fsmm
`
`360 Journal of Medicinal Chemistry, 1991, Vol 34, No. 1
`
`Roth et ai
`
`Table I
`
`RA^OR*
`
`X n N^^Ra
`
`y\//
`Ri
`
`X
`H
`H
`H
`F
`
`mp,"-6 0C
`% yield (method)
`no.
`R*
`R t
`Ra
`R2
`75(A)
`olF
`-CHJCHJ-
`Ph
`6a
`CHj
`COjEt
`36(A)
`oil5
`-CHJCHJ-
`fib
`Et
`Ph
`COjEt
`4(A)
`oU*
`COjEt
`-CHJCHJ-
`6c
`Pr
`Ph
`65(B)
`143-6
`COJCHJ
`11a
`Pr
`COJCHJ
`-CHJCHJ-
`70(B)
`COjEt
`lib
`i-Pr
`COjEt
`-CHjCHf-
`Oil4
`30(B)
`Ph
`146-8
`/•Pr
`-CH2CH2-
`He
`COjEt
`45(C)
`-CHJCHJ-
`158-9
`16a
`Pr
`Ph
`COjEt
`51(C)
`on*
`16b
`Pr
`COjCHjPh
`-CHJCHJ-
`Ph
`43(C)
`CONHPh
`-CH2CH2-
`161-3
`16c
`Pr
`Ph
`COjEt
`i-Pr
`-CH2CHJ-
`oil'
`16d
`4'CNPh
`88(C)
`64(D)
`oil*
`CH3
`Pr
`CH,
`-CHJCHJ-
`18
`71(E)
`Et
`84-7
`H
`i-Pr
`Ph
`23a
`Et
`76(E)
`Pr
`2*pyridyl
`84-6
`H
`23b
`Et
`i-Pr
`S-pyridyl
`64(E)
`96-8
`H
`F
`23c
`Et
`46(E)
`4-pyTidyl
`123-5
`Pr
`F
`23d
`H
`"All compounds possess 'H NMR spectra consistent with assigned structure. &Combustion analyses within ±0-4% of theoretical unless
`otherwise noted. 'This compound was pmified, but not analyzed before use hi the next step.
`
`F
`F
`F
`F
`F
`F
`F
`
`CHO
`
`N
`
`Rg
`
`f"1
`t\ n
`
`Table 11
`
`X. n
`
`Rs
`Kt
`Ra % yield mp^'C
`Rt
`no. X
`77
`7a
`H Ph
`CHj
`COjEt
`100-1
`oii<
`7b
`H Ph
`Et
`COjEt
`88
`7G
`oil'
`i-Pr
`K Ph
`100
`COjEt
`COSCH3
`90
`oilf
`i-Pr
`12a F C02CH3
`95
`i-Pr
`12b F COsEt
`COjEt
`oil'
`oil*
`90
`Ph
`i-Pr
`12c F COjEt
`127-8
`17a F Ph
`81
`i-Pr
`COjEt
`oile
`17b F Ph
`COjCH^h
`i-Pr
`60
`164-5
`17c F Ph
`CONHPh
`86
`i-Pr
`75
`oile
`17d F 4«CNPh
`i-Pr
`COjEt
`i-Pr
`oilc
`F CHj
`66
`19
`CH3
`85
`oile
`i-Pr
`24a F Ph
`H
`70
`24b F 2-pyridyl H
`i-Pr
`120-2
`93
`24c F 3-pyridyl H
`oil*
`i-Pr
`95
`oil*
`i-Pr
`24d F 4-pyridyl H
`i-Pr
`Ph
`oU*
`90
`28
`F H
`aAll compounds possessed ^ NMR and IR spectra consistent
`with assigned structure. ''Combustion analyes within ±0.4% of
`theoretical unless otherwise noted. 'This compound was purified
`by chromatography, but not analyzed before use in the next step.
`
`VIII).16 Thus, reaction of aldehyde 17c with the mag­
`nesium enolate of GSH+)'2-acetoxy-l»l,2-triphenylethanol
`afforded alcohol 31 in 60% yield and 97% ee. Trans-
`esterification (NaOCHa, CH3OH) followed by Claisen
`condensation with excess lithio tert-butylacetate produced
`-5-hydroxy-jS-keto ester 32 in 75% yield. After reduction
`with EtsB and NaBH^ base hydrolysis, and lactonization, •
`(+)-33 was isolated as a 98:2 mixture of stereoisomers.
`Fortuitously, the 6,1 pair selectively crystallized from ethyl
`acetate-hexanes and pure (+)-33 ([cr]2^ = +24.53°, 0.53%
`in CHCI3) could then be isolated from the mother liquors
`as a foamy solid.17
`
`'
`
`(16) Braun, M.; Devant, R. Tetrohedren Lett. 1984, 5031^<j g
`
`Scheme Vnr
`
`CHO
`
`p.
`
`01 J
`
`Ph
`
`F.
`
`7 -
`D1 i
`
`to
`
`Pn'
`
`JONHPn
`
`Pn'
`
`CONHPn
`
`n7e
`
`31
`
`F.
`
`HO,
`
`ol i
`
`XOjJBu
`
`o
`
`a-B '
`
`Pn'
`
`'CONHPn
`
`sa
`
`P. ar
`
`pn'
`
`CONHPn
`
`{*)•33
`
`O
`?H
`1
`•(a) CHj^oJcPh, 2LDA, MgBra. -78 •C; (b) NaOCHal
`Ph
`r
`Ph
`
`OLi
`(c) •^'OtBu (d) EtjB. NaBH; (e) HJOJ, CHaOH; (i) NaOH: (s) PhCH3, rellux.
`
`propane" and deprotection (Scheme VI, method E). Fi­
`nally, the 3,4-dichloro, 3,4-dibromo, and 3-trifluoroacetyl
`analogues (30a-c) were prepared from 1 by protection of
`the 4/-hydroxyl as the tert-butyldimethylsilyl ether, fol­
`lowed by electrophilic substitution on the pyrrole ring15
`and deprotection with n-6u4NF buffered with acetic acid
`(Scheme VII). The assignment of the regiochemistry of
`30c was made in a manner analogous to 11c and lid.
`• Chiral lactone (+)-33 was prepared by application of the
`asymmetric aldol procedure developed by Braun (Scheme
`
`(13) Broadbent, K. S.; Burnham, W. S.; Olsen, R. K.; Sheeley, R.
`M. J. Hetemycl. Chem. 1968,5, 757-67.
`(14) Suzuki, E.; Inone, 3.; Goto, T. Chem. Pkarm. Bull. 1968,76,
`933-8.
`(15) Aiello, E.; Dattolo, G.; Cirrincione, G.; Almerico, A. M.; D'As*
`dia, I. J. Hftencycl. Chem. 1982, 19, 977-9.
`
`i-1
`
`V'!:.
`'T"
`- v
`
`Sawai Ex 1005
`Page 3012 of 4322
`
`

`
`^
`
`ftl
`&
`
`i#!:.
`
`inhibitors 0/ Cholesterol Biosynthesis. 3
`
`Joumai 0/ Medicinal Chemistry, 1992, Vol. 34, No. 1 361
`
`Table III
`
`HQ ty
`r u N Rj
`
`\ /
`fi2
`
`X
`
`no.
`( 1.
`3b
`3c
`3d
`3e
`3f
`3g
`3h
`0i:)-3i
`3j
`3k
`31
`Sin
`3n
`3o
`3p
`30a
`30b
`30c
`(+)-33
`(-)-33
`
`X
`F
`H
`H
`H
`F
`F
`F
`F
`F
`F
`
`F
`F
`F
`F
`F
`F
`F
`F
`F
`F
`F
`
`Ri
`
`R4
`
`H
`C02Et
`CO:Et
`COjEt
`COJCHJ
`COjEt
`Ph
`COjEt
`COjCHjPh
`CONHPh
`COjEt
`CHj
`H
`H
`H
`H
`Ph
`ci
`Br
`H
`CONHPh
`CONHPh
`
`relative
`potency*
`ICgo + jtM
`H
`10.9
`023
`Ph
`0.6
`4.0
`Ph
`6.3
`089
`Ph
`23.5
`017
`COJCH3
`14^
`0.180
`COjEt
`0.35
`2.8
`C02Et
`100
`0.050
`Ph
`35.5
`0.20
`Ph
`0.040
`24.0
`Ph
`81.4
`0.025
`4-CN-Ph
`0.280
`16^
`0140
`16.0
`CHa
`0347
`Ph
`12.5
`2-pyridyl
`0.046
`76
`9.4
`3-pyridyl
`0071
`4-pyridyl
`0310
`2.1
`36.3
`H
`0120
`a
`78.6
`0028
`0.028
`78.6
`Br
`0.800
`COCF,
`8.8
`500
`0.007
`Ph
`13.9
`Ph
`0.440
`100
`0.030
`eompactin
`'Analytical results are within ±0.4% of theoretical values except where otherwise noted. 6CoA reductase Inhibition (COR) screen; a
`measure of the direct conversion of D,L-[MC]HMG-COA to mevalonic add. Assays of each inhibitor were performed at four concentrations
`in triplicate. The precision for eompactin was 37%. See ref 7 for experimental details. 'Calculated as follows: (ICM of compactin/ICjo of
`test compound determined simultaneously) x 100. Compactin arbitrarily assigned a value of 100.
`
`R3
`».Pr
`CHj
`Et
`i-Pr
`ffi
`i-Pr
`»-Pr
`».Pr
`i«Pr
`i-Pr
`j-Pr
`j.Pr
`i-Pr
`i-Pr
`».Pr
`».Pr
`i-Pr
`i-Pr
`{•Pr
`i-Pr
`
`mp, 0C
`105-6
`©U
`69-8
`157-9
`169-170
`121-3
`158-9
`159-160
`174-5
`104-110
`oil
`oil
`oil
`186-7
`70-4
`174-6
`135-6
`129-131
`141.2
`oil
`foam
`foam
`
`formula"
`CMHMFNO,
`C^HJJNOS
`CaH^NOj
`CaH^NOs
`CMHMFNO,
`CajH^PNO,
`CJJHJJFNOS .
`CJSHMFNQS
`QMH^FNOS
`C^HaFN^O,
`CaoHajFNjOj '
`CaHaFNOa
`CKHMFNO,
`CJSHJTFNA
`CjjHnFNjOa
`CJJHJTFNJOJ
`CaHjjFNO,
`CMHaCUFNOj
`Ca)HKBrjFNOa
`C2AHOF4N0,
`CsHsFNA
`CSHJJFNA
`
`'
`
`Alternatively, relatively pure (+)- and (-)-33 could be
`obtained by preparation of the corresponding diastereo-
`meric (flj-fr-methylbenzylamides, separation by prepara­
`tive HPLC, hydrolysis, and relactomzation.6b This process
`afforded 94.6% pure (+)-33 ([a]2^ = +25.5°, 0.51% in
`CHClg) and 97.8% pure (-)-33 ([a]2^ = -24.8% 0.51% in
`CHCI3).
`Biological Results and Discussion
`The compounds listed in Table III were all hydroly2ed
`to the corresponding dihydroxy acid sodium salts and
`evaluated for their ability to inhibit a partially purified-
`preparation of rat liver HMG-CoA reductase.3 Two con­
`clusions were readily apparent. The first was the confir­
`mation of the 5-isopropyl as the preferred substituent
`(compare 3c with 3a and 3b). The second was the sig­
`nificant increase in in vitro potency found with the in­
`troduction of certain lipophilic electron-withdrawing
`groups into the 3 and 4 positions of the pyrrole ring (e.g.,
`CI or Br, compare 1 with 30a and 30b), such that, these
`compounds displayed potency equivalent to compactin.
`This effect did not hold for the esters or ketones (COjMe,
`CO^Et, COCF3, compounds 3d, 3e, 30c), except when
`combined with a phenyl (compounds 3f, 3h, and 3i). There
`also appeared to be a positional effect, since the 3-carb-
`ethoxy-4-phenyl analogue (3f) was 4 times more potent
`than the 3*phenyl-4-carbethoxy analogue (3g). In vitro
`activity for the 3-phenyl analogues were improved sig­
`
`(17) A similer sequence was employed by Lynch et al.: Lynch, J.
`E.; Volante, R. P.; Wattley, R. V.; Shinkai, 1. Tetrahedron
`Lett. 1987,1385-8.
`
`nificantly by increasing the size of the 4-substituent
`(compare 3h, 3i, and 3g with 31). Potency was also in*
`creased when the 3-phenyl was replaced with a 3-(2>
`pyridyl) moiety (compound 3m). The 3-(3- and 4-pyridyl)
`isomers (3n and 3o) were equipotent to phenyl (31). In­
`troduction of the electron-withdrawing cyano group into
`the 4-position of the 3-phenyl (35) led to a slight reduction
`in potency. Finally, as others have reported, in the case
`of 31 essentially all of the biological activity was contained
`in the dextrorotatory stereoisomer ((+)-33 vs 3i).6b We
`speculate that the activity found in (-)-33 (97.8% pure)
`is derived from the 2% contamination with (+)-33.
`An attempt was made to confirm these observations with
`a quantitative structure-reactivity relationship (QSAR)
`analysis. In the early stages of the development of the
`series, there was an indication that size, as parameterized
`by MR of the combined 3* and 4-substituents, as well as
`electronic-withdrawing character might be possible con­
`tributors to activity and this preliminary analysis partially
`guided further synthesis. Synthetic constraints precluded
`the preparation of an optimally designed set, however, and
`the set of compounds described in this paper did not ul­
`timately support the derivation of a significant Hansch
`equation including these parameters. Furthermore,
`available parameters for electronic and lipophilic effects
`of these highly hindered functional groups are likely to be
`seriously inaccurate. Nevertheless, the trends observed
`from plots and single parameter correlations supported the
`observation that a size benefit exists, but derives mainly
`from the 4-substituent, as opposed to the 3-substituent.
`Polar functionality can be tolerated in this region, although
`suggestion that lipophilicity may ultimat^^ay
`there is a
`
`1
`
`•
`
`•.
`
`• •
`
`W-
`.••M IK
`
`r n i m . . . . *
`
`id
`
`r;
`
`i
`
`jj
`
`Sawai Ex 1005
`Page 3013 of 4322
`
`

`
`mw •••{
`m
`
`BMBwaaawgwaM
`
`362 Journal of Medicinal Chemistry, 1991, Vol. 34, No. J
`
`the dominant role among-the simple parameterized effects,
`since Pi^4 has one of the best single parameter correlations
`with activity (r = 0.46). Clearly, other factors not readily
`parameterized have equal or larger influence on relative
`activity in this series. The activity of polar-substituted
`analogues is enhanced when the polar group is "insulated"
`from the enzyme as in 3in vs 3a and 3o. Similarly, the
`better activity of 3f over 3g may derive from the better
`shielding of the polar ester group in the former compound
`by the flanking phenyl groups as opposed to a phenyl and
`isopropyl group in the latter. The activity of the halo-
`genated analogues 30a and 30b is better accommodated
`by a lipophilidty effect, rather that a size or dispersion
`effect reflected in MR. Other QSAR analyses of synthetic
`HMG-CoA reductase inhibitors have reached similar
`conclusions about structural variations in this region of
`related molecules.18-19
`In conclusion, although it is still most critical in this type
`to have the optimal substituents flanking the dihydroxy-
`glutarate side ftham, ie., 4-fiuorophenyl and isopropyl,7 this
`work shows that further modulation and improvement in
`potency at inhibiting HMG-CoA reductase may be ob­
`tained with a variety of additional substituents capable
`of interacting with an apparently fairly spacious hydro­
`phobic region distal from the side-chain location. The
`importance of this interaction is further supported by the
`potent inhibition evidenced by other inhibitors which
`possess substituents in this region.1 Preparation of the
`optically pure H^R-isomer ((+)«33) of the most potent
`compound in this series (3i) resulted in a compound which
`was 5 times more potent than the fungal metabolite com-
`pactin in vitro. Further in vivo studies with (+)-33 will
`be described in subsequent papers from this laboratory.
`Experimental Section
`'
`Unless otherwise noted, roaterials were obtained from com­
`mercial suppliers and were used without further purification. THF
`was distilled from sodium and benzophenone. All organic extracts
`were dried over MfS04 except when otherwise noted. Melting
`points were determined on a Thomas Hoover melting point ap­
`paratus and are uncorrected. Infrared spectra were determined
`on a Nicolet MX-1FT-IR spectrophotometer. NMR spectra were
`determined on either a Varian EM-39Q spectrometer, or a Varian
`XL-200 or Bruker 250 MHz instrument Chemical shifts are
`expressed as parts per million downfield from internal tetra-
`methylsilane. Elemental analyses for-carbon, hydrogen, and
`nitrogen were determined on a Perkin-Elmer Model 240C ele­
`mental analyzer and are within 0.4% of theory unless noted
`otherwise. Optical rotations were determined with use of a
`Perkin-Elmer 241 polarimeter. Routine HPLC analyses were
`performed with use of a Varian 5500 unit equipped with a Beodyne
`7126 loop injector, a Dupont variable wavelength detector, and
`an octadecylsSane (AUtech CIS 600RP, CH3CN-H2O eluant, 60:40,
`v/v) or silica gel column (Beckman Aitex Ultrasphere 5 pm)
`interfaced to Varian 402 data system for computation of peak
`areas. Chiral HPLC analyses were performed with use of a
`Cbiracel of lO-pm column (Diacel Chem. Ind., LTD).
`Method A. Ethyl 3-[2-(l^-Dioxolan-2-yl)ethyl]amino-2-
`pentenoate (4b). A solution of methyl propionylacetate (12£5
`mL, 100 mxnol), 2-(2-aimnoethyD*l,3-dioxolane8 (12.3 g, 105 mmol)
`and one drop of glacial acetic acid was stirred and heated in
`refluxing toluene (200 mL) for 2 h with azeotropic removal of
`water. The cooled solution was concentrated to provide 24 g of
`pure 4b, which was used without further purification.
`Ethyl 2-Ethyl-l-{2-(lf3-dioxolBii-2-yl)ethyl3-4^diphenyl-
`IH-pyrrole-S-carboxylate (6b). A mixture of benzoin (4.25 g,
`20 mmol), 4b (5.44 g, 22 mmol), and ZnClj (6 g, 44 mmol) in 50
`
`(18) Aggarwal, D.; Saha, R. N.; Gupta, J. K.; Gupta, S. P. <7.
`Pharmaeobio-Dyn. 1988,31, 591.
`(19) Prabbakar, Y. S.; Saxena, A K.; Doss, M. J. Drug Des. Deliv.
`1989,4,97;
`
`Roth et al.
`
`y
`
`mL of absolute ethanol was stirred and heated at reflux for 48
`h. The cooled solution was diluted with ether (500 mL), washed
`with water (50 mL), 2 M HC1 (2 X 50 mL), saturated aqueous
`bicarbonate (50 mL), and brine (50 mL), and dried. Flash
`chromatography (silica gel, 10:1 v/v hexane-ethyl acetate) pro­
`vided 3 g (36%) of 6b: 90-MHz NMR (CDClj) 5 0.98 (t, 3 H, J
`= 7 Hz), 1.34 (t, 3 H, J = 7 Hz), 1.85 (m, 2 H), 3.08 (q, 2 H, J
`= 7 Hz), 3.7-4.1 (m, 8 H), 4.60 (t, 1 H, J = 4 Hz), 7.1 (s, 5 H),
`7.22 (s, 5 H) ppm.
`Ethyl 2-£tbyl-l-[l-(3-oxopropyl)]-4,5-dipheny]-lir-
`pyrrole-3-carboxylate (7b). A solution of 6b (2.4 g, 5.7 mmol)
`in 100 mL of absolute ethanol containing 1 drop of concentrated
`HC1 was stirred and heated at reflux for 24 h. The cooled solution
`was concentrated and dissolved in 125 mL of 4:1 acetone-water,
`and 1 g of p-TSA-HsO was added. The resulting solution was
`stirred and heated at reflux for 24 h. The cooled solution was
`concentrated and partitioned between ether and water. The ether
`layer was then washed with saturated aqueous bicarbonate and
`brine and dried. Filtration and concentration afforded 1.9 g of
`7b (88%): 90-MHz NMR (CDCia) 61.0 (t, 3 H, J = 7 Hz), 1.28
`(t, 3 H, J = 7 Hz), 2.58 (m, 2 H), 3.10 (q 2 H, J = 7 Hz), 4.05 (q,
`2 H, J = 7 Hz), 4.2 (m, 2 H), 7.05 (s, 5 H), 7.1-7.4 (m, 5 H), 9.50
`(s, 1 H) ppm.
`Ethyl 3-[[2-(l,3-Dioxolan-2-yl)etbyl]ammo]-4-methyl-2-
`pentanoate (4c). A solution of ethyl isobutyrylacetate (6 g, 42
`mmol) and 2-(2-aminoethyl)-l,3-dioxolane (5.4 g, 46.7 nimol) in
`toluene (50 mL) containing 2 drops of glacial acetic acid was stirred
`and heated at reflux with azeotropic removal of water for 2 h.
`Concentration provided crude 4c which was used without further
`purification.
`Ethyl l-[2-(l,3-D:oxolan-2-yl)ethylJ-2-(]'methylethyl).
`4,5-diphenyl-lff-pyrrole-3-carboxylate (6c). A mixture of 4c
`(17 g, 80 mmol), benzoin acetate (75 mmol, 19 g), and ZnCij (20
`g, 147 mmol) in 100 mL of ethanol was stirred and heated at reflux
`for 2 days. The mixture was cooled to room temperature, poured
`into ether (1L), washed with water (200 mL), 2 M HC1 (100 mL),
`H20 (100 aL), and brine, and dried. Flash chromatography (silica
`gel, 10:1 v/v hexane-ethyl acetate) provided 1.2 g of 6c: 90-MHz
`NMR (CDCI3) 6 0.90 (t, 3 H, J =« 7 Hz), 1.45 (d, 6 H, J = 7 Hz),
`7 Hz), 3.8-4.1 (m, 8 H), 4.60
`1.90 (m, 2 H), 3.45 (septet, 1 H,
`(t, 1 H, J - 4 Hz), 7.0 (s, 5 H), 7.0-7.3 (m, 5 H) ppm.
`Ethyl l-(3-Oxopropyl)-5-(l-niethylethyl)-4,5-diphenyl-lH-
`pyrrole-3-carboxylate (7c). A solution of 6c (1.3 g, 3 mmol)
`and p-TSA-H20 (0.6 g, 3 mmol) in 50 mL of 4:1 acetone-water
`was stirred and heated at reflux overnight. The cooled mixture
`was poured into ether (200 mL), washed with saturated aqueous
`bicarbonate (2 X 50 mL), water (50 mL), and brine (50 mL), and
`dried. Filtration and concentration provided 1.0 g (100%) of pure
`7c which was used without further purification: 90-MHz NMR
`(CDCla) a 0.90 (t, 3 H, J = 7 Hz), 1.40 (d, 6 H, J = 7 Hz), 2.55
`<m, 2 H), 3.44 (septet, 1 H, J = 7 Hz), 3.95 (q, 2 H, J = 7 Hz),
`4.15 (m, 2 H), 7.0 (s, 5 H), 7-7.3 (m, 5 H), 9.43 (s, 1 H) ppm.
`Method B.
`JV-[2-(l,3-Dioxolan-2-yl)ethyl3-DL-valine,
`Methyl Ester (9). A solution of the methyl 2-hromo-3-
`methylbutyrate (4.6 g, 23.6 mmol), 2-(2-ammoethyl)-l,3-dioxolane
`(2.9 g, 25 mmol), and triethylamioe (3.5 mL, 25 mmol) in 25 mL
`of acetonitriie was stirred and heated at reflux for 20 h. The cooled
`solution was poured into ether (500 mL) and extracted with 2 M
`HQ (2 X 50 mL). The aqueous layer was made alkaline with 257o
`aqueous NaOH and extracted with ethyl acetate (2 X 100 mL).
`The combined ethyl acetate extracts were washed with brine and
`dried. Filtration and concentration provided 3 g (55%) of 9 as
`a yellow ofc 90-MHz NMR (CDCI3) S 0JB3 (d, J = 7 Hz, 6H), 1.70
`(br s, 1 H, 4NH), 1.86 (m, 2 H), 2.60 (m, 3 H), 2.94 (d, J « 6 Hz,
`1 H), 3.68 (s, 3 H), 3.85 (m, 4 H), 4.89 (t, J = 4 Hz, 1 H) ppm.
`iV-[2-(I^3-DioxoIan-2-y])ethyl]-Ar-(4-fluoroben2oyl)-DL-
`valine (10). To a stirred solution of 9 (3 g, 13 mmol) and tri-
`ethylamine (3.6 mL, 26 mmol) in 20 mL of CHjClj, cooled to 0
`0C, was added a solution of 4-fluorobenzoyl chloride (1.65 mL,
`14 mmol) in 10 mL of CHjCk* The solution was stirred 50 min
`at 0 0C and 60 min at room temperature. It was then poured into
`ether (200 mL), washed with water (2 X 50 mL), saturated aqueous
`bicarbonate (50 mL), and brine (50 mL), and dried. Hash
`chromatography (silica gel, 1:1 v/v hexane-ethyl acetate) provided
`3 g (65%) of crude (±)-methyl /v-(4-fluorobenzoyI)-N-[2-(2-
`ethyl)-l,3-dioxolanyl)vaUne: 90-MHz NMR (CDCI3) & O.Bfg^r
`
`M il. IP
`
`- : M
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`Inhibitors of Cholesterol Biosynthesis. 3
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`Journal of Medicinal Chemistry, 1991, Vol. 34, No. 1 363
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`tiiethylamme. The resulting mixture was cooled to 0 0C under
`dry nitrogen. A solution of 11 mL (105 mmol) of isobutyiyl
`chloride in 50 mL of CHgCl: was slowly added with stirring. After
`addition was complete, the mixture was stirred for an additional
`1 h and then poured into 100 mL of ether. The ether solution
`was washed successively with water (25 mL), 2 M HC1 (25 mL),
`saturated aqueous bicarbonate (25 mL), and brine (25 mL), and
`dried. Filtration and evaporation of the solvents yielded 35 g of
`a-[[2-(l,3-dioxoIan-2-yl)ethyl](2-methyl-l-oxopropyl)amint>]-4-
`fluorobenzeneacetic acid, ethyl esten 90-MHz NMR (CfiCls) &
`12. (m, 9 H), 1.7 (m, 2 H), 2.85 (m, 1 H), 3.35 (m, 2 H), 3.80 (m,
`4 H), 4.20 (q, 2 H, J * 7 Hz), 4.60 (t, 1 H, J = 4.5 Hz), 5.81 (s,
`1 H), 6.8-7.3 (m, 4 H) ppm.
`A solution of this ester (35 g) and 12 g (300 mmol) of NaOH
`in 480 mL of 5:1 methanol-water was stirred and heated at reflux
`for 2 h. The solution was cooled to room temperature, concen­
`trated, and diluted with 500 mL of water. The resulting solution
`was extracted with ether. The aqueous layer was then acidified
`with ice-cold 6 M HC1 and extracted with ethyl acetate (2 x 300
`mL).
`The combined ethyl acetate extracts were washed with brine,
`dried, filtered, and evaporated to yield 30 g of crude 15 as a gum
`which was used without further purification: 90-MHz NMR
`(CDCI3) 5 1.11 (d, 6 H, J = 7 Hz), 1.4-1.9 (m, 2 H), 2.85 (m, 1
`H), 3.32 (m, 2 H), 3.75 (m, 4 H), 4.52 (t, 1 H, J = 4.5 Hz), 5.73
`(s, 1 H), 6.8-7.3 (m, 4 H) ppm.
`l-[2-(l,3-Dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-(l-,
`methylethyl)-iV,4-diphenyl-lH-pyrrole-3-carboxainide (16b).
`A solution of 95 g (260 mmol) of 15 and 98 g (439 mmol) of
`//,3-diphenylpropynamide21 in acetic anhydride (200 mL) was
`heated at 90 0C with stirring for 4 h (vigorous gas evolution). The
`mixture was then cooled to room temperature, concentrated, and
`chromatographed twice on silica gel (4:1 v/v hexane-ethyl acetate)
`to separate the product (fy = 0.35,4:1 hexane-ethyl acetate) from
`the N,3*diphenylpropynamide (fy = 0.5). Recrystallization of the
`product from isopropyl ether provided 59.5 g (119 mmol) of 16b
`as colorless crystals: mp 159-162 0C; 200-MHz NMR (CDCI3)
`6 1.54 (d, 6 H, J = 7 Hz), 1.91 (m, 2 H), 3.60 (septet, 1 H, J =
`7 Hz), 3.7-4.1 (m, 6 H), 4.74 (t, 1 H, J = 4.3 Hz), 7.0-7.3 (m, 15
`H); IR (KBr) 3400,1658,1596,1530 cm"1. Anal. C, H. N.
`5-«-Fluorophenyl)-2-(l-methylethyI)-l-(3-oxopropyl)-
`AM-diphenyMH-pyrrole-S-carboxamide (17c). A solution
`of 59 g (118 mmol) of 16c and 0.4 mL of concentrated HC1 in 1200
`mL of absolute ethanol was heated under reflux with stirring for
`24 h. The mixture was cooled to room temperature and con­
`centrated and the residue taken up in 3:1 acetone-water (1200
`mL). p-TSA-HoO (5 g) was added. This mixture was heated
`under reflux with stirring for 2 days, cooled to room temperature,
`and partitioned between ether (1000 mL) and brine (200 mL).
`The organic layer was separated, washed successively with sat­
`urated aqueous bicarbonate (2 x 200 mL) and brine (100 mL),
`dried, filtered, and concentrated. The resulting oil was dissolved
`in the minimum amount of hot isopropyl ether, and the crystals
`which formed upon cooling were collected by filtration to yield
`36.8 g (81 mmol) of 17e, mp 164-5 ®C. A further crop of 9.8 g
`was obtained from the mother liquor: 200-MHz NMR (CDClj)
`61.52 (d, 6 H, J = 7 Hz), 2.68 (br t, 2 H, J = 4 Hz), 3.63 (septet,
`1H, J = 7 Hz), 4.27 (br t, 2 H, J = 4 Hz), 6.86 (br s, 1H), 7.0-7.2
`(m, 14 H), 9.60 (s, 1 H); IR (KBr) 3400,2966,1720,1673,1596,
`1511 cm"1. Anal. C, H, N.
`Methyl 7-[2-(4-Fluorophenyl)-5-(l-methylethyl)-3-
`phenyl-4-[(phenylamino)carbonyl3-lflp-pyrrol-l-yl]-3-
`hydroxy-5-oxo-l-heptanoate. A solution of methyl acetoacetate
`(26.4 mL, 243 mmol) in 250 mL of anhydrous THF was added
`dropwise to a stirred suspension of hexane-washed sodium hydride
`(6.4 g, 267 mmol) in 200 mL of THF at 0 0C. When gas evolution
`was complete, 97.2 mL of a 2.5 M solution of n-butyllithium in-
`hexanes was added dropwise over 1 h.
`The resulting solution was stirred for 30 min at 0 0C and cooled
`to -78 cC, and a solution of 36.8 g (81 mmol) of 17c in 100 mL '
`of THF was added over a period of 30 min. The resulting solution
`was stirred for 30 min at -78 0C, then warmed to 0 0CI and held
`for an additional 1 h.
`
`'
`
`(21) Cabre, J.; Palomo, A, L. Synthesis 1984, 413-7.
`
`521
`
`d, J « 7 Hz, 6 H), 1.8-2.5 (m, 3 H)t 3.45 (br dd, J « 6, 8 Hz, 1
`H), 3.72 (s, 3 H), 3.80 (m, 6 H), 4.80 (m, 1 H), 6.9-7.5 (m, 4 H)
`ppm.
`A solution of this methyl ester (1 g, 2.83 mmol) and NaOH (0.4
`g, 10 mmol) in 10 mL of 4:1 methanol-water was stirred and
`heated at reflux for 3 h. The cooled solution was diluted with
`water and extracted with ether. The aqueous layer was acidified
`with 6 M HC1 and extracted with ethyl acetate (2x). The com­
`bined ethyl acetate extracts were washed with brine and dried.
`Filtration and concentration provided 0.96 g (2.8 mmol) of 10 as
`(CDCI3) B 0.85 (m, 6 H), 1.8 (m, 2 H), 2.5
`a gum:
`(m, 1 H), 3.3-3.9 (m, 7 H), 4.6 (m, 1H), 6.8-7.4 (m, 4 H) ppm.
`Dimethyl l-[2-(lf3-Dioxolan-2-yl)ethyl]-2-(4-fluoro-
`phenylJ-S-U-methylethylJ-lH-pyrrole-S^-dicarboxylate
`(11a). Dimethyl acetylenedicarboxylate (1.3 tnL, 10.6 mmol) was
`added to a solution of 10 (1.8 g, 5.28 mmol) in 10 mL of acetic
`anhydride at room temperature. Carbon dioxide evolution began
`immediately. The solution was stirred a farther 2 h, concentrated
`to remove excess dimethyl acetylenedicarboxylate and solvent,
`and then filtered through silica gel. This provided 2 g (89%) of
`11a as a colorless solid. Reaystallization from isopropyl ether-
`hexane afforded colorless crystals: mp 143-146 "C; IR (KBr) 1719,
`1449,1241,1209,1178,945 cm"1; 200-MHz NMR (CDCI3) S 135
`(d, J = 7 Hz, 6 H), 1.80 (m, 2 H), 3.18 (septet, J = 7 Hz, 1 H),
`3.56 (s, 3 H), 3.7 to 4.0 (m, 6 H), 3.83 (s, 3 H), 4.64 (t, J = 4 Hz,
`1 H), 7-7.3 (m, 4 H) ppm. Anal. C, H, N.
`•
`Dimethyl 2-(4-Fluorophenyl)-5-(l-inethylethyl)-l-(3-oxo-
`. propyl)-li7-pyrrole-3,4-dicarboxylate (12a). A solution of 11a
`(0.5 g, 1.18 mmol) and p-TSAHH^O (0.23 g, 1.2 mmol) in 12 mL
`of 5:1 acetone-water was stirred and heated at reflux for 48 h.
`The cooled solution was concentrated, diluted with ether (200
`mL), washed with saturated aqueous bicarbonate (2 x 50 mL)
`and brine (50 mL), and dried. Flash chromatography on silica
`gel (4:1 v/v hexane-ethyl acetate) provided 0.4 g (90%) of pure
`12a: 90-MHz NMR (CDCI3) 11.35 (d, J = 7 Hz, 6 H), 2.61 (t,
`J « 7 Hz, 2 H), 3.18 (septet, J = 7 Hz, 1 H), 3.53 (s, 3 H), 3.81
`(s, 3 H), 4.03 (t, J = 7 Hz, 2 H), 6.9-7.3 (m, 4 H), 9.45 (s, 1 H)
`ppm.
`Ethyl l-[2-(l,3-Dioxolan-2-yl)ethyl]-2-(4-fluorophenyI)-
`5-(l-methylethyl}*4-phenyl-lJ7-pyrrole-3-carboxylate (11c).
`A mixture of 10 (3.0 g, 8.8 mmol), acetic anhydride (15 mL), and
`' ethyl phenylpropiolate (3.0 g, 17.6 mmol) was stirred at 110 "C
`for 5 h. The solution was then cooled and the excess acetic
`anhydride removed under vacuum. The residual dark oil was
`purified by flash chromatography on silica gel (4:1 v/v ethyl
`acetate-hexane). The product solidified on standing and was
`reciystallized from ether-hexane. The first crop gave 2.2 g (30%)
`of pure lie: 90-MHz NMR (CDClj) $ 0.65 (t, 3 H, J = 7 Hz),
`1.10 (d, 6 H, J = 7 Hz), 1.7-2.0 (m, 2 H), 3.00 (septet, 1 H, J =
`7 Hz), 3.6-4.0 (m, S H), 4.60 (t, 1 H, J = 4 Hz), 6.9-7.4 (m, 9 H)
`ppm.
`Method C. Ethyl a-[[2-(l,3-Dioxolaii-2-yl)ethyl]aniino]-
`4-fluorobenzeneacetate (14). A solution of 26 g (220 mmol)
`of 2-(2-aminoethyl)-l,3-dioxolane in 50 mL of acetonitrile was
`added at room temperature with stirring to a solution of 52 g (200
`mmol) of ethyl ir-bromo-^fluorobenzeseacetate30 and 42 mL (300
`mmol) of triethylamine in 350 mL of acetonitrile. The resulting
`mixture was stirred at room temperature overnight and then
`poured into ether (500 mL). The suspension which resulted was
`washed with water (300 mL) and 2 M HC1 (2 x 300 mL). The
`combined addic extracts were made alkaline with 25% aqueous
`NaOH and extracted with ethyl acetate (2 x 500 mL). The ethyl
`acetate extracts were combined, washed successively with water
`and brine, and dried. Filtration and concentration yielded 49.5
`g (82£%) of 14 as an oil: 90-MHz NMR (CDClj) 6 1.18 (t, 3 H,
`<7 = 7 Hz), 1.85 (m, 2 H), 2^0 (br s, 1 H), 2.6 (m, 2 H), 3.85 (m,
`4 H), 4.1 (q, 2 H, J = 7 Hz), 4.22 (s, 1H), 4.83 (t, 1 H, J = 4.5
`Hz), 6.8-7.3 (m, 4 H) ppm.
`ff-[{2-(l,3-Dioxo]an-2-y])ethy]3(2-methy]-l-oxopropyl)-
`&mino]-4-flaorobenzeneacetic Acid (15). 14 (30 g, 100 mmol)
`was dissolved in 200 mL of C^Clj with 28.6 mL (205 mmol) of
`
`(20) Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann,
`C. M.; McKenzie, T. C.; Saiir, S. R.; Osterberg, A. C.; Cosulich,
`D. B.; Lovell. F. M. J. Med. Chem. 1981,24, 481-90.
`
`p
`
`ft
`K
`
`S"
`
`.
`
`J
`
`j
`
`:
`
`5ifr
`
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`Page 3015 of 4322
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`

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`m n . -
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`•
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`364 Journal of Medicinal Chemistry, 1991, Vol. $4, No. 1
`
`The mixture was then ecidiiied by the dropwise addition of
`300 mL of ice-cold 3 M HC1, diluted with ether, washed with water
`and brine, dried, filtered, and evaporated. Flash chromatography
`on silica gel (3:1 v/v hexane-ethyl acetate) yielded 37.9 g of methyl
`7-[2-(4-fluorophenyl)-5-(l-methylethyl)-3-phenyl-4-[(phenyl-
`amino)carbonyl]-ltf-pyiTol-l-yl]-5-hydroxy-3-oxo-l-heptaiioate:
`90-MHz NMR (CDCI3) 6 1.50 (d, 6 H, J = 7 Hz), 1.8 (m, 2 H),
`2.45 (d, 2 H, J = 7 Hz), 2.8 (br s, 1 H), 3.33 {s, 2 H), 3.5 (m, 1
`H), 3.67 {s, 3 H), 3.8-4.0 (m, 2 H), 6.8-7.3 (m, 14 H) ppm.
`(i)-traiis-5-(4-Fluorophenyl)-2-(l-iaethylethyl)-JV,4-di-
`phenyl-l-[2-(tetrahydrCH4-hydroxy-6-oxo-2F-pyran-&-yl)-
`ethyl]-l£r-pyrroIe-3-carboxamide (3i). Air (60 mL) was
`bubbled via a syringe through a solution of methyl 7-[2-(4-
`fluorophenyl)-5-{l-methylethyl)-3-phenyl-4-[(phenylaamo)-
`carbonylJ-lH-pyrrol-l-yl)-5-hydroxy-3-oxo-l-heptanoate (48 g,
`84 mmol) and 92.5 mL of a 1M THF solution of tributylborane
`in 100 mL of anhydrous THF. The mixture was stirred overnight
`at room temperature and then cooled to -78 0C. Sodium boro-
`hydride (3.85 g, 102 mmol) was added to the cooled mixture in
`one portion. The vigorously stirred suspension was allowed to
`warm slowly to 0 0C over 3 h (vigorous gas evolution ensued).
`The dry ice-acetone bath cooling the reaction vessel was re­
`placed by an ice bath and 18.3 mL of glacial acetic add was added
`dropwise, followed by 204 mL of 3 N NaOH and 30.5 mL of 30%
`aqueous HjOi-
`The mixture was vigorously stirred and allowed to warm to
`room temperature overnight. The mixture was partitioned be­
`tween ether and water. The aqueous layer was separated, acidified,
`and extracted with ethyl acetate (2x).
`The ethyl acetate extracts were washed with brine, dried, and
`evaporated to yield crude (fl*tfl')-3,5-dihydroxy-7-[(4-fluoro-
`phenyl)-5-{l-methylethyl)-3-phenyl-4.[(phenylamino)-
`carbonyl]-lH-pynoH-yl]-l-heptanoic add which was used without
`further purification.
`The crude acid was taken up in toluene and heated at reflux
`for 6 h with azeotropic removal of water. Chromatography (silica
`gel, 1:1 v/v hexane-ethyl acetate) provided 30 g of 3i as a foamy
`solid, mp 90-97 0C.
`.
`This material was found by HPLC analysis to be a 9:1 mixture
`cis and trans isomers. Recrystailhation from toluene-ethyl acetate
`yielded essentially pure trans 3i: mp 148-9 0C; 200-MHz NMR
`(CDC13> 5 1.52 (m, 6 H), 1.6-2.0 (m, 4 H), 2.48 (br s, 1 H), 2.51
`(m, 2 H), 3.55 (septet, 1 H, J = 7 Hz), 4.0-4.2 (m, 2 H), 4.29 (m,
`1 H), 4.52 (m, 1 H), 6.90 (br s, 1 H), 7.0-7.3 (m, 14 H) ppm; IE
`(KBr) 3400,1734,1654,1597,1511 cm"1. Anal. C, H, N.
`Phenylmethyl l-[2-(l^-Dioxolan-2-yl)ethyl]-5-(4-fluoro-
`phenyl)-2-(l-methylethyl)-4-phenyl-l.H'-pyrrole-3-
`carboxylate (16a). A solution of 15 (10 g, 29 mmol) and benzyl
`phenylpropiolate (7.7 g, 44 mmol) was stirred and heated in 30
`mL of acetic anhydride at 90 ®C for 6 h. After cooling to room
`temperature, the solution was concentrated, diluted with ether,
`washed with water, saturated aqueous bicarbonate, and brine,
`and dried. Flash chromatography on silica gel (10:1 v/v hex­
`ane-ethyl acetate) provided 5.9 g (-45%) of crude 16a. Recrys-
`tallization from isopropyl ether provided 4.8 g of colorless 16a:
`mp 158-9 0C; m (KBr) 1683 cm"1; 200-MHz NMR (CDCI3) 6 0.93
`(t, 3 H, J = 7 Hz). 1.48 (d, 6 H, J - 7 Hz), 1.93 (m, 2 H), 3.50
`(septet, 1H, J = 7 Hz), 3.7-4.1 (m, 8 H), 4.71 (t, 1H, J = 4.4 Hz),
`6.95-7*2 (m, $ H) ppm. Anal. C, H, N.
`Method D.
`l-[2-(lT3-Dioxolan-2-yl)ethyl]-2-(4-fluoro-
`pheiiyl)-3,4-dimethyl-5*(l-methylethyl)-lB'-pyrrole (18). A
`solution of 11a (1.0 g, 2.37 mmol) in 5 mL of CHjClj was added
`dropwise to a stirred suspension of lithium aluminum hydride
`(0.3 g, 7.4 mmol) in 20 mL of ether at room temperature. When
`addition was complete, the mixture was heated to reflux for 30
`mln, cooled to room temperature, and quenched by dropwise
`addition of water (0.3 mL), 25% aqueous NaOH (0.2 mL), and
`water (0.9 mL). After stirring vigorously for 30 min, the mixture
`was filtered and washed well with CHjCl* The filtrated was dried,
`filtered, and concentrated, providing 0.78 g (90%) of pure diol.
`Trifluoroacetic add (5.2 mL, 67 mmol) was added to a stirred
`solution of the diol (1.23 g, 3.4 mmol) and triethylsilane (1.2 mL,
`7.5 mmol) in 10 mL of CHjClj cooled to 0 0C under dry nitrogen.
`The solution was stirred for 2 h at 0 0C before warming to room
`temperature for 1 h. It was then poured into 300 mL of 50:50
`ether-hexane and washed with saturated aqueous bicarbonate
`
`Roth et al.
`
`(3 X 50 mL) and brine (50 mL), and dried. Flash chromatography
`on silica gel (10:1 v/v hexane-ethyl acetate) provided 0.80 g (71%)
`of 18 as an oil: 90-MHz NMR (CDCI3) 6 1.32 (d, 6 H, J « 7 Hz),
`1.7-1.9 (m, 2 H), 1.86 (s, 3 H), 2.07 (s, 3 H), 3.10 (septet, 1 H, J
`»» 7 Hz), 3.7-4.0 (m, 6 H), 4.58 (t, 1 H, J = 4 Hz), 6.9-7.3 (m, 4
`H) ppm.
`Method E. Methyl 4-Methyl-3-oxo-2'(phenyl-
`methylene)pentanoate (21a). A mixture of methyl iso-
`butyzylacetate (144 g, 1 mol), benzaldehyde (116 g, 1.1 mol),
`piperidine (4 mL), and HOAc (12 mL) ia 200 mL of toluene was
`stirred and heated at reflux with azeotropic removal of water for
`3 h. The solution was cooled, poured into ether (1L), washed
`with 1M