Modulators of Multidrug Resistance
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aromatic H). 13C NMR (50 MHz, CDCl3): δ = 19.0, 19.1, 19.3, 19.4, 33.8,
34.2, 34.9, 37.0, 37.2, 37.4, 40.2, 40.8, 50.8, 51.0, 51.3, 52.4, 56.5, 56.6, 56.7,
110.9, 111.1, 111.6, 111.7, 112.0, 112.5, 112.7, 118.6, 119.2, 121.4, 121.5,
121.8, 131.2, 131.3, 132.2, 149.0, 149.2, 149.4, 149.5, 149.7, 150.0, 168.4,
168.6.– Anal. (C26H34N2O5) C, H, N.
and 1.10 (2 t, J = 7 Hz, 3 H, OCH2CH3); 1.40 and 1.47 (2 d, J = 7 Hz, 3 H,
2-CH3); 3.65 and 3.68 (2 q, J = 7 Hz, 1 H, 2-H); 4.04 (q, J = 7 Hz, 2 H,
OCH2CH3); 7.3–7.5 (m, 5 H, aromatic H); 7.35 and 7.69 (2 d, J = 9 Hz, 2
H,aromatic H); 8.19 and 8.22 (2 d, J = 9 Hz, 2 H, aromatic H).– Anal.
(C19H18N2O4) C, H, N.
Kugelrohr distillation gave an early solid fraction (oven temp. 130–
180 °C/0.5 Torr) which was recrystallized from EtO2/CH2Cl2 to yield 1.01 g
of 4-nitrobenzophenone (11, 35%), mp 134–138 °C; Rf identical with that of
4-nitrobenzophenone above.
Ethyl 2,2-Dimethyl-3-cyano-3,3-diphenylpropionate (9a)
The preparation of 9a by a procedure anologous to the following one has
been reported in a short communication providing no characterization
data.[13]
Ethyl 2,2-Dimethyl-3-cyano-3-phenyl-3-(4-nitrophenyl)propionate (9d)
To a solution of 0.25 g (2.2 mmol) of tBuOK in 6 ml of dry HMPA, a
solution of 410 mg (2.12 mmol) of diphenylacetonitrile in 2 ml of dry HMPA
was added dropwise with stirring at room temp. under nitrogen. The resulting
solution was cooled to 0 °C, and 0.32 ml (2.1 mmol) of ethyl bromodimethyl-
acetate was added. After 2.5 h, the mixture was diluted with water and
extracted with Et2O, and the ethereal phase was thoroughly washed with
water to remove the HMPA, anddried(Na2SO4). Kugelrohrdistillation(oven
temp. 239–240 °C/0.5 Torr) gave 563 mg of 9a (87%), thick liquid that
crystallized on prolonged standing, mp 51–53 °C.– 1H NMR (90 MHz,
CDCl3): δ = 0.98 (t, J = 7 Hz, 3 H, OCH2CH3), 1.37 (s, 6 H, 2-CH3), 4.03
(q, J = 7 Hz, 2 H, OCH2CH3), 7.1–7.4 (m, 10 H, aromatic H).– Anal.
(C20H21NO2) C, H, N.
To solution of 3.6 mmol of nBuLi in THF/n-C6H14 at 0 °C under nitrogen
(prepared from 1.8 ml of a 2.0 M solution of nBuLi in n-C6H14, and 3 ml of
dry THF), 0.50 ml (3.6 mmol) of iPr2NH (distilled from KOH) was added
dropwise with stirring, followed by dropwise addition of a solution of 1.20 g
(3.60 mmol) of 12 in 3 ml of dry THF and, then, by addition of 0.75 ml
(12 mmol) of MeI. After 3 d, the mixture wasdiluted withwaterand extracted
withEt2O, and the ethereal phase was washedwithwater anddried(Na2SO4).
Separation by TLC on silica gel with petroleum ether/EtO2 (4:1) as mobile
phase (Rf = 0.2) gave 98 mg of 9d (8%), mp 102–107 °C.– 1H NMR
(200 MHz, CDCl3): δ = 1.22 (t, J = 7 Hz, 3 H, OCH2CH3), 1.81 (s, 3 H,
2-CH3), 1.94 (s, 3 H, 2-CH3), 4.25 (m, 2 H, OCH2CH3), 7.0–7.4 (m, 7 H,
aromatic H), 8.11 (d, J = 9 Hz, aromatic H).– Anal. (C20H20N2O4) N; >
99.0% pure by HPLC.
Ethyl 2,2-Dimethyl-3-cyano-3-phenyl-3-(3,4-dimethoxyphenyl)propionate
(9b)
The procedure for 6a was followed using 0.51 g (4.5 mmol) of tBuOK in
6 ml of DMSO, 1.14 g (4.52 mmol) of phenyl-(3,4-dimethoxyphenyl)aceto-
nitrile in 6 ml of DMSO, 0.67 ml (4.5 mmol) of ethyl bromodimethylacetate
and a 5-h reaction time. Column chromatography on silica gel with petroleum
ether/EtO2 (7:3) as eluent (Rf = 0.2) gave 1.15 g of 9b (69%),viscous liquid
that crystallized on prolonged standing, mp 66–70 °C.– 1H NMR (200 MHz,
CDCl3): δ = 1.05 (t, J = 7 Hz, 3 H, OCH2CH3), 1.40 (s, 3 H, 2-CH3), 1.45
(s, 3 H, 2-CH3), 3.78 (s, 3 H, OCH3), 3.88 ( s, 3 H, OCH3), 4.09 (q, J = 7 Hz,
2 H, OCH2CH3), 6.7–7.0 (m, 3 H, aromatic H), 7.2–7.5 (m, 5 H, aromatic
H).– Anal. (C22H25NO4) C, H, N.
2,2-Dimethyl-3-cyano-3,3-diphenyl-N-methyl-N-(3,4-dimethoxyphenethyl)-
propionamide (4a)
To a solution of 1.2 mmol of nBuLi in THF/n-C6H14 at 0 °C under nitrogen
(prepared from 0.60 ml of a 2.0 M solution of nBuLi in n-C6H14, and 2 ml
of dry THF), 215 µl (1.17 mmol) of distilled 3,4-dimethoxy-N-methyl-
phenethylamine was added dropwise with stirring, followed by addition of a
solution of 353 mg (1.15 mmol) of 9a in 2 ml of dry THF. After 1 d at room
temp., the mixture was diluted with water and extracted with Et2O, and the
ethereal phase was washed with 1 M aqueous HCl and then with water, and
dried (Na2SO4). The crude liquid product was digested with 100 ml of
petroleum ether by vigorous stirring at room temp. overnight, upon which
the product solidified, and the sticky undissolved solid separated out from
the supernatant liquid. Recrystallization from Et2O/CH2Cl2 gave 156 mg of
4a (29%), mp 115–119 °C.– IR (KBr): ν = 2200 cm–1 (w, C≡N), 1620 (s,
C=O).– 1H NMR (200 MHz, CDCl3): δ = 1.56 (s, 6 H, 2-CH3), 2.80 (t, J =
7 Hz, 2 H, NCH2CH2Ar), 2.90 (s, 3 H, NCH3), 3.52 (t, J = 7 Hz, 2 H,
NCH2CH2Ar), 3.87 (s, 6 H, OCH3), 6.7–6.9 (m, 3 H, aromatic H), 7.2–7.5
(m, 10 H, aromatic H).– 13C NMR (50 MHz, CDCl3): δ = 25.2, 33.0, 37.4,
49.1, 53.2, 56.0, 60.9, 111.4, 112.2, 120.8, 124.0, 127.5, 127.8, 130.0, 131.5,
139.7, 147.7, 149.0, 173.8.– Anal. (C29H32N2O3) C, H, N.
2,2-Dimethyl-3-Cyano-3-phenyl-3-(3,4-dimethoxyphenyl)propionic Acid
(10)
A stirred mixture of 99 mg (0.27 mmol) of 9b and 4 ml of 50% aqueous
NaOH was heated at 90–100 °C for one week. An abundant solid was formed
by attack of the alkali on the glass flask. The mixture was diluted with water
and washed with EtO2. A supernatant oil consisting of the sodium salt of acid
10, insoluble in the strongly ionic aqueous phase, was separated out from the
aqueous phase and dissolved in pure water. This solution was acidified (pH
= 1) with concd. aqueous HCl, and the new oil formed was separated out and
reprecipitated from EtOH/water to give 34 mg of 10, 82% pure by HPLC (ca.
37%), noncrystalline solid.– IR (KBr): ν = 3200 cm–1 (br., OH), 2240 (w,
CN), 1730 (s, C=O).– 1H NMR (200 MHz, CDCl3): δ = 1.41 (s, 3 H, 2-CH3),
1.47 (s, 3 H, 2-CH3), 3.74 (s, 3 H, OCH3), 3.88 ( s, 3 H, OCH3), 6.7–7.0 (m,
3 H, aromatic H), 7.2–7.5 (m, 5 H, aromatic H).
2,2-Dimethyl-3-cyano-3-phenyl-3-(3,4-dimethoxyphenyl)-N-methyl-
N-(3,4-dimethoxyphenethyl)propionamide (4b)
The procedure for 4a was followed, using 0.70 ml (1.4 mmol) of the nBuLi
solution and 2 ml of THF, 255 µl (1.38 mmol) of 3,4-dimethoxy-N-methyl-
phenethylamine, 255 mg (0.695 mmol) of 9b in 2 ml of THF and a 3-h
reaction time. The crude liquid product was digested with 100 ml of petro-
leum ether/EtO2 (25:1) by vigorous stirring at room temp. overnight, upon
which the product solidified, and the sticky undissolved solid was separated
out from the supernatant liquid. By two additional digestions at room temp.
with 100 ml of petroleum ether and 100 ml of petroleum ether/EtO2 (25:1)
was obtained 50 mg of 4b (14%), noncrystalline solid. On concentration of
the supernatant liquid from the last digestion there precipitated an additional
66 mg of 4b (19%).– IR (KBr): ν = 2240 cm–1 (vw, C≡N), 1640 (C=O).–
1H NMR (200 MHz, CDCl3): δ = 1.56 (s, 3 H, 2-CH3), 1.57 (s, 3 H, 2-CH3),
2.82 (t, J = 8 Hz, 2 H, NCH2CH2Ar), 2.85 (s, 3 H, NCH3), 3.49 (t, J = 8 Hz,
2 H, NCH2CH2Ar), 3.77 (s, 3 H, OCH3), 3.86 (s, 9 H, OCH3), 6.7–7.0 (m, 6
H, aromatic H), 7.2–7.5 (m, 5 H, aromatic H).– 13C NMR (100 MHz,
CDCl3): δ = 25.5, 25.6, 33.0, 37.4, 49.4, 53.2, 55.8, 55.9, 55.96, 56.00, 60.6,
110.2, 111.4, 112.1, 113.9, 120.7, 122.4, 123.7, 127.6, 127.9, 129.7, 131.4,
131.8, 139.7, 147.7, 148.3, 148.4, 149.0, 174.0.– Anal. (C31H36N2O5) C,
H, N.
4-Nitrobenzophenone (11)
The procedure for 6a was followed, using 0.14 g (1.3 mmol) of tBuOK in
2 ml of dry DMSO, 300 mg (1.26 mmol) of phenyl-(4-nitrophenyl)acetoni-
trile in 2 ml of dry DMSO, 185 µl (1.26 mmol) of ethyl bromodimethyl-
acetate and a 4-d reaction time. The reaction mixture was diluted with water,
and a precipitate was filtered out and washed with water to give 277 mg of
11 (97%), mp 131–137 °C (ref.[24] 138 °C); IR and 1H NMR spectra in
agreement with structure 11.
Ethyl 2-Methyl-3-cyano-3-phenyl-3-(4-nitrophenyl)propionate (12)
The procedure for 6a was followed, using 1.41 g (12.6 mmol) of tBuOK
in 30 ml of dry DMSO, 3.01 g (12.6 mmol) of phenyl-(4-nitrophenyl)ace-
tonitrile in 10 ml of dry DMSO, 1.6 ml (12 mmol) of ethyl 2-bromo-2-
methylacetate and a 3-d reaction time. Kugelrohr distillation of the crude
product (oven temp. 200–210 °C/0.2 Torr) gave 1.33 g of 12 (31%), viscous
1
liquid.– H NMR (200 MHz, CDCl3; diastereomeric ratio = 1:1): δ = 1.06
Arch. Pharm. Pharm. Med. Chem. 333, 329–336 (2000)