Journal of Medicinal Chemistry
Article
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3.80−3.60 (m, 12H), 3.55 (s, 3H), 3.45 (t, JH−H = 5.5 Hz, 2H), 3.39
(m, 2H), 1.42 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 170.6, 160.9,
156.5, 129.5, 116.0, 80.5, 70.0 (several signals), 69.1, 63.7, 55.8, 53.0,
50.7, 43.2, 28.3. HRMS (ESI+): C23H37N5O10S + H+ calcd, 576.2334;
found, 576.2339; C23H37N5O10S + Na+ calcd, 598.2154; found,
598.2160. Anal. Calcd: C, 50.27; H, 6.19; N, 7.82. Found: C, 50.27;
H, 6.11; N, 7.66.
(C24H38N6O10S)2 + Na+ calcd, 1227.4611; found, 1227.4600. 1H
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NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.09 (d, JH−H = 7.8 Hz,
1H), 7.96 (ddd, 3JH−H = 7.8 Hz, 4JH−H = 1.7 Hz, 5JH−H = 1.2 Hz, 1H),
3
3
7.59 (t, JH−H = 7.8 Hz, 1H), 6.11 (s, 1H, NH), 5.12 (t, JH−H = 6.4
Hz, 1H, NH), 4.09−4.05 (m, 1H), 3.80−3.59 (m, 14H), 3.57 (s, 3H),
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3.53−3.43 (m, 2H), 3.37 (t, JH−H = 5.0 Hz, 2H), 2.26 (s, 1H, NH),
1.42 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 171.2, 165.7, 156.1,
140.2, 135.8, 132.1, 129.5, 129.4, 125.4, 80.1, 70.6, 70.5, 70.2, 69.9
(2 signals), 69.6, 56.1, 52.9, 50.7, 43.1, 40.1, 28.3. HRMS:
3- and 4-(Chlorosulfonyl)benzoyl Chloride (13a,b). The bis-
chlorination of monopotassium sulfobenzoic acids 12a and 12b was
accomplished by treating the solid salts with an excess of freshly
distilled thionyl chloride and a catalytic amount of DMF at reflux
under argon. In detail, from 1.80 g (4.20 mmol) of 12a and 20 mL of
thionyl chloride containing 100 μL of DMF, after filtration,
evaporation, and azeotropic distillation with toluene, product 13a
was obtained as a colorless solid in a yield of 97% (0.96 g, 4.01 mmol).
From 2.70 g (6.30 mmol) of 12b and 30 mL of thionyl chloride
containing 150 μL of DMF, 13b was obtained and as a colorless oil in
a yield of 98% (1.50 g, 6.28 mmol). 13a: 1H NMR (300 MHz, CDCl3)
δ 8.40−8.34 (m, 2H), 8.25−8.18 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 167.0, 148.9, 138.5, 132.2, 127.5. 13b: 1H NMR (300 MHz,
C24H38N6O10
S +
H+ calcd, 603.2443; found, 625.2444;
C24H38N6O10S + Na+ calcd, 625.2262; found, 625.2255.
Subsequent deprotection of the intermediates with HCl (4 M in
dioxane) gave 15a and 15b as monohydrochlorides in yields of 94%
(15a, 2.00 g, 3.71 mmol) and 96% (15b, 1.61 g, 2.98 mmol),
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respectively. 15a: H NMR (300 MHz, CD3OD) δ 8.04−7.93 (m,
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4H), 4.32 (dd, JH−H = 9.0 Hz, JH−H = 4.9 Hz, 1H), 3.72−3.56 (m,
3
16H), 3.44 (s, 3H), 3.34 (t, JH−H = 4.8 Hz, 2H), 3.29−3.33 (m, 1H)
3.10−2.93 (m, 1H). 13C NMR (101 MHz, CD3OD) δ 169.4, 168.6,
143.9, 139.9, 129.2, 128.6, 71.6, 71.5, 71.3, 71.1, 70.4, 68.1, 55.0, 53.5,
51.8, 42.1, 41.1. HRMS: C19H30N6O8S + H+ calcd, 503.1919; found,
503.1927; C19H30N6O8S + Na+ calcd, 525.1738; found, 525.1747. 15b:
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 3H), 8.07 (dd, 3JH−H = 24.0
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CDCl3) δ 8.77 (t, JH−H = 1.8 Hz, 1H), 8.49 (ddd, JH−H = 7.9 Hz,
4JH−H = 1.7 Hz, JH−H = 1.1 Hz, 1H), 8.36 (ddd, JH−H = 8.0 Hz,
5
3
4JH−H = 1.9 Hz, JH−H = 1.1 Hz, 1H), 7.85 (t, JH−H = 8.0 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ 166.5, 145.4, 136.9, 134.9, 132.8, 130.8,
129.4. GC-MS m/z (%): 203 (100), 175 (9), 139 (15), 104 (16),
76 (29), 50 (20).
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3
5
3
Hz, JH−H = 7.6 Hz, 5H), 7.70 (t, JH−H = 7.7 Hz, 1H), 4.33 (dd,
3JH−H = 8.8 Hz, JH−H = 4.7 Hz, 1H), 3.83−3.49 (m, 16H), 3.43
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(s, 3H), 3.34 (t, JH−H = 4.7 Hz, 2H), 3.29−3.33 (m, 1H), 3.18−2.87
(m, 1H). 13C NMR (75 MHz, CD3OD) δ 169.5, 168.4, 142.0, 136.8,
132.5, 131.1, 130.7, 127.6, 71.6, 71.5, 71.3, 71.1, 70.5, 68.2, 54.9, 53.5,
51.7, 42.1, 41.2. HRMS: C19H30N6O8S + H+ calcd, 503.1919; found,
503.1926; C19H30N6O8S + Na+ calcd, 525.1738; found, 525.1739.
3- and 4-Substituted Methyl-(S)-2-{[(2-{2-[2-(2-Azidoethoxy)-
ethoxy]ethoxy}ethyl)carbamoyl]phenylsulfonamido})-3-{3-[4-(pyri-
midin-2-ylamino)piperidin-1-yl]-5-(trifluoromethyl)benzamido]-
propanoates (16a,b). 3-[4-(Pyrimidin-2-ylamino)piperidin-1-yl]-5-
(trifluoromethyl)benzoic acid (3, 0.38 g, 1.00 mmol) was suspended
in DMF (15 mL) and cooled to 0 °C. N-Methylmorpholine (NMM,
0.20 g, 1.60 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)-
phosphonium hexafluorophosphate (BOP, 0.50 g, 1.10 mmol) were
added, and the mixture was stirred for 10 min at 0 °C. The amino
derivative (15a or 15b, 0.50 g, 0.94 mmol) was added, and the mixture
was stirred at room temperature overnight. After aqueous workup and
chromatographic purification (C-18-RP, MeOH/H2O, 3:2), the pro-
ducts were obtained in 56% (16a, 0.45g, 0.53 mmol) and 96% (16b,
0.77 g, 0.90 mmol) yield, respectively. 16a: 1H NMR (600 MHz,
3- and 4-[(2-{2-[2-(2-Azidoethoxy)ethoxy]ethoxy}ethyl)-
carbamoyl]benzene-1-sulfonyl Chloride (14a,b). The chlorosulfo-
nylbenzoyl chlorides 13a and 13b were treated with 2-{2-[2-(2-
azidoethoxy)ethoxy]ethoxy}ethylamine (0.9 equiv) and triethylamine
(0.9 equiv) in tetrahydrofuran (THF) at −78 °C via addition of
catalytic amounts of dimethylaminopyridine (DMAP). In detail, from
3.00 g (12.5 mmol) of 13a and 2.61 g (11.9 mmol) of the amine in
70 mL of THF containing 1.20 g (11.8 mmol) of triethylamine, the
carboxy-amide 14a was obtained after chromatographic purification
(cyclohexane/diethyl ether 1:1) in a yield of 72% (3.60 g, 8.57 mmol).
From 4.00 g (16.7 mmol) of 13b and 3.30 g (15.0 mmol) of amine in
70 mL of THF containing 1.50 g (15.0 mmol) of triethylamine, the
carboxy-amide 14b was obtained after chromatographic purification
(cyclohexane/diethyl ether 1:1) in a yield of 61% (4.20 g, 10.7 mmol).
14a: 1H NMR (300 MHz, CDCl3) δ 8.30−8.19 (m, 4H), 7.13 (s, 1H,
NH), 3.82−3.58 (m, 14H), 3.35 (t, JH−H = 5.0 Hz, 2H). 13C NMR
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(75 MHz, CDCl3) δ 165.2, 146.1, 140.8, 128.6, 127.2, 70.6, 70.4, 70.2,
69.9, 69.4 (2 signals), 50.6, 40.1. HRMS: C15H21ClN4O6S + H+ calcd,
421.0951; found, 421.0949; C15H21ClN4O6S + Na+ calcd, 443.0770;
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CDCl3) δ 8.26 (d, JH−H= 4.8 Hz, 2H), 7.87−7.78 (m, 4H), 7.47
(s, 1H), 7.36 (t, 3JH−H = 6.0 Hz, 1H, NH), 7.31 (s, 1H), 7.14 (s, 1H),
found, 443.0767. 14b: 1H NMR (300 MHz, CDCl3) δ 8.49 (t, 3JH−H
=
=
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7.09 (t, JH−H = 5.4 Hz, 1H, NH), 6.50 (t, JH−H = 4.8 Hz, 1H), 5.81
3
4
1.8 Hz, 1H), 8.28−8.22 (m, 1H), 8.16 (ddd, JH−H = 8.0 Hz, JH−H
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(d, JH−H = 7.7 Hz, 1H, NH), 4.20 (m, 1H), 4.01−3.94 (m, 1H),
1.8 Hz, 5JH−H = 1.1 Hz, 1H), 7.73 (t, 3JH−H = 7.9 Hz, 1H), 7.28 (s, 1H,
3.83−3.73 (m, 2H), 3.66−3.56 (m, 16H), 3.55 (s, 3H), 3.30 (t, 3JH−H
=
NH), 3.75−3.60 (m, 14H), 3.36 (t, JH−H = 5.0 Hz, 2H). 13C NMR
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4.9 Hz, 2H), 3.02−2.92 (m, 2H), 2.08 (t, JH−H = 8.6 Hz, 2H),
(75 MHz, CDCl3) δ 164.8, 144.5, 136.4, 134.1, 130.1, 129.3, 125.5,
70.6, 70.6, 70.4, 70.2, 69.9, 69.5, 50.6, 40.2. HRMS: C15H21ClN4O6S +
Na+ calcd, 443.0770; found, 443.0767.
1.60−1.52 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 170.1, 167.4,
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165.8, 161.4, 158.0, 151.4, 142.3, 138.4, 135.4, 131.6 (q, JC−F
=
1
32 Hz), 127.9, 127.1, 123.9 (q, JC−F = 273 Hz), 117.6, 114.8, 113.2,
110.5, 70.5, 70.4, 70.1, 69.9, 69.5, 55.7, 53.0, 50.6, 47.7, 47.4, 42.5, 40.0,
31.4. 19F-NMR (564 MHz, CDCl3) δ −62.7. HRMS: C36H45F3N10O9S
+ H+ calcd, 851.3165; found, 851.3166; C36H45F3N10O9S + Na+ calcd,
(S)-Methyl-N-alpha-arylsulfonamide-diaminopropionates
(15a,b). The PEGylated sulfonyl chlorides 14a and 14b were treated
with 9 to yield after deprotection the (S)-methyl-3-amino-2-(4-[(2-{2-[2-
(2-azidoethoxy)ethoxy]ethoxy}ethyl)carbamoyl]phenylsulfonamido)-
propanoates 15a and 15b. In detail, 1 equiv of 9 (0.93 g, 4.26 mmol) and
1.2 equiv of triethylamine (710 μL, 5.11 mmol) were diluted in
methylene chloride and cooled to 0 °C. After addition of 1.1 equiv
of 14a or 14b (1.96 g, 4.69 mmol), respectively, the mixtures were
stirred for 5 h at rt followed by aqueous workup. Purification by
column chromatography (cyclohexane/ethyl acetate 1:1) gave the
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873.2936; found, 873.2964. 16b: H NMR (600 MHz, DMSO-d6)
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δ 8.24 (d, JH−H = 4.7 Hz, 1H, NH), 8.20 (t, JH−H = 1.6 Hz, 1H),
8.02−7.96 (m, 1H), 7.84 (ddd, 3JH−H = 7.8 Hz, 4JH−H = 1.8 Hz, 4JH−H
1.1 Hz, 1H), 7.56 (t, 3JH−H = 7.8 Hz, 1H), 7.50 (s, 1H), 7.35 (s, 1H),
=
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7.28 (s, 1H), 7.09 (d, JH−H = 7.9 Hz, 1H, NH), 6.51 (t, JH−H
=
3
4.8 Hz, 1H), 4.14 (d, JH−H = 7.3 Hz, 1H), 3.96−3.87 (m, 1H), 3.83
3
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(d, JH−H = 13.0 Hz, 2H), 3.56−3.46 (m, 14H), 3.56−3.45 (m, 1H),
Boc-protected derivatives in 93 and 73% yield, respectively. H NMR
3.41 (s, 3H), 3.35−3.32 (m, 1H), 2.99−2.82 (m, 2H), 1.93 (d, 3JH−H
=
(400 MHz, CDCl3) δ 7.98−7.84 (m, 4H), 5.75 (s, 1H, NH), 4.99
10.3 Hz, 2H), 1.55 (dd, JH−H = 11.3 Hz, JH−H = 2.7 Hz, 2H). 13C
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(s, 1H, NH), 4.10−3.92 (m, 1H), 3.78−3.61 (m, 14H), 3.57−3.61
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NMR (151 MHz, DMSO-d6) δ 170.5, 166.2, 165.2, 162.1, 158.4,
(m, 3H), 3.54−3.41 (m, 2H), 3.36 (t, JH−H = 5.0 Hz, 2H), 1.95
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(s, 1H, NH), 1.54−1.34 (m, 9H,). 13C NMR (101 MHz, CDCl3)
δ 170.1, 165.8, 156.1, 142.1, 138.7, 128.0, 127.3, 80.2, 70.7, 70.5, 70.3,
70.0 (2 signals), 69.5, 56.1, 53.0, 50.6, 43.3, 40.0, 28.2. HRMS:
151.4, 141.5, 136.0, 135.5, 131.3, 130.5 (q, JC−F = 32 Hz), 129.6,
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129.3, 125.8, 124.6 (q, JC−F = 272 Hz), 117.6, 113.9, 113.0,
110.4, 70.2, 70.2, 70.1, 70.0, 69.7, 69.2, 55.2, 52.4, 50.4, 47.8,
C24H38N6O10
S
+
Na+ calcd, 625.2262; found, 625.2255;
47.5, 41.8, 36.9, 31.2. 19F-NMR (564 MHz, DMSO-d6) δ −61.6.
C
dx.doi.org/10.1021/jm501197c | J. Med. Chem. XXXX, XXX, XXX−XXX