636
J. F. Delhomel, S. Yous, P. Depreux and D. Lesieur
Vol. 38
exchangeable with D O), 6.40 (br s, 1H, OH exchangeable
6.80 (d, 2H, H , H , Jortho = 8.50 Hz), 7.10 (d, 2H, H , H ,
2
2
6
3
5
+
with D O), 6.79 (d, 2H, H , H , Jortho = 8.90 Hz), 7.00
Jortho = 8.50 Hz), 7.50 (m, 5H, C H ), 9.70 (br s, 2H, NH
2
2
6
6 5 2
(d, 2H, H , H , Jortho = 8.90 Hz).
exchangeable with D O).
3
5
2
Anal. Calcd. for C
Found: C, 66.01; H, 8.05; N, 5.75.
H NO : C, 65.80; H, 8.07; N, 5.90.
Anal. Calcd. for C
H NO •HCl: C, 65.23; H, 6.91; N, 4.00.
13 19 3
19 23 3
Found: C, 65.29; H, 6.95; N, 3.97.
[4-(2- tert-Butoxycarbonylaminoethyl)phenoxy]acetic Acid
Ethyl Ester (9).
[4-(2-{Benzyl-[2-(3-methyl-2(3H)-benzoxazolon-6-yl)-2-
oxoethyl]amino} ethyl)phenoxy)acetic Acid Ethyl Ester (14).
To a stirred solution of 8 (23.7 g, 100 mmol) in anhydrous
To a solution of 11 (7 g, 20 mmol) in ethanol (20 ml) were
added successively triethylamine (7 ml, 0.05 mol), and
compound 12 (5.6 g, 21 mmol). The reaction mixture was stirred
at reflux for 20 minites and then evaporated in vacuo. The residue
was taken up with ethylacetate. The organic layer was washed
with water, dried over magnesium sulfate, and evaporated.
Recrystallization from ethanol gave 14 in 67% yield: mp
79-80 °C; ir (potassium bromide): ν 1750 (2(3H)-benzoxazolone
acetone (100 ml) was added K CO (24 g, 170 mmol) and ethyl-
2
3
bromoacetate (30 ml, 140 mmol). After 12 hours of stirring under
reflux the reaction mixture was filtered . The filtrate was
evaporated under vacuum, the residue taken off with ethylacetate
and the organic layer was washed with a 0.5 M solution of
sodium hydroxyde, with water, dried and evaporated under
vacuum. The residue was recrystallized from cyclohexane to give
9 in 94% yield: mp 45-47 °C; ir (potassium bromide): ν 3340
-1
1
and ester CO), 1660 (ketone CO) cm ; H nmr (dimethyl-d -
6
-1
1
(NH), 1750 (ester CO) cm ; H nmr (deuteriochloroform): δ
1.28 (t, 3H, OCH CH , J = 6.90 Hz), 1.45 (s, 9H, C(CH ) ), 2.70
sulfoxide): δ (ppm) 1.21 (t, 3H, CH CH , J = 7.10 Hz), 2.70
2
3
(m, 4H, CH CH ), 3.38 (s, 3H, NCH ), 3.75 (s, 2H,
2
3
3 3
2
2
3
(t, 2H, CH CH N, J = 6.30 Hz), 3.40 (m, 2H, CH CH N), 4.25
NCH C H ), 3.95 (s, 2H, NCH CO), 4.16 (q, 2H, CH CH , J =
2
2
2
2
2
6
5
2
2
3
(q, 2H, OCH CH , J = 6.90 Hz), 4.64 (br s, 1H, NH
7.10 Hz), 4.70 (s, 2H, CH O), 6.75 (d, 2H, H , H , Jortho =
2
3
2
2'
6'
exchangeable with D O), 4.75 (s, 2H, COCH ), 6.85 (d, 2H, H ,
8.30 Hz), 7.00 (d, 2H, H , H , Jortho = 8.30 Hz), 7.26-7.31
2
2
2
3'
5'
H , Jortho = 8.80 Hz), 7.15 (d, 2H, H , H , Jortho = 8.80 Hz).
(m, 6H, H , H
), 7.78 (d, 1H, H , Jmeta = 2.35 Hz), 7.85
6
3
5
4
benzyl
7
Anal. Calcd. for C
H NO : C, 63.14; H, 7.79; N, 4.33.
(dd, 1H, H , Jortho = 8.20 Hz, Jmeta = 2.35 Hz).
17 25 5
5
Found: C, 63.34; H, 8.00; N, 4.44.
Anal. Calcd. for C
H N O ; C, 69.31; H, 6.02; N, 5.57.
29 30 2 6
Found: C, 69.19; H, 5.95; N, 5.58.
[4-(2-Aminoethyl)phenoxy]acetic Acid Ethyl Ester Hydro-
chloride (10).
[4-(2-{Benzyl-[2-(3-methyl-2(3H)-benzothiazolon-6-yl)-2-
oxoethyl]amino}ethyl)phenoxy)acetic Acid Ethyl Ester (15).
Compound 9 (32.3 g, 100 mmol) was dissolved in a saturated
hydrochloric acid solution of acetic acid (55 ml). After stirring
for 1 hour at room temperature, the precipitate was filtered,
washed with diethylether and recrystallized from absolute
ethanol to give 10 in 90% yield: mp: 162-164 °C; ir (potassium
The reaction was carried out as described for compound 14.
Recrystallization from ethanol gave 15 in 60% yield: mp
164-165 °C; ir (potassium bromide): ν 1750 (ester CO), 1670
-1
1
(2(3H)-benzothiazolone and ketone CO) cm
; H nmr
-1
1
bromide): ν 1750 (ester CO) cm ; H nmr (deuteriochloroform)
δ (ppm) 1.21 (t, 3H, OCH CH , J = 7.10 Hz), 2.85 (t, 2H,
(dimethyl-d -sulfoxide): δ 1.21 (t, 3H, CH CH , J = 7.00 Hz),
6
2
3
3.06 (m, 2H, CH CH N), 3.35 (m, 2H, CH CH N), 3.47
2
3
2
2
2
2
CH CH N, J = 8.30 Hz), 2.95 (m, 2H, CH CH N), 4.18 (q, 2H,
(s, 3H, NCH ), 4.16 (q, 2H, CH CH , J = 7.00 Hz), 4.55
2
2
2
2
3
2
3
OCH CH , J = 7.10 Hz), 4.75 (s, 2H, COCH ), 6.88 (d, 2H, H ,
(m, 2H, CH C H ), 4.74 (s, 2H, CH O), 5.15 (m, 2H,
2
3
2
2
2
6
5
2
H , Jortho = 8.10 Hz), 7.35 (d, 2H, H , H , Jortho = 8.10 Hz),
NCH CO), 6.88 (d, 2H, H , H , Jortho = 8.10 Hz), 7.18
6
3
5
2
2
2'
6'
+
8.19 (br s, 3H, NH exchangeable with D O).
(d, 2H, H , H , Jortho = 8.10 Hz), 7.44-7.70 (m, 6H, H ,
3
3'
5'
4
Anal. Calcd. for C
Found: C, 55.42; H, 6.99; N, 5.42.
H
NO •HCl: C, 55.49; H, 6.98; N, 5.39.
H
), 8.03 (dd, 1H, H , Jortho = 8.40 Hz, Jmeta = 2.36
12 17
3
benzyl
5
+
Hz), 8.38 (d, 1H, H , Jmeta = 2.36 Hz), 10.67 (br s, 1H, NH
exchangeable with D O).
Anal. Calcd. for C
5.05. Found: C, 62.52; H, 5.72; N, 5.03.
7
2
[4-(2-Benzylaminoethyl)phenoxy]acetic Acid Ethyl Ester
Hydrochloride (11).
H N O S•HCl ; C, 62.75; H, 5.72; N,
29 30 2 5
To a solution of 10 (1 g, 3.8 mmol) in ethanol (20 ml) was
added triethylamine (0.7 ml, 5 mmol) and benzaldehyde
(0.5 ml, 5 mmol). After stirring for 30 minutes, sodium
borohydride (0.22 g, 5.80 mmol) was added portionwise and
stirring was continued for 14 hours. Ethanol was evaporated
and the residue taken off with water (300 ml). The aqueous
mixture was extracted with ethylacetate. The organic phase
was dried and evaporated under vacuum. The residue was
treated with diethylether saturated with gaseous hydrochloric
acid. The precipitate was filtered, washed with diethylether
and recrystallized from absolute ethanol to give 11 in 55%
yield: mp 202-204 °C; ir (potassium bromide): ν 1750
(4-{2-[2-(3-Methyl-2(3H)-benzoxazolon-6-yl)-2-oxoethyl-
amino]ethyl} phenoxy)acetic Acid Ethyl Ester Hydrochloride (16).
To a solution of 14 (2 g, 4 mmol) in methylene chloride (20 ml)
was added 1-chloroethyl chloroformate (0.65 ml, 6 mmol). After
heating at reflux for 1 hour, methylene chloride was evaporated
and methanol (40 ml) was added. The reaction mixture was
stirred at reflux for 30 minutes. After cooling the precipitate was
filtered and recrystallized from ethanol to give 16 in 70% yield:
mp 248-249 °C; ir (potassium bromide): ν 1760 (2(3H)-benzoxa-
-1
1
zolone and ester CO), 1670 (ketone CO) cm
; H nmr
(dimethyl-d sulfoxide) δ (ppm) 1.22 (t, 3H, CH CH , J = 7.10
6
2
3
-1 1
(ester CO) cm ; H nmr (dimethyl-d sulfoxide) δ (ppm) 1.21
Hz), 3.04 (m, 2H, CH CH N), 3.18 (m, 2H, CH CH N), 3.41
6
2
2
2
2
(t, 3H, OCH CH , J = 7.10 Hz), 2.70 (t, 2H, CH CH N, J =
(s, 3H, NCH ), 4.18 (q, 2H, CH CH , J = 7.10 Hz), 4.76 (s, 2H,
2
3
2
2
3 2 3
7.10 Hz), 3.00 (m, 2H, CH CH N), 4.10 (s, 2H, C H CH ),
CH O), 4.82 (m, 2H, NCH CO), 6.91 (d, 2H, H , H , Jortho =
2 2 2' 6'
2
2
6
5
2
8.50 Hz), 7.21 (d, 2H, H , H , Jortho = 8.50 Hz), 7.48 (d, 1H,
4.20 (q, 2H, OCH CH , J = 7.10 Hz), 4.80 (s, 2H, COCH ),
3' 5'
2
3
2