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C. Wu et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
2.24–2.25 (d, 2H, –CH2), 2.34–2.39 (q, 2H, –CH2), 3.44–3.50 (m, 1H,
–CH2), 3.67–3.72 (m, 1H, –CH2), 3.86–4.04 (m, 2H, –CH2), 4.54–
4.69 (q, 2H, –CH2), 6.69–7.57 (m, 8H, –Ar–H); 13C-NMR (100 MHz,
CDCl3): d 13.7, 18.4, 19.4, 22.3, 26.7, 27.5, 33.6, 41.3, 42.6, 122.8,
125.9, 128.0, 129.4, 130.8, 130.9, 131.2, 136.5, 138.2, 140.9, 169.6,
170.8, 172.1, 176.0; MS (m/z): 548 [M–1]þ, m.p.: 120–121.58C.
129.4, 130.7, 130.9, 131.2, 136.4, 138.3, 140.9, 155.5, 169.0, 170.8,
175.1, 175.9; MS (m/z): 564 [M–1]þ, m.p.: 119.4–120.78C.
(S)-Methyl 2-((S)-2-(N-((20-(1H-tetrazol-5-yl)biphenyl-4-yl)-
methyl)pentanamido)-3-methylbutanamido)-3-
phenylpropanoate (11)
Following general method A with 1.1 g (5 mmol) of phenyl-
alanine methyl ester hydrochloride to obtain white crystal solid
(0.7 g).
(S)-Methyl 2-((S)-2-(N-((2’-(1H-tetrazol-5-yl)biphenyl-4-yl)-
methyl)pentanamido)-3-methylbutanamido)propanoate (7)
Following general method A with 1.39 g (10 mmol) of alanine
methyl ester hydrochloride to obtain white crystal solid (1.5 g).
Yield 29%: 1H-NMR (400 MHz, CDCl3): d 0.91–0.97 (m, 9H,
–CH3), 1.25–1.32 (q, 3H, –CH3), 1.39–1.44 (q, 2H, CH2), 1.70–
1.77 (m, 2H, CH2), 2.55–2.57 (d, 2H, CH2), 2.71 (1H, –CH), 3.62
(s, 3H, –OCH3), 4.25–4.46 (m, 2H, CH2), 4.73–4.87 (m, 2H, –CH2),
7.12–8.19 (m, 8H, –Ar–H); 13C-NMR (100 MHz, CDCl3): d 14.1, 17.8,
18.3, 19.5, 19.7, 22.7, 27.2, 27.7, 27.8, 34.7, 48.1, 52.5, 128.5,
128.6, 129.6, 129.7, 130.5, 131.4, 139.0, 140.5, 172.9, 173.1,
175.4; MS (m/z): 520 [M]þ, m.p.: 99.7–101.58C.
Yield 23%: 1H-NMR (400 MHz, CDCl3): d 0.83–0.84 (d, 3H, –CH3),
0.86–0.88 (d, 3H, –CH3), 0.98–1.02 (t, 3H, –CH3), 1.41–1.48 (m, 2H,
–CH2), 1.71–1.79 (m, 2H, –CH2), 2.46–2.50 (m, 2H, –CH2), 2.74–
2.81 (q, 2H, –CH2), 3.21–3.26 (dd, 1H, –CH), 4.18 (1H, –CH2), 4.68
(1H, –CH2), 4.52–4.57 (m, 1H, –CH), 6.71–7.61 (m, 13H, –Ar–H);
13C-NMR (100 MHz, CDCl3): d 13.9, 19.3, 19.4, 22.6, 26.7, 27.4,
34.6, 37.8, 52.2, 52.3, 53.6, 123.0, 126.9, 128.4, 128.7, 129.4,
130.3, 131.2, 131.3, 136.8, 136.9, 138.6, 140.2, 153.9, 171.5,
174.9; MS (m/z): 596 [Mþ1]þ, m.p.: 100.3–1028C.
(S)-2-((S)-2-(N-((20-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl)-
pentanamido)-3-methylbutanamido)-3-phenylpropanoic
acid (12)
(S)-2-((S)-2-(N-((20-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl)-
pentanamido)-3-methylbutanamido)propanoic acid (8)
Following general method B with 1.5 g of compound 7 to obtain
white crystal solid (1.2 g).
Following general method B with 0.5 g of compound 11 to obtain
white crystal solid (0.42 g).
Yield 82%: 1H-NMR (400 MHz, CDCl3): d 0.82–0.89 (m, 9H,
–CH3), 1.23–1.30 (m, 2H, –CH2), 1.32–1.34 (d, 2H, –CH3), 1.50–
1.66 (m, 2H, –CH2), 2.20–2.29 (t, 1H, –CH), 2.34–2.42 (m, 2H,
–CH2), 4.19–4.22 (t, 1H, –CH), 4.35–4.46 (d, 1H, –CH2), 4.74–
4.78 (d, 1H, –CH2), 7.03–7.92 (m, 8H, –Ar–H); 13C-NMR
(100 MHz, CDCl3): d 13.8, 17.2, 18.9, 19.3, 22.3, 27.1, 27.4, 34.1,
48.3, 122.7, 127.0, 128.1, 129.4, 130.6, 130.9, 131.2, 136.4, 138.4,
140.6, 154.7, 171.1, 174.8, 175.9; MS (m/z): 505 [M–1]þ, m.p.:
131.3–134.88C.
Yield 88%: 1H-NMR (400 MHz, CDCl3):
d 0.49 (s, 3h,
–CH–CH–CH–CH3), 0.86–0.93 (t, 6H, –CH3), 1.29–1.41 (t, 2H,
–CH2), 1.63–1.65 (d, 2H, –CH2), 2.28–2.34 (2H, –CH2), 2.67 (2H,
–CH2), 1.12 (1H, –CH), 1.03 (1H, –CH2), 1.17 (1H, –CH2), 4.72–4.76
(d, 1H, –CH), 6.49–7.93 (m, 13H, –Ar–H); 13C-NMR (100 MHz,
CDCl3): d 13.8, 18.5, 19.1, 22.5, 27.3, 29.6, 34.5, 37.4, 54.4,
122.8, 126.9, 127.5, 128.0, 128.4, 129.4, 129.6, 130.7, 131.0,
131.1, 135.1, 137.1, 138.3, 140.8, 154.5, 173.6, 175.4; MS (m/z):
605 [MþNa]þ, m.p.: 135.4–137.48C.
(R)-Methyl 2-(2-((S)-2-(N-((2’-(1H-tetrazol-5-yl)biphenyl-
4-yl)methyl)pentanamido)-3-methylbutanamido)-
acetamido)-propanoate (9)
Following general method A starting with compound 3 and
alanine methyl ester hydrochloride to obtain white crystal solid
(1.7 g).
Yield 44%: 1H-NMR (400 MHz, CDCl3): d 0.87–0.95 (m, 9H,
–CH3), 1.31–1.39 (m, 5H, –CH2, –CH3), 1.62–1.71 (m, 2H, –CH2),
2.35–2.56 (m, 3H, –CH2, –CH), 3.67 (3H, –OCH3), 3.48–3.52 (d, 1H,
–CH2), 3.73–3.77 (d, 1H, –CH2), 4.44–4.55 (m, 2H, –CH2), 4.68–4.72
(d, 1H, –CH), 7.04–7.60 (m, 8H, –Ar–H); 13C-NMR (125 MHz,
CDCl3): d 13.8, 13.9, 18.6, 19.6, 22.4, 26.5, 27.6, 33.8, 41.0, 42.8,
52.4, 60.4, 126.7, 128.1, 129.5, 130.7, 131.1, 136.8, 138.5, 140.6, 168.9,
170.4, 171.1, 175.2; MS (m/z): 1154 [2M]þ, m.p.: 131.3–134.88C.
(S)-Dimethyl 2-((S)-2-(N-((20-(1H-tetrazol-5-yl)biphenyl-4-
yl)methyl)pentanamido)-3-methylbutanamido)-
pentanedioate (13)
Following general method A with 1.1 g (5 mmol) of glutamic
acid dimethyl ester hydrochloride to obtain white crystal solid
(0.6 g).
Yield 20%: 1H-NMR (400 MHz, CDCl3): d 0.90–0.95 (m, 9H,
–CH3), 1.34–1.43 (m, 2H, –CH2), 1.67–1.74 (m, 2H, –CH2), 1.89–
1.96 (m, 1H, –CH2), 2.01–2.12 (m, 1H, –CH2), 2.25–2.39 (m, 2H,
–CH2), 2.48–2.58 (m, 2H, –CH2), 2.66 (1H, –CH), 3.02 (s, 3H, –CH3),
3.66 (s, 3H, –CH3), 4.32–4.38 (q, 2H, –CH2), 4.87–4.91 (d, 1H, –CH),
7.10–8.11 (m, 8H, –Ar–H); 13C-NMR (100 MHz, CDCl3): d 14.1, 19.5,
19.7, 22.7, 26.9, 27.4, 27.7, 30.2, 34.7, 51.7, 52.1, 52.6, 123.2,
128.5, 129.7, 130.6, 131.4, 136.5, 138.9, 140.6, 171.6, 171.9,
173.2, 175.6; MS (m/z): 592 [M]þ, m.p.: 78.7–79.98C.
(R)-2-(2-((S)-2-(N-((20-(1H-Tetrazol-5-yl)biphenyl-4-yl)-
methyl)pentanamido)-3-methylbutanamido)acetamido)-
propanoic acid (10)
Following general method B with 0.5 g of compound 9 to obtain
white crystal solid (0.4 g).
(S)-2-((S)-2-(N-((20-(1H-Tetrazol-5-yl)biphenyl-4-yl)methyl)-
pentanamido)-3-methylbutanamido)-5-methoxy-5-
oxopentanoic acid (14)
Yield 82%: 1H-NMR (400 MHz, CDCl3): d 0.83–0.86 (m, 9H,
–CH3), 1.87–1.28 (m, 2H, –CH2), 1.35–1.36 (d, 3H, –CH3), 1.56–
1.62 (m, 2H, –CH2), 3.42–3.45 (d, 1H, –CH), 3.64–3.66 (d, 1H, –CH),
4.38–4.45 (m, 2H, –CH2), 4.68–4.72 (d, 1H, CH), 7.00–7.61 (m, 8H,
–Ar–H); 13C-NMR (100 MHz, CDCl3): d 13.8, 13.9, 17.5, 18.5, 19.3,
19.4, 22.4, 26.8, 27.5, 33.7, 42.7, 48.4, 48.5, 122.8, 126.1, 127.9,
Following general method B with 0.4 g of compound 13 to obtain
white crystal solid (0.32 g).
Yield 84%: 1H-NMR (400 MHz, CDCl3): d 0.77–0.93 (m, 9H,
–CH3), 1.18–1.27 (m, 2H, –CH2), 1.53–1.57 (m, 2H, –CH2), 2.00–
2.42 (m, 7H, ꢀ3ꢂCH2, –CH), 4.23 (s, 1H, –CH2), 4.47 (s, 1H, –CH2),
4.71–4.80 (t, 1H, –CH), 6.967–7.89 (m, 8H, –Ar–H); 13C-NMR
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