RCHH HARM
A P
Arch. Pharm. Chem. Life Sci. 2017, 350, e1600394
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temperature 50°C. After removal of redundant NaHCO3 by
filtration, alcohol was distilled off and the product was
crystallized from cyclohexane. Yields: 65–73%; c3: 1H NMR
(CD3OD): d 0.93–0.98 (t, J ¼ 7.5 Hz, 3H, CH2CH3); 1.58–1.68 (m,
2H, CH2CH3); 2.52 (s, 3H, COCH3); 3.48–3.52 (t, J ¼ 6.6 Hz, 2H,
OCH2CH2); 4.54 (s, 2H, Ar-CH2); 6.83–6.85 (d, J ¼ 8.4 Hz, 1H,
Ar5H); 7.79–7.83 (dd, J ¼ 2.2, J ¼ 10.8 Hz, 1H, Ar6H); 7.96 (s, 1H,
Ar2H).
1H NMR (DMSO-d6) d 2.50 (s, 3H, COCH3); 2.54–2.98 (m, 10H,
CH2N, pip2,3,5,6); 3.37 (s, 3H, CH2OCH3); 3.77 (s, 3H, ArOCH3);
4.01–4.07 (m, 2H, ArOCH2); 4.11–4.13 (m, 1H, CH2CHOH); 4.48
(s, 2H, ArCH2); 6.60 (s, 2H, fumar); 6.86–6.94 (m, 4H, pip-Ar);
7.10–7.13 (d, J ¼ 9.3 Hz, 1H, Ar5H); 7.9–7.93 (m, 2H, Ar2,6H);
13C NMR (DMSO-d6) d 26.39, 49.88, 53.64, 55.30, 58.00, 60.76,
66.16, 68.23, 71.31, 111.11, 111.88, 117.89, 120.82, 122.40,
126.74, 128.07, 129.40, 129.86, 134.19, 141.13, 151.95, 159.81,
166.33, 196.37. Anal. calcd. for C48H64N4O10.C4H4O4, Mr
973.12; % C 64.12, % H 6.99, % N 5.75, found % C 63.84,
% H 6.71, % N 5.45.
General procedure for the preparation of 1-[3-
(alkoxymethyl)-4-(oxirane-2-ylmethoxy)phenyl]ethanones
(d1–5)
To a stirred solution of (3-alkoxymethyl-4-hydroxyphenyl)-
ethanones (c1–5) (0.15 mol; c1: 27.03 g; c2: 29.13 g; c3: 31.24 g;
c4: 33.34 g; c5: 33.64 g) in 3 mol (235 mL) of (ꢁ)-chloromethyl-
oxirane, 0.17 mol of 85% KOH (9.54 g; water: 1.7 mL) was
added. The mixture was stirred at 50–55°C under nitrogen for
4 h. The inorganic salts were filtered off and the (ꢁ)-chlor-
omethyloxirane was distilled off under reduced pressure.
Distilled water (50 mL) was added and the residue was
extracted three times with diethylether (3 ꢃ 100 mL). The
organic phase was separated and dried with anhydrous
Na2SO4. The filtered solution was concentrated under
reduced pressure and the remaining oil was used without
previous purification in the next reaction step. Yields: 64–
84%. d1: 1H NMR (CDCl3): d 2.52 (s, 3H, COCH3); 2.75–2.78 (d,
J ¼ 9 Hz, 1H, CH2oxirane); 2.93–2.97 (m, 1H, CH2oxirane); 3.02–
3.07 (m, 1H, CHoxirane); 3.28 (s, 3H, OCH3); 3.96–3.99
(d, J ¼ 9 Hz, 1H, CH2CH); 4.06–4.09 (d, J ¼ 9 Hz, 1H, CH2CH);
4.41 (s, 2H, ArCH2); 6.84–6.86 (d, J ¼ 8.4 Hz, 1H, Ar5H); 7.78–
7.83 (m, 1H, Ar6H); 7.95 (s, 1H, Ar2H).
(2RS)-bis-1-[3-(4-Acetyl-2-ethoxymethyl)phenoxy-2-
hydroxypropyl]-4-(2-methoxyphenyl)piperazinium
fumarate (A2)
Yield: 65%, m.p. 138–140°C, ꢀFTIR cmꢀ1: 2586 (R3NHþ), 1672
–
–
–
(C O), 1599 (C C), 1355 (COO ), 1242 (Ar–O–C), 1022 (C–O–C);
–
1H NMR (DMSO-d6) d 1.17–1.22 (t, J ¼ 7.1 Hz, 3H, CH2CH3); 2.50
(s, 3H, COCH3); 2.60–2.98 (m, 10H, CH2N, pip2,3,5,6); 3.53–3.60
(q, J ¼ 7.0 Hz, 2H, CH2CH3); 3.77 (s, 3H, ArOCH3); 4.02–4.13 (m,
3H, CH2CHOH); 4.52 (s, 2H, ArCH2); 6.60 (s, 2H, fumar); 6.85–
6.95 (m, 4H, pip-Ar); 7.09–7.12 (d, J ¼ 9.3 Hz, 1H, Ar5H); 7.89–
7.92 (m, 2H, Ar2,6H); 13C NMR (DMSO-d6) d 15.16, 26.38, 49.81,
53.60, 55.30, 60.71, 65.47, 66.11, 66.22, 71.26, 111.06, 111.89,
117.90, 120.82, 122.42, 127.12, 128.01, 129.42, 129.84, 134.24,
141.10, 151.95, 159.79, 166.43, 196.38. Anal. calcd. for
C
50H68N4O10.C4H4O4, Mr 1001.17; % C 64.72, % H 7.19, % N
5.59, found % C 64.34, % H 7.12, % N 5.46.
(2RS)-bis-1-[3-(4-Acetyl-2-propoxymethyl)phenoxy-2-
hydroxypropyl]-4-(2-methoxyphenyl)piperazinium
fumarate (A3)
General procedure for the preparation of (2RS)-bis-1-[3-(4-
acetyl-2-alkoxymethyl)phenoxy-2-hydroxypropyl]-4-(2-
methoxyphenyl)piperazinium fumarates (A1–5)
Yield: 63%, m.p. 148–150°C, ꢀFTIR cmꢀ1: 2582 (R3NHþ), 1674
–
–
–
(C O), 1599 (C C), 1355 (COO ), 1241 (Ar–O–C), 1024 (C–O–C);
–
1H NMR (DMSO-d6) d 0.89–0.94 (t, J ¼ 7.3 Hz, 3H, CH2CH3);
1.58–1.60 (m, 2H, CH2CH3); 2.50 (s, 3H, COCH3); 2.60–2.95 (m,
10H, CH2N, pip2,3,5,6); 3.44–3.49 (t, J ¼ 7.5 Hz, 2H, OCH2CH2);
3.78 (s, 3H, ArOCH3); 4.01–4,12 (m, 3H, CH2CHOH); 4.52 (s, 2H,
ArCH2); 6.50 (s, 2H, fumar); 6.86–6.97 (m, 4H, pip-Ar); 7.09–
7.12 (d, J ¼ 9.0 Hz, 1H, Ar5H); 7.89–7.92 (m, 2H, Ar2,6H);
13C NMR (DMSO-d6) d 10.63, 22.50, 26.37, 43.48, 48.00, 50.09,
55.29, 55.35, 66.36, 71,36, 71.76, 111.08, 111.89, 117.87,
120.82, 123.12, 127.14, 127.98, 129.39, 129.81, 141.24, 151.96,
159.84, 167.26, 196.37. Anal. calcd. for C52H72N4O10.C4H4O4,
Mr 1029.22; % C 65.29, % H 7.38, % N 5.44, found % C 65.02,
% H 7.19, % N 5.14.
The solution of the oxirane derivative (d1–5) (80 mmol; d1:
18.90 g; d2: 20.02 g; d3: 21.14 g; d4: 22.27 g; d5: 22.43 g) and 1-
(2-methoxyphenyl)piperazine (16.34 g; 85 mmol) in ethanol
(150 mL) was kept at 30°C for 2 h and was then heated for an
additional 5 h at reflux temperature. The solvent was distilled
off.Distilledwater(50 mL)wasaddedtotheresidue,whichwas
then washed three times with diethylether (3 ꢃ 100 mL). The
combined organic layers were washed with water, separated,
and dried with K2CO3. The filtered solution was concentrated
under reduced pressure and the remaining oil was crystallized
from hexane to afford the final base. The salts were prepared
by quantitative reaction of anhydrous ether solution of base
andanhydrousethersolutionof fumaricacid. The crystalswere
collected by filtration and recrystallized from ethyl acetate or
propan-2-ol to give fumarate salt as a white solid.
(2RS)-bis-1-[3-(4-Acetyl-2-butoxymethyl)phenoxy-2-
hydroxypropyl]-4-(2-methoxyphenyl)piperazinium
fumarate (A4)
Yield: 59%, m.p. 129–131°C, ꢀFTIR cmꢀ1: 2578 (R3NHþ), 1674
–
–
–
(2RS)-bis-1-[3-(4-Acetyl-2-methoxymethyl)phenoxy-2-
hydroxypropyl]-4-(2-methoxyphenyl)piperazinium
fumarate (A1)
(C O), 1599 (C C), 1355 (COO ), 1242 (Ar–O–C), 1021 (C–O–C);
–
1H NMR (DMSO-d6) d 0.87–0.92 (t, J ¼ 7.3 Hz, 3H, CH2CH3);
1.33–1.41 (m, 2H, CH2CH3); 1.54–1.59 (m, 2H, CH2CH2CH3); 2.50
(s, 3H, COCH3); 2.58–2.98 (m, 10H, CH2N, pip2,3,5,6); 3.48–3.53
(t, J ¼ 6.5 Hz, 2H, OCH2CH2); 3.77 (s, 3H, ArOCH3); 4.02–4.12 (m,
Yield: 61%, m.p. 156–158°C, ꢀFTIR cmꢀ1: 2583 (R3NHþ), 1669
–
–
–
(C O), 1598 (C C), 1354 (COO ), 1242 (Ar–O–C), 1024 (C–O–C);
–
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