2364 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12
O’Brien et al.
a m id e (23). (a ) 1H-Tetr a zole-5-p r op a n oic Acid , Meth yl
Ester (17b). To a stirred solution of 3-cyanopropanoic acid,
methyl ester (16b) (109 g, 0.96 mol) in N,N-dimethylformamide
(1 L) was added ammonium chloride (51.5 g, 0.96 mol) and
sodium azide (62.7 g, 0.96 mol), respectively. The suspension
was stirred for 6 h at 100 °C, then cooled, filtered, and
concentrated in vacuo, leaving a yellow liquid. Water (500 mL)
was added, and the solution was cooled to 5 °C and acidified
with concentrated HCl (170 mL). The product was extracted
with several portions of ethyl acetate (400 mL), then combined
and washed with brine, dried, and concentrated to give 17b
(102 g, 68%) as a viscous oil: 1H NMR (DMSO-d6) δ 3.6 (s,
3H), 3.5 (bs, 1H), 3.1 (t, 2H), 2.8 (t, 2H) ppm; CI-MS m/ e 157
(M + 1)+. Anal. (C5H8N4O2) C, H, N.
temperature, water (500 mL) was added and the product was
extracted with several portions of ethyl ether (2 × 150 mL).
The extracts were combined, washed with brine, dried, and
filtered. Evaporation of the filtrate gave 26 (14.5 g, 98%) as
a viscous orange liquid: 1H NMR (CDCl3) δ 5.8 (m, 1H), 4.9
(m, 2H), 2.3 (t, 2H), 2.0 (m, 2H), 1.6 (m, 2H), 1.3 (bs, 12H)
ppm.
(c) 11-Dod ecen oic Acid (27). A solution of 26 (14.4 g,
0.080 mol) in methanol (150 mL) was treated with 25%
aqueous NaOH (40 g) in one portion. The solution was
refluxed for 24 h and cooled to room temperature, and the
methanol was concentrated in vacuo. The aqueous concentrate
was diluted with water (150 mL), washed with ethyl ether (1
× 100 mL), and neutralized (pH ) 6.0) with concentrated HCl.
The product was exracted with ethyl acetate (150 mL), washed
with brine, dried, and filtered. Evaporation of the filtrate gave
27 (10.6 g, 67%), isolated in the form of a viscous liquid which
gradually solidified to a wax on standing: 1H NMR (CDCl3) δ
5.8 (m, 1H), 4.9 (m, 2H), 2.3 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H),
1.3 (s, 12H) ppm.
(d ) 11-Dod ecen -1-ol. Lithium aluminum hydride (2.2 g,
0.058 mol) was suspended in dry tetrahydrofuran (50 mL) and
cooled to 0 °C. The suspension was treated dropwise with a
solution of 27 (10.6 g, 0.053 mol) in dry tetrahydrofuran (160
mL). The reaction mixture gradually warmed to room tem-
perature and was stirred for 16 h. Excess hydride was
cautiously quenched with aqueous HCl (0.1 M), followed by
the addition of ethyl acetate (200 mL). The suspension was
filtered through Celite, and the filtrate was dried and concen-
trated to dryness, isolating the title compound as a yellow
liquid (5.9 g, 60%): 1H NMR (CDCl3) δ 5.8 (m, 1H), 4.9 (m,
2H), 3.6 (t, 2H), 2.0 (m, 2H), 1.9 (bs, 1H), 1.6 (m, 2H), 1.3 (s,
12H) ppm.
(e) 11-Dod ecen yl Meth a n esu lfon a te (28). Following the
procedure previously described for 25, the alcohol (5.9 g, 0.032
mol) prepared from step d yielded mesylate 28 (8.27 g, 99%)
as an orange liquid: 1H NMR (CDCl3) δ 5.8 (m, 1H), 4.9 (m,
2H), 4.2 (t, 2H), 3.0 (s, 3H), 2.0 (m, 2H), 1.7 (m, 2H), 1.3 (bs,
12H) ppm. The product was used in the coupling with 3
without further purification.
Gen er a l P r oced u r e for Va r yin g t h e Tet r a zole Sid e
Ch a in . Met h od F : (()-2-(11-Dod ecen yl)-r-p h en yl-N-
(2,4,6-tr im eth oxyph en yl)-2H-tetr azole-5-acetam ide (30d).
(a ) (()-2-(11-Dod ecen yl)-r-p h en yl-2H-tetr a zole-5-a cetic
Acid , Eth yl Ester (29). The mesylate of 11-dodecen-1-ol 24
(8.2 g, 0.032 mol) was added dropwise to a stirred solution
containing 3 (7.4 g, 0.032 mol), triethylamine (3.3 g, 0.032 mol),
and acetonitrile (100 mL). The solution was refluxed for 16
h, cooled, and concentrated in vacuo. The residue was
triturated with ethyl acetate and filtered, and the filtrate was
washed with aqueous HCl (1 M) and brine, dried, and filtered.
Evaporation of the filtrate gave a viscous liquid containing a
2.5:1 mixture of the 2- and 1-regioisomers, respectively. Only
the faster eluting 2-isomer 29 was isolated from the mixture
as a pale yellow liquid (4.6 g, 36%) using silica gel chroma-
tography (elution with 75% hexane/25% ethyl acetate): 1H
NMR (CDCl3) δ 7.5 (m, 2H), 7.3 (m, 3H), 5.8 (m, 1H), 5.3 (s,
1H), 4.9 (m, 2H), 4.6 (t, 2H), 4.2 (q, 2H), 2.0 (m, 4H), 1.4-1.3
(m, 14H), 1.2 (t, 3H) ppm.
(b) (()-2-(11-Dod ecen yl)-r-p h en yl-2H-tetr a zole-5-a ce-
tic Acid . Using the same procedure as that for compound 4,
hydrolysis of 29 (4.5 g, 0.011 mol) yielded the title compound
(4.1 g, 98%) as a yellow liquid: 1H NMR (CDCl3) δ 7.5 (m,
2H), 7.3 (m, 3H), 5.8 (m, 1H), 5.4 (s, 1H), 4.9 (m, 2H), 4.6 (t,
2H), 2.0 (m, 4H), 1.3 (m, 14H) ppm.
(c) (()-2-(11-Dod ecen yl)-r-p h en yl-N-(2,4,6-t r im et h -
oxyp h en yl)-2H-tetr a zole-5-a ceta m id e (30d ). The acid (4.1
g, 0.011 mol) prepared in step b was dissolved in a solution
containing 2,4,6-trimethoxyaniline (2.0 g, 0.011 mol) and
dichloromethane (75 mL), cooled to 0 °C, and treated with DCC
(2.3 g, 0.011 mol) in one portion. The suspension was stirred
at room temperature for 16 h, then diluted with ethyl acetate,
and filtered. The filtrate was washed with aqueous HCl (1
M), aqueous NaOH (1 M), and brine and dried. The solution
was concentrated in vacuo, and the residue was purified using
silica gel chromatography (elution with 90% hexane/10% ethyl
(b) 2-Dod ecyl-2H-tetr a zole-5-p r op a n oic Acid , Eth yl
Ester (18b). The tetrazole 17b (29.2 g, 0.18 mol) was diluted
with acetonitrile (500 mL) and treated with 1 equiv of
triethylamine (18.1 g, 0.018 mol). The solution was heated to
reflux, followed by the addition of 1-bromododecane (49.5 mL,
0.20 mol). After 24 h of reflux, the solution was cooled and
filtered. Evaporation of the filtrate gave a viscous liquid, from
which the 2-isomer 18b (12.0 g, 20%) was isolated as a white
solid using silica gel chromatography (elution with petroleum
1
ether/ethyl acetate (15:1)): mp 39-42 °C; H NMR (DMSO-
d6) δ 4.7 (t, 2H), 3.6 (s, 3H), 3.1 (t, 2H), 2.8 (t, 2H), 1.9 (m,
2H), 1.2 (m, 18H), 0.9 (t, 3H) ppm; EI-MS m/ e 325 (M+). Anal.
(C17H32N4O2) C, H, N.
(c) 2-Dod ecyl-2H-tetr a zole-5-p r op a n oic Acid . The ester
18b (11.5 g, 0.035 mol) was dissolved in a solution containing
potassium hydroxide (2.5 g, 0.045 mol) and absolute ethanol
(210 mL). The solution was stirred for 72 h at room temper-
ature and then concentrated in vacuo. The residue was
dissolved in water (300 mL), cooled to 5 °C, and acidified with
concentrated HCl (10 mL). Dichloromethane was added, the
layers were separated, and the organic phase was dried,
filtered, and concentrated to give the title compound as a white
1
solid (10.6 g, 96%): mp 63-65 °C; H NMR (DMSO-d6) δ 4.6
(t, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 1.8 (m, 2H), 1.2 (m, 18H), 0.9
(t, 3H) ppm.
(d ) 2-Dod ecyl-N-[2,6-bis(1-m eth yleth yl)p h en yl]-2H-tet-
r a zole-5-p r op a n a m id e (23). A portion of the acid (1.2 g, 3.87
mmol) prepared in step c was dissolved in tetrahydrofuran (35
mL), followed by the addition of CDI (0.65 g, 3.98 mmol). The
mixture was stirred at room temperature for 1 h, before 2,6-
diisopropylaniline (0.70 g, 3.98 mmol) was added in one
portion. After 168 h of reflux, the suspension was cooled and
filtered, and the filtrate was concentrated to dryness. The
resulting oil was diluted with ethyl acetate (40 mL) and
washed with aqueous NaOH (1 M), aqueous HCl (1 M), water,
and brine, respectively. The organic phase was dried and
concentrated to an oil. The crude product was purified using
silica gel chromatography (elution with 75% petroleum ether/
25% ethyl acetate) to give 23 as a tan solid: mp 41-43 °C; 1H
NMR (DMSO-d6) δ 9.3 (s, 1H), 7.2-7.1 (m, 3H), 4.6 (t, 2H),
3.1 (t, 2H), 2.9 (m, 2H), 2.8 (t, 2H), 1.9 (m, 2H), 1.2 (s, 18H),
1.0 (m, 12H), 0.9 (t, 3H) ppm; EI-MS m/ e 469 (M+). Anal.
(C28H47N5O) C, H, N.
Similar conditions were used for preparing 22 in Table 3.
11-Dod ecen yl m eth a n esu lfon a te (28) was utilized in the
synthesis of 30d . (a ) 10-Un d ecen yl Met h a n esu lfon a t e
(25). Alcohol 24 (30.4 g, 0.18 mol) was diluted with dichloro-
methane (360 mL), cooled to 0 °C, and treated with triethyl-
amine (18.1 g, 0.18 mol) in one portion. Methanesulfonyl
chloride (22.4 g, 0.19 mol) was then added at such a rate so as
to maintain a solution temperature of 0 °C. After stirring at
0 °C for 3 h, the product was partitioned between dichloro-
methane and brine. The layers were separated, and the
organic phase was dried and filtered, and the filtrate was
concentrated in vacuo, leaving 25 as a viscous yellow liquid
(35.9 g, 81%): 1H NMR (CDCl3) δ 5.8 (m, 1H), 4.9 (m, 2H), 4.2
(t, 2H), 3.0 (s, 3H), 2.1 (m, 2H), 1.8 (m, 2H), 1.3 (bs, 12H) ppm.
(b) 11-Dod ecen en itr ile (26). To a solution of mesylate
25 (20.5 g, 0.082 mol) in dimethyl sulfoxide (250 mL) was
added potassium cyanide (16.0 g, 0.24 mol). The solution was
stirred at 80 °C for 10 min, resulting in the formation of a
gelatinous precipitate. After the mixture was cooled to room