PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4271
compound 10. The title product was prepared according to
removed at reduced pressure. Crystallization from dichloro-
ethane/hexane gave 2-cyano-4-fluoroanisole, 72.
1
route A: mp 166 °C; H NMR (250 MHz, DMSO-d6) δ 11.23
(t, 1H), 10.80 (s, 1H), 8.18 (d, 1H), 8.06 (dd, 1H), 7.33 (q, 1H),
7.21 (d, 1H), 6.87 (t, 2H), 4.07 (q, 2H), 3.91 (q, 2H), 3.03 (t,
2H), 1.41 (t, 3H). Anal. (C16H17BrFN3OS) H, N; C: calc, 48.2;
found, 47.7.
Lithium diisopropylamide was added dropwise to a solution
of compound 72 (4.65 g, 34 mmol) in 200 mL of THF at -70
°C. The reaction mixture was heated to -55 °C and kept at
this temperature for 1 h. The mixture was cooled again to
-70 °C, and DMF (4 mL) was added. Acetic acid (3.6 g) was
added after 30 min at -55 °C, and then ((ethoxycarbonyl)-
methylene)triphenylphosporane (12.0 g, 34 mmol) was added.
The mixture was allowed to come to room temperature and
was left overnight. Purification on a silica gel column eluted
with ethyl acetate/hexane gave a cis-trans mixture of ethyl
3-(2-cyano-3-methoxy-6-fluorophenyl) propenoate, 74.
Compound 74 was added to 100 mL of methanol, and 100
mg of 10% Pd/C was added. The stirred mixture was hydro-
genated at atmospheric pressure until H2 consumption ceased
(3 h). The solution was filtered, and the solvent was evapo-
rated. The product, ester 76, was then hydrolyzed for 30 min
in a refluxing mixture of NaOH (2 g, 50 mmol) in 50 mL of
ethanol/water, 1:1. Acidification (HCl), extraction to dichloro-
methane, drying (Na2SO4), and crystallization from dichloro-
ethane/hexane gave 2.55 g of 3-(2-cyano-3-methoxy-6-fluoro-
phenyl)propanoic acid, 78.
N-[2-(2,3-Diflu or o-6-et h oxyp h en et h yl)]-N′-[2-(5-b r o-
m op yr id yl)]th iou r ea (23). 2,3-Difluoro-6-ethoxyphenethyl-
amine (64e) was prepared from 2,3-difluorophenol as described
for compound 10. The title product was prepared according
1
to route A: mp 170.7 °C; H NMR (250 MHz, CDCl3) δ 11.22
(s, 1H), 8.20 (s, 1H), 8.13 (d, 1H), 7.73 (dd, 1H), 7.00(dd, 1H),
6.18 (d, 1H), 6.07 (m, 1H), 4.0 (m, 4H), 3.13 (m, 2H), 1.45 (t,
3H). Anal. (C16H16BrF2N3OS) C, H, N.
N-[2-(2,3-Diflu or o-6-m eth oxyp h en eth yl)]-N′-[2-(5-br o-
m op yr id yl)]t h iou r ea (24). 2,3-Difluoro-6-methoxyphen-
ethylamine (64j) was prepared from 2,3-difluorophenol as
described for compound 10. The title product was prepared
according to route A: mp 160 °C;
1H NMR (250 MHz, CDCl3)
δ 11.35 (s, 1H), 9.65 (s, 1H), 8.15 (d, 1H), 7.7 (m, 1H), 7.05-
6.8 (m, 2H), 6.55 (m, 1H), 4.0 (s, 2H), 3.8 (s, 3H), 3.1 (m, 2H).
Anal. (C15
H14BrF2N3OS) C, H, N.
N-[2-(3,6-Dim eth oxy-2-flu or op h en eth yl)]-N′-[2-(5-ch lo-
r op yr id yl)]th iou r ea (25). To a solution of 1,4-dimethoxy-
benzene (56) (15.0 g, 0.109 mol) in 300 mL of dry THF was
added 2.5 M n-BuLi (45.6 mL, 0.114 mol) at room temperature
under nitrogen. After addition was complete, the solution was
stirred for 1 h. The mixture was cooled to -70 °C, and
N-fluorobenzenesulfonimide (36.0 g, 0.114 mol) in 150 mL of
THF was added slowly, keeping the temperature below -60
°C. The solution was allowed to warm to room temperature
overnight. Then 100 mL of saturated NH4Cl(aq) was added
and the mixture extracted with diethyl ether/THF. The
organic phase was washed with 1 M NaOH (2 × 60 mL), dried
over MgSO4, and evaporated. Column chromatography (silica
gel, n-hexane followed by 1, 5, and 10% EtOAc in n-hexane)
provided 11.43 g of a mixture of 1,4-dimethoxy-2-fluorobenzene
(61k ) and 1,4-dimethoxybenzene (4.3:1). 3,6-Dimethoxy-2-
fluorophenethylamine (64k ) was prepared from 1,4-dimethoxy-
2-fluorobenzene (61k ) as described for compound 10. The title
product was prepared according to route C: mp 172-173 °C;
1H NMR (250 MHz, CDCl3) δ 11.28 (s, 1H), 9.20 (s, 1H), 8.04
(d, 1H), 7.55 (dd, 1H), 6.81 (m, 2H), 6.54 (dd, 1H), 3.97 (m,
Compound 78 was dissolved in a mixture of triethylamine
(30 mmol) and 30 mL of THF. Diphenyl phosphorazidate
(4.125 g, 15 mmol) was added and the mixture heated to 50
°C for 1 h. The solvent was removed, and the residue was
partitioned between water and dichloromethane. The organic
phase was dried, and the solvent was removed. The residue
was dissolved in toluene (50 mL) and heated to near reflux
until N2 evolution ceased (about 15 min). The solvent was
removed, the residue was redissolved in 50 mL of dioxane, and
50 mL of concentrated HCl was added. The mixture was then
refluxed for 3 h. The solvent was removed, and the residue
was dissolved in 30 mL of 2 M HCl(aq) and washed with
dichloromethane. The aqueous phase was made strongly basic
with 40% NaOH(aq). 2-Cyano-3-methoxy-6-fluorophenethyl-
amine (84e) was extracted with dichloromethane. The title
1
product was prepared according to route A: mp 177.7 °C; H
NMR (250 MHz, CDCl3) 11.35 (t, 1H), 9.05 (s, 1H), 8.18 (m,
1H), 7.72 (m, 1H), 7.2 (m, 1H), 6.8 (m, 2H), 4.1 (q, 2H), 3.93
(s, 3H), 3.3 (t, 2H). Anal. (C16H14BrFN4OS) C, H, N.
N-[2-(2-Cya n o-6-flu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-
cya n op yr id yl)]th iou r ea (18). Starting amine 84e was the
same as for compound 17. The title product was prepared
according to route B: mp 215 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.40 (t, 1H), 11.15 (s, 1H), 8.58 (m, 1H), 8.24 (m, 1H),
7.65 (m, 1H), 7.35 (m, 1H), 7.26 (m, 1H), 4.05 (m, 2H), 3.95 (s,
3H), 3.22 (t, 2H). Anal. (C17H14FN5OS) C, H; N: calc, 19.61;
found, 20.65.
N-[2-(2-Cya n o-6-flu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-
ch lor op yr id a zyl)]th iou r ea (19). Starting amine 84e was
the same as for compound 17. The title product was prepared
according to route B: mp 211 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.20 (t, 1H), 11.05 (s, 1H), 7.97 (d, 1H), 7.64 (m, 2H),
7.23 (dd, 1H), 4.10 (m, 2H), 3.98 (s, 3H), 3.25 (t, 2H). Anal.
(C15H13ClFN5OS) C, N; H: calc, 3.5; found, 3.0.
2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.09 (m, 2H). Anal. (C16H17
ClN3O2S) C, H, N.
-
N-[2-(3-Eth oxy-2-flu or o-6-m eth oxyp h en eth yl)]-N′-[2-(5-
ch lor op yr id yl)]th iou r ea (26). A suspension of 2-fluoro-4-
methylacetophenone (54) (10.0 g, 0.059 mol), mCPBA (26.0 g,
0.128 mol), and MgSO4 (30.0 g) in 500 mL of CHCl3 was stirred
for 12 h at room temperature. The mixture was then filtered,
washed with 2 M NaOH, dried over Na2SO4, and concentrated
in vacuo to give 1-acetyl-2-fluoro-4-methoxybenzene (55) as a
solid (10.7 g, 98%).
A solution of the compound 55 (5.3 g, 0.029 mol) in 100 mL
of MeOH and 20 mL of 25% NH3(aq) was stirred for 1 h at
room temperature. The mixture was then concentrated in
vacuo, diluted with water, extracted with EtOAc, dried over
Na2SO4, and concentrated in vacuo to give 2-fluoro-4-methoxy-
phenol as an oil (3.85 g, 94%). Alkylation of this compound
with EtI as described for compound 10 gave 2-ethoxy-1-fluoro-
4-methoxybenzene, 61f. 3-Ethoxy-2-fluoro-6-methoxyphen-
ethylamine (64f) was prepared from compound 61f as de-
scribed for compound 10. The title product was prepared
according to route C: mp 194-196 °C; 1H NMR (250 MHz,
CDCl3) δ 11.24 (br s, 1H), 9.00 (br s, 1H), 8.10 (d, 1H), 7.55
(dd, 1H),6.88-6.69 (m, 2H), 6.50 (d, 1H), 4.10-3.89 (m, 4H),
N-[2-(2,5-Dim eth oxyph en eth yl)]-N′-[2-(5-ch lor opyr idyl)]-
th iou r ea (20). 2,5-Dimethoxyphenethylamine (64q) was
prepared from 2,5-dimethoxybenzaldehyde (62q) as described
for compound 10. The title product was prepared according
1
to route A: mp 130.5 °C; H NMR (250 MHz, CDCl3) δ 11.19
(br s, 1H), 8.82 (br s, 1H), 8.12 (d, 1H), 7.69 (dd, 1H), 6.83-
6.67 (m, 4H), 4.00 (dd, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.00 (dd,
2H). Anal. (C16H18BrN3O2S) H, N; C: calc, 48.5; found, 48.0.
N-[2-(2,5-Dieth oxyp h en eth yl)]-N′-[2-(5-br om op yr id yl)]-
th iou r ea (21). 2,5-Diethoxyphenethylamine (64p ) was pre-
pared from 2,5-dihydroxybenzaldehyde (59) as described for
compound 10. The title product was prepared according to
route A: mp 162 °C;1H NMR (250 MHz, DMSO-d6) δ 11.24
(br s, 1H), 10.80 (s, 1H), 8.26 (d, 1H), 8.07 (dd, 1H), 7.21 (d,
1H), 6.99-6.85 (m, 3H), 4.03 (t, 4H), 3.91 (q, 2H), 2.97 (t, 2H),
1.41 (t, 6H). Anal. (C18H22BrN3O2S) C, H, N.
3.75 (s, 3H), 3.10 (m, 2H), 1.45 (t, 3H). Anal. (C17H19
ClFN3O2S) C, H, N.
-
N-[2-(2,3-Dim eth oxy-6-flu or op h en eth yl)]-N′-[2-(5-br o-
m op yr id yl)]t h iou r ea (27). 2,3-Dimethoxy-6-fluorophen-
ethylamine (64g) was prepared from 4-fluoroveratrole (61g)
as described for compound 10. The title product was prepared
according to route A: mp 159-160 °C; 1H NMR (250 MHz,
CDCl3) δ 11.26 (s, 1H), 8.71 (s, 1H), 8.14 (d, 1H), 7.69 (dd, 1H),
6.77 (d, 2H), 6.68 (d, 1H), 3.98 (m, 2H), 3.88 (s, 3H), 3.85 (s,
3H), 3.09 (m, 2H). Anal. (C16H17BrFN3O2S) C, H, N.
N -[2-(2-E t h oxy-6-flu or op h e n e t h yl)]-N ′-[2-(5-b r om o-
p yr id yl)]th iou r ea (22). 2-Ethoxy-6-fluorophenethylamine
(64a ) was prepared from 3-fluorophenol as described for