Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor ZARNESTRA

Article abstract of DOI:10.1002/ejoc.200300538

The discovery that post-translational farnesylation of Ras oncoprotein was an essential step in exercising its biological effect led to the design of farnesyl protein transferase inhibitors (FTIs) in order to control growth of tumors bearing Ras mutations. Pre-clinical studies on murine models have confirmed their inhibitory effect on tumor growth and enabled clinical development. R115777 (ZARNESTRA) is currently undergoing clinical evaluation and recent studies have confirmed its antitumor potential and low toxicity. We wish to describe here the chemical synthesis routes that our group have developed to access ZARNESTRA. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300538

FULL PAPER
Synthesis Routes Towards the Farnesyl Protein Transferase Inhibitor
ZARNESTRATM
Patrick R. Angibaud,*[a] Marc G. Venet,[b] Walter Filliers,[c] Rudy Broeckx,[c]
Yannick A. Ligny,[a] Philippe Muller,[c] Virginie S. Poncelet,[c] and Dave W. End[d]
Keywords: Antitumor agents / Heterocycles / Farnesyl protein transferase inhibitors / ZARNESTRA / R115777
The discovery that post-translational farnesylation of Ras
oncoprotein was an essential step in exercising its biological
effect led to the design of farnesyl protein transferase inhib-
undergoing clinical evaluation and recent studies have con-
firmed its antitumor potential and low toxicity. We wish to
describe here the chemical synthesis routes that our group
itors (FTIs) in order to control growth of tumors bearing Ras have developed to access ZARNESTRATM
mutations. Pre-clinical studies on murine models have con-
.
firmed their inhibitory effect on tumor growth and enabled
clinical development. R115777 (ZARNESTRATM) is currently
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
transferase[6] (FPT). This key limiting reaction involves the
covalent attachment of a 15-carbon farnesyl moiety
through a thioether bond to a single cysteine of the C-ter-
minal CAAX motif, where C is cysteine, A is any aliphatic
amino acid and X is serine, methionine, glutamine or ala-
nine. The prenylated product undergoes proteolytic cleavage
of the C-terminal tripeptide followed by a methyl esterifi-
cation of the new C-terminal farnesylcysteine.[7,8]
Furthermore, recent findings have highlighted the role of
other prenylated proteins, such as RhoB or CENP-E and
CENP-F, in tumor cell proliferation.[9,10] All of these pro-
teins undergo this critical farnesylation step, and inhibition
of FPT can suppress human tumor cell proliferation related
to these proteins. Thus, FPT is a valuable pharmacological
target and compounds inhibiting this enzyme could have a
significant potential in cancer therapy not limited to Ras-
dependent tumors.
R115777 (1) has emerged as a novel, selective, nonpeptide
farnesyl protein inhibitor showing in vitro activity in the
nanomolar range.[11] As an orally active antitumor agent 1
is currently undergoing human clinical trials.[12] We have
previously described the structure-activity relationships of
quinolinone-based inhibitors of FPT as part of our efforts
to develop orally active FTIs.[13,14] Herein we wish to de-
scribe the synthesis routes we have developed to access 1.
Ras was the first human transforming oncogene disco-
vered.[1] Studies on clinical specimens have revealed a sig-
nificant prevalence of Ras mutations with 25% incidence in
lung, bladder and thyroid cancers[1Ϫ3] and higher incidences
of 53% and more than 90% in colon[4] and pancreatic can-
cer,[5] respectively. The Ras oncoprotein is involved in the
intracellular signaling pathways leading to cell prolifer-
ation. These initial results prompted several investigations
to define therapeutic agents which targeted the aberrant cell
signaling caused by the Ras oncogenes.
To function in signal transduction, Ras must attach to
the plasma membrane, but the physico-chemical properties
of the newly synthesized Ras protein do not induce translo-
cation to the membrane. Post-translational modifications of
Ras and related CAAX-containing proteins are required to
transport these proteins to functional membrane locations
within cells. The first and most important step of these
modifications is catalyzed by the enzyme farnesyl protein
[a]
Department of Medicinal Chemistry, Johnson & Johnson
Pharmaceutical Research & Development (J&JPRD),
Campus de Maigremont, BP615, 27106 Val de Reuil, France
Fax: (internat.) ϩ 33-2-32617298
E-mail: pangibau@prdfr.jnj.com
[b]
SERIPHARM, rue Democrite 72000 Le Mans, France
E-mail: marc.venet@seripharm.com
[c]
Chemical Process Research J&JPRD,
Results and Discussion
Turnhoutseweg 30, 2340 Beerse, Belgium
E-mail: wfillier@prdbe.jnj.com
[d]
Oncology Drug Discovery, J&JPRD L.L.C.,
Historically, we prepared 4-(3-chlorophenyl)-3,4-dihydro-
2(1H)-quinolinone (3) by intramolecular cyclization of the
amide 2 in PPA at 100 °C (Scheme 1).[15] Interestingly, ad-
Welsh and McKean Roads, Spring-House, PA 19477-0776,
USA
E-mail: dend1@prdus.jnj.com
Eur. J. Org. Chem. 2004, 479Ϫ486
DOI: 10.1002/ejoc.200300538
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
479

P. R. Angibaud et al.
FULL PAPER
Figure 1. R115777
ding 4-chlorobenzoic acid to this mixture and further heat-
ing provided the appropriate quinolinone 6-isomer 4 in
good yield. Derivative 4 was oxidized to 5 and N-meth-
ylation was performed under phase-transfer catalysis (PTC)
to provide 6.[16Ϫ18]
Scheme 2. a) Ethylene glycol, para-toluenesulfonic acid (PTSA),
toluene, 110 °C, 24 h (98%); b) (3-Cl-C6H4)CH2CN, NaOH,
MeOH, 60 °C, 1 h (86%); c) TiCl3, H2O/THF, room temp., 16 h;
d) Ac2O, toluene, 110 °C, 2 h; e) tBuOK (4 equiv.), DME, room
temp., 3 h (87%)
The same scheme was applied to 4-bromo-1-nitrobenzene
(Scheme 3) to provide 6-bromo-4-(3-chlorophenyl)-2(1H)-
quinolinone (16). Conversion of 16 into the corresponding
2-methoxyquinoline 18 was performed by chlorination
using phosphorus oxychloride as solvent followed by substi-
tution using sodium methoxide. After bromine/lithium ex-
change 18 was treated with 4-chloro-N-methoxy-N-methyl-
Scheme 1. a) Polyphosphoric acid (PPA), 100 °C, 16 h; b) 4-chloro-
benzoic acid, 140 °C, 48 h (45%); c) Br2, C6H5Br, 160 °C, 16 h
(93%); d) CH3I, benzyltriethylammonium chloride (BTEAC),
NaOH, THF, room temp., 16 h (75%)
However, this scheme did not allow a wide variety of sub-
stitution on the 4-phenyl ring and we looked for an alterna-
tive synthesis of 6. Davis and Pizzini[19] had described the
synthesis of 1,2-benzisoxazoles, and reduction of these com-
pounds to ortho-aminobenzophenones was known.[20]
Starting from 4-chloro-4Ј-nitrobenzophenone (7), we first
protected the carbonyl moiety by ketalization, then treated
it with 3-chlorobenzyl cyanide to provide the 1,2-benzisox-
azole 9, which crystallized from the reaction medium and
was removed by filtration. The reaction must be carried out
with caution as it generates 1 equiv. of sodium cyanide as
a by-product. Reduction by Lewis acid (TiCl3) in a water/
THF mixture removed the ketal function and provided the
ortho-aminobenzophenone 10, which was then acylated.
The resulting amide 11 was cyclized to quinolinone 12
which was not isolated, as an excess of potassium tert-bu-
toxide allowed in situ elimination to provide 5 in a good
yield (Scheme 2).
Scheme 3. a) (3-Cl-C6H4)CH2CN, NaOH, MeOH, room temp.,
16 h (35%); b) TiCl3, H2O/THF, room temp., 16 h (85%); c) Ac2O,
toluene, 110 °C, 2 h; d) tBuOK (4 equiv.), DME, room temp., 16 h
(81%); e) POCl3, 80 °C, 16 h; f) MeONa/MeOH, 60 °C, 16 h (86%);
g) (4-Cl-C6H4)C(O)N(CH3)OCH3, nBuLi, THF, Ϫ70 °C, 0.5 h
(75%); h) HCl (6 ), MeOH, 60 °C, 72 h, (80%)
480
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 479Ϫ486

Farnesyl Protein Transferase Inhibitor ZARNESTRATM
FULL PAPER
benzamide to provide 19. Finally, acidic cleavage of the
2-methoxy moiety gave us another route to key intermedi-
ate 5.
The N-methylimidazole moiety was then introduced by
the following sequence (Scheme 4): N-methylimidazole was
deprotonated at carbon-2 by addition of n-butyllithium and
the resulting carbanion silylated by addition of triethylsilyl
chloride. Another equivalent of n-butyllithium at a tem-
perature maintained below Ϫ50 °C, formed the 5-lithio-1-
methyl-2-triethylsilylimidazole to which the ketone 6 was
added giving 20 in moderate yield (52%), together with 5%
of 21.
Scheme 4. a) 1. N-methylimidazole, nBuLi, ClSiEt3, THF, Ϫ78 °C;
2. nBuLi, Ϫ78 °C, 20 (52%), 21 (4%); b) 1. N-methylimidazole, n-
hexyllithium, ClSi(iBu)3, THF, Ϫ78 °C; 2. n-hexyllithium, Ϫ78 °C,
20 (75%), 21 (< 0.3%)
Scheme 5. a) SOCl2 40 °C or HCl, SOCl2, N,N-dimethylimidazolid-
inone, room temp.; b) NH4OH, THF, 80 °C (65%) or NH3/MeOH,
room temp. (70Ϫ75%); c) enantiomer separation by HPLC on chi-
ral phase (32.5%); d) -(Ϫ)-dibenzoyltartaric acid monohydrate,
acetone, room temp. (37%); e) NH4OH, EtOH, 80 °C (86%)
The racemic compound 23 was resolved by HPLC on a
Chiracel OD column to afford the active (ϩ)-(R)-enanti-
omer 1 (R115777). R115777 was also obtained by resolu-
tion, the racemic form 23 being treated with -(Ϫ)-diben-
zoyltartaric acid (DBTA) to obtain the diastereomeric tar-
trate salt 24 which is treated with aqueous ammonium hy-
droxide, to form the crude R115777 which is then purified
by recrystallization from ethanol (Scheme 5; steps d, e).
However, carrying out this process at a temperature as
low as Ϫ78 °C is inconvenient and costly on a commercial
scale in view of the specialized equipment required to per-
form a large-scale process at such a low temperature. There
was a need to improve the above reaction step so that it
could be carried out in an efficient and economical manner
on a commercial scale. We have discovered that improve-
ments in yield (75%), impurity profile (less than 0.3% of 21)
and commercial ease of operation can be achieved by the
use of n-hexyllithium in place of n-butyllithium and the use
of triisobutylsilyl chloride in place of triethylsilyl chloride,
with particularly advantageous results obtained at tempera-
tures between Ϫ15 and 0 °C.[21] This selectivity at such
relatively high temperatures is remarkable in view of
suggestions in the literature that the silyl group is unsuitable
as a blocking group, owing to the 2- to 5-position migration
Conclusion
R115777 can be accessed by at least three principal routes
which were also applied to further broaden the SAR of qui-
nolinone series FTIs.[13,14] An efficient synthetic process for
the production of R115777 is reported allowing the large-
scale preparations required for development purposes.
R115777 is currently undergoing phase II trials in hematol-
ogical cancers and solid tumors.
of
2-(trialkylsilyl)-substituted
5-lithio-N-methylimid-
azoles.[22,23]
Replacement of the hydroxy group by the amino moiety
to reach the racemic analogue of 1 was initially achieved in
two steps by first treating 20 with thionyl chloride to pro-
vide 6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-
methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone
(22) and then substituting the chlorine atom in 22 by aque-
ous ammonia to give 23 (Scheme 5). On a preparative scale
this procedure was further improved by performing the
chlorination step in N,N-dimethylimidazolidinone and by
using ammonia in methanol at a lower temperature.[21]
Experimental Section
General Remarks: Proton NMR spectra were recorded at 400, 300
or 200 MHz with a Bruker Avance 400, 300 or a Bruker AMC 200
spectrometer, with Me4Si as internal standard. Chemical shifts (δ)
are reported in parts per million (ppm) and signals are reported as
s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet).
Coupling constants are given in Hertz (Hz). Electrospray mass
Eur. J. Org. Chem. 2004, 479Ϫ486
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
481

P. R. Angibaud et al.
FULL PAPER
spectra were recorded with an Applied Biosystems API 100 spec-
δ ϭ 3.73 (s, 3 H, CH3), 6.69 (s, 1 H, 3-H), 7.47Ϫ7.67 (m, 3 H,
C6H4-3-Cl), 7.57(d, 1J ϭ 2 Hz, 1 H, 5-H), 7.61 (d, 1J ϭ 8.5 Hz, 2 H,
trometer. Optical rotations were performed with a PerkinϪElmer
341 polarimeter. Elemental analyses were realized with a Fisons C6H4-4-Cl), 7.73Ϫ7.82 (m, 1 H, C6H4-3-Cl), 7.76 (d, 1J ϭ 8.5 Hz, 2
instrument EA1108 or EA1110. Melting points were determined
with a Mettler Toledo FP62 apparatus and are uncorrected. All
reactions were routinely checked by TLC on silica gel Merck 60F
254. Column chromatography was carried out on Millipore silica
gel (25Ϫ45 µm). The enantiomeric purity of final compounds was
monitored by HPLC using Chiracel OD or Chiralpak AD col-
umns.
H, C6H4-4-Cl), 7.79 (d, 1J ϭ 8.7 Hz, 1 H, 8-H), 8.06 (dd, 1J ϭ
8.6 Hz and 2 Hz, 1 H, 7-H) ppm. C23H15Cl2NO2 (408.29): calcd.
C 67.66, H 3.70, N 3.43; found C 67.72, H 3.64, N 3.34.
2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (8): A mixture of
4-chloro-4Ј-nitrobenzophenone[24] (7) (10 g, 0.0382 mol), ethylene
glycol (4.3 mL, 0.0764 mol) and para-toluenesulfonic acid (PTSA)
(3.6 g, 0.19 mol) in toluene (150 mL) was stirred and refluxed with
azeotropic removal of water for 24 h. The mixture was washed with
10% aq. K2CO3 and then with water. The organic layer was dried
(MgSO4), filtered and the solvents were evaporated to afford
6-(4-Chlorobenzoyl)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-
quinolinone (4): N-Phenyl-3-(3-chlorophenyl)-2-propenamide[18]
(58.6 g, 0.2275 mol) and polyphosphoric acid (580 g) were stirred
at 100 °C overnight to yield crude 4-(3-chlorophenyl)-3,4-dihydro-
2(1H)-quinolinone (3). 4-Chlorobenzoic acid (71.2 g, 0.455 mol)
was added and the mixture was further stirred at 140 °C for 48 h,
cooled, poured into ice/water and filtered. The precipitate was
washed with water, then with a dilute NH4OH solution and taken
up in CH2Cl2. The organic layer was dried (MgSO4), filtered and
the solvents were evaporated. The residue was purified by column
chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 99:1:0.1).
The pure fractions were collected and the solvents evaporated, and
recrystallized from CH2Cl2/MeOH/diisopropyl ether, to afford 40 g
(45%) of 4. M.p. 195 °C. 1H NMR (200 MHz, [D6]DMSO, 22 °C):
1
11.42 g (98%) of 8. M.p. 111 °C. H NMR (400 MHz, [D6]DMSO,
1
22 °C): δ ϭ 4.03 (s, 4 H), 7.42 (d, J ϭ 8.6 Hz, 2 H, C6H4Cl), 7.47
(d, 1J ϭ 8.6 Hz, 2 H, C6H4Cl), 7.71 (d, 1J ϭ 8.7 Hz, 2 H,
1
C6H4NO2), 8.21 (d, J ϭ 8.6 Hz, 2 H, C6H4NO2) ppm. 13C NMR
(101 MHz, [D6]DMSO, 22 °C):
δ ϭ 65.4 (CH2ϪO), 107.8
(OϪCϪO), 124.0 (C-3Ј, C-5Ј), 127.4 (C-2Ј, C-6Ј), 128.0 (C-2, C-6),
128.8 (C-3, C-5), 133.5 (CϪCl), 140.6 (C-1), 147.6 (CϪNO2), 149.2
(C-1Ј) ppm.
3-(3-Chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-2,1-
benzisoxazole (9): 8 (25 g, 0.0818 mol) and 3-chlorobenzyl cyanide
(17.4 mL, 0.147 mol) were added to a mixture of NaOH (16.4 g,
0.409 mol) in MeOH (100 mL). The mixture was stirred and re-
fluxed until complete dissolution (1 h). Ice and then ethanol were
added. The product was allowed to crystallize from the mixture.
The precipitate was filtered, washed with ethanol and dried to af-
ford 58 g (86%) of 9. M.p. 120 °C. 1H NMR (300 MHz,
[D6]DMSO, 22 °C): δ ϭ 4.07 (s, 4 H, OCH2), 7.33 (dd, 1J ϭ 9.3 Hz
1
1
δ ϭ 2.90 (d, J ϭ 6.9 Hz, 2 H, 3-H), 4.52 (t, J ϭ 6.8 Hz, 1 H, 4-
H), 7.10 (d, 1J ϭ 8.3 Hz, 1 H, 8-H), 7.23 (d, 1J ϭ 9.7 Hz, 1 H,
C6H4-3-Cl), 7.35Ϫ7.41 [m, 4 H, 5-H ϩ C6H4-4-Cl (2 H) ϩ C6H4-
3-Cl (1 H)], 7.55Ϫ7.69 [m, 5 H, 7-H ϩ C6H4-4-Cl (2 H) ϩ C6H4-
3-Cl (2 H)], 10.73 (s, NH) ppm. C22H15Cl2NO2 (396.28): calcd. C
66.68, H 3.82, N 3.53; found C 66.57, H 3.75, N 3.45.
1
6-(4-Chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone (5): Bro-
mine (3.4 mL, 0.066 mol) in bromobenzene (80 mL) was added
dropwise at room temperature to a solution of 4 (26 g, 0.066 mol)
in bromobenzene (250 mL) and the mixture was stirred at 160 °C
overnight. The mixture was cooled to room temperature and made
basic with NH4OH. The solvents were evaporated, the residue was
taken up in CH3CN and filtered. The precipitate was washed with
and 1.3 Hz, 1 H, 6-H), 7.42 (d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 7.55
1
(d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 7.61Ϫ7.72 (m, 2 H, C6H4-3-Cl),
1
7.70 (d, J ϭ 8.6 Hz, 1 H, 7-H), 8.04Ϫ8.07 (m, 3 H, 4-H ϩ C6H4-
3-Cl) ppm. C22H15Cl2NO3 (412.28): calcd. C 64.09, H 3.67, N 3.40;
found C 64.40, H 3.65, N 3.40. HR-MS: calcd. for C22H15Cl2NO3
412.051; found 412.052. Caution! The reaction generates sodium
cyanide. Cyanide-containing layers are typically decomposed by the
addition of 1 equiv. of aqueous H2O2 at a pH range of 9.5Ϫ10.5,
and at a temperature range of 30Ϫ50 °C. At higher pH (Ͼ 11)
the reaction may slow down, and cause H2O2 to decompose. After
decomposition, the cyanide content is checked and should be Ͻ
3 ppm. If not, an additional amount of H2O2 is added.
1
water and air-dried to give 24 g (93%) of 5. M.p. 230Ϫ235 °C. H
NMR (200 MHz, [D6]DMSO, 22 °C): δ ϭ 6.58 (s, 1 H, 3-H),
1
7.47Ϫ7.60 (m, 4 H, C6H4-3-Cl ϩ 8-H), 7.59 (d, J ϭ 8.6 Hz, 2 H,
C6H4-4-Cl), 7.65 (s, 1 H, C6H4-3-Cl), 7.70Ϫ7.75 (m, 1 H, 5-H),
1
1
7.76 (d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 8.00 (dd, J ϭ 8.6 Hz and
2 Hz, 1 H, 7-H), 12.33 (s, NH) ppm. 13C NMR (75 MHz,
[D6]DMSO, 22 °C): δ ϭ 116.6 (C-8), 117.6 (C-10), 122.9 (C-3),
128.0 (C6H4-3-Cl), 128.9 (C6H4-3-Cl), 128.9 (C6H4-4-Cl, 2 C),
129.4 (C6H4-3-Cl), 129.8 (C-5), 130.0 (C-6), 131.0 (C6H4-3-Cl),
131.7 (C6H4-4-Cl, 2 C), 131.9 (C-7), 133.8 (C6H4-3-Cl, CϪCl),
136.2 [C6H4-4-Cl, CϪC(O)], 137.6 (C6H4-4-Cl, CϪCl), 138.3
(C6H4-3-Cl, C-quinolinone), 142.9 (C-9), 150.2 (C-4), 161.7 (C-2),
193.3 (ketone) ppm. HR-MS: calcd. for C22H13Cl2NO2 394.040;
found 394.0397.
[2-Amino-5-(4-chlorobenzoyl)phenyl](3-chlorophenyl)methanone
(10): Titanium() chloride (350 mL, 15% w/w solution in H2O,
0.34 mol) was added at room temperature to a mixture of 9 (58 g,
0.14 mol) in THF (350 mL). The mixture was stirred at room tem-
perature overnight, then poured on ice and extracted with CH2Cl2.
The organic layer was separated, washed with 10% aq. K2CO3,
dried (MgSO4), filtered and the solvent was evaporated to afford
1
61 g (100%) of 10. M.p. 142 °C. H NMR (300 MHz, [D6]DMSO,
1
22 °C): δ ϭ 7.00 (d, J ϭ 8.6 Hz, 1 H, 6-H), 7.53Ϫ7.57 (m, 4 H),
6-(4-Chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone
(6): Iodomethane (6.2 mL, 0.1 mol) was added to a mixture of 5
(20 g, 0.05 mol) and benzyltriethylammonium chloride (5.7 g, 0.025
mol) in THF (200 mL) and NaOH (10 ) (200 mL). The mixture
was stirred at room temperature overnight, EtOAc was added and
the mixture was decanted. The organic layer was washed with
1
7.63Ϫ7.72 (m, 5 H), 7.82 (dd, J ϭ 8.6 Hz and 1.9 Hz, 1 H, 5-H),
8.01 (s, NH2) ppm. C20H13Cl2NO2 (370.24): calcd. C 64.88, H 3.54,
N 3.78; found C 64.88, H 3.40, N 3.74.
N-[2-(3-Chlorobenzoyl)-4-(4-chlorobenzoyl)phenyl]acetamide (11):
Acetic anhydride (29 mL, 0.284 mol) was added to a mixture of 10
water, dried (MgSO4), filtered and the solvents were evaporated to (52.6 g, 0.142 mol) in toluene (510 mL). The mixture was stirred at
dryness. The residue was purified by column chromatography on
silica gel (CH2Cl2/MeOH/NH4OH, 99.75:0.25:0.1). The pure frac-
tions were collected and the solvents evaporated, to afford 12.3 g
(75%) of 6. M.p. 155 °C. 1H NMR (300 MHz, [D6]DMSO, 22 °C):
120 °C for 20 h. The solvent was evaporated to dryness to afford
1
60 g of 11. H NMR (400 MHz, [D5]pyridine, 22 °C): δ ϭ 2.12 (s,
3 H, CH3), 7.36 (t, 1J ϭ 7.8 Hz, 1 H, C6H4-3-Cl 5Ј-H), 7.52 (d,
1J ϭ 8.4 Hz, 2 H, C6H4-4-Cl 3Ј-H ϩ 5Ј-H), 7.51Ϫ7.56 (m, 1 H,
482
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 479Ϫ486

Farnesyl Protein Transferase Inhibitor ZARNESTRATM
FULL PAPER
1
C6H4-3-Cl 4Ј-H), 7.81Ϫ7.87 (m, 1 H, C6H4-3-Cl 6Ј-H), 7.86 (d, 9.3 Hz, 1 H, 3-H), 7.52 (d, J ϭ 2.6 Hz, 1 H, 6-H), 7.57(m, 3 H,
1J ϭ 8.4 Hz, 2 H, C6H4-4-Cl 2Ј-H ϩ 6Ј-H), 8.04 (m, 1 H, C6H4-3-
C6H4Cl), 7.71 (m, 1 H, C6H4Cl), 7.78 (dd, 1J ϭ 9.3 Hz and 2.6 Hz,
Cl 2Ј-H), 8.11 (dd, 1J ϭ 8.6 Hz and 2 Hz, 1 H, 5-H), 8.21 (d, J ϭ 1 H, 4-H), 10.17 (s, 1 H, NH) ppm.
2 Hz, 1 H, 3-H), 8.48 (d, 1J ϭ 8.6 Hz, 1 H, 6-H) 11.39 (s, NH)
1
6-Bromo-4-(3-chlorophenyl)-2(1H)-quinolinone (16): tBuOK (183 g,
ppm. 13C NMR (101 MHz, [D5]pyridine, 22 °C): δ ϭ 25.1 (CH3),
123.4 (C-6), 127.9 (C-4), 129.6 (C6H4-3-Cl C-2Ј), 129.9 (C6H4-4-Cl
C-3Ј ϩ C-5Ј), 130.9 (C6H4-3-Cl C-6Ј), 131.1 (C6H4-3-Cl C-5Ј),
132.6 (C6H4-4-Cl C-2Ј ϩ C-6Ј), 132.8 (C-2), 133.7 (C6H4-3-Cl C-
4Ј), 134.8 (C-3), 135.3 (C6H4-3-Cl C-1Ј), 135.7 (C-5), 137.0 (C6H4-
4-Cl C-1Ј), 139.6 (C6H4-4-Cl C-4Ј), 140.7 (C6H4-3-Cl C-3Ј), 143.7
(CϪNH), 172.5 (NHϪCϭO), 194.0 (3-ClϪC6H4ϪCϭO), 195.9 (4-
ClϪC6H4ϪCϭO) ppm. C22H15Cl2NO3 (412.28): calcd. C 64.09, H
3.67, N 3.40; found C 64.27, H 3.89, N 3.32.
1.635 mol) was added portionwise at room temperature to a solu-
tion of 15 (115.6 g, 0.328 mol) in 1,2-dimethoxyethane (1200 mL)
and the mixture was stirred at room temperature overnight. The
solvents were evaporated to dryness, the residue was poured into
water and ice and decanted. The oily residue was taken up in diiso-
propyl ether, the precipitate was filtered, washed with EtOAc,
acetonitrile and diethyl ether and dried, yielding 88.6 g (81%) of
16, M.p. 266 °C. 1H NMR (400 MHz, [D6]DMSO, 22 °C): δ ϭ
1
6.50 (s, 1 H, 3-H), 7.35 (s, 1 H, 5-H), 7.36 (d, J ϭ 8.6 Hz, 1 H, 8-
6-(4-Chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone (5): H), 7.45 (d, 1J ϭ 6.5 Hz, 1 H, C6H4Cl), 7.58Ϫ7.63 (m, 3 H,
tBuOK (62.8 g, 0.56 mol) was added to a solution of 11 (57.7 g,
0.14 mol) in 1,2-dimethoxyethane (550 mL). The mixture was
stirred at room temperature for 3 h, then H2O was added and the
mixture was extracted with CH2Cl2. The organic layer was sepa-
C6H4Cl), 7.71 (dd, 1J ϭ 8.6 Hz and 2 Hz, 1 H, 7-H), 12.08 (s, NH)
ppm. 13C NMR (101 MHz, [D6]DMSO, 22 °C): δ ϭ 114.0 (CϪBr),
118.4 (C-8), 120.3 (C-10), 123.2 (C-3), 127.8 (C6H4Cl), 128.1 (C-
5), 128.7 (C6H4Cl), 129.3 (C6H4Cl), 131.0 (C6H4Cl), 133.7 (CϪCl),
rated, dried (MgSO4), filtered and the solvent was evaporated. The 133.9 (C-7), 138.4 (C6H4Cl, C-quinolinone), 138.7 (C-9), 149.1 (C-
residue was crystallized from Et2O. The precipitate was filtered and
4), 161.2 (CϭO) ppm. HR-MS: calcd. for C15H9BrClNO 333.963;
dried to afford 47.8 g (87%) of 5 (already described above).
found 333.965.
5-Bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (13): NaOH (24.8 g,
6-Bromo-2-chloro-4-(3-chlorophenyl)quinoline (17): 16 (56 g, 0.16
0.62 mol) was dissolved in MeOH (100 mL) and the mixture was mol) was stirred and refluxed in phosphorus oxychloride (500 mL)
cooled to room temperature. 1-Bromo-4-nitrobenzene (25 g, 0.124
mol), followed by 3-chlorobenzyl cyanide (26.3 mL, 0.223 mol),
overnight. The solvents were evaporated to dryness, the residue was
taken up in ice and water, made basic with NH4OH and extracted
was added dropwise, the temperature rose to 50 °C and the mixture with CH2Cl2. The organic layer was decanted, dried (MgSO4), fil-
was stirred at room temperature overnight. The mixture was
poured into water and ice, the precipitate was filtered, washed with
water and extracted with CH2Cl2 and MeOH. The organic layer
was dried (MgSO4), filtered and the solvents were evaporated to
dryness. The residue was taken up in Et2O, filtered and dried to
afford 13.3 g (35%) of 13. Using mechanical stirring enabled us to
raise the yield to 60%. M.p. 163 °C. 1H NMR (400 MHz, [D5]pyri-
tered and the solvents were evaporated. The residue was crystallized
in CH2Cl2/Et2O, filtered and dried to afford 46.9 g (83%) of 17.
M.p. 136 °C. 1H NMR (400 MHz, [D6]DMSO, 22 °C): δ ϭ 7.56
(ddd, 1J ϭ 7 Hz 1.5 Hz and 1.5 Hz, 1 H, C6H4-3-Cl 6Ј-H), 7.62
1
(dd, J ϭ 8 Hz, 1 H, C6H4-3-Cl 5Ј-H), 7.64Ϫ7.66 (m, 1 H, C6H4-
3-Cl 4Ј-H), 7.67 (s, 1 H, 3-H), 7.68Ϫ7.71 (m, 1 H, C6H4-3-Cl 2Ј-
H), 7.86 (s, 1 H, 5-H), 7.88Ϫ8.02(m, 2 H, 7-H ϩ 8-H) ppm. 13C
dine, 22 °C): δ ϭ 7.39 (dd, 1J ϭ 9.6 Hz and 1.5 Hz, 1 H, 6-H), 7.43 NMR (101 MHz, [D6]DMSO, 22 °C): δ ϭ 121.3 (C-9), 123.5 (C-
(t, 1J ϭ 7.7 Hz, 1 H, C6H4-3-Cl 5Ј-H), 7.49 (ddd, 1J ϭ 7.7 Hz 3), 126.6 (C-10), 127.7 (C-5), 128.6 (C6H4-3-Cl C-6Ј), 129.5 (C6H4-
1
1.1 Hz and 1.1 Hz, 1 H, C6H4-3-Cl 4Ј-H), 7.62 (d, J ϭ 9.6 Hz, 1 3-Cl C-2Ј), 129.6 (C6H4-3-Cl C-4Ј), 131.1 (C-8 ϩ C6H4-3-Cl C-5Ј),
1
H, 7-H), 7.90 (ddd, J ϭ 7.7 Hz 1.1 Hz and 1.1 Hz, 1 H, C6H4-3-
134.0 (C6H4-3-Cl C-3Ј), 134.4 (C-7), 137.7 (C6H4-3-Cl C-1Ј), 146.6
1
Cl 6Ј-H), 8.09 (dd, J ϭ 1.1 Hz and 1.1 Hz, 1 H, C6H4-3-Cl 2Ј-H), (CϪBr), 149.2 (C-4), 150.5 (NϭCϪCl) ppm. HR-MS: calcd. for
7.26 (br. s, 1 H, 4-H) ppm. 13C NMR (101 MHz, [D5]pyridine, 22
°C): δ ϭ 115.9 (CϪBr), 117.5 (C-7), 119.1 (C-9), 122.9 (C-4), 125.0
(C6H4-3-Cl C-6Ј), 126.6 (C6H4-3-Cl C-2Ј), 129.5 (CϪCl), 130.7
(C6H4-3-Cl C-4Ј), 131.2 (C6H4-3-Cl C-5Ј), 135.0 (C-6), 134.4
(C6H4-3-Cl C-1Ј), 156.5 (CϭN), 162.5 (CϪO) ppm. HR-MS: calcd.
for C13H7BrClNO 307.948; found 307.943.
C15H8BrCl2N 351.9295; found 351.9304.
6-Bromo-4-(3-chlorophenyl)-2-methoxyquinoline (18): Sodium me-
thoxide (30% w/w in MeOH, 96 mL, 0.16 mol) was added to a
solution of 17 (56 g, 0.16 mol) in MeOH (500 mL) and the mixture
was stirred and refluxed overnight. The solvents were evaporated
to dryness, the residue was taken up in CH2Cl2, washed with water
and decanted. The organic layer was dried (MgSO4), filtered and
(2-Amino-5-bromophenyl)(3-chlorophenyl)methanone
(14):
Ti-
tanium() chloride (1050 mL, 15% w/w solution in H2O, 1.0 mol) the solvents were evaporated. The residue was taken up in Et2O
was added at room temperature to a solution of 13 (120 g, 0.386
mol) in THF (1350 mL) and the mixture was stirred at room tem-
and diisopropyl ether, the precipitate was filtered and dried, to af-
ford 48 g (86%) of 18. M.p. 137 °C. 1H NMR (400 MHz,
perature for 2 h. The mixture was poured into water and ice and [D6]DMSO, 22 °C): δ ϭ 4.02 (s, 3 H, CH3), 7.04 (s, 1 H, 3-H), 7.49
1
extracted with CH2Cl2. The organic layer was decanted, washed
(dt, J ϭ 7 Hz and 1.5 Hz, 1 H, C6H4-3-Cl 6Ј-H), 7.59Ϫ7.67 (m, 3
with 10% aq. K2CO3, dried (MgSO4), filtered and the solvents were H, C6H4-3-Cl), 7.69 (s, 1 H, 5-H), 7.80Ϫ7.83 (m, 2 H, 7-H ϩ 8-H)
evaporated to yield 102 g (85%) of 14. M.p. 110 °C. 1H NMR
ppm. 13C NMR (101 MHz, [D6]DMSO, 22 °C): δ ϭ 53.8 (OCH3),
114.2 (C-3), 117.5 (C-9), 125.0 (C-10), 127.4 (C-5), 128.4 (C6H4-3-
Cl C-6Ј), 129.2 (C6H4-3-Cl C-2Ј ϩ C-4Ј), 130.0 (C8), 131.0 (C6H4-
1
(400 MHz, [D6]DMSO, 22 °C): δ ϭ 6.87 (d, J ϭ 9.7 Hz, 1 H, 3-
H), 7.28 (d, 1J ϭ 2 Hz, 1 H, 6-H), 7.31 (s, 2 H, NH2), 7.42 (dd, 1J ϭ
9.7 Hz and 2 Hz, 1 H, 4-H), 7.48Ϫ7.69 (m, 4 H, C6H4Cl) ppm. 3-Cl C-5Ј), 133.2 (C-7), 133.9 (CϪCl), 138.7 (C6H4-3-Cl C-1Ј),
145.6 (CϪBr), 148.7 (C-4), 162.2 (NϭCϪO) ppm. HR-MS: calcd.
N-[4-Bromo-2-(3-chlorobenzoyl)phenyl]acetamide (15): A solution
of 14 (101.9 g, 0.328 mol) and acetic anhydride (61.6 mL, 0.656
for C16H11BrClNO 347.9791; found 347.9788.
mol) in toluene (1200 mL) was stirred and refluxed overnight. The (4-Chlorophenyl)-[4-(3-chlorophenyl)-2-methoxyquinolin-6-yl]-
solvents were evaporated and the product was used without further
purification to yield 116 g (quant.) of 15. 1H NMR (400 MHz,
[D6]DMSO, 22 °C): δ ϭ 1.72 [s, 3 H, C(O)CH3], 7.34 (d, 1J ϭ
methanone (19): n-Butyllithium (2 mL, 0.0316 mol) was added
dropwise at Ϫ70 °C to a mixture of 18 (1 g, 0.00287 mol) in THF
(10 mL). The mixture was stirred at Ϫ70 °C for 30 min and a solu-
Eur. J. Org. Chem. 2004, 479Ϫ486
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
483

P. R. Angibaud et al.
FULL PAPER
tion of 4-chloro-N-methoxy-N-methylbenzamide[25] (0.49 g, 3-Cl), 7.33 (d, 1J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 7.40 (dd, 1J ϭ 1.5 Hz
0.00244 mol) in THF (3 mL) was added. The mixture was stirred
at Ϫ70 °C for 30 min, hydrolyzed and extracted with CH2Cl2. The C6H4-3-Cl), 7.54 (ddd, J ϭ 8 Hz 1.5 Hz and 1.5 Hz, 1 H, C6H4-
organic layer was separated, dried (MgSO4), filtered and the sol-
vent was evaporated to dryness. The residue was purified by col-
umn chromatography on silica gel (CH2Cl2/cyclohexane, 50:50).
The pure fractions were collected and the solvents evaporated to
afford 0.74 g (75%) of 19. M.p. 146 °C. 1H NMR (400 MHz,
and 1.5 Hz, 1 H, C6H4-3-Cl), 7.50 (dd, 1J ϭ 8 Hz and 9.6 Hz, 1 H,
1
3-Cl), 7.61 (m, 2 H, 7-H ϩ 8-H) ppm. 13C NMR (101 MHz,
[D6]DMSO, 22 °C): 29.6 (NQuinolinoneϪCH3), 34.6
δ
ϭ
(NImidazoleϪCH3), 77.4 (CϪOH), 115.1 (C-8), 118.1 (C-10), 121.2
(C-3), 123.9 (CHϪNImidazoleϪMe), 125.0 (C-5), 125.6 (CHϭ
NImidazole), 127.9 (C6H4-3-Cl C-6Ј), 127.9 (C6H4-4-Cl C-3Ј ϩ C-5Ј),
[D6]DMSO, 22 °C): δ ϭ 3.09 (s, 3 H, CH3), 7.14 (s, 1 H, 3-H), 128.8 (C6H4-3-Cl C-2Ј), 128.9 (C6H4-4-Cl C-2Ј ϩ C-6Ј), 129.0
1
7.56Ϫ7.60 (m, 3 H, C6H4-3-Cl), 7.63 (d, J ϭ 8.7 Hz, 2 H, C6H4-
(C6H4-3-Cl C-4Ј), 130.8 (C6H4-3-Cl C-5Ј), 131.1 (C-7), 132.0
(C6H4-4-Cl C-Cl), 133.6 (C6H4-3-Cl C-Cl), 138.6 (C6H4-3-Cl C-1Ј),
139.3 (C-9), 139.9 (C-6), 144.8 (C6H4-4-Cl C-1Ј), 149.0 (C-4), 149.4
1
4-Cl), 7.72 (s, 1 H, C6H4-3-Cl), 7.84 (d, J ϭ 8.7 Hz, 2 H, C6H4-4-
1
1
Cl), 8.01 (d, J ϭ 9.5 Hz, 1 H, 8-H), 8.05 (d, J ϭ 2 Hz, 1 H, 5-
H), 8.11 (dd, 1J ϭ 9.5 Hz and 2 Hz, 1 H, 7-H) ppm. 13C NMR (NϭCϪN), 160.8 (CϭO) ppm. HR-MS: calcd. for C27H21Cl2N3O2
(300 MHz, [D6]DMSO, 22 °C): δ ϭ 53.9 (OCH3), 114.1, 122.2,
128.4, 128.8 (2 C), 129.2 (2 C), 129.6, 129.8, 130.8, 131.7 (2 C),
132.1, 133.6, 134.0, 137.6, 138.4 (C6H4-3-Cl, C-quinoline), 149.2
(C-9), 150.3 (C-4), 163.5 (C-2), 193.8 (CϭO) ppm. C23H15Cl2NO2
(408.283): calcd. C 67.66, H 3.70, N 3.43; found C 67.11, H 3.69,
N 3.35.
490.1089; found 490.1085.
Alternative Procedure: Dry tetrahydrofuran (110 ml) was added to
1-methylimidazole (7.6 mL, 0.0946 mol) and the resulting solution
cooled to Ϫ15 °C. n-Hexyllithium (2.5  in hexane, 37.8 mL,
0.0946 mol) was added, while the temperature was maintained be-
tween Ϫ5 and 0 °C. After addition, the reaction mixture was stirred
for 15 min while cooling to Ϫ12 °C. Triisobutylsilyl chloride
6-(4-Chlorobenzoyl)-4-(3-chlorophenyl)-2(1H)-quinolinone (5):
A
mixture of 19 (0.4 g, 0.001 mol) in 6  HCl (4 mL) and MeOH (26.2 mL 0.0964 mol) was added, while the temperature was main-
(2 mL) was stirred and refluxed for 72 h, poured on ice, filtered,
washed several times with water, then with 2-propanol/diethyl ether
and dried to afford 0.31 g (80%) of 5 (already described).
tained between Ϫ5 and 0 °C. After addition, the reaction mixture
was stirred for 15 min, while being cooled to Ϫ13 °C. n-Hexylli-
thium (2.5  in hexane, 37.2 mL, 0.0930 mol) was added, while the
temperature during addition was maintained between Ϫ5 and 0 °C
(some precipitation occurred). After addition, the reaction mixture
was stirred for 15 min while cooled to Ϫ14 °C. Dry tetrahydrofuran
(128 mL) was added to 6 (26.22 g, 0.0642 mol) and stirred until
dissolution. This solution was added to the reaction mixture, while
the temperature during addition was maintained between Ϫ5 and
0 °C. After addition, the reaction mixture was stirred between Ϫ5
and 0 °C for 15 min. Water (128 mL) was added to the reaction
mixture, followed by acetic acid (10.6 mL). The mixture was then
heated to 40 °C and stirred for 2 h. The layers were separated and
the organic layer washed with water (32 mL). Water (64 mL) and
aqueous NaOH 50% (7.8 mL) were added to the organic layer
which was stirred at room temperature for 1 h. The layers were
separated and the organic layer concentrated under reduced press-
ure to yield 51.08 g (75.6%) of 4-(3-chlorophenyl)-6-[(4-chlorophen-
yl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-
quinolinone (20).
4-(3-Chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-
imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone (20): Under dry
N2 flow, 1-methylimidazole (4.83 g, 0.058 mol) was dissolved in
THF (100 mL), and the solution was cooled to Ϫ75 °C before
dropwise addition of n-butyllithium (1.6  in hexane, 36.7 mL,
0.059 mol) at a temperature maintained below Ϫ70 °C. The mix-
ture was stirred for 15 min, triethylsilyl chloride (9.87 mL, 0.058
mol) was added dropwise at Ϫ70 °C. The reaction mixture was
warmed to room temperature (20 °C) and then stirred for 30 min.
The mixture was cooled to Ϫ75 °C, n-butyllithium (1.6  in hexane,
36.7 mL, 0.059 mol) was added dropwise at a temperature main-
tained below Ϫ70 °C, and this mixture was stirred for 1 h at a
temperature below Ϫ70 °C, then warmed to Ϫ15 °C, then re-cooled
to Ϫ75 °C. A solution of 6 (20 g, 0.048 mol) in THF (40 mL) was
then added dropwise at a temperature maintained below Ϫ70 °C,
the reaction mixture was stirred for 1 h and warmed to Ϫ50 °C.
Water (100 mL) was added dropwise. The aqueous layer was ex-
tracted with EtOAc, the organic layer was dried (MgSO4) and the
solvents were evaporated and the residue was purified by silica gel
(؉-)-6-[Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-
4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (23): 20 (3 g, 0.0061
chromatography (CH2Cl2/MeOH/NH4OH, 97:3:0.1) to afford mol) was added at room temperature to thionyl chloride (25 mL).
12.4 g (52%) of 20. M.p. 234 °C. 1H NMR (300 MHz, [D6]DMSO,
22 °C): δ ϭ 3.35 (s, 3 H, CH3 imidazole), 3.67 (s, 3 H, CH3 quinoli-
none), 6.06 (s, 1 H, 4Imidazole-H), 6.58 (s, 1 H, 3-H), 6.90 (s, 1 H,
The mixture was stirred at 40 °C overnight. The solvent was evapo-
rated to dryness to give 3.49 g of 6-[chloro(4-chlorophenyl)-
(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-
2(1H)quinolinone monohydrochloride (22). The product was used
without purification in the next step. A mixture of 22 (22.2 g,
1
1
OH), 7.17 (d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 7.21 (d, J ϭ 1.8 Hz,
1
1 H, 5-H), 7.29 (ddd, J ϭ 7.3 Hz 1.6 Hz and 1.6 Hz, 1 H, C6H4-
3-Cl), 7.36 (d, 1J ϭ 8.6 Hz, 2 H, C6H4-4-Cl), 7.41 (dd, 1J ϭ 1.6 Hz 0.0408 mol) in THF (200 mL) was poured quickly into NH4OH
1
and 1.6 Hz, 1 H, C6H4-3-Cl), 7.50 (dd, J ϭ 7.3 Hz and 8.2 Hz, 1 (200 mL). The mixture was stirred and refluxed at 80 °C for 30 min
H, C6H4-3-Cl), 7.54 (ddd, 1J ϭ 8.2 Hz 1.8 Hz and 1.8 Hz, 1 H,
and then decanted. The aqueous layer was extracted with CH2Cl2.
C6H4-3-Cl), 7.62 (s, 1 H, 2Imidazole-H), 7.62 (m, 2 H, 7-H ϩ 8-H) The combined organic layers were dried (MgSO4), filtered and the
ppm. C27H21Cl2N3O2 (490.39): calcd. C 66.13, H 4.32, N 8.57;
found C 66.19, H 4.29, N 8.45. A second fraction gave 0.23 g (4%)
solvent was evaporated. The residue (21.9 g) was purified by col-
umn chromatography on silica gel (toluene/2-propanol/NH4OH,
of
4-(3-Chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H- 79:20:1). The pure fractions were collected and the solvent was eva-
imidazol-2-yl)methyl]-1-methyl-2(1H)-quinolinone
154 °C. H NMR (200 MHz, [D6]DMSO, 22 °C): δ ϭ 3.42 (s, 3 H,
(21):
M.p.
porated. The residue (13 g, 65%) was crystallized from CH2Cl2/
MeOH/CH3CN. The precipitate was filtered and dried to afford
10.3 g (52%) of 23. M.p. 214 °C. 1H NMR (300 MHz, [D6]DMSO,
1
CH3Imidazole), 3.69 (s, 3 H, CH3 quinolinone), 6.57 (s, 1 H, 3-H),
6.72 (d, 1J ϭ 1 Hz, 1 H imidazole), 6.99 (s, 1 H, OH), 7.12 (d, 1J ϭ 22 °C): δ ϭ 3.10 (s, NH2), 3.38 (s, 3 H, CH3Imidazole), 3.68 (s, 3 H,
1
8.6 Hz, 2 H, C6H4-4-Cl), 7.14 (d, J ϭ 1 Hz, 1 H imidazole), 7.18
CH3Quinolinone), 5.92 (s, 1 H, 4Imidazole-H), 6.55 (s, 1 H, 3-H), 6.94
(s, 1 H, 5-H), 7.31 (ddd, 1J ϭ 9.6 Hz 1.5 Hz and 1.5 Hz, 1 H, C6H4- (d, J ϭ 1.6 Hz, 1 H, 5-H), 7.14 (d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl),
1
1
484  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 479Ϫ486

Farnesyl Protein Transferase Inhibitor ZARNESTRATM
FULL PAPER
1
1
7.23 (d, J ϭ 7.5 Hz, 1 H, C6H4-3-Cl), 7.35 (d, J ϭ 8.6 Hz, 2 H, mixture heated to reflux and stirred at reflux for 1 h. The reaction
C6H4-4-Cl), 7.36 (s, 1 H, C6H4-3-Cl), 7.45 (d, 1J ϭ 7.5 Hz, 1 H,
mixture was then cooled to 20 °C and stirred for 16 h at this tem-
C6H4-3-Cl), 7.49 (dd, 1J ϭ 7.5 Hz and 7.5 Hz, 1 H, C6H4-3-Cl), perature. The product was filtered, washed with water (2 ϫ 8 mL)
7.55 (s, 1 H, 2Imidazole-H), 7.65 (d, 1J ϭ 9.6 Hz, 1 H, 8-H), 7.80 and dried at 50 °C in vacuo to yield 16.87 g (86%) of 1. Ethanol
(dd, 1J ϭ 9.6 Hz and 2 Hz, 1 H, 7-H) ppm. HR-MS: calcd. for
(265 mL) was added to 1 (19.9 g, 0.04mol) and the mixture warmed
while stirring to reflux temperature (78 °C) and then stirred at re-
flux temperature for 15 min before cooling the solution to 75 °C.
Activated carbon (1.0 g of Norit A Supra) was then added to the
mixture which was stirred at reflux temperature for 1 h, filtered
while warm and the filter then washed with warm ethanol (20 mL).
The filtrate and wash solvent were combined (the product spon-
taneously crystallized at 48 °C), and the mixture warmed to reflux
temperature and concentrated by removing 203 mL of ethanol. The
resulting suspension was cooled to 22 °C, stirred at 22 °C for 18 h,
cooled to 2 °C and stirred at 2 °C for a further 5 h. The precipitate
was filtered, washed with ethanol (4 mL) and the product dried at
50 °C in vacuo to yield 17.25 g (86%) of R115777.
C27H22Cl2N4O 489.1249; found 489.1241.
(؉)-(R)-6-[Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)meth-
yl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (1, R115777): 23
(4 g) was separated into its enantiomers by chiral column chroma-
tography on Chiralcel OD (25 cm; eluent: 100% ethanol; flow:
0.5 mL/min; wavelength: 220 nm). The pure fractions were col-
lected and the solvents evaporated. The residue was crystallized
from 2-propanol. The precipitate was filtered to yield 1.3 g (32.5%)
of 1. M.p. 234 °C. 1H NMR (300 MHz, [D6]DMSO, 22 °C):
δ ϭ 3.10 (s, NH2). 3.38 (s, 3 H, CH3Imidazole), 3.68 (s, 3 H,
CH3Quinolinone), 5.92 (s, 1 H, 4Imidazole-H), 6.55 (s, 1 H, 3-H), 6.94
1
1
(d, J ϭ 1.6 Hz, 1 H, 5-H), 7.14 (d, J ϭ 8.6 Hz, 2 H, C6H4-4-Cl),
1
1
7.23 (d, J ϭ 7.5 Hz, 1 H, C6H4-3-Cl), 7.35 (d, J ϭ 8.6 Hz, 2 H,
C6H4-4-Cl), 7.36 (s, 1 H, C6H4-3-Cl), 7.45 (d, 1J ϭ 7.5 Hz, 1 H,
C6H4-3-Cl), 7.49 (dd, 1J ϭ 7.5 Hz and 7.5 Hz, 1 H, C6H4Ϫ3Cl),
7.55 (s, 1 H, 2Imidazole-H), 7.65 (d, 1J ϭ 9.6 Hz, 1 H, 8-H), 7.80 (dd,
1J ϭ 9.6 Hz and 2 Hz, 1 H, 7-H) ppm. C27H22Cl2N4O (489.41):
calcd. C 66.26, H 4.53, N 11.45; found C 66.32, H 4.38, N 11.38.
Acknowledgments
The authors wish to thank S. Gaurrand and L. Queguiner for
NMR and mass analyses as well as Dr. Luc Van Hijfte for his final
revision of the manuscript.
ee Ͼ 99% (HPLC). [α]D ϭ ϩ22.86 (c ϭ 0.98 MeOH).
20
Large-Scale Synthesis of R115777
[1]
N. E. Mills, C. L. Fishman, W. N. Rom, N. Dubin, D. R. Jacob-
son, Cancer Res. 1995, 55, 1444Ϫ1447.
N. Moriyama, T. Umeda, H. Akaza, J. Taniguchi, T. Kitamura,
T. Murakami, K. Kawabe, Y. Aso, Urol. Int. 1989, 44,
260Ϫ263.
J. L. Bos, Cancer Res. 1989, 49, 4682Ϫ4689.
K. Forrester, C. Almoguera, K. Han, W. E. Grizzle, M. Per-
ucho, Nature 1987, 327, 298Ϫ303.
K. Grunewald, J. Lyons, A. Frohlich, H. Feichtinger, R. A.
Weger, G. Schwab, J. W. G. Janssen, C. R. Bartam, Int. J. Can-
cer 1989, 43, 1037Ϫ1041.
Y. Reiss, J. L. Goldstein, M. C. Seabra, P. J. Casey, M. S.
a) A 1-L reaction vessel was charged with 20 (105.4 g, 0.2 mol,
hydrochloric acid salt) and N,N-dimethylimidazolidinone (400 mL)
was added at 22 °C. The mixture was stirred vigorously at 22 °C
for 15 min and became homogeneous. Thionyl chloride (32.1 mL)
was added to the reaction mixture over 10 min, the reaction tem-
perature rising from 22 to 40 °C. After addition of the thionyl chlo-
ride, the reaction mixture was cooled from 40 to 22 °C and stirred
at the latter temperature for 3 h to provide a solution of 4-(3-
chlorophenyl)-6-[chloro-(4-chlorophenyl)(1-methyl-1H-imidazol-
5-yl)methyl]-1-methyl-2(1H)-quinolinone (21).
[2]
[3]
[4]
[5]
[6]
b) Ammonia in methanol (7 , 429 mL) was cooled to 5 °C in a 3-
L reaction vessel and the solution obtained in stage a) added, while
stirring, over 10 min, with an exothermic reaction, the temperature
rising from 5 to 37 °C. After the addition was complete, the reac-
tion mixture was cooled to 22 °C and stirred for 20 h. Water
(1000 mL) was then added over 20 min, the addition being slightly
exothermic, so the reaction mixture was cooled to maintain the
temperature below 30 °C. The mixture was then stirred at 22 °C
for 22 h, the resulting precipitate filtered and the precipitate washed
with water (3 ϫ 100 mL) to provide 67.9Ϫ72.8 g (70Ϫ75%) of 23.
Brown, Cell 1990, 62, 81Ϫ88.
[7]
L. Gutierrez, A. I. Magee, C. J. Marshall, J. F. Hancock,
EMBO J. 1989, 8, 1093Ϫ1098.
K. Kato, A. D. Cox, M. M. Hisaka, S. M. Graham, J. E. Buss,
C. J. Der, Proc. Natl Acad. Sci. USA 1992, 89, 6403Ϫ6407.
H. R. Ashar, L. James, K. Gray, D. Carr, S. Black, L. Arm-
strong, W. R. Bishop, P. Kirschmeier, J. Biol. Chem. 2000,
275, 30451Ϫ30457.
C. Baum, P. Kirschmeier, Curr. Oncol. Rep. 2003, 5, 99Ϫ107.
D. W. End, G. Smets, A. V. Todd, T. L. Applegate, C. J. Fuery,
[8]
[9]
[10]
[11]
P. Angibaud, M. Venet, G. Sanz, H. Poignet, S. Skrzat, A. De-
vine, W. Wouters, C. Bowden, Cancer Res. 2001, 61, 131Ϫ137.
[12]
c) A 3-L reaction vessel was charged with 23 (146.8 g, 0.3mol) and
-(Ϫ)-dibenzoyltartaric acid monohydrate (301.1 g, 0.8mol), ace-
tone (1200 mL) and the reaction mixture was stirred vigorously at
22 °C for 10 min to form a solution which was seeded with 100 mg
of the final tartrate salt product (obtained from previous screening
experiments) and then stirred at 22 °C for 22 h. The resulting pre-
cipitate was filtered, washed with acetone (2 ϫ 75 mL) and the
product dried at 50 °C in vacuo to yield 114.7 g (37%) of R-(Ϫ)-6-
[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-
chlorophenyl)-1-methyl-2(1H)-quinolinone [R-(R*,R*)]-2,3-bis-
(benzoyloxy)butanedioic acid (1:1.5) (24). ee ϭ 97% (HPLC).
P. Norman, Curr. Opin. Invest. Drugs 2002, 3, 313Ϫ319.
[13]
M. G. Venet, D. W. End, P. R. Angibaud, Curr. Top. Med.
Chem. 2003, 3, 1095Ϫ1102.
M. G. Venet, Abstract of papers, 222nd National Meeting of
the American Chemical Society, Chicago, IL, Aug 26Ϫ30,
2001; American Chemical Society, Washington, DC, 2001,
69BUZP.
[14]
[15]
M. Natarajan, V. T. Ramakrishnan, Ind. J. Chem., Sect. B
1984, 23, 720Ϫ727.
[16]
L. A. Sorbera, R. Fernandez, J. Castaner, Drugs Future 2001,
26, 453Ϫ461.
[17]
D. W. End, M. G. Venet, P. R. Angibaud, G. C. Sanz (Janssen
Pharmaceutica N. V.), WO 9716443, 1997 [Chem. Abstr. 1997,
d) 24 (41.08 g, 0.04mol) and ethanol (80 mL) were stirred at 22 °C
for 15 min. Concentrated aqueous ammonium hydroxide (12.0 mL)
was added over 2 min, and the reaction mixture stirred at 25 °C
for 1 h. Water (160 mL) was added at 25 °C over 10 min and the
127, 34143].
[18]
M. G. Venet, P. R. Angibaud, P. Muller, G. C. Sanz (Janssen
Pharmaceutica N. V.), WO 9721701, 1997 [Chem. Abstr. 1997,
127, 95280].
Eur. J. Org. Chem. 2004, 479Ϫ486
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
485

P. R. Angibaud et al.
FULL PAPER
[19]
[22]
[23]
[24]
[25]
R. B. Davis, L. C. Pizzini, J. Org. Chem. 1960, 25, 1884Ϫ1888.
G. Shapiro, M. Marzi, Tetrahedron Lett. 1993, 34, 3401Ϫ3404.
G. Shapiro, B. Gomez-Lor, J. Org. Chem. 1994, 59, 5524Ϫ5526.
J. O. Morley, Synthesis 1977, 1, 54Ϫ55.
J. A. Turner, W. S. Jacks, J. Org. Chem. 1989, 54, 4229Ϫ4231.
Received August 28, 2003
[20]
G. N. Walter, J. Org. Chem. 1962, 27, 1929Ϫ1930.
[21]
W. F. M. Filliers, R. L. M. Broeckx, S. M. H. Leurs (Janssen
Pharmaceutica N. V.), WO 0272574, 2002 [Chem. Abstr. 2002,
137, 252655].
486
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 479Ϫ486