HMC-COA Reductase Inhibitors, i.
`
`i/ournai 0/ Medieinat Chemistry, i990, Vol, 33, No. 2 63
`
`Table 1. Inhibition of Solubiiued Rat LWar HMC-CoA Reducuue in Vitro4 for Compounds of the Genera] Structure 1,' 2,' and 13*
`HO V^COjR'
`O?' rH
`
`i
`
`H\
`
`s*
`A
`
`no.
`
`la
`lb
`2b
`13b
`ic
`2c
`Id
`2d
`le
`2e
`l i t
`If
`
`Rl
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`Na
`
`Rl
`CH3
`j-Pr
`i-Pr
`i-Pr
`CH,
`CH,
`CH,
`CH,
`i-Pr
`i-Pr
`j'-Pr
`i-Pr
`
`R*
`Ph
`Ph
`Ph
`Ph
`Ph
`Ph
`i.Pr
`i»Pr
`i'Pr
`i-Pr
`t'-Pr
`
`R4
`H
`H
`H
`H
`CH,
`CH,
`H
`H
`H
`H
`H
`
`2f
`
`Na
`
`Na
`Na
`Na
`
`i-Pr
`
`i-Pr
`i-Pr
`i-Pr
`
`Ph
`Ph
`Ph
`
`H
`
`CH,
`CH,
`CH,
`
`Q H
`0
`
`& R*
`1
`RJ
`I' a * . and 1 3 *
`R4
`A-B
`p-C,H«F CH-CH
`p-C«H4F
`CH-CH
`P-C1H4F
`CHtCHt
`p-C|H«F
`CHjCH,
`P'C(H«F CH-CH
`CHJCHJ
`p-C,H4F
`p«CtH«F CH-CH
`P'CfHjF
`CHjCH?
`p.C,H4F CH-CH
`p-C|H«F
`CHjCH}
`p-CtH.F
`CH?CHa
`p.C,H4F CH-CH
`
`formula
`CuHsFN04Na
`C.HT,FN04N»
`CHH9FNO«Na
`C^HJIFNO^NI
`CuHuFNO^a
`C»HnFNO,Na
`C^HoFNO^Na
`C,|HtTFN04Na
`CoH»FN0,Nt
`CsHsiFNO^Na
`CaK»FNO«Na
`CNHuFNO«Na
`
`anal.'
`C, H, N
`C, H, N
`C, H.N
`C, H.N
`C.H.N
`C, H, N
`C.H.N
`C. H.N
`C,H.N
`C. H.N
`C. H.N
`C. H. N
`
`IC^ nM
`65
`7
`6
`3
`2SQ
`70
`330
`100
`in
`IS
`9
`69
`
`reH pot..
`12
`no
`128
`25?
`3
`11
`2
`9
`6
`42
`8S
`12
`
`p-C,H4F
`
`CHJCHJ
`
`Ca,HuFNO«Na
`
`C. H.N
`
`9
`
`P'C4H«F
`p-C,H«F
`p-CtH<F
`
`CH—CH
`CH,CH}
`CHjCHt
`
`C.H.N
`C.H.N
`C, H, N
`
`92
`m
`6
`CT|H«FNO«Na
`i e
`149
`CnH»FN04Na
`S
`28
`24
`13K
`300
`CflHs>FNO«Na
`8
`100
`C^HyO.Na
`mevinolin
`•The aisay sy«tm dtsctibed in ref \ waau»ed. *Rin;>opened »odium dihydroxy carboxylate form,optically pure. 'Racemic. 'Optically
`active
`configuration. 'Analytical results were within *0.4% of the theoretical value. 'ICw values were determiaed by uaing four or
`(ivc concentraiions of each inhibitor. ' For estimation of relative inhibitory potencies, mevinolin was assigned a value of 100. The IC* value
`of lest compound was compared with that of mevinolin, corrected for the somewhat different molecular weight.
`
`*
`
`1
`
`1
`
`]
`
`Scheme V
`
`B'A-AK, —
`19
`
`I
`H
`
`22
`
`Ph
`
`R*
`
`-i-
`
`Scheme VI*
`
`O O
`R4
`I
`AJL
`RsCH=CNO? • R*
`OEl —~
`
`15
`
`19
`
`o
`•N*Ph
`H
`R*
`
`-S±- 4
`
`* |
`
`s
`
`[
`
`|
`
`HN^R*"
`I
`R'
`
`23
`
`R^^N'
`I
`R®
`24
`/(a) PhNHt/AcOH; (b) R3NH,/AcOH/-H,0; (c) 15/^; (d)
`KaH/CHjI/toluene/^; (e) LiAlH4/A; (O CrOj/pyridine-
`
`I
`
`£
`
`4
`
`> r .
`
`functionality much faster than the keto group of 19. In
`this case, it was necessary to preform the anilides 22
`(Scheme V). Addition of aliphatic or aromatic primary
`amines R*NHj to 22 under add catalysis gave 23, which
`were cyclocondensed with nitroethenes 15 to give 3'
`Pyrroiecarbanilides 24. While amides on LAH reduction
`usually lead to the corresponding amines, carbasilides 24
`could be reduced to the corresponding aldehydes 4 via
`N'inethylation, LAH treatment, and subsequent oxidation.
`A new three-component coupling reaction allowed a
`one-pot synthesis of ethyl lt2-diisopropyI-4-(4-fluoro-
`Phsny]).lH-pyrrole-3-carboxylate (21. Scheme VI).
`When a methanolic solution of /S-nitro-p-fluorostyrene
`<15: R« = H. R5 = p-C6H,F>, jj-keto ester 19 (R* = i-Pr).
`isopropylaniine was stirred at ambient temperature,
`t"* pyrrole ester 21 was obtained in 50% yield. LAH
`'eduction followed by ruthenium(II)-catalyzed oxidation
`
`-
`
`RisC OiB t
`
`b.e
`
`R»
`
`R>
`21: R* » R* »i'Pt.
`R* * H,
`*•-0-'
`'(a) R3NHj/CHjOH/25 *0/1 day; (b) UA1H<; (c) 4 equiv of
`<Q "*** /0.02 equiv of (Ph^),RuCl,.
`
`of the alcohol with N-methylmorpholine-N-oxide11 gave
`the corresponding aldehyde 4. Tliis convenient three-
`component coupling may also be applicable for the
`syntheses of pyrrole esters 21 with other substitution
`patterns for R^-R*.
`Biological Results and Discussion
`The racemic sodium salts (1 asd 2, Rl * Na) as well as
`the optically active sodium salts 13 (R1«.Na) were eval­
`uated for their ability to inhibit solubilized, partially pu­
`rified rat liver HMG-CoA reductase in vitro (Table 1) and •
`
`(11) Sharpless, K. B.; Akashi, Oshima. K. Tttrahedron Lttt.
`1976,29.2503.
`
`426
`
`Sawai Ex 1005
`Page 2389 of 4322
`
`

`
`Jendrclta et a I.
`
`Table III. Inhioiiion of Hepatic Cholesterol "De Novo"
`Sv-nihesis in Vivo {Rat. Ora!ly),
`HO
`V^COjR'
`
`TH
`
`R\
`
`A
`
`R*
`
`I
`RJ
`
`relative
`potency
`
`J and 2
`% cholesterol
`"de novo* synthesis
`100
`no drug
`100
`14
`mevinolin*
`235
`5.5
`lbc
`250
`5.6
`2b(
`2f
`9
`156
`2r
`233
`6.0
`'Lactone form, optically pure, 5
`'Assay described in ref 16.
`mg/kg bw. 'Raeemic sodium salts, 10 mg/kg bw. For definition of
`R'-R4 and A-B see Table I.
`
`For better comparison of structure-activity relationships
`in I and 2 as well as with extensive work on analogues of
`the phenolic type (isocydic central aromatic, A = oxygen,
`B « CHj),14,15 R5 was kept constant as p-fluorophenyl. -
`The work on analogues of the phenolic type14,15 has
`shown that alkyl substitution of the second ortho position
`is essential and leads to optimal biological activity for an
`isopropyl substituent.
`We concentrated on R2 = methyl or isopropyl, since
`ortho substituents smaller (methyl, ethyl, longer n-alkyl)
`or larger (cydopentyl, feri-butyl) than the isopropyl group
`decreased activity in analogues of the phenolic type14,1* and
`since halogen substituents (CI, Br) led to good activity but
`increased toxicity.
`Table 1 shows that the isopropyl derivatives were more
`potent than the methyl derivatives by a factor of 10-40
`(e.g. lb vs la, Ig vs 1c, 2g vs 2c).
`There is much tolerance concerning R3. Variation of R3
`(Ph, i-Pr, cyclohexyl) led to only small activity changes (e.g.
`2b vs 2e vs 2f, lb vs le vs If, la vs Id).
`Substitution of R4 = hydrogen for a methyl group either
`slightly decreased (e.g. la vs le) or slightly increased (2b
`vs 2g and lb vs lg) activity, depending on the nature of
`the other substituents. Hydrogenation of the trans olefmic
`bridge (A-B * (£)-HC—CH) had little influence on the
`biological activity of 1 in vitro (e.g. lb vs 2b, 1c vs 2c; Id
`vs 2d, le vs 2e, If vs 2f, lg vs 2g); however, the hydro*
`genated derivatives 2 were much less acid sensitive (vide
`supra) and much more active in vivo.
`.
`;
`In the HEP G2 cell-test (Table II) the racemic com­
`pounds lb, 2b, and 2e are 3.5, 5.0, and 25 times, respec­
`tively, more active than optically pure mevinolin sodium
`salt of the same concentration. General trends in Tables
`I and II are comparable. The superiority of lb, 2b, and
`
`(14) Baader, E.; Bartmann, W.; Beck, G.; Bergmann. A.; Granxer
`E.: Jendralla, H.; von Kerekjarto, B.; Kesseier, K.: Krause, R
`Wess, G. International Symposium on Cholesterol Control And
`Cardiovascular Diseases: Prevention And Therapy, Mila»
`(Italy) July 7-9,1987; Abstract book page 133.
`'
`(15) European Application 0216 127,1987.
`(16) Dieuchy, J. M.; Spady, D. K. J. Lipid Res. 1984 , 25, 1469-
`Alfln-Slater, R. B.; Deuel. H. J., Jr.; Scholtz, M. C.; Shimodfc
`F. K. Group Report Nc. N3, 1950; University of Southero
`California. Consolidated Eng. Corp.
`
`427
`
`64 Journal of Medicinal Chemistn,', 1990, Vol. 33, No. 1
`
`Table II. Inhibition of Cellular JiMG-CoA Reductase in
`Cultures of HEP G2 Cells* for Sodium Salts of the General
`Formula 1( and 2'
`
`'
`
`HO
`Y^COJR'
`L^OI
`A X-
`
`fH
`s*
`
`R»
`
`R\
`
`R*
`
`I
`R'
`leand 2e
`relative* potency
`ICw* fiM
`mevinolin*
`0.05
`100
`0.83
`la
`6
`350
`lb
`0.014
`>500
`<0.01
`2b
`1
`5.0
`1c
`9
`0.57
`2c
`1
`Id
`6.0
`19
`0.27
`2d
`100
`0.05
`le
`2500
`2e
`0.002
`47
`If
`0.106
`275
`2f
`0.018
`'Ring-opened sodium
`•Assay described in the preceding paper.1
`dihydroxy carboxylate form, optically pure. 'Racemic. For defi­
`nition of R'-R* and A-B see Table 1. ' ICu values varied some­
`what for different batches of eel)*. Mevinolin sodium salt averaged
`ICJO a 5 x 10"* M and was used in every run as an internal stand­
`ard. The measured IC's for test compounds 1 and 2 were corrected
`for deviations of mevinolin'a IC from its average value. 'Mevinolin
`was assigned a value of 100. Potencies were obtained by compari­
`son of racemic test compounds 1 or 2 with the internal standard
`mevinolin.
`
`to inhibit cellular HMG-CoA reductase in cultures of
`hepatic cells (HEP G2, a human hepatoma cell line), as
`determined by the inhibition of the incorporation of so­
`dium [14C]aeetate into cholesterol (Table 12).
`Selected compounds were evaluated for their ability to
`inhibit hepatic cholesterol "de novo" synthesis in male rats
`after po administration, as determined by the inhibition
`of the incorporation of sodium (14C]octanoate12 into hepatic
`cholesterol (Table III).
`Selected compounds were further evaluated for their
`ability to decrease plasma cholesterol levels in normoli-
`pemic rabbits and dogs after po administration.
`All tests were also conducted under the same experi­
`mental conditions with optically pure mevinolin. The
`respective results are included in Tables MIL For sub­
`stitution patterns "b", "e", and "g", we prepared and tested
`the racemic 2 as well as the optically active 3ft, 5ft sodium
`salt 13. Optically active compounds 13 proved to have
`twice the potency in HMG-CoA reductase inhibition than
`the structurally identical but racemic 2 (Table 1). This
`result was expected, since the antipode of the configuration
`drawn for 1,2, and 13, is biologically inactive.13
`
`(12) Dieuchy, J. M.; McGarry, J. D. J. Biol. Chtm. 1974,249, 52.
`Andersen. J. M.; Dieuchy, J. M. J. Lipid Ret. 1979,20,740.
`Stenge, E. F.; Dieuchy, J. M. J. Lipid Rta. 1983,24,72.
`(13) 3-epi, 5-epi, and "3,5-bis epi isomers of compactin and mevi­
`nolin have been reported to be biologically inactive: Heathy
`cock, C. H.; Hadley, C. R.; Rosen. T.; Theisen, P. D.; Hecker,
`S. J. J. Med. Chem. 1987,30,1858. Stokker, G. E.; Rooney,
`C. S.; Wiggins, J. M.; Hirshfield. J. J. J. Org. Chem. 1986,51,
`4931. The biological inactivity of synthetic compactin ana­
`logues with 3S configuration has also been reported: Lee, T.-J.
`Trends Phormaeoi. Set. 1987, 8. 442 and references cited
`therein.
`
`• -
`
`Sawai Ex 1005
`Page 2390 of 4322
`
`

`
`HMG'COA Reductase Inhibitors. 2^.
`
`Journal of M f '' :iol Chemistry, 1990, VoL 33, No. I 65'
`
`especially 2e compared with mevinw.Ji is more pronounced
`in the cell test, inhibition of hepatic cholesterol "de novo"
`synthesis in vivo by oral lb or 2b is about 2.5 times
`stronger than that for mevinolin (Table UI). In normally
`fed rabbits (n = 6), 20 mg/kg racemic 2b decreased total
`plasma cholesterol levels by 34% after oral administration
`' for 10 days (optically pure mevinolin at 10 mg/kg for 10
`days* 25%), wile lb was totally inactive under the same
`conditions. The reason for the lack of activity of lb in the
`rabbit experiment is currently not known.32 The chemi­
`cally demonstrated add sensitivity of lb (vide supra) would
`suggest that, contrary to 2b, lb may not survive the
`_ | stomach passage. However this view is not consistent with
`B
`the comparable activity of lb and 2b to inhibit hepatic
`_ I;
`cholesterol Nde novo" synthesis in rats after po adminis-
`[
`tration (Table III). In normally fed rabbits (n = 4), 10
`mg/kg racemic 2e decreased total plasma cholesterol levels
`by 42% after oral administration for 6 days (optically pure
`I
`| mevinolin at 10 mg/kg for 6 days, 25%).17'1B
`••
`In normally fed male beagle dogs (n = 4), 20 mg/kg
`2
`racemic 2b decreased LDL-cholesterol levels by 48% and
`- P
`J* \
`increased HDL-cholesterol levels by 14% after oral ad-
`^ ministration for 14 days (optically pure mevinolin at 10
`u mg/kg for 19 days: LDL>cholesterol -18%, HDL-chole-
`pS \
`sterol +2%).18
`In conclusion, some compounds of general formula 2
`,ni 1
`exceeded mevinolin in their ability to inhibit HMG-CoA
`reductase in vitro and to inhibit cholesterol biosynthesis
`yj' i
`^ \
`in vivo. They are promising candidates for development
`as antiarterosclerotic agents.
`on :
`an
`Experimental Section
`For general remarks see the preceding paper in this issue.1 lH
`ice 5
`NMR spectre were recorded in CDClj, unless noted otherwise.
`yl) 1
`All starting materials were commercially available unless indicated
`>up R
`otherwise.
`ind f
`l-(p*Fluorophenyl)>2«n>tropropeDe (15). A solution of
`p-fluorobenzaldehyde (84 g), nitroethene (69.4 g), and n-butyl-
`sut 1
`amine (4 mL) in xylol (110 mL) was tefluxed for 20 h under a
`i
`ore g Dean-Stark trap. On cooling to 0 *C. 21.7 g of the product
`-40 li
`crystaUized (mp 64-^5 eC). To the filtrate were added nitroethene
`-•
`(41.4 g) and n.butylamine (3 mL). and the solution was refluxed
`• oi (
`for 14 h under a Dean-Stark trap. The solution was evaporated
`| in vacuo and the residue was digerated with methanol at 0 "C,
`e-8' {
`until crystallization occurred. The crystals were collected and
`Q washed with cold methanol (53.8 g, mp 65-66 *C). Anal. (Cj-
`•her| HJFNOJ) C. H. F, N.
`(2b
`Ethyl 3-(Phenylamino)«but'2(£)-enoate (20). A solution
`;
`eof
`aniline(45J>mL,0.5mol),ethylacetoacetate(615mUO^mol),
`Inic •
`8nd glacial acetic acid (1 mL) in toluene (100 mL) was refluxed
`the
`for 4 h under a Dean-Stark trap. The solvent was evaporated
`- id I
`an^ ^ residue was distilled to give 57.9 g of colorless oil: bp
`S \ (C„H15NO})C.H.N.
`j *
`t H8-120 -C (1.5 mm); MS CuHMNO< m/e « 205 (M*). Anal.
`
`x
`
`- - L I
`
`N.^V.Bis(3-(4*fluorophenyl)-4-(methoxycarbonyl)-5-
`. 5
`n)ethyl-2^.dihydrofuran-2-yl]hydroxylamine (17). To a
`•
`on* | stirred solution of sodium methanolate (2.92 g, 54 mmol) in
`pCC* [ methanol (54 ml) was added methyl acetoacetate (20.9 g. 180
`iu0 [
`"tmol) dropwise at 0 *C followed by 4-Auorfr-d-nitrostyrene19 (30.1
`blci | K. 180 mmol). After 15 min, a thick mash formed that was allowed
`an<) | toWand for 2 h at 0*C. The sdid was collected hy suction, washed
`with keloid methanol and dried over P^Om in vacuo to give 22.0
`C of colorless solid: mp 139-141 "C; 7.0 g of product were obtained
`from the mother liquor; NMR i 2.25 (6 H. s). 3.32 (3 H, s). 3.50
`<3 H. s). 4.30 (2 H. dd). 5.40 t7H. d). 7.16 (8 H. d), 8.72 (1 H. s);
`
`inttf'
`•.e. £•
`l A f f
`MiWi
`
`146»
`mod1,
`.the14
`
`Hypocholeaterolemic activity in rabbiu was tested following
`the protocol described in ref 1.
`.
`U8) Hypocholeaterolemic activity in animal studies will be de-
`scribed in detail in a future publication.
`(1°) Qatiernann.Wieland Die Praxis det Organischeri Chemikers,
`43rd ed.; W. de Gruyter. Berlin, 1982; P 361.
`
`MS CscHaFjNOt FAB m/e - 502 (M + H*), 458. 235. Anal.
`(CMHSSFjNO?) C, H. F, N.
`l«Phenyl»2*met)iyl*3»(iDethoxycarbonyl)-4-(4'fluoro.
`phenyl)-l£r.pyrrole (18a). Aniline (5^9 g, 60 mmol) was added
`to a solution of hydroxy lam tno compound 17 (15 g, 30 mmol) in
`ethanol (600 mL). The mixture was refluxed for 24 h. Aniline
`(1.1 g) was added and the mixture was refluxed for 16 h. The
`solvent was removed in vacuo and the residue was distributed
`between dichloromethane and 1N hydrochloric add. The organic
`layer was washed with saturated sodium bicarbonate solution and
`then with brine, dried, and concentrated. Tbe residue was
`chromatographed with n-hexane/ether/dichloromethane
`(16&.5&5) over silica, giving 4.0 g of reddish, thick oil: NMR
`S 2.43 (3 H, s), 3.70 (3 H, s), 6.70 (i H, s), 6J7~7.66 (9 H. m); MS
`CuHuFNO, m/e « 309 (M+), 276,248. Anal (QJHJ^FNOJ) C.
`H. F. N.
`Msopropyl-2-niethyI-3-(n!ethoxycarbonylM*(4*fluoro»
`phenylH-ff-pyrrole (18d). Isopropylamine (3.6 g, 60 mmol)
`was added to a suspension of hydroxylamino compound 17 (15
`g. 30 mmol) in methanol (500 mL). 'Hie suspension was heated
`for 2 h at 40 CC and for 5 h at SO 0C, changing to a clear solution.
`The solvent was removed in vacuo and the residue was chro­
`matographed with n-hexane/ether (4:1) over silica to yield 7.3
`g of pale reddish crystals: mp 97-99 0C; NMR & 1.42 (6 H, d),
`2.53 (3 H. s). 3.65 (3 H. s). 4.37 (1H. sept). 6.60 (1H, s), 6.80-7.46
`(4 H. m); MS C,8H„FNO, m/e = 275 (M+), 244,202,201. Anal
`(C.jHJBFNO,) C. H.F, N.
`Ethyl l-Phenyl*2.5-dimcthy].4*(4'fluoropheDyl)*lJY-
`pyrrole^.carboxylate (21c). A solution of 20 (23.1 g, 113 mmol)
`and 15 (20.5 g, 113 mmol) in ethanol (250 mL) was refluxed for
`30 h. The solvent was evaporated in vacuo and the residue was
`chromatographed over silica (1 kg) with cydohexane/ethyl acetate
`(95:5) to give 26.0 of a colorless oil: NMR 6 1.05 (3 H. t), 1.85
`(3 H. s). 13 {3 H. s). 4.1 (2 H, q), 6.9-7.6 (9 H, m); MS C,, H»FNOj
`m/e = 337 <M+). 308, 292. Anal. (CjtHjoFNOj) C, H. F, N.
`Preparation of Substituted liTPyrrole&carboxaldehydes
`4 from Substituted 3-(AlkoxycarboDyl)*l/f•pyrroles 18 or
`21. General Procedure. A solution of ester 18 or 21 (82 mmol)
`in ether (150 mL) was added dropwise at 0-5 *C to the stirred
`suspension of lithium aluminum hydride (7.8 g, 200 mmol) in ether
`(300 mL). The suspension was stirred for 1 h at 0 *C and then
`for 2 h at room temperature. At 0 *C. 35 mL of ethyl acetate and
`then 16 mL of water followed by 24 mL of 2 N aqueous sodium
`hydroxide were added dropwise. The suspension was stirred for
`30 min at room temperature and filtered. The filtrate was con­
`centrated in vacuo and the residue was chromatographed over
`1 kg of silica with cydohexane/ethyl acetate (2:1) containing 0.2%
`triethylamine (yield 85-95%).
`To a solution of the substituted 3-(hydroxyinethyl)pyrrole (70
`mmol) in ether (1.2 L) and triethylamine (12 mL) was added
`activated manganese dioxide (1823 g). The suspension was stirred
`at room temperature under nitrogen. After 24 h, the same amount
`of manganese dioxide was added. After 24 h the soUd was removed
`and washed with ether. The filtrates were concentrated in vacuo;
`the residue was chromatographed over silica with cyctohexane/
`ethyl acetate (6:1) containing 0.1% triethylamine (yield 65-85%).
`l-Phenyl.2,5>dimethyl.3*(hydroxymethyl).4~(4-fluoro.
`phenylM/f-pyrrole: colorless oil. crystallizing on standing;
`NMR J 1.3 (1 H. br s). 2.0 (3 H, s). 2.1 (3 H. s), 4.55 (2 H. s).
`6.9-7.65 (9 H. m); MS C„H,$FNO m/e « 295 (M*), 278 (M* -
`OH). Anal (CwH,eFN0) C, H, F, N.
`l'Phenyl>2>methyl.3-(bydroxyniethyl).4-(4>fluoro.
`phenylM/f-pyrroJe: pale yellow, resinous solid: NMR & 13 (1
`H, br s), 126 (3 H. s). 4.63 (2 H. s), 6.87 (1H, s). 6.93r7.70 (9 H.
`m); MS CuH,6FN0 m/e = 281 (M+). 264 (M" - OH). Anal.
`• (CwHwFNO) C, H. F, N.
`l-Isopropyl-2'methyl-3-(hydroxyraetbyl)-4-(fIuorO'
`phenylWtf-pyrrole: colorless oil; MS C^HuFNO m/e «= 247
`(M* - OH). 188. Anal. (C,sH,8FNO) C, H, F, N.
`l-Phenyl*2*methyl'4'(4.fluoropheny])*lff-pyrrole-3«
`carboxaldehyde (4a): yellow, resinous solid; NMR 6150 (3 H,
`s). 6.80 (1H, s), 6.85-7.70 (9 H. m). 10.03 (1 H, a); MS CUHMFNO
`m/e - 279 (M*), 278 (M* - H). Anal. (CwHwFNO) C. H, F, N.
`l*Pheayl*2,5'dimethyl*4-(4-nuorophenyl)*lif'pyrrole«3*
`carboxaldehyde (4c): yellow solid; NMR 6 1.94 (3 H, a), 2.35
`(3 H, J), 6.95-7.7 (9 H, m), 9.85 (1 H. s); MS CwHj.FNO m/e =
`
`428
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`66 Journoi
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`of Medicinal C^pmistry, 1990. Vo/. 33, No. I
`
`.
`293 {M+). Anal. (C19H1SFNU C. H, F, N.
`l-Isopropyl-2-mcthyl-4-(4-nuoropheDyl)-lH-pyrrole-3-
`carboxaldehyde <4d): colorless oil; NMR S 1.43 (6 H. d), 2.60
`(3 H. s), 4.30 (1 H. sept). 6.68 (1 H, s). 6.9-7.56 (4 H. m). 9.92 (1
`H, s); MS C19H|(FNO m/e a 245 (M*), 202. Anal. (C,5Hl6FN0)
`C, H, F, N,
`3*Oxo>4*methylpeDtanoic Acid Aoilide (22). A solution of
`ethyl 3>ox>4»methyipenLanoate9 (47.4 g. 0.3 mol), aniline (27.93
`g, 27.3 mL, 0.3 mol), and acetic acid (0.6 mL) in toluene (360 mL)
`was refluxed for 4 h with a Dean-Stark trap. The cold mixture
`was washed twice with 0.5 N hydrochloric acid, twice with satu­
`rated sodium bicarbonate solution, once with brine, dried, con­
`centrated, and chromatographed with toluene/ethyl acetate (10:1)
`over 1 kg of silica, giving 40.5 g (66% yield) of a pale pink oil:
`NMR S 1.2 (6 H. d), 2.6 (1 H. sept), 3.65 (2 H. s), 7.0-7.75 (5 H.
`m), 9.1-9.4 (1H, br s); MS C^HJJNOJ m/e « 205 (M+). 93. Anal.
`(CJIHUNO,) C. H, F, N.
`3'(Phenylamino)<4-mothylpent*2(£)-«noic Acid Anilide
`(23b). A solution of ethyl 3-oxo^-methylpentanoate9 (31 mL,
`0.2 mol), aniline (37 mL, 0.41 mol), and acetic acid (1.0 mL) in
`toluene (50 mL) was refluxed for 6 h with a Dean-Stark trap. The
`solvent was removed in vacuo. On cooling the residue crvstallized.
`It was recrystailized from toluene/petroleum ether (80-110 aC)
`(2:1) to yield 38.7 g of colorless solid: mp 147-148 *C; a second
`crop of crystals can be obtained from the mother Hquor, NMR
`6 1.1 (7 H, d + m), 2.9 (I H. sept), 4.75 (1 H. s), 6.8-7.6 (10 H,
`m). 11.1 (1 H. br s). Anal. {CiaHwN,0) C, H. N.
`3-(IsopropylajD!oo)'4>mcthy)pent>2(£)-«noic Acid Anilide
`(23e). To a solution of anilide 22 (35.7 g, 174 mmol) and acetic
`acid (0.6 mmol) in toluene (GOO ml), refluxing under a Dean-Stark
`trap, was added isopropylamine (20.6 g, 348 mmol) dropwise over
`3 h. The mixture was refluxed for 16 h, concentrated in vacuo,
`and cooled, leading to crystallization. The solid was digerated
`with diisopropyi ether/petroleum ether (1:1), collected with suction
`nitration, and washed with petroleum ether, giving 28.9 g of
`colorless solid: mp 152-153 *C; NMR a 1.1 (6 H, d). 1.25 (6 H,
`d), 2.73 (1 H, sept). 3.8 (t H. m), 4.43 (1 H, s), 6.7 (1 H, s). 6.9-7.6
`(5 H. m), 9.1-9.6 (1 H. br s); MS CJJHMNJO CI m/e = 247 (M
`+ m. 154. Anal. (CjjHnNjO) C. H. N.
`3-(Cyclohcxylaimno)-4-mcthyipeDt-2(£)-«noie Acid Ani>
`Jide (230. A solution of anilide 22 (31.6 g, 154 mmol). acetic acid
`(1.5 mL), and cyclohexylamine (30.55 g, 308 mmol) in toluene (750
`mL) was refluxed for 20 h under a Dean-Stark trap. The solvent
`was removed in vacuo, the residue was swirled with 150 mL of
`diisopropyi ether, collected with suction filtration, and washed
`with petroleum ether to give 27.1 g of a colorless solid (an addition
`8.9 g came from the mother liquor): yield 82%: mp 123-132 CC;
`NMR a 1.15 (6 H. d). 1.0-2.1 (10 H. ro). 2.7 (1 H. sept). 3.45 (I
`H. m), 4.4 (I H. s). 6.55 (I H. m), 6.9-7.6 (5 H, m). 9.5 (1 H, br
`s) MS C,8HMN]0 m/e » 286 (M*), 194,93. Anal. (C,8HJ,N.O)
`C, H. N.
`*
`"
`Preparation of Substituted l.ff-Pyrrole-3'CarboxanUides
`24 from Enamino Anilidcs 23. General Procedure. A solution
`of the nitro olefin 15 (95 mmol) and enamino carboxanilide 23
`(100 mmol) in ethanol (300 mL) was refluxed for 12 h under
`nitrogen. Most of the solvent was removed in vacuo. Cooling
`of the residue in an ice bath gave crystals that were swirled in
`cyclohexane/ethyl acetate (200 mL), collected, and recrystailized.
`l-Phenyi*2-isopropyl-4-(4-nuorophenyl)-lif-pyrrole-3*
`carboxanilide (24b): yield 78%; mp 192-194 0C (from meth­
`anol); NMR a 1 JO (6 H. d), 3.14 (1H, sept), 6.73 (I H, s), 7.00-7.70
`(10 H, ro). Anal. (CMHJJFNJO) C, H, F, N.
`l^-Djisopropyl-4-(4-fluoropheDyl)-li?'pyrrole-3-carbox-
`anilide (24e): yield 50%; mp 131-133 ®C (not recrytt); NMR
`6 1.45 (6 H. d), 1.35 (6 H. d). 3.75 (1 H. sept). 4.6 (1 H. sept), 6.7
`(1H. s), 6.7-7.6 (10 H. m); MS CaHjjFNjO m/e = 364 (M*), 272,
`230. Anal. (CjjHyFNjO) C, H, F, N.
`l-Cyclohexyl-2-is6propyl*4-(4>nuoropheDylMJ7>pyrrole-
`3-carboxanilide (24f): yield 52%; mp 215-216 eC (not recrvst);
`NMR a 0.9-2.2 (16 H. d + m), 3.5-4.3 (2 H, m). 6.65 (1 H. s),
`6.8-7.6 (10 H,'m) MS CMH»FNjO CI m/e « 405 (M + H"). 312,
`230. Anal. (C„HnFNjO) C, H, F, N.
`!-Phenyl-2-isopropyM-(4-fluoropheDyl)-5-inethyMi/-
`pyrrole-3-carboxanilide (24K)'.
`80%; mp 190-192 0C (from
`cyclohexane/ethyl acetate); NMR a 1.3 (6 H, d), 1.83 (3 H. s). 3.2
`(1 H. sept), 6.8-7.6 (15 H, m); MS C^HaFNiO m/e = 412 (M*).
`
`Jendrolla et e
`
`320 (M* - PhNH). Anal. (C^F^O) C. H. F, N.
`Preparation of Substituted lH-Pyrn>Ie-3-carboxaldehydc
`4 from Substituted I/f-Pyrrole-3-carboxanilides 24. Gencn
`Procedure, (a) N-Methylation. To a mechanically stirre
`solution of anilide 24 (55 mmol) in toluene (300 mL) was adde
`a 50% dispersion of NaH in mineral oil (5.5 g, 115 mmol) at 2
`0C under a nitrogen atmosphere. The suspension was warme
`for 30 min at 60 0C and for 10 min at 100 0C. The suspensio
`was cooled to 20 eC and methyl iodide (62.5 g, 440 mmol) we
`added. It was refluxed (bath at 75 eC) for 4-16 h, depending o-
`steric hindrance (TLC control). With external cooling with dr
`ice/methanol, first water (80 mL) was added dropwise, follow*
`by ether (400 mL). The organic phase was separated, washed wit*
`brine, dried, and concentrated in vacuo. The residues ofte:
`crystallized when swirled with n-hexane or diisopropyi ether t
`a colorless to pale yellow solid. Oily products were purified b'
`chromatography with cyclohexane/ethyl acetate/ triethylamin
`(8:2:0.01) over silica.
`l>Phenyl>2>isopropyl-4>(4>fIuorophenyl)-N>methy]-lA>
`pyrrolC'S-carboxaoiiide: yield 94%; mp 126-127 °C (not re
`cryst); MS CAHJJFNJO m/e = 412 (M*), 306,262. Anal. (Cr
`HJJFNjO) C.'H, F, N.
`lt2-Dii$opropyl-4-(4-fiuorophenyl)-^-methyl-li/
`pyrrole-3-carboxanilidc: yield 737o; oil; NMR S 1.40 (12 H, d)
`3.23 (4 H, s + sept), 4.40 (1 H. sept). 6.50 (1H, s), 6.5-7.5 (9 H
`m); MS Cj.H^FN^O m/e = 378 (M*), 272,91. Anal. (C„HnF
`NjO) C, H, F, N. *
`l-Cyclohexyl-2*isopropyl-4-(4-nuorophenyl)*A,-mcthyI
`l/f-pyrrole-S-carboxanilidc: visld 98%; mp 102-105 aC (no:
`recryst): NMR i 1.35 (3 H. d), 1.50 (3 H, d), 1.1-2.2 (11 H, m) ..
`3.25 (3 H, br s) 3.95 (1 H, m), 6.4-7.4 (10 H, m); MS CjrH^FN.C
`CI m/e = 419 (M + H+), 312. Anal. (Cn^FN,©) C, H, F, N
`l-Pheny]-2-isopropyi-4-(4.riuarophenyI)-5>mcthyI-W-
`mcthyMf/-pyrrolc-3-carboxanilidc: yield 84%; mp 62-63 "C
`{not recryst); NMR a 1.2 (3 H. d). 1.3 (3 H. d), 1.8 (3 H, s), 2.E
`(1 H. sept). 3.17 (3 H, s), 6.fr-7.5 (14 H. m); MS CnHnFNjO m/e
`- 426 (M*), 320 (M* - PhNCHj). Anal. (CJJHTTFNJO) C, H, F.
`N.
`(b) Reduction. To a suspension of lithium aluminum hydride
`(60 mmol) in dry THF (120 mL) under nitrogen was added
`dropwise a solution of N-methylaniUdes (29 mmol) in THF (120
`mL). The mixture was refluxed for 20 h and then cooled to 0 "C.
`Ethyl acetate (15 mL) and then water (5 mL) followed by 2 N
`sodium hydroxide solution (10 mL) were added dropwise. The
`mixture was stirred for 30 min at 25 aC. The solids were removed
`and washed with ether.
`The filtrate was concentrated in vacuo. The residues often
`crystallized when swirled with n-pentane.. Oily products were
`purified by chromatography with toluene/ethyl acetate/tri-
`ethylamine (20:1:0.01) over silica.
`l-Phenyl-2-isopropyl-3-(hydroxymethylM-(4-fIuoro-
`phenyJHJJ.pyrroie: yield 92%; oil; NMR 6 1.28 (7 H. d + m),
`3.03 (1 H. sept), 4.70 (2 H. s), 6.73 (1 H. s), 6.90-7.70 (9 H, m);
`MS CWHRFNO m/e - 309 (M*), 294,276. Anal. (CRHJOFNQ)
`C.H.F.N.
`l^-Diisopropyl-3-(hydroxyniethyl)-4-(4-fluorophenyl)-
`lif-pyrrole: yield 75%; pale yellow oil that slowly crystallized;
`NMR 6 1.2-1.6 (12 H, m), 2.35 (1 H, br s), 3.33 (1 H, sept), 4.40
`(2 H, s), 4.50 (1 H. sept), 6.70 (1 H, s), 6.8-7.65 (4 H, m); MS
`C,THBFNO CI m/e = 275 (M*), 258,242,200. Anal. (CL7HAFN0)
`C.H.F.N.
`l*Cyclohexyl*2-isopropyl-3-(hydroxymethyl)-4.{4*nuoro-
`phenyl)-ltf-pyrrole: yield 67%; mp 114-116 'C (not recryst);
`NMR 41.37 (6 H, d), 1.2-2.1 (10 H, ro). 3.30 (1 H. sept), 3.96 (1
`H. ro). 4.38 (2 H, s). 6.70 (1 H. s), 6.95 (2 H, m), 7.47 (2 H, m);
`MS CMHMFNO m/e « 315 (M+), 300, 282, 200. Anal. (C»-
`HMFNO) C, H, F, N.
`l-Phenyl-2-isopropyl-3-(hydroxymethyl)-4*(4Tfluoro-
`phenyl)-5-njethyl-lH-pyrrole: yield 63%; colorless solid; NMR
`5 1.25 (6 H. d), 1.9 (3 H, s), 2.8 (1 H, m), 4.35 (1 H, s), 4.55 (2 H, •
`s), 6.85-7.75 (9 H, m); MS C-jH^FNO m/e = 323 (M+), 308 (M*
`- CHj), 290 (M* - CHj - H;0). Anal. (Cj.HnFNO) C.H, F. N.
`(c) Oxidation. Variant A. To a mechanically stirred sus­
`pension of Celite (50 g) and finely powdered CrOj (25 g, 250 mmol)
`in dry dichloromethane (250 mL) at 15 0C was added dropwise
`a solution of dry pyridine (39.5 g, 500 mmol) in CHjClj (250 mL).
`
`429
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`<
`
`•
`•
`
`After stirring Bt room temperature (20 min), a solution of the
`substituted (hydroxymethyOpyrrole (25 mmol) in CH3C13 (250
`(ot) was added dropwise but quickly. The reaction temperature
`^ept between 20 and 24 0C. After 15 min cyclohexane (500
`was
`» mL) was added. The solid was suction filtered and washed with
`^ dichloromethane/cyclohexane (3.7)
`filtrate was concentrated
`ajid chromatoKTaphed with cydohexane/ethyl acetata/triethyl-
`amine (4:1:0.01) over 500 g of silica.
`Variant B." To a solution of N-methyimorphoiine N-oxide
`(46.8 g, 400 mmol) in acetone (400 mL, dried over K3C03) was
`added tris(triphenylphosphine)rutheDium(ID dichloride (3.8 g,
`4.0 mmol). The mixture was stirred 20 min at 20 "C. A solution
`of the substituted (hydroxymethyDpyrrole (100 mmol) in dry
`sceume (600 mL) was added dropwise. The mixture was stirred
`for 10-20 h at room temperature. After complete reaction' (TLC,
`cydohexane/ethyl acetate/triethylamine 4:1:0.1), the mixture was
`filtered through a short, thick siiica pad. The pad was washed
`with ether (3 L); the filtrate was concentrated in vacuo. The
`residue, pure 4, usually crystallized, when digerated with n-pentane
`at 0 BC.
`i.pheoyl*2'isopropyl-4-(4-nuorophenyl)-lH-pyrrole-3-
`' ;
`s carboxaldehyde (4b): yield (variant A) 35%, (variant B) 87%;
`| pele yellow solid: mp 119-120 0C; NMR 6 1.36 (6 H, d), 3.16 (1
`I H, sept), 6.65 (1 H, s), 7.0-7.7 (9 H, m), 10.1 (1 H, s); MS C„-
`5 H.JFNOm/e = 307(M*),292. Anal. (CJOHUFNOC.H.F.N.
`U.Dil80propyl-4-(4-nuoropheDyl)-lH'pyrrole-3-carbox-
`1
`• aldehyde (4e): yield (variant B) 877o; yellow oil; NMR i 1.43
`' " (6 K, d), 1.47 (6 H, d). 3.80 (1 H. sept). 4.57 (1 H, sept). 6.62 (1
`1 i H.s)I7.06(2H,m).7.37{2H,m).9.89(lH,s);MSC,7HJoFNO
`•
`\ m/e - 273 (M*), 258, 244. Anal. (CpHjoFNO) C. H, F, N.
`| l-Cyclohexyl-2-isopropyM-(4.fluorophenyl)-lH-pyrrole-
`t 3*carboxaldehyde (4f): yield (variant B) 98%; colorless crystals;
`' '
`t mp 134-135 #C; NMR i 1.45 (6 H,d), 1.1-2.2 (10 H.m), 3.55-4.35
`^
`' I (2H.m + sept),6.65(IH.s).6.9-7.6(4 H.m),9.95(lH,s);MS
`\ CHHMFNO m/e- 313 (M*), 298,231,216. Anal. (CJOHJ^FNO)
`3
`E P C.H.F.N.
`l-PbeDyl«2«isopropyM*(4*nuorophenyl)-5-raethyl-ltf*
`B pyrrole-3-carboxaldehyde (4g): yield (variant A) 45%; pale
`] | yellqnv solid; NMR i 1.3 (6 H. d),2.1 (3H.s).3.1 (1H. sept). 6.9-7.6
`! e (9H.m).10.0(lH.s);MSC„HwFNOin/«*321(Ma Ana).
`? } (CnHjoFNO) C. H. F, N.
`I
`Synthesis of 1.2-Dit3opropyl-4-(4-nuorophenyl)-lff•
`e [ pyrrole-3-carboxaldehyde (4e) via Three>CompoDent Cou-
`• piing Reaction According to Scheme VI. (a) Three-Corn-
`4
`• pooent Coupling. Ethyl l^!-Diisopropyl-4-(4-nuoro-
`n i phenyl)'lH-pyrroie-3-carboxylate (21e). To a suspension of
`£ 4«nuoro-d>niirostyrene1' (209 g. 1.25 mol) in absolute methanol
`j. I (500 mL) was added ethyl S-oxo^-methylpentanoaU9 (214 g. US
`j mol) under ice cooling followed by isopropyUmine (128 mL. 1^0
`- [ mol). both in one portion. Absolute methanol (1L) was added.
`. [ the ice bath was removed, and the reaction mixture was stirred
`were
`7. s
`'or 48 h in a tightly stoppered flask. Volatile components
`'' ** removed in vacuo. The brown, viscous oil was filtered with
`toluene/0.1% triethylamine through 5 kg of silica ge! (70-200 fim)
`•g to give 197 g (49.7% yield) of a yellow solid: mp 72-74 *C; NMR
`'I g (CDjCl,) 6 1.07 (3 H. t), 1.36 (6 H. d), 1.42 (6 H. d). 3.73 (1 H.
`10 1
`4-06 (2 H. q), 4.50 (1 H. sept). 6.60 (1 H. a). 6.80-7.40 (4
`«. m); MS (DC!, posit, isobutane) CnH^FNOj m/e = 318 (M
`IS
`+ «•). 317t 302. Anal. (C^H^FNOj) C. H. F, N.
`0)
`. — _ (b) Reduction. l^-Diisopropyl-3-(hydroxyiDethyl)-4-(4-
`B "uorophenyD-lH-pyxroIe. A solution of the ethyl ester (197
`H t' 0£2 mol) in ether (750 mL) was added dropwise at 0 "C to a
`(1 6 ^Ptuion of lithium aluminum hydride (47.2 g, 1.24 mol) in ether
`• (1.5 L). The reaction mixture was stirred for 1 h at 0 0C and for
`.ik
`m * h ®t 20 "C. At ChlO 'C ethyl acetate (150 mL) was added
`oropwise, and then water (38 mlj followed by 2 N sodium hy-
`•0* R f x^e solution (75 mL) was added. The mixture was stirred
`R
`15 min at room temperature. The inorganic solids were re­
`moved by suction filtration and washed thoroughly with ether.
`H.
`H Triethylamine (1 mL) was added to the combined filtrate and
`N- B "^'"gs.and the solvent was removed in vacuo to give a yellow
`JS; B ^ (131 g. 77%. yield) that had spectra identical with those of
`thc authentic material described above.
`10I)
`•-fee •
`Oxidation was performed as described above to give 4e
`y. B ** a yellow solid in 92% yield.
`
`i
`
`z
`
`fiMC'CoA Reductase Inhibitors. 2
`
`Journal of Medici
`
`Chemistry, 1990, Vol. 33, No. I 67
`
`Pyrrole-Substituted Acryionitriles 5. General Procedure.
`At 0 eC a solution of diisopropyl (eyanomethyDphosphonate (13.5
`g, 66.0 mmol) in dry THF (200 mL) was added dropwise to a
`suspension of sodium hydride (3,78 g of a 50% dispersion in
`mineral oil. 78.7 maol) in dry THF. (700 mL). After 40 min at
`0 0C, a solution of aldehyde 4 (44,0 mmol) in THF (100 mL) was
`added d