Solid-Phase Organic Syntheses
.pdf28 Solid-Phase Synthesis of Ureas on MicroTubes
1H, NH), 6.89 (t, J ¼ 7.65 Hz, 1H), 6.97 (brs, 1H, NH), 7.20 (t, J ¼ 7.82 Hz, 2H), 7.25 (brs, 1H, NH), 7.35 (d, J ¼ 8.05 Hz, 2H), 8.10 (d, J ¼ 7.64 Hz, 1H, NH) and 8.64 (s, 1H, NH) ppm. MS/EI (C16H24N4O3) calculated: 320; observed: 343 (þNaþ ).
N-( p-Methoxyphenylcarbamoyl)-L-Nle-L-Ala-NH2 (1B5)
1H NMR (DMSO) : 0.85 (t, J ¼ 7.04 Hz, 3H, CH3), 1.21 (d, J ¼ 7.24 Hz, 3H, CH3), 1.27 (m, 6H), 3.68 (s, 3H, OCH3), 4.16– 4.23 (m, 2H), 6.24 (d, J ¼ 7.86 Hz, 1H, NH), 6.80 (d, J ¼ 7.10 Hz, 2H), 6.97 (brs, 1H, NH), 7.25–7.27 (m, 3H), 8.07 (d, 1H, NH), and 8.44 (s, 1H, NH) ppm. MS/EI (C17H26N4O4) calculated: 350, observed: 373 (þNaþ).
N-( p-Nitrophenylcarbamoyl)-L-Nle-L-Ala-NH2 (1B6)
1H NMR (DMSO) : 0.86 (t, J ¼ 6.83 Hz, 3H, CH3), 1.22 (d, J ¼ 6.99 Hz, 3H, CH3), 1.28 (m, 4H), 1.52–1.55 (m, 1H), 1.65– 1.68 (m, 1H), 4.22–4.26 (m, 2H), 6.68 (d, J ¼ 7.96 Hz, 1H, NH), 6.98 (brs, 1H, NH), 7.27 (brs, 1H, NH), 7.59–7.61 (d, J ¼ 9.03 Hz, 2H), 8.14 (d, J ¼ 8.93 Hz, 2H), 8.18 (d, J ¼ 7.68 Hz, 1H, NH), and 9.44 (s, 1H, NH) ppm. MS/EI (C16H23N5O5) calculated: 365, observed: 388 (þNaþ).
N-(Phenylcarbamoyl)-L-Phe-L-Ala-NH2 (1C4)
1H NMR (DMSO) : 1.22 (d, J ¼ 6.97 Hz, 3H, CH3), 2.72– 2.88 (dd, J1 ¼ 8.37 Hz, J2 ¼ 8.41 Hz, 1H), 3.03–3.07 (dd, J1 ¼ 4.63 Hz, J2 ¼ 4.72 Hz, 1H), 4.22–4.25 (m, 1H), 4.49–4.51 (m, 1H), 6.27 (d, J ¼ 7.95 Hz, 1H, NH), 6.87 (t, J ¼ 6.92 Hz, 1H), 7.02 (brs, 1H, NH), 7.18–7.32 (m, 10H), 8.21 (d, J ¼ 7.67 Hz, 1H, NH), and 8.67 (s, 1H, NH) ppm. MS/EI (C19H22N4O3) calculated: 354; observed: 377 (þNaþ ).
Appendix 29
N-( p-Methoxyphenylcarbamoyl)-L-Phe-L-Ala-NH2 (1C5)
1H NMR (DMSO) : 1.22 (d, J ¼ 7.14 Hz, 3H, CH3), 2.78– 2.82 (dd, J1 ¼ 8.19 Hz, J2 ¼ 8.21 Hz, 1H), 3.02–3.05 (dd, J1 ¼ 4.59 Hz, J2 ¼ 4.63 Hz, 1H), 3.67 (s, 3H, OCH3), 4.21–4.24 (m, 1H), 4.50 (m, 1H), 6.16 (d, J ¼ 7.96 Hz, 1H, NH), 6.78 (d, J ¼ 8.92 Hz, 2H), 7.02 (brs, 1H, NH), 7.17–7.28 (m, 7H), 8.18 (d, 1H, NH), and 8.48 (s, 1H, NH) ppm. MS/EI (C20H24N4O4) calculated: 384; observed: 407 (þNaþ ).
N-( p-Nitrophenylcarbamoyl)-L-Phe-L-Ala-NH2 (1C6)
1H NMR (DMSO) : 1.25 (d, J ¼ 7.38 Hz, 3H, CH3), 2.82– 2.86 (dd, J1 ¼ 8.11 Hz, J2 ¼ 8.13 Hz, 1H), 3.06–3.10 (dd, J1 ¼ 4.58 Hz, J2 ¼ 4.73 Hz, 1H), 4.23–4.31 (m, 1H), 4.54–4.59 (m, 1H), 6.57–6.58 (d, J ¼ 8.04 Hz, 1H, NH), 7.03 (brs, 1H, NH), 7.17–7.28 (m, 6H), 7.56 (s, 2H), 8.13 (d, J ¼ 9.16 Hz, 2H), 8.31 (d, J ¼ 7.67 Hz, 1H, NH) and 9.46 (s, 1H, NH) ppm. MS/EI (C19H21N5O5) calculated: 399; observed: 422 (þNaþ).
N-(Phenylcarbamoyl)-L-Cha-L-Phg-NH2 (2A4)
1H NMR (DMSO) : 0.83–0.92 (m, 2H), 1.07–1.22 (m, 3H), 1.33–1.79 (m, 8H), 4.37–4.41 (m, 1H), 5.39–5.42 (m, 1H), 6.37 (d, J ¼ 8.23 Hz, 1H, NH), 6.87–6.91 (m, 1H, NH), 7.16 –7.43 (m, 10H), 7.68 (d, J ¼ 7.97 Hz, 1H, NH), 8.52 (d, J ¼ 10.41 Hz, 1H, NH), and 8.59 (d, J ¼ 8.18 Hz, 1H, NH) ppm. MS/EI (C24H30 N4O3) calculated: 422; observed: 445 (þNaþ ).
N-( p-Methoxyphenylcarbamoyl)-L-Cha-L-Phg-NH2 (2A5)
1H NMR (DMSO) : 0.83–0.91 (m, 2H), 1.07–1.43 (m, 5H), 1.47–1.78 (m, 6H), 3.69 (s, 3H, OCH3), 4.34–4.38 (m, 1H), 5.38–
30 Solid-Phase Synthesis of Ureas on MicroTubes
5.41 (m, 1H), 6.26 (d, J ¼ 8.16 Hz, 1H, NH), 6.80–6.82 (m, 2H), 7.21–7.34 (m, 5H), 7.40–7.43 (m, 2H), 7.68 (s, 1H, NH), 8.39 (d, J ¼ 10.05 Hz, 1H, NH) and 8.48 (d, J ¼ 8.06 Hz, 1H, NH) ppm. MS/EI (C25H32N4O4) calculated: 452, observed: 475 (þNaþ ).
N-( p-Nitrophenylcarbamoyl)-L-Cha-L-Phg-NH2 (2A6)
1H NMR (DMSO) : 0.85–0.92 (m, 2H), 1.07–1.20 (m, 3H), 1.34–1.48 (m, 2H), 1.50–1.89 (m, 6H), 4.50 (m, 1H), 5.45 (m, 1H), 6.69 (d, J ¼ 8.31 Hz, 1H, NH), 7.18 (brs, 1H, NH), 7.25–7.44 (m, 6H), 7.59 (d, J ¼ 9.45 Hz, 2H), 8.14 (m, 2H), 8.63 (d, J ¼ 8.13 Hz, 1H, NH), and 9.39 (d, 1H, NH) ppm. MS/EI (C24H29N5O5) calculated: 467, observed: 490 (þNaþ ).
N-(Phenylcarbamoyl)-L-Nle-L-Phg-NH2 (2B4)
1H NMR (DMSO) : 0.7–0.8 (tt, J1 ¼ 7.38 Hz, J2 ¼ 6.79 Hz, 3H), 1.29–1.41 (m, 4H), 1.52–1.70 (m, 2H), 4.45 (m, 1H), 5.45 (m, 1H), 6.45 (d, J ¼ 8.33 Hz, 1H, NH), 6.9 (m, 1H, NH), 7.20– 7.44 (m, 9H), 7.70 (m, 1H), 8.61 (d, J ¼ 7.98 Hz, 1H, NH), and 8.65 (s, 1H) ppm. MS/EI (C21H26N4O3) calculated: 382; observed: 405 (þNaþ).
N-( p-Methoxyphenylcarbamoyl)-L-Nle-L-Phg-NH2 (2B5)
1H NMR (DMSO) : 0.7–0.8 (tt, J1 ¼ 7.01 Hz, J2 ¼ 6.87 Hz, 3H, CH3), 1.27 (m, 4H), 1.60 (m, 2H), 3.68 (s, 3H, OCH3), 4.35 (m, 1H), 5.45 (m, 1H), 6.35 (d, J ¼ 8.10 Hz, 1H, NH), 6.80 (m, 2H), 7.25 (d, 1H, NH), 7.26 –7.32 (m, 5H), 7.42 (m, 2H), 7.70 (s, 1H, NH), 8.42 (s, 1H, NH), and 8.55 (d, J ¼ 8.04 Hz, 1H, NH)
ppm. MS/EI (C22H28N4O4) calculated: 412; observed: 435 (þNaþ ).
Appendix 31
N-( p-Nitrophenylcarbamoyl)-L-Nle-L-Phg-NH2 (2B6)
1H NMR (DMSO) : 0.86–0.90 (tt, J1 ¼ 7.44 Hz, J2 ¼ 7.36 Hz, 3H, CH3), 1.29 (m, 4H), 1.55–1.75 (m, 2H), 4.50 (m, 1H), 5.45 (m, 1H), 6.75 (d, J ¼ 8.10 Hz, 1H, NH), 7.20 (s, 1H, NH), 7.32–7.45 (m, 5H), 7.59 (m, 2H), 7.75 (s, 1H, NH), 8.13 (m, 2H), 8.65 (d, J ¼ 8.10 Hz, 1H, NH), and 9.43 (s, 1H, NH) ppm. MS/EI (C21H25N2O5) calculated: 427; observed 450 (þNaþ).
N-(Phenylcarbamoyl)-L-Phe-L-Phg-NH2 (2C4)
1H NMR (DMSO) : 2.85 (m, 1H), 3.05 (m, 1H), 4.70 (m, 1H), 5.45 (m, 1H), 6.35 (m, 1H, NH), 6.95 (m, 1H), 7.19–7.32 (m, 15H), 7.45 (s, 1H, NH), and 8.70 (s, 1H, NH) ppm. MS/EI (C24H24N4O3) calculated: 416; observed: 439 (þNaþ).
N-( p-Methoxyphenylcarbamoyl)-L-Phe-L-Phg-NH2 (2C5)
1H |
NMR |
(DMSO) : 2.82–2.86 (dd, |
J1 ¼ 8.31 Hz, |
J2 ¼ |
8.35 Hz, |
1H), |
3.02–3.06 (dd, J1 ¼ 4.69 Hz, |
J2 ¼ 4.73 Hz, |
1H), |
3.67 (s, 3H, OCH3), 4.65 (m, 1H), 5.45 (m, 1H), 6.25 (m, 1H, NH), 6.78 (d, 2H), 7.21–7.26 (m, 12H), 7.43 (d, 2H), 7.75 (d, 1H, NH), and 8.50 (s, 1H, NH) ppm. MS/EI (C25H26N4O4) calculated: 446; observed: 469 (þNaþ).
N-( p-Nitrophenylcarbamoyl)-L-Phe-L-Phg-NH2 (2C6)
1H NMR (DMSO) : 2.87–2.91 (dd, J1 ¼ 8.02 Hz, J2 ¼ 8.06 Hz, 1H), 3.07–3.11 (dd, J1 ¼ 4.54 Hz, J2 ¼ 4.61 Hz, 1H), 4.75 (m, 1H), 5.45 (m, 1H), 6.60 (d, J ¼ 8.19 Hz, 1H, NH), 7.19–7.40 (m, 10H), 7.50 (d, 2H), 7.55 (m, 2H), 8.11 (m, 2H), 8.79 (d, J ¼ 8.16 Hz, 1H, NH), and 9.45 (s, 1H, NH) ppm. MS/EI (C24H23N5O5) calculated: 461; observed: 484 (þNaþ).
32 Solid-Phase Synthesis of Ureas on MicroTubes
N-(Phenylcarbamoyl)-L-Cha-L-Leu-NH2 (3A4)
1H NMR (DMSO) : 0.82 (d, J ¼ 6.70 Hz, 3H, CH3), 0.86 (d, J ¼ 6.64 Hz, 3H, CH3), 1.10–1.20 (m, 3H), 1.30–1.51 (m, 6H), 1.62–1.69 (m, 7H), 4.25 (m, 2H), 6.35 (d, J ¼ 7.86 Hz, 1H, NH), 6.87–6.97 (m, 1H, NH), 7.22 (t, J ¼ 8.29 Hz, 3H), 7.35 (d, J ¼ 8.25 Hz, 2H), 8.05 (d, J ¼ 8.31 Hz, 1H), and 8.60 (s, 1H) ppm. MS/EI (C22H34N4O3) calculated: 402; observed: 425 (þNaþ ).
N-( p-Methoxyphenylcarbamoyl)-L-Cha-L-Leu-NH2 (3A5)
1H NMR (DMSO) : 0.82 (d, J ¼ 8.85 Hz, 3H, CH3), 0.87 (d, J ¼ 8.98 Hz, 3H, CH3), 1.10 –1.70 (m, 16H), 3.69 (s, 3H, OCH3), 4.25 (m, 2H), 6.20 (m, 1H, NH), 6.81 (d, J ¼ 8.85 Hz, 2H), 7.0 (s, 1H, NH), 7.23 (s, 1H, NH), 7.27 (d, J ¼ 7.09 Hz, 2H), 8.0 (d, J ¼ 8.56 Hz, 1H, NH), and 8.42 (s, 1H, NH) ppm. MS/EI (C23H36N4O4) calculated: 432; observed: 455 (þNaþ ).
N-( p-Nitrophenylcarbamoyl)-L-Cha-L-leu-NH2 (3A6)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.25 Hz, 3H, CH3), 0.87 (d, J ¼ 6.66 Hz, 3H, CH3), 1.15 (m, 4H), 1.31–1.60 (m, 6H), 1.65– 1.79 (m, 6H), 4.29 (m, 2H), 6.65 (d, 1H, NH), 7.0 (s, 1H, NH), 7.25 (s, 1H, NH), 7.60 (d, J ¼ 8.91 Hz, 2H), 8.09 (d, J ¼ 9.10 Hz, 1H, NH), 8.14 (d, 2H), and 9.41 (s, 1H, NH) ppm. MS/EI (C22H33N5O5) calculated: 447; observed: 470 (þNaþ ).
N-(Phenylcarbamoyl)-L-Nle-L-Leu-NH2 (3B4)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.64 Hz, 3H, CH3), 0.86 (t, 3H, CH3), 0.89 (d, J ¼ 6.72 Hz, 3H, CH3), 1.25–1.28 (m, 4H), 1.45–1.60 (m, 5H), 4.25 (m, 2H), 6.36 (d, J ¼ 7.22 Hz, 1H, NH), 6.87–6.97 (m, 1H, NH), 7.21 (t, J ¼ 8.25 Hz, 2H), 7.27 (s, 1H,
Appendix 33
NH), 7.36 (d, J ¼ 7.57 Hz, 2H), 8.04 (d, J ¼ 8.44 Hz, 1H, NH), and 8.65 (s, 1H, NH) ppm. MS/EI (C19H30N4O4) calculated: 362; observed: 385 (þNaþ).
N-( p-Methoxyphenylcarbamoyl)-L-Nle-L-Leu-NH2 (3B5)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.55 Hz, 3H, CH3), 0.87 (d, J ¼ 6.68 Hz, 3H, CH3), 0.89 (m, 3H, CH3), 1.26–1.65 (m, 9H), 3.69 (s, 3H, OCH3), 4.09–4.30 (m, 2H), 6.3 (d, J ¼ 7.69 Hz, 1H, NH), 6.80 (d, J ¼ 7.07 Hz, 2H), 6.82–6.97 (m, 1H, NH), 7.25 (d, J ¼ 7.15 Hz, 2H), 7.35 (d, J ¼ 8.83 Hz, 1H, NH), 8.0 (s, 1H, NH) and 8.45 (s, 1H, NH) ppm. MS/EI (C20H32N4O4) calculated: 392; observed: 415 (þNaþ).
N-( p-Nitrophenylcarbamoyl)-L-Nle-L-Leu-NH2 (3B6)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.62 Hz, 3H, CH3), 0.85 (t, 3H, CH3), 0.88 (d, J ¼ 6.37 Hz, 3H, CH3), 1.27 (m, 3H), 1.4–1.60 (m, 6H), 4.25 (m, 2H), 6.65 (d, J ¼ 7.82 Hz, 1H, NH), 6.97 (s, 1H, NH), 7.29 (s, 1H, NH), 7.59 (d, J ¼ 8.93 Hz, 2H), 8.14 (d, J ¼ 8.99 Hz, 2H), and 9.47 (s, 1H, NH) ppm. MS/EI (C19H29N5O5) calculated: 407; observed: 430 (þNaþ ).
N-(Phenylcarbamoyl)-L-Phe-L-Leu-NH2 (3C4)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.69 Hz, 3H, CH3), 0.87 (d, J ¼ 6.74 Hz, 3H, CH3), 1.45–1.49 (m, 2H), 1.55–1.59 (m, 1H), 2.81–2.85 (dd, J1 ¼ 7.88 Hz, J2 ¼ 7.89 Hz, 1H), 3.02–3.05 (dd,
J1 ¼ 4.81 Hz, J2 ¼ 4.85 Hz, 1H), 4.24–4.27 |
(m, 1H), 4.50–4.52 |
|||
(m, 1H), 6.27 (d, J ¼ 7.83 Hz, 1H, NH), 6.88–7.00 (m, 1H, NH), |
||||
7.17–7.27 (m, 9H), 7.32 (d, |
J ¼ 7.73 Hz, |
1H, |
NH), |
8.14 (d, |
J ¼ 8.05 Hz, 1H, NH), and |
8.68 (s, 1H, |
NH) |
ppm. |
MS/EI |
(C22H28N4O3) calculated: 396; observed: 419 (þNaþ).
34 Solid-Phase Synthesis of Ureas on MicroTubes
N-( p-Methoxyphenylcarbamoyl)-L-Phe-L-Leu-NH2 (3C5)
1H NMR (DMSO) : 0.83 (d, J ¼ 6.60 Hz, 3H, CH3), 0.87 (d, J ¼ 6.72 Hz, 3H, CH3), 1.45–1.49 (m, 2H), 1.56–1.57 (m, 1H), 2.80–2.85 (dd, J1 ¼ 7.91 Hz, J2 ¼ 7.93 Hz, 1H), 3.00–3.04 (dd, J1 ¼ 4.81 Hz, J2 ¼ 4.85 Hz, 1H), 3.68 (s, 3H, OCH3), 4.25–4.27 (m, 1H), 4.49–4.50 (m, 1H), 6.16 (d, J ¼ 7.44 Hz, 1H, NH), 6.78 (d, J ¼ 8.93 Hz, 2H), 7.00 (s, 1H, NH), 7.17–7.27 (m, 8H), 8.11 (d, J ¼ 8.33 Hz, NH), and 8.50 (s, 1H, NH) ppm. MS/EI (C23H30N4O4) calculated: 426; observed: 449 (þNaþ ).
N-( p-Nitrophenylcarbamoyl)-L-Phe-L-Leu-NH2 (3C6)
1H NMR (DMSO) : 0.84 (d, J ¼ 6.69 Hz, 3H, CH3), 0.88 (d, J ¼ 6.44 Hz, 3H, CH3), 1.46–1.49 (m, 2H), 1.57–1.60 (m, 1H), 2.84–2.89 (dd, J1 ¼ 7.71 Hz, J2 ¼ 8.32 Hz, 1H), 3.05–3.09 (dd, J1 ¼ 4.70 Hz, J2 ¼ 4.79 Hz, 1H), 6.56 (d, J ¼ 7.96 Hz, 1H, NH), 7.02 (s, 1H, NH), 7.17–7.27 (m, 6H), 7.57 (d, J ¼ 9.50 Hz, 2H), 8.12 (d, J ¼ 9.11 Hz, 2H), 8.25 (d, J ¼ 8.51 Hz, 1H, NH), and 9.48 (s, 1H, NH) ppm. MS/EI (C22H27N5O5) calculated: 441; observed: 464 (þNaþ).
Appendix 3.2
Analytical Data of the Urea Library
|
|
|
þ |
b Quantity c |
|
Chemical |
Code |
Structure |
[MþNa] |
a |
|
Entry Formula |
(exact mass |
) Purity |
(percent) |
||
|
|
|
|
|
|
1 C19H28N4O3 |
1A4 |
|
383(360) |
high |
99 |
2 C20H30N4O4 1A5 |
413(390) high |
96 |
Appendix |
35 |
Appendix 3.2 (Continued)
|
|
|
|
þ |
b Quantity c |
|
|
Chemical |
Code |
Structure |
[MþNa] |
a |
|
Entry Formula |
(exact mass |
) Purity |
(percent) |
|||
|
|
|
|
|
|
|
3 |
C19H27N5O5 |
1A6 |
|
428(405) |
high |
89 |
4 |
C16H24N4O3 |
1B4 |
|
343(320) |
high |
90 |
5 |
C17H26N4O4 |
1B5 |
|
373(350) |
high |
87 |
6 |
C16H23N5O5 |
1B6 |
|
388(365) |
high |
99 |
7 |
C19H22N4O3 |
1C4 |
|
377(354) |
high |
86 |
8 |
C20H24N4O4 |
1C5 |
|
407(384) |
high |
96 |
9 |
C19H21N5O5 |
1C6 |
|
422(399) |
high |
99 |
10 |
C24H30N4O3 |
2A4 |
|
445(422) |
high |
99 |
11 |
C25H32N4O4 |
2A5 |
|
475(452) |
high |
97 |
12 |
C24H29N5O5 |
2A6 |
|
490(467) |
high |
80 |
36 Solid-Phase Synthesis of Ureas on MicroTubes
Appendix 3.2 (Continued)
|
|
|
|
þ |
b Quantity c |
|
|
Chemical |
Code |
Structure |
[MþNa] |
a |
|
Entry Formula |
(exact mass |
) Purity |
(percent) |
|||
|
|
|
|
|
|
|
13 |
C21H26N4O3 |
2B4 |
|
405(382) |
high |
82 |
14 |
C22H28N4O4 |
2B5 |
|
435(412) |
high |
99 |
15 |
C21H25N5O5 |
2B6 |
|
450(427) |
high |
92 |
16 |
C24H24N4O3 |
2C4 |
|
439(416) |
high |
96 |
17 |
C25H26N4O4 |
2C5 |
|
469(446) |
high |
94 |
18 |
C24H23N5O5 |
2C6 |
|
484(461) |
high |
96 |
19 |
C22H34N4O3 |
2A4 |
|
425(402) |
high |
97 |
20 |
C23H36N4O4 |
3A5 |
|
455(432) |
high |
89 |
21 |
C22H33N5O5 |
3A6 |
|
470(447) |
high |
80 |
22 |
C19H30N4O3 |
3B4 |
|
385(362) |
high |
99 |
Appendix |
37 |
Appendix 3.2 (Continued)
|
|
|
|
þ |
b Quantity c |
|
|
Chemical |
Code |
Structure |
[MþNa] |
a |
|
Entry Formula |
(exact mass |
) Purity |
(percent) |
|||
|
|
|
|
|
|
|
23 |
C20H32N4O4 |
3B5 |
|
415(392) |
high |
99 |
24 |
C19H29N5O5 |
3B6 |
|
430(407) |
high |
90 |
25 |
C22H28N4O3 |
3C4 |
|
419(396) |
high |
98 |
26 |
C23H30N4O4 |
3C5 |
|
449(426) |
high |
80 |
27 C22H27N5O5 3C6 |
464(441) high |
98 |
aData were obtained by electron spray mass spectrometry analysis.
bEstimated by 1H NMR analysis (DMSO). High, > 80% pure; medium, 50–80% pure; low, < 50% pure.
cEstimated by 1H NMR analysis with an internal standard (TMS).