ ,bmmmc’ Influuwmclhyl’
`carboicyl, hydroxyl, by linear or branched alkoxy or
`alkoxycarbonyl each having up to 4 carbon atoms, or
`by linear or branched alkyl having 1Ip to 4 carbon
`atoms, which itself can be substituted by hydroxyl or by m
`linear or branched alkoxy having up to 3 carbon atoms,
`"I" represents cyclobutyl, cyclopentyl, cyclohexyl,
`cycloheptyl, cyclooctyl, or
`represents linear or
`branclicd alkyl having up to 10 carbon atoms,
`O represents hvdroxyl or represents an activating radical, H
`and their salts.
`'
`Particularly preferably, compounds ofthe general formula
`(I) are prepared by the process according to the invention in
`which
`
`A represents a radical of the formula
`R
`R1
`
`l
`
`|
`
`UI
`
`R‘
`
`R3
`
`N
`I
`
`I,\/
`Di
`Q
`_/K‘
`I‘
`
`/.qA('
`LL
`X J
`_\i"\
`M
`
`En
`
`35
`
`3::
`
`10
`T represents cyclopentyl, cyclohexyl, cyeloheptyl,
`cyclooctyl or linear or branched alkyl having up to 6
`carbon atoms,
`0 represents hydroxyl or an activating radical,
`and “mi, Falls,
`Very particularly preferably, the compounds of the gen-
`I formula (I)
`in which
`‘
`,
`_
`’
`cm
`A rcpmscms a radical 01 lhc formula
`
`R,
`
`H
`
`R
`
`C-Us
`
`\\
`
`0r
`
`_/
`1‘
`
`CH.‘
`
`l
`
`I
`
`N
`l
`
`(H)
`
`\ \
`
`X >:/
`
`CH3
`
`in which
`1
`I
`‘
`‘
`'
`‘
`R3 and fl“=phcnyl ring
`and having the radical “(.H—l’—(.OQ in the paraposi—
`lion and Q=chlonne, 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 itot change under the reaction conditions. These
`35 preferably include ethers, such as diethyl ether, duisopropyl
`in which
`ether, tert-biityl methyl ether, dioxane, tetrahydrofuran, gly-
`A, D, E, G, L and M are identical or different and denote
`col dimethyl ether, or hydrocarbons, such as benzene,
`hydrogcn, fluorine, chlorine, bromine, trifluoromothyl,
`toluene, xylene, hexane, eyelohexane or mineral oil
`earboxyl, hydroxyl,
`linear or branched alkoxy or
`fractions, or halogenated hydrocarbons, such as
`r'llk0XYCI'U'b0U)’l 551917 ha"lUE. UP [0 3 Carbon al0m5. 01'
`dcnmc linwr OT branched alklfl h3"i"S “P 10 3 C3l'b0" 4U dichloromethane,
`triehloro-methane,
`tetrachloromethane,
`atom-"*=
`dichloroethylene,
`trichloroethylene or chlorobenzene, or
`linking lllcms
`R1 and Rgs including ill‘: d0"l3l"~5 b01l(l
`ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide,
`T“g°Tl"3T f°f"” 3 Ph‘3"'5'l ring '37 PYVMYI 1'l"'g"T 3 ring 0f
`dimethylformamide, N-methylpyrrolidone, hexameth-
`lb“ f°”“”la
`ylphosphoric triamide, acetonitrile, acetone or nitromethane,
`45 methanol or ethanol. It is equally possible to use mixtures of
`the said solvents. 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” C. to +lUU° (3., preferably at —1U° C.
`to
`50 +30“ (3., at atmospheric pressure.
`Suitable bases for the diastereoselective alkylation are the
`customary basic compounds. These include alkali metal
`hydrides, such as sodium hydride, alkyli metal amides such
`in which
`as sodium amide, alkali metal alkoxides, such as sodium
`R’ denotes hydrogen or methyl,
`R3 ,—.1-K1 R",
`inctudjng the dgubte bond 111-lkjng 11135,, 55 melhoxide, sodium ethoxide, potassium methoxide, potas-
`together
`form a phenyl
`ring or a cyclopentene,
`siuin ethoxide or potassium tei1-butoxide, or organic amines,
`cyclohexene, cyclohe ptene, cyclooctc ne ,
`such as trialkylamines, e.g. triethylarriine, or organolithium
`oirocyclopentene, oxocyclohexene,oxocycloheptene or
`compounds, such as biityllithium or phenyllithium. Prefer-
`oxocyclooclene fildicilli
`once is given to potassium tcrt—butoxide.
`where all ring systems listed under R‘fR° and l{3rR" are an
`In the diastereoselective alkylation, the base is used in an
`optionally tip to disnbstittited identically or differently
`amount from 1 mol to 10 mol, preferably from 1.2 mol to 3
`by fluorine, chlorine, bromine,
`trifluoromcthyl,
`rnol, based on 1 mol of the compounds of the general
`carboicyl, hydroxyl, by linear or branched alkoxy or
`formula (II).
`alkoxyearbonyl each havingup to3carhon atoms or by
`Suitable solvents for the halogenation of the compound
`linear or branched alkyl having up to 4 carbon atoms 65 for the general formula (IV) are customary solvents which
`which itself can by substituted by hydroxyl, met hoxy or
`do not change under the reaction conditions. These preter-
`ethoxy.
`ably include tetrachloromethane, chlorobenzene,
`
`_\-R5
`
`O
`
`6 of 17
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`PENN EX. 2213
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`lPR20l5-01836
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`
`5,952,498
`
`11
`dichlorobenzene, acetonitrile, acetic acid, sulphuric acid,
`nitrobenzene, 'l,2—dichloroethane, diehloromethane, trichlo-
`romethane.
`
`For the halogenation, customary halogenating agents are
`suitable, such as bromine, chlorine, NBS, NCS,
`dichlorodimethylhydantoin, dibromodimethylhydantoin,
`trichlorisocyanuric acid, chloramine-T.
`Suitable free-radical starters are, for example, AIBN,
`peroxides, such as
`ilibeuzoyl peroxide,
`t—butyl
`hydroperoxide, dilauryl peroxide,
`t—butyl peroxide, butyl
`perbenzoate, di-t-butyl peroxalate, and photochemical meth-
`ods.
`in the solvents listed
`The halogertation is carried out
`above, if appropriate under a protective gas atmosphere, at
`temperatures of 20° (7.
`to 180° (3., 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 I mol of the
`compounds of the general formula (I).
`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. Tl1ese
`preferably include ethers, such as diethyl ether, diisopropyl
`ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, gly-
`col dimethyl ether, or hydrocarbons, such as benviene,
`toluene, xylene. hexane, eyelc-hexane or mineral oil
`fractious, or halogenated hydroca rbuus, such as
`dichloromethane,
`trichloromethane,
`tetrachloromethane,
`diehloroethylene,
`trichloroethylenc or chlorobenzene, or
`ethyl acetate, triethylamiue, pyridine, dimethyl sulpltoxide,
`dimelhylfortnamide, N-methylpyrrolidone, hexamelh-
`ylphosphoric triatnide, acetonitrilc, acetone or nitromethane.
`It is equally possible to use mixtures of the said solvents.
`Preference is given to dimethylformamide,
`toluene and
`tetrahydrofuran.
`The alkylation is carried out in the solvents listed above,
`if appropriate under a protective gas atmosphere, at tem-
`peratures of —20° C. to +100° (7., preferably at —l0° 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 alkoxides or alkaline earth metal
`alkoxides, such as sodium methoxide or potassium
`methoxide, sodium ethoxide or potassium ethoxidc or potas-
`sium tertbutoxide, or organic amines (trialkyl((f,—(f6)
`amines), such as trietbylaminc, or heterocylclcs, such as
`l,4—diazabicyclo[2,2,2]octane (DABCO), 1,8—diazabicyclo
`[5,4,U]undec—7—ene (DBU), pyridine, diaminopyridine,
`methylpiperdine or morphioline.
`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
`tert-butoxide, DBU or DABCO.
`In the alkylation, the base is used in an amount of l mol
`to l0 mol, preferably of 1.2 mol to 3 mol, based on l 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
`
`10
`
`I5
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`12
`acids are suitable, such as acetic acid, formic acid, tril‘luo—
`roacetic acid, rnethanesulphonic 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 audfor sulphuric
`acid. Very particular preference is given to the mixture acetic
`acid/sulphuric acid and also formic acidfhydrobromic acid
`and formic acidfsulphuric 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 (I°
`C. to +l50° (3., preferably from 40° C. to l00° (I.
`It can generally be carried out at atmospheric pressure, but
`optionally alternatively at superatmospheric 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 vvaterftoluene, waterf
`isopropanol, vvater/methanol or vvaterfethanol mixture, the
`acids are worked up by a customary n:teIh0d.
`Suitable bases for the neutralization are alkali metal
`
`hydroxides, such as sodium hydroxide or potassium 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. These preferably
`include ethers, such as diethyl ether, diisopropyl ethcr,
`tert-butyl methyl ether, dioxane,
`tetrahydrofuran, glycol
`dimethyl ether, or hydrocarbons, such as benzene, toluene,
`xylene, hexane, cycle-hexane or mineral oil fractions, or
`halogenated hydrocarbons, such as dichloromethane,
`trichloromethane,
`tetrachloromethane, dichloroethylene,
`trichloroethylcne 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
`dichloromethane.
`
`For the activation, conventional activation agents are
`suitable,
`for example oxalyl chloride, phosphorus
`trichloride, phosphorus pentachloride, trichloroisocyanuric
`acid, thionyl chloride, phosphorus tribromide, phosphorus
`pentabromide, mesyl chloride,
`tosyl chloride, phosgene,
`trifluoromcthanesulphonyl chloride, sulphuryl chloride.
`Preference is given to thionyl chloride, oxalyl chloride and
`phosgenc.
`The activation is carried out in the solvents listed above,
`if appropriate under a protective gas atmosphere, at
`tem-
`peratures of -20” C. to 120° C., 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 1 mol of the 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((I,—(I,,]amines],
`such as triethylamine, or heterocycles, such as
`l,4—
`dia7.abicyclo[2,2,2]octane (DABCO), 1,8-diazabicyclo[S,4,
`0]undec-T-ene (DBU), pyridine, diaminopyridine, methylpi-
`peridine or morpboline. If appropriate,
`the activated
`derivatives can be prepared starting from carboxylic salts of
`alkali metals and alkaline earth metals by reaction with, e.g.,
`oxalyl chloride.
`
`701']?
`
`PENN EX. 2213
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,952,498
`
`14
`then convening the esters (XII) by halogenation into the
`enantiomerically pure compounds of the general for-
`mula (XIII)
`
`(11:
`
`
`
`CO-—.t—BuW ‘’
`
`T
`
`RT
`
`I “
`
`"3 \
`
`in which
`
`'1' has the meaning specified above and
`R7 represents a typical leaving group, such as chlorine,
`bromine,
`iodine,
`tosylate or mesylate, preferably
`bromine,
`in a further step, by reaction with compounds of the
`general formula (VI)
`
`A II
`
`in which
`
`(VI;
`
`A has the meaning specified above,
`preparing the enantiomerically pure compounds of the
`general formula (I)
`
`\
`
`yr
`_ CO_ Q
`N/T
`
`A I C
`
`I-I3
`
`in which
`
`A and T have the meaning specified above and
`0 represents tert—|)utyl,
`and in the ease of the compounds of the general formula
`(I) where Q=0I-I, carrying out a hydrolysis.
`'l‘crt—butyl esters are generally saponilicd with acids, for
`example hydrochloric acid or triftuoroacetic acid,
`in the
`presence ofone of the above specified solvents anrlfor water
`or their mixtures, preferably with dioxane or tetrahydrofu—
`ran.
`
`The compounds of the general formula (X) are prepared
`from the corresponding esters disclosed in the literature by
`hydrolysis according to methods disclosed in the literature.
`
`Cl 13
`
`UII[raeJ phenetltylainine
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`13
`The compounds of the general formula (II),
`
`CH,
`
`
`
`in which
`
`R“ represents a chiral alcohol radical,
`are obtained by esterilying compounds of the general for-
`mula (IX)
`
`(I-‘ii
`
`
`
`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-butoxy are novel and
`can be prepared by first converting racemic earhoxylic acids
`of the general formula (X)
`
`(X)
`
`in which
`
`Thas 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 enam-
`tiomerically pure compounds of the general formula
`(X1)
`
`IXIJ
`
`in which
`
`"I" has the meaning specilied above,
`converting these in a further step with isobutene, in inert
`solvents and in the presence of acids, into the enantio-
`merically pure esters (XII)
`
`-
`
`(Km
`
`on,
`
`0
`
`-
`("B / I
`*|‘|
`T
`
`\\
`
`("V0-1l‘P.n
`
`in which
`
`T has the meaning specified above,
`
`6“
`
`as
`
`3 of 17
`
`on
`
`:_
`
`PENN EX. 2213
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`C113
`
`15
`—continued
`
`0
`
`5,952,498
`
`16
`EXAMPLE 11
`
`o—‘*___
`
`bE1.,+
`
`EXAMP1 .13 1
`
`2(RtS)—2—Cyelopentyl—2—(4—methylphcnyl)—acetic
`acid
`
`0
`
`01-1
`
`2.0 kg (7.2 mol) of tert—hutyl 2(R,S)—2—eyc1opcntyl—2—(4—
`methylpheny1)—aeetate are dissolved in 41o[dioxartc in a 40
`l agitated vessel fitted with an attached washing tower. Aliter
`addition of 4.5 1 of concentrated hydrochloric acid,
`the
`mixture is stirred at 50° C. to complete conversion (3h). 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 phase is washed with
`dilute sodium hydroxide solution and the combined aqueous
`phases are adjusted to pH=1, with oooling, with ooneen—
`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.
`
`RJ,=0.2O (petroleum ether: ethylaeetate=4:1)
`
`111-NMR (Cl)(."l3, 200 M111, TMS): 3:11.98 (H1, 111):
`1.20-1.71 (m, 611); 1.82-2.05 (m, 111}; 2.31 (s, 311); 2.52
`(m,1H);3.21(d,1H); 7.10 (m, 2H); 7.21 (m, 2H); 11.90 (br,
`111) ppm.
`
`5
`
`1U
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`61]
`
`65
`
`(S)-2-Cyclopentyl-2-(4-methylphenyl)-acetic acid
`
`Me
`
`011
`
`2.4 1 o1'1'I!15 and 129.7 g (1.28 mol) of triethylamine are
`added, with stirring, to a suspension of 560 g (2.57 mol) of
`the compound from Example 1
`in 4.8 l of water. The
`resulting solution is heated to 60° C, 155.4 g (1.28 mmol)
`of (S)—(—]—p11etiethylatnitte 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 off by suction,
`washed with 2.4 1 of water,/1'H1-' (2:1) and dried under
`reduced pressure.
`Yield: 360 g of phenethylammonium salt; 41.3% of
`theory.
`745 g (2.2 mol) of phenethylammonium salt are sus-
`pended in 3 1 of water, acidified [pH=1) with dilute hydro-
`chloric acid (1:1) and stirred for 30 minutes. The oily
`sttspension is washed 3 times, each time with 1
`l of
`dichloromethane,
`the combined organic phases are now
`washed with water, dried over sodium sulphate and
`concentrated, the residue eryslallizing ottt.
`Yield: 475 g; 37.3% of theory, based on racemate of
`I.-Example No. 1
`cc: ‘)6.3’;‘%» (1 IPLC)
`Melting point: 66° C.
`By crystallization of the phcnethylammonium salt from
`THE, as described above, the pure enantiomer is obtained:
`ee: >-99.5% (1-1P]_(T)
`Specific rotation: [o.],,3°=+59.55 [ethar1o11e=U.85)
`The HPLC method for deterrnination of the ee Value is as
`follows:
`
`Colttmn:
`Particle size:
`1’t1c.kirtg'.
`Mobile phase‘.
`Flow rate:
`1n|.cLp-t'essut'c.'
`
`Cltiracel OJ [Daicelj
`111 _.rr
`250 X 2 mm ((.irorrt_]
`n-hcptane: 2-propztnol = 97:3
`U2 rnlfmin
`23 bar
`
`1jXAM1’Ll_i 111
`
`Te rt-butyl (S;-2 -cyc|ope;tty1- 2 -(-1- methyl p be 115:] ) acetatr
`Me
`
`O
`
`Otliu
`
`6 ml ofeoneentrated sulphuric acid are added to a solution
`of4(iS g(2.13 mol) ofthe compound from Example 11 in 1.4
`
`90117
`
`PENN EX. 2213
`
`CFAD V. UPENN
`lPR20l5-01836
`
`

`
`5,952,498
`
`17
`l of dichloromethane, a temperature of approximately 10° C.
`being established. 550 ml (5 mol) of isobutene are con-
`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 (1 ml of
`concentrated sulphuric acid and 500 ml of isobuterie 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 l of diehloromcthane, the combined organic phases are
`washed with 5 l 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° (T.
`
`R1,-0.90 (toluene: ethyl acetate-8:2}
`
`EXAMPLE IV
`
`Tert-butyl (S)-2-(4-bromomethylphenyl)-L
`cyclopentyl—aeetate
`
`Br
`
`()t|3u
`
`In a 10 l flask. 480 g (1.75 mol) of the compound from
`Example Ill are dissolved under reflux in 3.4 [of tetrachlo-
`romethane and 70 g ofa total amount ol‘3ll g ( [.75 mol) of
`NBS and 14 g (0.085 mol) of AIBN are added. The reaction
`begins after, refluxing for approximately "I h; after it decays,
`liurther 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° (3., the succin-
`imide is filtered oil with suction and washed with 600 ml of
`tetraehloromethane. The combined filtrates are concentrated
`
`and residual solvent is removed under reduced pressure to
`constant weight.
`
`Crude yield: 570 g; approximately 100% of theory
`
`I-lPI.t'T: 68.8% (l5.5*7*E: starting material, 10.1 ‘T11’; rlihromo
`compound)
`
`The pure substance is obtained by column chromatogra-
`phr
`
`Rf0.42 (petroleum ether, ethyl acetate=2U1’ 1)
`
`ti-=0.98 (m, 111);
`‘II-NMR (CDCI3, 200 M112, TMS):
`1.22-1.71 (m, 611); -1 .40 (5, 911); 'l.90(m, 111), 2.47 (m, 111);
`3.16 (d, 111); 4.49 (5. 211); 7.32 (m, 411) ppm.
`
`IU
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`oil
`
`65
`
`18
`EXAMPLE V
`
`(l.)—menthyl 2—(4—tolyl)—acetate
`
`3.15 kg of p—tolylaeetie acid and 9.45 l of toluene are
`introduced. 3.115 kg of L—111e11tl1ol and 21.4 1111 o[111etl1a11e—
`sulphonic acid are added with stirring, and cooling. The
`mixture is then heated to reflux temperature and the corre-
`sponding amount of water is separated olI in the course of
`"Iii to 20 hours via a water separator. After cooling to room
`temperature,
`the mixture is stirred once with 4.41 l of
`saturated sodium hydrogen carbonate solution and twice,
`each time with 4.41 l of water. The organic phase is freed
`from solvent and gives 5.725 kg of the wanted compound
`((i(I 99.9%, retention time 19.49 min).
`
`‘II-NMR ((:1)(:1,, ppm): 7.05-7.15 (411, rn); 4.55 (111,
`txd); 3.5 (211, .4); 2.8 (311, s); 0.55 (311, s).
`
`EXAMPLE VI
`
`(L)—menthyl 2—(S)—2—eyclopentyl—2—(4—toly1)—acetate
`
`Me
`
`fie
`
`"L575 kg of potassium tert-butoxide are dissolved in 3.75
`lofDMl~‘ at room temperature. The mixture is cooled to 10°
`C. and,
`in the course of 45 minutes, 2.678 kg of the
`compound from Example V are run in at this temperature
`and rinsed with 0.375 1 of DMF. Then, with [all cooling,
`1.658 kg ofcyclopentyl bromide are pumped in in the course
`of 1 to 2 hours. The suspension is further sti