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`ll36M/0619A
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`TITLE OF THE INVENTION
`OXO-ANALOGS OF MEVINOLIN-LIKE ANTIHYPER(cid:173)
`CHOLESTEROLEMI C AGENTS
`
`SUMMARY OF THE INVENTION
`This invention is concerned with novel
`compounds of structural formula I:
`
`BO~O. ll~
`
`.·
`
`.
`
`J
`
`I
`
`5
`
`10
`
`15 wherein z is a variety of mono- and bi~carbocyclic
`moieties wi~p various substituents well known to·
`those skilled in the art "of 3-hydroxy"-3-methyl~
`glutaryl Coenzyme A (HMG-CoA).reductase inht°bitors
`useful in the treatment of familial hyper-
`cholesterolemi.a, ·hyperlipemia and atherosclerosis.
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`TITLE OF THE INVENTION
`OXO-ANALOGS OF MEVINOLIN-LIKE ANTIHYPER(cid:173)
`CHOLESTEROLEMI C AGENTS
`
`SUMMARY OF THE INVENTION
`This invention is concerned with novel
`compounds of structural formula I:
`
`BO~O. ll~
`
`.·
`
`.
`
`J
`
`I
`
`5
`
`10
`
`15 wherein z is a variety of mono- and bi~carbocyclic
`moieties wi~p various substituents well known to·
`those skilled in the art "of 3-hydroxy"-3-methyl~
`glutaryl Coenzyme A (HMG-CoA).reductase inht°bitors
`useful in the treatment of familial hyper-
`cholesterolemi.a, ·hyperlipemia and atherosclerosis.
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`The invention is also concerned with novel
`processes for the prep•rat:ion of the novel compounds1
`pharmaceutical formulations comprising a·novei
`compound as active ingredient1 and a method of
`treating familial hypercholesterolemia, hyperlipemia,
`and atherosclerosis.
`
`BACKGROUND OF THE INVENTION
`Over the past several years a number.of·
`structurally related antihypercholesterolemic agents
`acting by inhibition. o·f HMG-CoA reductase have been
`reported in the patent literature and elsewhere. The
`compounds h·ave varied from the natural fermentation'
`products, compactin and ""'vinoiiC&~o
`
`CB3
`
`r:ii,~2
`all
`.2.,
`Compactin (R 2mH)
`Mevinolin. (R2=cH3)
`
`to di- and t·etrabydro derivatives thereof: to analogs
`with different esters in the 8-position of the
`polyhydronaphthalene moiety, to totally synthetic
`analogs, wherein the polyhydronaphthalene moi~ty is
`replaced by substituted mono- and bicyclic aromatics,
`and biphenyls. But in all instances the active
`compound included a 4-hydroxytetrahydropyran-2-one
`ring or the corresponding 3,S~dihydroxy acid, or
`derivatives ther~of, formed by opening the pyranone
`ring such as:
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`5
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`or
`
`E
`I
`z
`
`Ila
`
`II
`
`4-hydroxytetrahydropyran-2-one
`
`3,5-dihydroxy-acid
`
`In all of these compounds the 3,5-dihydroxy acid or
`corresponding lactone moiety is present and the
`particular stereochemistry depicted is essential for
`manifestation of the optimum enzyme inhibitory
`activity.
`Now with the present invention there are
`provided compounds structurally related to those
`lactones and dihydroxy acids that do not have the
`5-hydroxy functionality, do not form a lactone ring,
`and are incapable of stereochemical variation at the
`5-position of the acid because the 5-parbon is not
`asymmetric. On the contrary, the 5-carbon carries an
`oxo function which greatly faci1itates the total
`synthesis of active compounds in that by eliminating
`one asymmetric center it is unnecessary to separate.
`di~stereoisomers or to conduct a stereoselective
`synthesis to obtain optimum enzyme inhibitory
`activity. It is believed that structures .!. are
`reduced in situ to generate the. "active" ~nhibitors
`of structure II or Ila.
`The active compounds of this invention are
`useful in either the racemic form or as the
`3(R)-isomer. Those compounds produced by total
`synthesis are obtained initially as racemates, but
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`may ·be resolved by standard methods into 3(R)- .and
`.
`3(S)•isomers. Compounds of Structure I which are·
`synthesized starting from natural fermentation ·
`products such as mevinolin and its analogs are
`obtained as the optically pure 3(R)-isomers.
`
`.
`
`DETAILED DESCRIPTION OF THE INVENTION ·
`The novel compounds of this invention have
`str.ucttiral formula:
`
`E
`
`I
`z
`
`wherein
`R1 is
`
`1)
`2)
`3)
`4)
`
`hydrogen,
`c1
`_
`alkyl,
`4
`2 1 3-dihydroxypropyl,
`+
`alkali metal cation, such as Na , or
`+ K , or
`
`ammonium of formula :R3R~RSR6
`wherein R3 , R4 , Rs and R6 are
`independently hydrogen or c1_4alkyl
`or two of R3 , R4 , RS and R6 are
`joined together to form a 5 or
`6-membered heterocycle such as
`pyrrolidino or piperidino with the
`. nitrogen to which they are attached;
`Eis - CH2ce2-, -CH=CH-, or (CH2) 3-: and.
`Z is 1)
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`s
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`wherein the dotted lines represent all of the
`possible oxidation states of the bicyclic system such
`as naphthalene, dihydro-, tetrahydro-, hexahydro-,
`octahydro-, and decahydronaphthalerie:
`
`X is -o- or ~NR 9 wherein
`
`2)
`
`wherein R10 , R11 and R12 are
`independently
`a) hydrogen,
`b) halogen, such as .bromo, chloro or flu.oro,
`c) c 1 _4alkyl,
`d) halo~c1 _ 4 alkyl,
`e) phenyl either unsubsti.tuted or
`· substituted with one or mor~ of
`i) c 1_ 4alkoxy,
`ii) c 1 _4alkyl,
`iii) c 2_8alkanoyloxy, or
`_4alkyl,
`iv) halo-c
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`v) halo, such as bromo, chloro or
`fluo.ro,
`f) OR13. wherein R13 is
`hydrogen,
`i)
`ii)
`c1-aa.lkanoyl,
`benzoyl,
`iii)
`phenyl,
`iv)
`halophenyl,
`v)
`phenyl-c1 _3alkyl, either
`vi)
`unsubstituted or substituted with
`one or more of halogen,
`cl-4alkoxy, cl-4alkyl or
`halo-c1 _4alkyl,
`vii) c1_9alkyl,
`viii) cinnamyl,
`ix) halo~c1 _4 alkyl,
`x) allyl,
`xi) c3 _6cycloalkyl-C1_3alkyl,
`xii) adamanty1-c1 _3alkyl,
`
`3)
`
`wherein n is 0-2, and R14 is halo such as·
`chloro, bromo or fluoro, or c1 _4 alkyl,
`and
`4; RiAo
`
`w~l
`
`(R15)
`m
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`wherein the dotted lines represent possibie'
`double bonds there being O,
`l or 2 double bonds; ·
`m represents 1, 2 or 3; and
`RlS is
`l.) methyl,
`2) hydroxy,
`3) c1_4 alkoxy,
`4) OXO or
`5) halo.
`
`Preferred embodiments of the novel compounds
`are those in which.:
`R1 is hydrogen, an alkali metal cation or an
`ammonium cation;
`E is -CH=CH- or -CH2CH2-1 and
`z is 1)
`
`s.
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`0
`wherein R -c- is 2-methylbutyryl or 2,2-
`7 "
`dimethylbutyryl~
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`lllO~ Rll ~ R
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`12
`11 .
`10
`.
`.wherein R
`, R
`and R
`independentl.y
`a) halogen,
`
`are
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`b) c1
`4alkyl, ·
`_
`c) halo-c1_4alkyl,
`d) phenyl with 1 to 3 substituents selected
`fro; halo, c 1_4alkyl or c 1 _4alkoxy,
`e) OR1 , wherein a13 is ·
`1) phenyl,
`ii) halophenyl,
`iii) phenyl substituted with 1-3
`substituents selected from
`halogen, and c 1_4alkyl,
`iv) phenyl-c1_3 alkyl, either
`unsubstituted or substituted with
`one or more of halogen,. c1 _4
`alkoxy, c 1_4 alkyl or
`halo-c1_4 alkyl1 or
`
`3)
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`ZS
`
`wherein n is O, l or 2 and R14 is methyl
`and the ring·· system is naphthalene or 5,6,7,8-
`tetrahydronaphthalene.
`
`One novel process for preparing the novel
`compounds of this invention is particularly usefu·i
`JO when starting with compounds with a pre·formed
`4-hydroxytetrahydropyran-2-one moiety or the
`corresponding 3,5-dihydroxy acid and is illustrated
`as follows:
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`tfw ~6 BOY.16
`
`+~1oy
`
`I
`
`16
`R
`H
`
`5
`
`->
`
`E
`
`I z
`
`--:?'>
`
`i
`z
`
`i
`z
`
`15
`
`10 wherein R16 is c1_ 4alkyl, especially methyl.
`After protecting the 4-hydroxyl of the lactone with a
`dimethyl-~-butylsilyl group and preparing an alkyl
`ester by known procedu~es, the resulting 5-hydroxy of
`the open-chain acid is oxidized to the ketone.
`Suitable oxiding agents include: pyridinium
`chlorochromate in a chlorinated alkane such as
`methylene chloride or chloroform at about 0° to about
`25°C for about l to 4 hour; oxalyl chloride in
`dimethylsulfoxide at about -70° to about -40°C for
`about 0.25 to 0.5 hours: trifluoroac~tic anhydride in
`dirnethylsulfoxide at about -70°. to -40°C for about
`0.25 to 0.5 hour; and pyridinium dichromate in
`dimethyl formamide at 0° to 25°C for 1 to 8 hours.
`The silyl ether group is then hydrolyzed by
`treatment with acetic acid and tetrabutylammonium
`fluoride in tetrahydrofuran.·
`A related procedure is available for
`preparing compounds of this invention wherein E
`represents -ca 2-ca2-. It obviates the need for
`protection of the 3-hydroxy group before oxidizing
`the 5-hydroxy and is represented as follows:
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`BO
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`0
`16
`
`Mno2
`(activated)
`
`z
`
`z
`
`In the first step the dihydroxy compound is trea.ted
`with activated manganese dioxide in a chlorinated
`hydrocarbon such as chloroform, methylene chloride,
`1,2-dichloroethane or the like at about 0°C to 40°C
`preferably at ambient temperature for about 15 to 30
`hours. The 5-oxo compound produced is then treated
`with tri-n-butyltin hydride and tetrakis(triphenyl(cid:173)
`phosphine)palladium(O) in an ethereal solvent such as
`ether, TBF, 1,2-dimethoxyethane or the like, .at about
`ambient temperature for about 15 to 30 hours.
`Alternatively, if the 3-hydroxy-S-oxo-
`carboxylic acid moiety. is being synthesized, the
`5-oxo group is realized directly by a process which
`is another embodiment of this invention and which is
`exemplified as follows:
`
`.(~16
`I
`
`B :>
`2
`
`i
`i
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`The nitro compound is treated with a
`cl-4alkyl 3-butenoate, preferably methyl
`3-butenoate, and an aromatic isocyanate such as
`p-toluoyl isocyanate, p-chlorophenyl isocyanate,
`phenyl isocyanate or the like, preferably the .latt~r,
`and a bit of triethylamine as a catalyst in an inert
`organic solvent such as toluene, benzene, xylene, or
`the like at about 15 to 30°C, preferably about room
`temperature for about 5 to about 24 hours.
`The resulting isoxazoline is reduced
`catalytically with palladium on carbon, platinum
`oxide or the like in an inert organic solvent such as
`a c1 _3alkanol, acetic acid or the like containing a
`little water in the presence of ~oric acid at about"
`15 to 30°C and about 1-2 atmospheres of hydrogen
`pressure for about l to 6 hours.
`The ester resulting from either of the
`foregoing synthetic schemes is readily saponif ied to
`the corresponding carboxylic acid salt by treatment
`20 with aqueous alkali such as potassium,. or sodium
`hydroxide to form the potassium or sodium salt
`respectively or with a quaternary ammonium hy.droxide
`of formula HONR3R4R5R6 wherein none of the R
`groups is hydrogen to form the quaternary ammonium
`salt.
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`Acidifying any of these salts with a mineral
`acid results in the formation of the free carboxylic
`acid.
`
`The acids are readily converted back to
`salts by treatment with the appropriate base or to
`esters by treatment with a c 1_4alkanol in the
`presence of a catalytic amount of an acid such as
`hydrogen chloride at about SO to 100°C for about 3 to
`6 hours.
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`The previously described salts are converted
`back to esters by treatment with an alkyl halide such
`es 2,3-dihydroxypropyl iodide in an aprotic solvent
`such as N,N-dimethylformamide, N-methylpyrrolidone or
`hexamethylphosphoramide at about 25 to 100°C·for
`about 18 to 36 hours.
`Those compounds, wherein Z is of the sub~
`type (4), i.e., in which the polyhydronaphthalerie
`moiety is substituted with hydroxy or oxo, halo :or
`alkoxy are prepared from the corresponding substrate
`in which the 5-oxo group of the heptenoic acid is
`already in place. The processes, as applied to the
`5-hydroxy analogs or the corresponding lactones, are.
`disclosed in EP application 76601, British patents
`2,lll,052 and 2,075,013, EP application 74222, and
`Japanese published applications J58010572 and
`J57155995. Using those processes there are produced
`the fallowing compounds: RO
`
`0
`
`I
`
`Double Bonds
`3,4:4a,5
`3,4:4a,5
`4,4a
`4,4a
`4,4a:5,6
`4,4a:5,6
`
`R7
`· 1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`
`..
`(Rl52
`m,--
`
`6-0H
`6-0H
`3-0H, 5-0H
`3-0H, 5-0H
`3-0H
`3-0H
`6-0H
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`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dirnethylpropyl
`1-methylpropyl
`1,1-dirnethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dirnethylpropyl
`i-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`1-methylpropyl
`1,1-dimethylpropyl
`
`6-0H
`3..:oH
`3-0H
`6-0H
`6-0H
`3-0H
`3-0H
`6-0H
`6-0H
`3-0H
`3-0H
`3-0H, 5=9
`3-0H, 5=0
`3=0, Sc:O
`3=0, 5=0·
`3-0H, 5-0H
`3-0H, 5-0H
`3-Cl, 5-Cl
`3-Cl, 5-Cl
`3-0CH3 , 5-0H
`3-0CH3 , 5-08
`3-0C2H5 , 5-0H
`3-0C2HS.' 5-0H
`3-0C4H9 , 5-0H
`3-0C4H9 , 5-0H
`6-CH3 , 3-0H, 5-0H
`. 6-CH3, 3-0H, 5-0B
`
`;
`
`4,4a
`4,4a
`4,4a
`4,4a
`4a,5
`4a,5
`4a,5
`4a,5
`4,4a
`4,4a
`4,4a
`4,4a
`
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`4,4a
`
`The novel pharmaceutical composition of this
`invention comprises at least one of the compounds of
`formula I in association with a pharmaceutical
`vehicle or diluent. The pharmaceutical composition
`can be formulated in a classical manner utilizing
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`solid or liquid vehicles or diluents and pharma(cid:173)
`ceutical additives of a type appropriate to the mode
`of desired administration. The compounds can be
`administered by an oral route, for example, in the
`form of tablets, capsules, granules or powders, or·
`they can be administered by a parenteral route in ~he:
`form of injectable preparations.
`A typical capsule for oral administration
`contains active ingredient (25 mg), lactose (75 mg)
`and magnesium stearate (15 mg). The mixture is
`passed through a 60 mesh sieve and packed into a No.
`1 gelatin capsule.
`A typical injectable preparation is produced
`by asceptically pl.acing 25 mg of a water solubl.e salt
`of sterile active ingredient into a vial, asceptically
`freeze-drying and sealing. For use, the contents of.
`the vial are mixed with 2 ml of physiological saline,
`to produce an injectable preparation.
`The novel method of treating
`atherosclerosis, familial hypercholes~erolemia, or
`hyperlipemia of this invention comprises
`administration of an effective
`antihypercholesterolemic amount of a compound of
`Formula I to a patient in need of such treatment.
`The dose to be administered depends on the
`unitary dose, the symptoms, and the age and the body
`weight of the patient. A dose for adults is
`preferably between 20 and 2,000 mg per day, which can
`be administered in a slngle dose or in the form of
`individual doses from 1-4 times per day.
`The compounds of this invention also have
`useful antifungal activities. For example, they may
`be used to control strains of Penicillium .!!.e•r
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`Asperqillus niger, Cladosporium .!.P·• Cochliobolus
`miyabeorus and Helminthosporium cynodnotis. For
`those utilities they are admixed with suitable
`formulating agents, powders, emulsifying agents or.
`solvents such as aqueous ethanol and sprayed or.
`dusted on the plants to be protected.
`This invention can be illustrated by the
`following examples.
`
`EXAMPLE 1
`7-[2(5),6(R)-Dimethyl-B(S)-(2(5)-methylbutyryloxy)(cid:173)
`l,2,6,7,8,Ba(R)-hexahydro-l(S)-naphthyl]-3(R)-hydroxy-
`5-oxoheptanoic acid
`Step A: Preparation of 6(R)-[2-(B(S)-(2(S)-methyl(cid:173)
`butyryloxy)-2(S) ,6(R)-dimethyl-li2,6,7,B,
`Ba(R)-hexahydronaphthyl-l(S))-ethyl]-4(R)•
`(dimethyl-~-butylsilyloxy)-3,4,5,6-tetra
`hydro-2H-pyran-2-one
`Mevinolin (4.04 g, 0.01 mol) was dissolved
`in 25 ml of dry dimethylf ormamide (DMf) and treated
`with 2.7 g (0.04 mol) of imidazole and 3 g (0.02 mol)
`of dimethyl-tert-butylsilyl chloride, a~d the
`solution was stirred under nitrogen overnight. The
`mixture was poured into 200 ml of ether, washed with
`2 X 50 ml of water, 1 X 25 ml of lN hydrochloric .
`acid, 1 X 25 ml of saturated aqueous sodium carbonate
`and .2 X 50 ml of brine, dried over MgSO 4 and·
`concentrated to dryness. The residue was chromato(cid:173)
`graphed on a "Still" column of silica gel (6.0 X 17.7
`cm, 230-400 mesh) by elution with 45% ether in hexane
`(V/V) collecting 20 ml fractions. The fractions
`containing the product (21-52) were combined and
`concentrated to dryness to give 5.2 ·of oil.
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`Step B: Preparation of Methyl 7-[2(S}, 6(R)-Dimethyl-
`8(S)-(2(S)-methylbutyryloxy)-l,2,6,7,8,8a(R)-.
`hexahydro-l(S)-naphthyl]-3(R)-(tert-butyl~i
`methylsilyloxy)-5(R)-hydroxyheptanoate
`The silyl ether from Step A (1.03 g, 0.002
`mol) was dissolved in 10 ml 'of methanol, treated with
`2 ml of lN aqueous sodium hydroxide and the mixture
`was stirred for 2 hours at room temperature. The '
`methanol was evaporated under reduced pressure and
`the residue was freed_ of water by azeotropic
`distillation of 4 X 10 ml of toluene. The solid
`residue was dissolved in 5 ml of dry DMF, treated
`with 300 111, (0.68 g, 0.0048 mol) of methyl iodide
`and the mixtu·re was s~irred overnight at room
`temperature. The mixture was poured into 100 ml of
`ether and washed with 20 ml of water and 20 ml of
`brine, dried (Mgso4 ) and concentrated to dryness to
`give l.O g of residue (contained DMF). This material
`was chromatographed on a· 11Still 11 column of silica 'gel
`(6.0 X 17.7 cm, 230-400 mesh} by elutaon with 45%
`ether in hexane (V/V) collecting 20 ml fractions.
`Fractions 32-50 containing the major component were
`combined and concentrated to dryness to give 576 mg
`of oily product.
`
`Step C: Preparation of Methyl 7-[2(8), 6{R)-Dimethyl-
`8(S)-(2{S)-methylbutyryloxy)-l,2,6,7,8,8a(R)(cid:173)
`hexahydro-l(S)-naphthyl]-3(R)-(tert-butyldi(cid:173)
`methylsilyloxy)-5-oxoheptanoate
`The ester from Step B (586 mg, o.ooi mol)
`was dissolved in 10 ml of methylene chloride ·and
`cooled to 0°C. Pyridine chlorochromate (0.56 g,
`0.0026 mol) was added and the stirred mixture was
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`16991
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`allowed to warm spontaneously over 2 hours.
`Additional pyridine chlorochromate (224 mg, 0.001
`mol) was added and stirring was continued anot~er
`hour. The methylene chloride was evaporated in
`vacuo. The residue was suspended in S ml. ether,
`placed on top of a· 4 X · 40 cm column of silica gel
`(70-230 mesh) and eluted with 40% ether in hexane
`(V/V) collecting 15 ml fractions. Fractions 10-23
`were combined and concentrated to.130 mg. of oily
`product.
`
`Step D: Preparation of Methyl 7- [2(S), 6 (~) -Dimet~)"l_-
`8 (S) - (2 (S) -methylbutyryloxy) -l~ 2,6, 7, 8,8a (R)'~
`. .
`hexahydro-l(S)-naphthyl]-3(R)-hydroxy-5-oxo-
`~h-e.p~t_a~n~o_a~t~e"'--~~~~~~~~~~~~~~~~~
`The silyl ether from Step C (230 mg, 0.00024
`mol) was dissolved in 5 ml of tetrahydrofuran (TBF)
`and treated with 54 ul., (0.057 9, 0.00095 mol) of
`acetic acid and 710 µl (lM in TBF, 0.00071 mol) of
`
`.
`
`: .. ··
`
`.
`+ -
`tetrabutylammonium fluoride (Bu 4N F) and the
`mixture was stirred overnight at room temperature. --
`
`+ -
`Another 57 µl of acetic acid and 710 µl of Bu 4N F
`were.added and stirring was continued an additional
`24 hours. The mixture was poured into 100 ml of
`ether and washed with 1 x 5 ml of lN hydrochloric
`acid, l x 10 ml of saturated aqueous sodium
`bicarbonate and 2 x 10 ml of brine and dried
`(MgS04 ). Concentration to dryness gave 120 mg of
`an oil. The oil was chromatographed on a •still"
`column of silica gel (1.5 x 17.7 cm, 230-400 mesh) by
`elution with 5% acetone in methylene chloride (v/v)·
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`
`collecting 5 ml fractions. Fractions 12-20
`containing the product were combined and concentrated
`.
`to dryness to give 53 mg of solid (m.p. 64-66°C).·
`Recrystallization of a sample from hexane gave
`material with m.p. 67-68°C.
`Analysis for c25e38o6 .(434.55): Calct C, 69.09; •
`H, 8.81.
`Found:
`
`C, 69.30; H, 9.38.
`
`5
`
`10
`
`Step E: Preparation of 7-(2(S),6(R)-Dimethyl-8(S)(cid:173)
`(2(S)-methylbutyryloxy)-l,2,6,7,8,8a(R)-hexa(cid:173)
`hydro-l(S)-naphthyl]-3(R)-hydroxy-5-oxohept(cid:173)
`anoic acid
`The ester from Step D (43 mg, 0.0001 mol)
`15 was dissolved in 5 ml of methanol and treated with 2·
`ml of O.lN sodium hydroxide (0.0002 mol) and stirred
`overnight at room temperature. The methanol·was
`evaporated i!! vacuo and the residue was acidified
`with lN hydrochloric acid and extracted with· ether·.
`The ether extract was washed with 3 X.· 10 ml of. brine
`and dried over MgS04 • Con~entration to·dryness
`provided 36 mg_of solid which after recrystallization
`from ether/hexane had m.p. 102-103°C.
`Analysis for c24H36o6 (420.53): Cale: C, 68.54;
`2~ H, 8.63.
`Found:
`
`20
`
`30
`
`C, 68.57; H, 8.88.
`Employing the procedure substantially a·s
`described in Example 1, Steps A through E, but
`substituting for the mevinolin used in Step· A,
`equimolar amounts of the lactones described in Table
`I there are produced the corresponding 5-oxo(cid:173)
`carboxylic acids, salts, and esters also described in
`Table I in accordance with the following reaction
`scheme:
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`16991
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`.
`
`I
`
`--->..:.. + SfOVo
`-i'
`J
`
`BO'OO
`10 +f1oy ~ 3
`t
`
`I!.
`E
`
`I z
`
`!
`
`5
`
`15
`
`I .
`
`CH3
`
`i
`I
`
`.Z
`
`By· Na
`
`...-:::
`
`E
`
`J
`
`1
`/ I (B
`
`•Na)
`
`By~3
`
`>
`
`E
`
`I z
`
`I (Rl • CH )
`3
`
`20
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`25
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`30
`
`z
`I (R.1 • B)
`
`
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`- 20 -
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`TABLE I
`
`-
`
`E
`
`I
`I
`z
`
`l)
`
`R7~-
`
`5
`
`10
`
`l.5
`
`2(S)-methylbutyryl
`2(S)-methylbutyryl
`2(R)-methylbutyryl
`2.2-dimethylbutyryl
`2.2-dimethylbutyryl
`2.2-dimetbylbutyryl
`acetyl
`2(S)-methylbutyryl
`2.2-dimethylbutyryl
`2,2-dimethylbutyryl
`2.2-diðyl.butyryl
`2-metbyl-2-ethylbutyryl
`2-metbylbutyryl
`4-fluorobenzoyl
`25 .. 4-fluo.z:.opheoylacetyl
`
`20
`
`4-~-butylbenzoyl
`acetyl
`acetyl
`2.2-dimethylbutyryl
`2.2-dimetbylbutyryl
`
`30
`
`RS
`
`RB
`
`-CH3
`-CH3
`-CH 3
`-CH3
`-CH3
`-CH3
`-CH 3
`H
`
`H
`H
`
`-CH3
`-CH3
`-CH3
`-CH 3
`~ca
`3
`-CH
`3
`-CH
`3
`-CH
`3
`-:-CH3
`-CH
`3
`
`x
`
`0
`
`0
`0
`0
`0
`0
`0
`0
`
`.-
`
`0
`0
`NH
`NH
`NH
`NH
`NH
`NH
`
`NH
`NCH
`NCH
`NH
`
`3
`3
`
`CH3
`
`a
`
`'b'
`
`dou~le
`double
`double
`single
`double
`single
`double
`
`sinqle
`. double
`single' single
`double
`double
`single
`single
`double
`single
`double
`single
`single
`single
`single
`single
`single
`single
`double
`single
`single
`double
`
`sin~le
`single
`single.
`single
`single
`single
`single·
`double
`single
`single
`double
`
`l
`
`y
`
`'
`
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`(2)
`
`' E
`l
`
`z
`
`-
`
`RlO
`
`Rll
`
`RlO
`6-(4-fluoro-3-methylphenyl)-
`6-(4-fluorophenyl)-
`6-(4-chlorophenyl)-
`6-(3,4-dichlorophenyl)-
`6-(4-fluoro-3-methylphenyl)-
`6-(3,4-dichlorophenyl)-
`6-(3,5-dimethylphenyl)-
`6-(3,4-dichlorophenyl)-
`6-(4-fluorophenyl)-
`6-(4-fluoro-3-methylphenyl)-
`6-(4-fluorobenzyloxy)
`6-(4~£luoro-3-methylphenyl)
`
`all
`2-methyl
`2-chloro
`2-chloro
`2-cbloro
`2-chloro
`2-methyl
`2-chloro
`2-methyl
`2-methyl
`2-niethyl
`2-chloro
`2-chloro
`
`R 12
`4-metbyl
`4-chloro
`4-chloro
`4-chloro
`4-chloro
`4-methyl
`4-chloro
`5-methyl
`4-methyl
`4-chloro
`4-chloro
`4-methyl
`
`E
`
`z
`
`3)
`
`n
`1
`0
`2
`1
`
`al4
`
`2-methyl
`
`2, 6-dimethyl
`2-methyl
`
`napbthyl •
`naphthyl.
`naphthyl'
`5,6,7,8-tetra(cid:173)
`.hydronaphthyl
`
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`5
`
`10
`
`EXAMPLE 2
`7-(4'-Fluoro-3,3',5-trimethyl-[l,l'-biphenyl]-2-yl)-3-.
`hydroxv-5-oxoheptanoic acid
`Step A: Preparation of Methyl 3-(4'-Fluoro~~,3',5-
`trime.thyl- [l, l 'biphenyl]-2-yl} propionate '
`A solution of 1.716 g (13 mmol) of dimethyl.
`malonate in 5 ml of DMF was added dropwise to a
`stirred suspension of sodium hydride (50% oil
`dispersion, o.-624 g, 13 mmol) in 15 ml of DMF and
`stirring was continued under nitrogen for 0.5 hour.
`The mixture was treated with ice bath cooling, with a
`solution of 3.1 g (ll.8 mmol) of 2-chloromethyl-4'(cid:173)
`fluoro-3,3' ,5-trimethyl-l,l'-biphenyl in 10 ml of
`DMF. The resulting mixture was stirred at 0°C for 10
`15 minutes, at room temperature for 0.5 hour, and heated
`on a steam bath for 1 hour. Sodium chloride {0.759 9,
`13 mmol) and 0.234 ml (13.mmol) of water were added
`to the reaction mixture and it was heated at reflux
`for 16 hours. The reaction mixture was cooled,
`poured into cold water. and extracted )lith ether
`twice.
`·The combined extracts were washed with dilute
`hydrochloric acid, dried over Mgso4 , filtered and·
`concentrated to dryness in vacuo to give 3.42 (11.38
`JnJnol, 96%) of the desired product as a brown oil
`25 which was used 'directly in the next step without
`purification.
`(CDC1 3 ) ~ : 2. 27 (6H, a methyl singlet and a
`nmr
`methyl doublet}, 2.3 (2H, m), 2.34 (3H, s}, 2.9 (2H,
`m}, 3.60 {3H, s), 6.84 (H, bs}, 7.1-7.2 (4H, m}.
`
`20
`
`30
`
`Step B: Preparation of 3-(4'-fluoro-3,3',5-trimethyl(cid:173)
`(l,l'-biphenyll-2-yl)propanol
`A solution of 3.42 g (11.4 mmol) of the
`ester from Step A in 25 ml of ether was added
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`16991 .
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`dropwise to a stirred suspension of 0.38 g (10 mmol).
`of lithium aluminum hydride in 75 ml of ether at 0°C.
`under nitrogen. After completion of the addition,
`the mixture was stirred at room temperature for 15
`minutes, refluxed for l.hour, cooled in ice and
`treated with successive additions of 0.4 ml of .water,
`0.35 ml of 20' .<w/v) aqueous sodium hydroxide ~nd l~i
`ml of water. The resulting mixture was stirred at
`0°C for t>.5 hour, treated with anhydrous Mgso4 ,
`stirred for 15 minutes and filtered. The filtrate
`was concentrated.!!! vacuo to give 3.08 g (11.3 mmol)
`(99t) of pale yellow oily product which. was used
`directly in the next step without purification.
`nmr ( CDCl 3 ) 6 : l. 4 5-1. 7
`( 2B '· m) , 2. 2 5 ( 6H, s) , 2 • 3 3
`(3H, s), 2.45 ~2.7 (2H, m), 3~45 (2H, t, J=6Hz), 6.85
`(H, bs), 6.95-7.2 (4H, m).
`
`Step C: Preparation of 2-(3-Bromopropyl)-4'-fluoro~
`3,3',S-trimethyl-1,1 1 -biphenyl
`A solution of 1.08 9 (4 mmoLJ of PBr 3 in
`10 ml of ether was added dropwise to a stirred
`solution of 3.08 9 (11.3 mmol) of the alcohol from
`Step B in 40 ml of ether at 0°C. The mixture was
`stirred at· room temperature for l hour, refluxed for
`0.5 h.our, cooled to ·room -temperature, poured into :foe
`water and extracted with ether. The extract was
`washed with water and saturated aqueous sodium
`bicarbonate, dried over Mgso4 , filtered and
`evaporated ·to dryness .!!! vacuo. The residue was
`purified by flash chromatography on silica gel
`(230-400 mesh) by elution with methylene
`chloride/hexane (1:3, v/v). Combination and
`evaporation of the appropriate fractions gave the
`
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`~O
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`.. . . . ,
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`~ 24 -
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`desired bromide as a pale yellow oil, (1.9 g, ·5.67·
`mmol, 48% overall Steps A, Band C).
`nmr (CDC13) i' : l. 7-2. 0 (2B, m), 2. 27 (6B,. a methyl
`singlet and a methyl doublet), 2.35 (3H, s), 2.55~2.8
`<,2H, m), 3_.23 (2H,_ t, J=_6Hz), 6.85 (H, bs), 6.95-7.2
`(4H, m).
`
`Step D: Preparation of 4'-Fluoro-3,3',5-trimethyl-
`2-(3-nitropropyl)-l,l'-biphenyl
`A solution of 1.90 9 (5.66 mmol) of the
`bromopropyl compound from Step C in S ml of ether was
`added to a stirred suspension of 1.31 g (8.S mmol) of
`silver nitrite in 5 ml of ether at 0°C. The
`resulting mixture was stirred under nitrogen at 0°C
`for 7 hours, warmed to room temperature and stirred
`for an additional 16 hours. Another 1.0 g of silver
`nitrite was added and stirring was continued·for
`another 20 hours.
`The reaction mixture was filtered and the
`filtrate was concentrated to l~ave a cesidue which
`was purified by flash chromatography on.silica gel
`(230-400 mesh)·by elution with methylene chloride/
`hexane (1:4, v/v) to give, first, the recovered
`starting bromide, then the desired product, (0.64 g,
`2.12 mmol, 78%). nmr (CDC1 3)6 :l.8-2.2 (2B, m),
`2.30 (6H, a methyl singlet and a methyl doublet);'
`2~33 (3H, s), 2.5-2.7 (2H, m), 4.18 (2H, t, J~6Hz),
`6.88 (H, bs), 7.0-7.2 (4H, m).
`IR (neat) 1550, 1500
`cm-1 •
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`Step E: Preparatioll of Methyl 3-[2-(4'-fluoro~3,3',S-·
`trimethyl[l,l'-biphenyl]-2-yl)ethyl)-4,5.;,di(cid:173)
`hydro-5-isoxazoleacetate
`A solution of O.l g (l.O nunol) of methyl
`3-butenoate and 0.174 ml (1.6 mmol) of phenyl
`isocyanate in l ml of toluene was added with stirrill9 ·
`to a solution of 0.240 g (0.8 mmol) of the nitro-:
`propyl compound from Step D and 2 drops of triethyl(cid:173)
`amine in l ml of toluene. The resulting mixture was
`stirred at room temperature _for 3 hours. Additional
`quantities of methyl 3-butenoate (0 •. 1 ml), triethyl(cid:173)
`amine (0.l ml) and phenyl isocyanate (0.15 ml) were
`.
`added successively and stirring was continued over-
`night (18 hours). The mixture was filtered and the
`filtrate was concentrated.!.!! vacuo to a·residue which
`was purified by flash chromatography.on silica gel
`(230-400 mesh), first being eluted with methylene
`chloride to remove the impurities. Continued elution
`with acetone/methylene chloride (1:50, v/v) gave the
`desired product (0.218 g, 0.57 mmol, Ql%) as a pale
`viscous oil. nmr (CDC13 )": 2.28 (6H, s) .' 2.32' (3H,
`s), 2.2-3.0 (6H, m), ,3.70 (3H, S)i 4.6-5.0 (H, m)~
`IR (neat) 1735 cm·l~
`6.85 (H, bs), 7.0-7.2 (4H, m).
`Analysis calculat.ed for c 23H26FN03 : C 72. 04; ·
`H, 6.83; N, 3.65.
`Found:
`C, 72.35; H, 6.99; N, 3.88.
`
`'
`
`Step F: Preparation of Methyl 7-(4'-fluoro-3,3 1 ,5-
`trimethyl-[l,l'-biphenyl]-2-yl)-3-hydroxy-5-
`
`~o~x~o~h~e~p~t~a=n~o~a~t~e=--~----~--~~~~----------~
`A mixture of 0.1 g (0.26 mmol) of the
`isoxazoline from Step E, 50 mg of 10% palladium on
`carbon catalyst and 48 mg (0.78 mmol) of boric acid
`
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`. .. . .
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`• • • C'' t:
`
`. . . . .
`.. , ...
`'tJ14'21 ~6:
`
`. . . .
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`- 26 -
`
`16991
`
`in· 3 ml of methanol and 0.3 ml of water was stirred·
`under hydrogen (1 atmosphere) at room temperature• fQr
`2.5 hours. The mixture was filtered and the f~ltrate
`was poured into brine and extracted with ether. The
`ethereal extract was washed with 51 (w/v) aqueous
`sodium bicarbonate solution, dried (Mgso4),
`filtered and evaporated to dryness to give 92 mg
`(0.23 mmol, 891) as a pale yellow oil. nmr (CDC1 3 )
`': 2.30 (6H, a methyl singlet and a methyl doublet),
`2.33 (3H, s), 2.35-2.5 (6H, m), 2.75-2.85 (2H, m),
`3.30 (H, d), 3.70 (3H, s}, 4.37 (H, m), 6.83 (H, bs),
`IR (neat) 34501 1710 cm-1 •
`6.95-7.1 (4H, m).
`
`Step G: Preparation of 7-(4'-fluoro-3,3',S-trimethyl-
`[l,l'-biphenyl]-2-yl)-3-hydroxy-5-oxoheptanoic
`acid
`Employing the procedure substantially as
`described in Example 1, Step E, the ester from Step G
`of this Example 2 is saponif ied .to the subject 5-keto
`acid.
`
`Employing the procedure substantially as
`described in Example 2, Steps A through G, but
`substituting for the chloromethylbiphenyl employed in
`. T.-strep ri. rtheceof, equimolar amounts of the chloromethyl
`compounds described in Table II, there are produced
`the 5-keto esters, salts and acids also described in
`Table II in accordance with the following reaction
`sequence:
`
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`0142146'
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`- 28 -
`
`16991
`
`TABLE II
`
`10 R
`
`I E
`J
`
`alO
`
`Rll
`
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