2244
C.-Y. Chang, T.-K. Yang / Tetrahedron: Asymmetry 14 (2003) 2239–2245
4.5. (2S,3%S)-2-(2-Oxo-2,3,4,5-tetrahydro-1H-benzo[b]-
azepin-3-ylamino)-4-phenyl-butric acid ethyl ester,
11 and the (2S,3%R) isomer 12
128.3, 128.2, 127.6, 126.6, 125.8, 122.1, 81.8, 60.4, 60.1,
56.8, 51.1, 37.6, 34.9, 32.0, 28.4, 27.9, 14.0; MS (FAB):
m/z 481 (MH+, 100%), 425, 351, 319, 246, 190, 144, 91,
57. Anal. calcd for C28H36N2O5: C, 69.98; H, 7.55; N,
5.83; O, 16.65. Found: C, 70.05; H, 7.48; N, 5.82; O,
16.13.
A mixture of 10c (1.81 g, 5 mmol) and LHPE (3.10 g,
15 mmol) in N,N-dimethylacetamide (5 ml) was heated
at 50°C for 2.5 days and gave the two isomers in a ratio
of 89:11 by HPLC. The reaction mixture was purified
by flash chromatography (hexane/ethyl acetate=2:1) to
give 11 (1.43 g, 78%) as a white solid: [h]D=−168.1 (c
1.09, CHCl3); mp 110-111°C; IR (neat): 3224, 2948,
1734, 1676, 1494, 1160 cm−1; 1H NMR (400 MHz,
4.7. (2S,3%S)-2-(1-Carboxymethyl-2-oxo-2,3,4,5-tetra-
hydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric
acid ethyl ester hydrochloride, Benazepril HCl 4
To a solution of 13 (2.4 g, 5 mmol) in toluene (50 ml)
was bubbled HCl gas at 0°C for 30 min. The reaction
solution was then allowed to proceed at rt for 1 h. The
reaction solution was concentrated in vacuo to give a
crude white solid and washed with hexane (3×30 ml) to
afford Benazepril HCl 4 (2.07 g, 90%) with d.e. >98%
based on the HPLC analysis: [h]D=−142.6 (c 0.98,
EtOH) [lit.1e [h]D=−141.0 (c 0.9, EtOH)]; mp 188-
189°C (lit.1e mp 188-190°C); IR (neat): 3460, 2988,
1738, 1674, 1216 cm−1; 1H NMR (600 MHz, CD3OD) l
CDCl3) l 7.76 (br, 1H, CONH
6.99 (d, J=8.0 Hz, 1H, CH
CO2CH2CH3), 3.33-3.26 (m, 2H, CH
1H, CH2), 2.75-2.61 (m, 3H, CH2), 2.55-2.42 (m, 1H,
CH2), 2.10-1.88 (m, 3H, CH2), 1.15 (t, J=7.2 Hz, 3H,
CO2CH2CH3
); 13C NMR (100 MHz, CDCl3) l 175.3,
6
), 7.29-7.13 (m, 8H, CH
), 4.12-4.03 (m, 2H,
NH), 2.91-2.84 (m,
6 ),
6
6
6
6
6
6
6
6
174.2, 141.3, 136.6, 134.3, 129.6, 128.3, 128.2, 127.5,
125.9, 125.8, 122.0, 60.5, 60.0, 56.6, 37.8, 35.0, 32.1,
28.9, 14.1; MS (FAB): m/z 367 (MH+, 100%), 293, 206,
154, 91, 77, 51. Anal. calcd for C22H26N2O3: C, 72.11;
H, 7.15; N, 7.64; O, 13.10. Found: C, 71.88; H, 7.36; N,
7.63; O, 12.77. and 12 (0.18 g, 10%) as a white solid:
[h]D=+63.5 (c 1.10, CHCl3); mp 100-101°C; IR (neat):
2944, 1732, 1674, 1492, 1192 cm−1; 1H NMR (400
7.42-7.18 (m, 9H, CH
4.08 (m, 2H, CO2CH2
CHNH·HCl), 3.40-3.28 (m, 1H, CH2
4H, CH2), 2.40-2.15 (m, 3H, CH2), 1.20 (t, J=7.2 Hz,
3H, CO2CH2CH3
); 13C NMR (150 MHz, CD3OD) l
6
), 4.62 (s, 2H, CH
CH3), 3.98-3.89 (m, 2H,
), 2.90-2.55 (m,
6 2CO2H), 4.26-
6
6
6
6
6
6
MHz, CDCl3) l 7.66 (br, 1H, CONH
8H, CH), 6.97 (d, J=7.2 Hz, 1H, CH
2H, CO2CH2
3.10 (m, 1H, COCH
2.72-2.60 (m, 3H, CH2
1.80 (m, 3H, CH2
6
), 7.26-7.11 (m,
171.6, 169.4, 168.1, 141.0, 140.9, 135.5, 130.7, 129.6,
129.5, 128.8, 127.5, 124.0, 63.8, 60.1, 58.9, 51.4, 34.7,
33.0, 31.8, 28.1, 14.3; MS (FAB): m/z 425 (MH−HCl+,
100%), 351, 190, 154, 91, 77, 51. Anal. calcd for
C24H29ClN2O5: C, 62.54; H, 6.34; N, 6.08; O, 17.35.
Found: C, 62.37; H, 6.34; N, 5.62; O, 17.02.
6
6 ), 4.20-4.05 (m,
6
CH3), 3.28-3.23 (m, 1H, COCH
NH), 2.97-2.85 (m, 1H, CH2
), 2.55-2.40 (m, 1H, CH2
), 1.25-1.10 (m, 3H, CO2CH2CH3
6
NH), 3.13-
6
6
),
6
6
), 2.09-
6
6
);
13C NMR (100 MHz, CDCl3) l 175.2, 174.2, 141.5,
136.5, 134.4, 129.6, 128.4, 128.3, 127.6, 126.0, 125.8,
122.1, 60.7, 59.3, 56.7, 37.9, 34.6, 31.6, 28.9, 14.2; MS
(FAB): m/z 367 (MH+ 100%), 307, 293, 206, 154, 136.
Anal. calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64;
O, 13.10. Found: C, 71.97; H, 7.07; N, 7.68; O, 13.18.
Acknowledgements
Support from the National Science Council of the
Republic of China (NSC 91-2113-M-005-008) is grate-
fully acknowledged. We thank Taiwan Wisdom Tech-
nology for the gift sample of L-homophenylalanine
ethyl ester hydrochloride. We thank Ms. Lin Ping-Yu
for analyzing mass spectra. Also we thank Dr. Chaud-
hari, B. A. for discussions before publication.
4.6. (2S,3%S)-2-(1-tert-Butoxycarbonylmethyl-2-oxo-
2,3,4,5-tetrahydro-1H-benzo[b]-azepin-3-ylamino)-4-
phenylbutyric acid ethyl ester, 13
To a solution of 11 (0.732 g, 2 mmol) and tetra-
butylammonium bromide (64 mg, 0.2 mmol) in anhy-
drous THF (20 ml) was added KOH (0.16 g, 85%, 2.4
mmol) at 0°C. The reaction solution was stirred at 0°C
for 30 min, after which t-butyl chloroacetate (0.36 g,
2.4 mmol) added and the reaction solution allowed to
proceed at rt for 5 h. The resulting solution was passed
through a short column with silica gel and then purified
by flash chromatography (hexane/ethyl acetate=3:1) to
afford 13 (0.94 g, 98%) as a colorless liquid: [h]D=−
145.6 (c 1.05, CHCl3); IR (neat): 3344, 2988, 1738,
References
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1
1670, 1370, 1162 cm−1; H NMR (400 MHz, CDCl3) l
7.30-7.09 (m, 9H, CH
NCH2), 4.33 (d, J=17.2 Hz, 1H, NCH2
2H, CO2CH2CH3), 3.35-3.20 (m, 3H, NHCH
2.73-2.65 (m, 2H, CH2), 2.59-2.38 (m, 2H, CH2
1.95 (m, 3H, CH2), 1.43 (s, 9H, C(CH3)3), 1.13 (t,
J=7.0 Hz, 3H, CO2CH2CH3
); 13C NMR (100 MHz,
CDCl3) l 173.9, 173.6, 167.7, 141.3, 140.9, 136.0, 129.3,
6
), 4.58 (d, J=17.2 Hz, 1H,
), 4.13-4.01 (m,
, CH2),
), 2.15-
6
6
6
6
6
6
6
6
6
6