A ring expansion strategy in antiviral synthesis: A novel approach to TAK-779

Article abstract of DOI:10.1081/SCC-120037909

A synthesis of TAK-779 that relies on construction of a key carboxylic acid intermediate by a ring expansion with TMSCHN2 is described.

Full text of DOI:10.1081/SCC-120037909

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 11, pp. 1973–1980, 2004
A Ring Expansion Strategy in Antiviral
Synthesis: A Novel Approach to TAK-779
*
Terrence L. Smalley Jr.
GlaxoSmithKline, Inc., M&V CEDD Chemistry, Research Triangle Park,
North Carolina, USA
ABSTRACT
A synthesis of TAK-779 that relies on construction of a key carboxylic
acid intermediate by a ring expansion with TMSCHN2 is described.
Key Words: Ring transformations; Amines; Suzuki reactions; Coupling
reaction.
INTRODUCTION
Discovering effective medicines for the treatment of AIDS has long been
a goal of the pharmaceutical industry. Current therapies include a cocktail
of reverse transcriptase and protease inhibitors;[1] however, mutations of
*
Correspondence: Terrence L. Smalley Jr., GlaxoSmithKline, Inc., M&V CEDD
Chemistry, Five Moore Drive, , Research Triangle Park, North Carolina 27709,
USA; Fax: (919) 315-0430; E-mail: terry.l.smalley@gsk.com.
1973
DOI: 10.1081/SCC-120037909
Published by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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Smalley
the HIV virus have resulted in resistance to conventional treatments.[1] Con-
sequently, new and innovative treatments are sought that can treat patients
who become resistant to classical anti-HIV therapeutics.
A recent publication disclosed a class of molecules that may potentially
inhibit the progression of HIV by a novel mechanism involving antagonism of
the CCR5 chemokine receptor.[2] In particular, TAK-779 1 (Fig. 1) has shown
excellent in vitro inhibition of the HIV virus, and its effectiveness as a treatment
for HIV is currently being evaluated in the clinic. Because of our own interest
in treating HIV, we sought to obtain 1 for use as an in-house research tool.
At the outset of this work no details regarding the synthesis of 1 had been
described, although the details of the synthesis were disclosed upon
completion of the present approach.[2] The original procedure initially used a
Friedel–Crafts acylation reaction with bromobenzene to construct the
6,7-fused ring system. A lengthy sequence of functional group transformations
was used to access key carboxylic acid 2. Additionally, a process route to 1
employing a 12 step sequence has recently been reported starting from
4-(4-methylphenyl)benzonitrile.[3] The goal of the work presented here was to
employ a short synthetic route to 2 avoiding the use of excess toxic reagents.
The retrosynthesis for the present work initiated with the obvious
disconnection of the amide bond to give carboxylic acid 2 and amine 3
(Sch. 1). Carboxylic acid 2 could arise from suberone 4 by functional group
modification. It was envisioned that 4 could arise from a suitably functionalized
tetralone by simple ring expansion. For this reason, commercially available
7-methoxy-1-tetralone was chosen as the starting point in the synthesis.
7-Methoxy-1-tetralone was elaborated to 7-(4-methylphenyl)-1-tetralone
(5) by sequential demethylation with HBr,[4] conversion of the resulting
phenol to the triflate with Tf2O[5] and subsequent Suzuki coupling[2] with
4-methylbenzeneboronic acid (Sch. 2). Ring expansion of tetralone 5 was
[6]
accomplished with trimethylsilyldiazomethane and BF3 OEt2 to provide
.
the corresponding suberone 6 as a single regioisomer. The regiochemistry
1
of the ring expansion was assigned on the basis of the H NMR spectrum,
which showed a singlet at d 3.78 corresponding to the a-keto benzylic protons.
Figure 1. Structure of TAK-779 (1).

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1975
Scheme 1.
Initial attempts to convert 6 to the vinyl triflate 7 were focused on the use of
Tf2O as the electrophile. Treatment of 6 with Tf2O and Et3N at 08C led to a
10 : 1 mixture of the desired product 7 and its isomeric vinyl triflate in a com-
bined 45% yield. Changing the base to Na2CO3 provided 7 in 59% yield as the
sole product. Moreover, it was discovered the yields could be improved by chan-
ging the triflating reagent. Deprotonation of 7 with LiHMDS followed by quench-
ing of the enolate with PhNTf2[7] led to 7 in 60% yield. Alternatively, quenching
of the enolate with 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine[8]
led to 7 in a much improved 81% yield. The carboxylic acid moiety was
installed by palladium mediated carbonylation[9] of 7 to provide a,b-unsaturated
ester 8 in 77% yield. The key intermediate 2 was isolated upon saponification
of 8. The aniline 3[2] was coupled to carboxylic acid 2 with EDC and HOBt to pro-
vide tertiary amine 11. Reaction of 11 with excess CH3I as reported[2] provided 1.
In summary, the discovery of 1 as a CCR5 inhibitor is a significant
advance for the treatment of HIV infected patients. The synthesis of this excit-
ing molecule was completed in nine linear steps from 7-methoxy-1-tetralone,
a method which compares quite favorably with that described by previously.[2]
The synthesis presented in this communication could be easily adapted for
creating analogs of 1.
EXPERIMENTAL SECTION
General
All chemicals and reagents were purchased from commercial sources
except where noted and were used as received. Anhydrous THF, CH2Cl2,

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Smalley
Scheme 2. (a) HBr/HOAc; (b) Tf2O, Et3N, CH2Cl2; (c) 4-methylphenylboronic
.
acid, Pd(PPh3)4, K2CO3, PhCH3, EtOH, H2O, 1108C, 67% overall; (d) BF3 OEt2,
Me3SiCHN2, 08C, 47%; (e) LiHMDS, THF, 2788C then 2-[N,N-bis(trifluoromethyl-
sulfonyl)amino]-5-chloropyridine, 81%; (f) CO, Et3N, PdCl2(PPh3)2, EtOH, 808C,
.
77%; (g) LiOH, 4/1/1 THF/EtOH/H2O, 78%; (h) EDC HCl, HOBt, CH2Cl2, 50%;
(i) CH3I, DMF.
and toluene were purchased from Aldrich and used as received. Silica gel
chromatography was performed on an Isco Sg100c single channel purification
instrument using RediSepTM cartridges. NMR spectra were performed on
Varian 400 and 300 MHz spectrophotometers. Melting points were deter-
mined on a Thomas Hoover melting point apparatus and are uncorrected.
Elemental analyses were performed by Atlantic Microlab (Norcross, GA).
3-(4-Methylphenyl)-5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-
one (6). 7-(4-Methylphenyl)-3,4-dihydronaphthalen-1(2H)-one[2] (5, 7.93 g,
33.6 mmol) was suspended in Et2O (34 mL) and cooled to 08C under
.
N2. BF3 OEt2 (4.70 mL, 37.1 mmol) was added followed by dropwise
addition of TMSCHN2 (18.5 mL, 37.0 mmol). The mixture was stirred at
08C for 45 min and sat. aq. NaHCO3 (100 mL) was carefully added. The
two layers were separated and the aqueous layer was extracted with Et2O
(2 ꢀ 25 mL). The organics were dried (MgSO4) and concentrated. The residue
was purified by silica gel chromatography (RediSepTM 120 g cartridge, 85 : 15
hexane : EtOAc) to provide 6 as a yellow solid (3.99 g, 47%), mp ¼ 82–838C.

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Novel Approach to TAK-779
1977
1H NMR (CDCl3): d 7.46 (d, J ¼ 8.0 Hz, 2H), 7.41 (dd, J ¼ 8.0, 1.8 Hz, 1H),
7.4 (m, 1H), 7.22 (d, J ¼ 8.0 Hz, 2H), 7.20 (d, J ¼ 8.0 Hz, 1H), 3.78 (s, 2H),
2.97 (t, J ¼ 6.9 Hz, 2H), 2.60 (t, J ¼ 6.9 Hz, 2H), 2.38 (s, 3H), 2.0 (m, 2H)
ppm. Elemental analysis calculated for C18H18O: C, 86.4%; H, 7.3%.
Found: C, 86.31%; H, 7.22%.
2-(4-Methylphenyl)-6,7-dihydro-5H-benzo[a][7]annulen-8-yl trifluoro-
methanesulfonate (7). LiHMDS (13.6 mL, 13.6 mmol) was dissolved in THF
(5 mL) and cooled to 2788C under N2. A solution of 3-(4-methylphenyl)-
5,7,8,9-tetrahydro-6H-benzo[a][7]annulen-6-one (6, 2.96 g, 11.8 mmol) in
THF (6 mL) was added dropwise and the solution was stirred for 50 min.
A solution of 5-chloro-2-N,N-bis(triflouromethyl)aminopyridine (4.83 g,
12.3 mmol) in THF (5 mL) was added and the mixture was stirred at 2788C
for 60 min then at RT for 60 min. H2O (15 mL) was added and the two layers
were separated. The aqueous layer was extracted with Et2O (2 ꢀ 10 mL). The
organics were washed with 10% NaOH (25 mL), dried (MgSO4), and concen-
trated. The residue was purified by silica gel chromatography (RediSepTM 40 g
cartridge, 95 : 5 hexane : EtOAc) to provide the product as a colorless oil
(3.67 g, 81%). 1H NMR (CDCl3): d 7.50 (d, J ¼ 8.0 Hz, 2H), 7.45 (dd,
J ¼ 8.0, 1.8 Hz, 1H), 7.4 (m, 1H), 7.28 (d, J ¼ 8.0 Hz, 2H), 7.21
(d, J ¼ 8.0 Hz, 1H), 6.69 (s, 1H), 2.96 (t, J ¼ 5.8 Hz, 2H), 2.85
(t, J ¼ 6.5 Hz, 2H), 2.43 (s, 3H), 2.1 (m, 2H) ppm. Elemental analysis
calculated for C19H17F3O3S: C, 59.7%; H, 4.5%. Found: C, 59.82%; H,
4.46%.
Ethyl2-(4-methylphenyl)-6,7-dihydro-5H-benzo-[a][7]annulene-8-car-
boxylate (8). 2-(4-Methylphenyl)-6,7-dihydro-5H-benzo[a][7]annulen-8-yl
trifluoromethanesulfonate (7, 3.67 g, 9.60 mmol) was dissolved in EtOH
(15 mL). Et3N (1.60 mL, 11.5 mmol) and PdCl2(PPh3)2 (0.4178 g,
1.01 mmol) were added and the atmosphere was changed to CO (1 atm).
The solution was heated to 808C for 90 min then was cooled to RT and
concentrated. The residue was purified by silica gel chromatography
(RediSepe 40 g cartridge, 9 : 1 hexane : EtOAc) to provide the product as a
1
yellow oil (2.07 g, 70%). H NMR (CDCl3): d 7.75 (s, 1H), 7.5 (m, 1H),
7.46 (d, J ¼ 8.0 Hz, 2H), 7.41 (dd, J ¼ 8.0, 1.8 Hz, 1H), 7.22 (d, J ¼ 8.0 Hz,
2H), 7.18 (d, J ¼ 8.0 Hz, 1H), 4.26 (q, J ¼ 7.1 Hz, 2H), 2.82 (t, J ¼ 5.6 Hz,
2H), 2.64 (t, J ¼ 6.5 Hz, 2H), 2.37 (s, 3H), 2.1 (m, 2H), 1.34 (t, J ¼ 7.1 Hz,
3H) ppm. Elemental analysis calculated for C21H22O2: C, 82.3%; H, 7.2%.
Found: C, 82.49%; H, 7.12%.
2-(4-Methylphenyl)-6,7-dihydro-5H-benzo-[a][7]annulene-8-carboxylic
acid (2). Ethyl 2-(4-methylphenyl)-6,7-dihydro-5H-benzo-[a][7]annulene-8-
carboxylate (8, 2.07 g, 6.76 mmol) was dissolved in THF (12 mL), EtOH
(3 mL), and H2O (3 mL). LiOH (0.8527 g, 20.3 mmol) was added and the solu-
tion was heated to 508C for 24 hr. The mixture was cooled to RT and sat. aq.

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KH2PO4 (25 mL) was added. The mixture was extracted with Et2O
(4 ꢀ 10 mL) and the organics were dried (Na2SO4) and concentrated. The
residue was triturated with hexane : Et2O (9 : 1) to provide the product
1
(1.18 g, 63%) as a pale yellow solid, mp ¼ 184–1868C (dec.). H NMR
(CDCl3): d 7.90 (s, 1H), 7.54 (d, J ¼ 1.4 Hz, 1H), 7.47 (d, J ¼ 8.0 Hz, 2H),
7.44 (dd, J ¼ 8.0, 1.8 Hz, 1H), 7.23 (d, J ¼ 8.0 Hz, 2H), 7.20 (d, J ¼ 8.0 Hz,
1H), 2.87 (t, J ¼ 5.5 Hz, 2H), 2.68 (t, J ¼ 5.5 Hz, 2H), 2.38 (s, 3H), 2.1 (m, 2H)
.
ppm. Elemental analysis calculated for C19H18O2 0.15H2O: C, 81.2%; H,
6.6%. Found: C, 81.11%; H; 6.40%.
2-(4-Methylphenyl)-N-(4-f[methyl(tetrahydro-2H-pyran-4-yl)amino]
methylgphenyl)-6,7-dihydro-5H-benzo[a][7]annulene-8-carboxamide (9).
2-(4-Methylphenyl)-6,7-dihydro-5H-benzo-[a][7]annulene-8-carboxylic acid
(2, 0.2015 g, 0.724 mmol) was dissolved in CH2Cl2 (1.40 mL) and cooled to
.
08C. HOBt (0.1173 g, 0.868 mmol) and EDC HCl (0.1668 g, 0.870 mmol)
were added and the mixture was stirred for 40 min. TAK aniline (0.1600 g,
0.727 mmol) and (i-Pr)2NEt (0.130 mL, 0.746 mmol) were added and the mix-
ture was warmed to RT and stirred for 2 hr. H2O (15 mL) was added and the
mixture was extracted with CH2Cl2 (2 ꢀ 10 mL). The organics were dried
(MgSO4) and concentrated. The residue was purified by silica gel chromato-
graphy (9 : 1 CH2Cl2 : MeOH) to provide the product (0.1740 g, 50%) as a
1
white solid, which was used without further purification. H NMR (CDCl3):
d 7.67 (s, 1H), 7.57 (d, J ¼ 8.0 Hz, 2H) 7.50 (d, J ¼ 1.4 Hz, 2H), 7.46
(d, J ¼ 8.0 Hz, 2H), 7.41 (dd, J ¼ 8.0, 1.8 Hz, 1H), 7.4 (m, 2H), 7.20
(d, J ¼ 8.0 Hz, 2H), 4.02 (dd, J ¼ 11.0, 3.8 Hz, 2H), 3.64 (s, 2H), 3.34 (dt,
J ¼ 11.7, 1.8 Hz, 2H), 2.86 (t, J ¼ 8.6 Hz, 2H), 2.7 (m, 1H), 2.69
(t, J ¼ 6.3 Hz, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 2.1 (m, 2H), 1.8 (m, 2H), 1.7
(m, 2H) ppm. LRMS calcd for C32H36N2O2: m/z ¼ 480. Found: m/z ¼ 481
(M þ Hþ).
N,N-Dimethyl-N-[4-(f[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]
[7]annulen-8-yl]carbonylgamino)benzyl]tetrahydro-2H-pyran-4-aminium
iodide
(1). 2-(4-Methylphenyl)-N-(4-f[methyl(tetrahydro-2H-pyran-4-yl)
amino]methylgphenyl)-6,7-dihydro-5H-benzo[a][7]annulene-8-carboxamide
(9, 0.1210 g, 0.252 mmol) was dissolved in DMF (8 mL). CH3I (0.100 mL,
1.61 mmol) was added and the mixture was stirred at RT overnight. The
mixture was concentrated and the residue was triturated with EtOAc. The
solid was recrystallized from EtOAc/EtOH (3 : 1) to provide the product as
1
a yellow solid. H NMR (d6-DMSO): d 10.18 (s, 1H), 7.82 (d, J ¼ 8.5 Hz,
2H), 7.63 (s, 1H), 7.54 (d, J ¼ 8.0 Hz, 2H), 7.48 (d, J ¼ 8.5 Hz, 2H), 7.32
(s, 1H), 7.26 (d, J ¼ 8.0 Hz, 2H), 7.23 (d, J ¼ 8.0 Hz, 2H), 4.41 (s, 2H),
4.00 (dd, J ¼ 11.0, 1.8 Hz, 2H), 3.53 (t, J ¼ 1.8 Hz, 1H), 2.83 (s, 6H), 2.81
(t, J ¼ 6.0 Hz, 2H), 2.60 (t, J ¼ 6.0 Hz, 2H), 2.30 (s, 3H), 2.12
(d, J ¼ 11.0 Hz, 2H), 2.0 (m, 2H), 1.8 (m, 2H) ppm. Elemental analysis for

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Novel Approach to TAK-779
1979
.
C33H39IN2O2 3H2O: C, 58.56%; H, 6.71%; N, 4.14%. Found: C, 58.62%; H,
6.34%; N, 4.55%. LRMS calcd for C33H39N2O2: m/z ¼ 496. Found:
m/z ¼ 496.
ACKNOWLEDGMENTS
The author would like to thank Mr. Virgil L. Styles, Dr. Wieslaw
Kazmierski, and Dr. Paul Feldman for informative discussions during the
course of this work and for critical reading of this manuscript.
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Received in the USA January 6, 2004

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