+
+
Synthesis and Activity of Tebuquine Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 447
1296, 1237, 1209, 1094, 747; MS m/ z 265 (M+, 76), 183 (100),
163 (12); HRMS 265.031 04 (C13H9NO2FCl requires 265.030 58).
3-(4′-Ch lor op h en yl)-4-flu or o-5-[[(ter t-bu tyla m in o)m e-
th yl]a n ilin o]n itr oben zen e. 2-Fluoro-3-(4′-chlorophenyl)-5-
nitrotoluene (1.00 g, 3.77 mmol) was brominated with NBS
(1.34 g, 7.54 mmol) and AIBN (catalytic) by heating in carbon
tetrachloride for 8 h (TLC analysis revealed the completion of
the reaction). The solvent was removed under reduced pres-
sure, without further purification tert-butylamine (excess) was
added with toluene (35 mL), and the reaction mixture was
heated to reflux for 10 h under nitrogen. The reaction mixture
was allowed to cool and filtered. The solvent was removed
and the residue purified by flash column chromatography on
silica gel using dichloromethane/methanol (95:5) as eluent to
give the product as a pale yellow foam: 1H NMR (CDCl3, 200
MHz) δ 8.40 (1H, dd, J H-F ) 5.50 Hz, J H-H ) 2.75 Hz, Ar-H),
8.20 (1H, dd, J H-F ) 5.50 Hz, J H-H ) 2.75 Hz, Ar-H), 7.55 (4H,
m, Ar-H, RC6H4Cl), 3.95 (2H, s, CH2N), 1.23 (9H, s, tBu). Anal.
(C17H18NO2FCl).
mL) was added and the solution gently heated in order to
dissolve all of the starting material. When the clear solution
boiled, the condenser and heat source were removed. Sodium
nitrite (2.00 g) was added in two portions, and the condenser
was reconnected while the reaction took place; additional
heating was used to complete the reaction. The solution was
allowed to cool down and placed in a refrigerator overnight.
The crude product was filtered off and washed with ethanol
and then water to remove sodium sulfate. The material was
of sufficient purity for use in the next reaction: mp 87-90
°C; 1H NMR (CDCl3, 200 MHz) δ 8.16-8.20 (1H, m, Ar-H),
7.96-8.00 (1H, m, Ar-H), 7.64-7.68 (1H, m, Ar-H), 2.47 (3H,
s, -CH3); IR (Nujol mull) 2930, 1535, 1458, 1377, 1348, 1300,
879, 872, 839, 737; MS m/ z 217/215 (M+, 69/67), 169 (33), 89/
90 (92/100); HRMS 214.958 04 (C7H6NO2Br requires
214.958 19).
3-(4′-Ch lor op h en yl)-5-n itr otolu en e (11). 3-Bromo-5-ni-
trotoluene was subjected to the Suzuki reaction as described
1
for compound 10. The yield was 75%: mp 90 °C ; H NMR
F lu or otebu qu in e (7a ). The nitro compound 16 (0.50 g,
1.48 mmol) was reduced using tin/HCl and the resulting amine
coupled with 4,7-dichloroquinoline to give the required product
as a yellow solid following column chromatography (dichlo-
(CDCl3, 200 MHz), δ 8.22 (1H, s, Ar-H), 8.04 (1H, m, Ar-H),
7.68 (1H, m, Ar-H), 7.50 (4H, m, Ar-H), 2.60 (3H, s, -CH3); IR
(Nujol mull) 2918, 2856, 1526, 1490, 1459, 1376, 1362, 1291;
MS m/ z 247 (M+, 100), 201 (17), 165 (60); HRMS 247.040 09
(C13H10NO2Cl requires 247.039 99).
1
romethane/methanol, 8:2): mp 179 °C; H NMR (CDCl3, 200
MHz) δ 8.55 (1H, dd, J H-H ) 4.95 Hz, Ar-H), 8.02 (1H, dd,
J H-H ) 2.20 Hz, Ar-H), 7.89 (1H, d, J H-H 8.80 Hz, Ar-H), 7.31-
7.51 (6H, m, RC6H4Cl, Ar-H), 7.20 (1H, dd, J H-H ) 6.05, 2.20
Hz), 6.85 (1H, d, J H-H ) 5.50 Hz), 3.85 (2H, s, CH2NHtBu),
1.07 (9H, s, tBu); MS m/ z 467 (M+, 4.2), 455 (15), 452 (100),
395 (32), 380 (47), 360 (47), 227 (21), 170 (41), 162 (33); HRMS
467.131 53 (C26H24N3FCl2 requires 467.133 15). Anal.
(C26H24N3FCl2) C,H,N.
3-(4′-Ch lor op h en yl)-4-flu or o-5-[(d ieth yla m in o)m eth yl]-
n itr oben zen e. 2-Fluoro-3-(4′-chlorophenyl)-5-nitrotoluene (20)
(1.00 g, 3.77 mmol) was brominated with NBS (1.34 g, 7.54
mmol) and AIBN (catalytic) by heating in carbon tetrachloride
as described for (16). The solvent was removed under reduced
pressure, without further purification diethylamine (0.55 g,
7.54 mmol) was added with toluene (35 mL), and the reaction
mixture was allowed to reflux for 10 h under nitrogen. The
reaction mixture was allowed to cool and filtered. The solvent
was removed and the residue purified by flash column chro-
matography on silica gel using dichloromethane/methanol (95:
5) as eluent to give the product as a pale yellow foam (0.83 g,
65%): 1H NMR (CDCl3, 200 MHz) δ 8.43 (1H, dd, J H-F ) 6.05
Hz, J H-H ) 2.75 Hz, Ar-H), 8.19 (1H, dd, J H-F ) 6.05 Hz, J H-H
) 2.75 Hz, Ar-H), 7.43-7.50 (4H, m, Ar-H, RC6H4Cl), 3.71 (2H,
s, -CH2N), 2.60 (4H, q, NCH2CH3), 1.08 (6H, t, NCH2CH3); MS
m/ z 336 (M+, 8), 321 (100), 264 (80), 183 (73); HRMS
336.103 77 (C17H18N2O2ClF requires 336.104 10).
F lu or oa m otebu qu in e (7b). 3-(4′-Chlorophenyl)-4-fluoro-
5-[(diethylamino)methyl]nitrobenzene (0.50 g, 1.48 mmol) was
dissolved in concentrated hydrochloric acid (5 mL), and an
excess of tin turnings was added (ca. 1.40 g, 11.84 mmol). The
mixture was stirred for 1 h and then heated for 45 min to
complete the reduction. The mixture was allowed to cool and
concentrated sodium hydroxide solution (80 mL) added. The
amine was extracted with dichloromethane by several wash-
ings of the aqueous layer. The organic extracts were dried
(MgSO4), and the solvent was removed to give the amine as a
pale yellow oil. The amine was dissolved in ethanol (15 mL)
and 4,7-dichloroquinoline (0.20 g, 1 mmol) added. The ethanol
solution was acidified (pH ) 5.5) and then heated under reflux
for 8 h. The product was obtained by basification and
filtration. The solid product was dried and purified by column
chromatography using dichloromethane/methanol (5:1) to give
an off-white solid (0.52 g, 76%): 1H NMR (CDCl3, 200 MHz) δ
8.56 (1H, dd, J H-H ) 4.95 Hz, Ar-H), 8.04 (1H, d, J H-H ) 1.65
Hz, Ar-H), 7.93 (1H, d, J H-H ) 8.80 Hz, Ar-H), 7.40-7.60 (7H,
m, Ar-H, RC6H4Cl), 6.90 (1H, d, J H-H ) 4.95 Hz), 3.72 (2H, s,
-CH2N), 2.65 (4H, q, NCH2CH3), 1.10 (6H, t, NCH2CH3); MS
m/ z 467 (M+, 3), 452 (45), 396 (88), 380 (45), 227 (30), 170
(36), 162 (27). Anal. (C26H24N3FCl2) C, H, N.
3-[(t er t -B u t y la m in o )m e t h y l]-5-(4′-c h lo r o p h e n y l)-
n itr oben zen e. 3-(4′-Chlorophenyl)-5-nitrotoluene was bro-
minated and allowed to react with tert-butylamine as described
for 16: mp 90-92 °C; 1H NMR (CDCl3, 200 MHz) δ 8.26 (1H,
m, Ar-H), 8.22 (1H, m, Ar-H), 7.90 (1H, s, Ar-H), 7.50 (4H, m,
Ar-H), 3.95 (2H, s, -CH2N), 1.20 (9H, s, tBu); IR (Nujol mull)
2915, 2853, 1601, 1533, 1497, 1458, 1376, 1219, 1164; MS m/ z
317 (M+, 1), 303 (100), 246 (45), 165 (26). Anal. (C17H18N2O2-
Cl) C,H,N.
Deh yd r oxytebu qu in e (7c). 3-[(tert-Butylamino)methyl]-
5-(4′-chlorophenyl)nitrobenzene was reduced using tin/HCl as
described in the synthesis of 7b: 1H NMR (CDCl3, 200 MHz)
δ 7.40 (4H, m, Ar-H), 6.90 (1H, m, Ar-H), 6.70-6.75 (m, 2H,
Ar-H), 3.89 (2H, s, -CH2N), 1.17 (9H, s, tBu); IR (Nujol mull)
3182, 2915, 2853, 1601, 1533, 1497, 1458, 1376, 1219, 1164;
MS m/ z 288 (M+, 11), 273 (68), 216 (100), 180 (24); HRMS
288.139 59 (C17H21N2Cl requires 288.139 31).
The amine was coupled with 4,7-dichloroquinoline as des-
ribed for 7b to give the product dehydroxytebuquine (7c) as a
yellow solid following column chromatography on silica gel,
10% MeOH, 90% dichloromethane: 1H NMR (CDCl3, 200 MHz)
δ 9.59 (1H, s, NH), 9.01 (1H, d, J H-H ) 9.40 Hz), 8.55 (1H, d,
J H-H ) 6.58 Hz, Ar-H), 8.18 (d, J H-H ) 2.20 Hz, Ar-H), 8.10
(1H, s, Ar-H), 7.85 (4H, m, Ar-H, RC6H4Cl), 7.60 (1H, d, J H-H
) 8.80 Hz, Ar-H), 7.20 (1H, d, J H-H ) 7.14 Hz), 4.20 (2H, s,
-CH2N), 1.41 (9H, s, tBu); MS m/ z 449 (M+, 10), 434 (100),
377 (30), 362 (27); HRMS 449.142 12 (C26H25N3Cl2 requires
449.142 55).
Ack n ow led gm en t. We thank the Wellcome Trust
(B.K.P., S.A.W.), M.R.C. (S.R.H.), Roche (Welwyn)
(P.M.O.), and the University of Liverpool for financial
support. The authors also thank Dr. J . L. Maggs for
EI+ mass spectrometry and Lawrence Bishop (Wellcome
Vacation Studentship) and Sandra Lust for technical
assistance. The authors also thank Prof. R. J . Abraham
(Liverpool University) for helpful discussion.
Refer en ces
(1) WHO Practical Chemotherapy of Malaria; Technical Report
Series No. 805; World Health Organization: Geneva, 1990.
(2) Hawley, S. R.; Bray, P. G.; O’Neill, P. M.; Park, B. K.; Ward, S.
A. The Role of Drug Accumulation in 4-Aminoquinoline Anti-
malarial Potency: The Influence of Structural Substitution and
Physicochemical Properties. Biochem. Pharmacol. 1996, 52,
723-733.
(3) Werbel, L. M.; Cook, P. D.; Elslager, E. F.; Hung, J . H.; J ohnson,
J . L.; Keston, S. J .; McNamara, D. J .; Ortwine, D. F; Worth, D.
F., Synthesis, Antimalarial Activity and Quantitative Structure-
Activity Relationships of Tebuquine and a Series of Related 5-[(7-
chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl][1,1′-biphenyl]-
2-ols and N-oxides. J . Med. Chem. 1986, 29, 924-939.
3-Br om o-5-n itr otolu en e. 2-Amino-3-bromo-5-nitrotoluene
(5 g, 0.021 mol) was dissolved in ethanol (60 mL) and toluene
(15 mL) in a 250 mL round-bottomed flask. Sulfuric acid (3.5