3.1.2. Synthesis
tert-Butyl-2-amino-5-(3-chloropropoxy)benzoate (2)
To a vigorously stirred flask containing
tert-butyl-5-(3-chloropropoxy)-2-nitrobenzoate [
32]
1 (5.17 g, 16.4 mmol) in ethanol (100 mL), was added 10% wt palladium on carbon (0.17 g). The reaction mixture was flushed with hydrogen (3×) and then stirred under an atmosphere of hydrogen for 15 h. The reaction mixture was filtered through Celite, the Celite thoroughly rinsed with methanol and the combined organics concentrated
in vacuo. The residue was taken up in diethyl ether (150 mL) and washed with water and brine, then dried (MgSO
4) and concentrated to afford the title compound as an oil (4.18 g, 89%). This compound was used in subsequent transformations without further purification. δ
H (CDCl
3) 1.62 (s, 9H), 2.25 (m, 2H), 3.75 (t,
J = 6.2 Hz, 2H), 4.15 (t,
J = 6.0 Hz, 2H), 7.17 (dd,
J = 3.0, 8.8 Hz, 1H), 7.52 (d,
J = 3.0 Hz, 1H), 7.90 (d,
J = 8.8 Hz, 1H); δ
C (CDCl
3) 28.1, 31.9, 41.1, 64.9, 84.5, 117.3, 119.9, 123.8, 125.7, 127.0, 158.0, 166.0;
m/z (EI
+):
m/z (%): 285.1 (30) [M]
+, 229.0 (100) [M − C
4H
9]
+.
tert-Butyl-2-(6-bromohexanamido)-5-(3-chloropropoxy)benzoate (3)
6-Bromohexanoyl chloride (2.1 mL, 14 mmol) was added dropwise to the aniline 2 (3.72 mg, 13.0 mmol) and triethylamine (2.7 mL, 19 mmol) dissolved in dry DCM (70 mL). The reaction mixture was stirred at RT for 20 h and then poured into 2 M HCl (50 mL). The layers were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated sodium bicarbonate and brine, then dried (MgSO4) and concentrated in vacuo to afford the amide 3 as an oil (6.02 g, quant.); δH (CDCl3) 1.49–1.99 (complex, 6H), 1.61 (s, 9H), 2.23 (m, 2H), 2.44 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 6.8 Hz, 2H), 3.75 (t, J = 6.2 Hz, 2H), 4.11 (t, J = 6.0 Hz, 2H), 7.08 (dd, J = 3.0, 9.2 Hz, 1H), 7.47 (d, J = 3.0 Hz, 1H), 8.62 (d, J = 9.2 Hz, 1H), 10.93 (br s, 1H). δC (CDCl3) 24.6, 27.7, 28.2, 32.2, 32.5, 33.5, 38.2, 41.4, 64.7, 82.6, 116.3, 117.7, 120.2, 121.8, 135.4, 153.3, 167.3, 171.3; m/z (ESI+, 50 eV): m/z (%): 486.0 (100) [M + Na]+, 484.0 (70), 464 [M + H]+, 462.0 (20).
tert-Butyl-2-(6-azidohexanamido)-5-(3-azidopropoxy)benzoate (4)
The diazide
4 was prepared from the dihalide
3 (5.92 g, 12.8 mmol) by treatment with trimethylsilylazide (95% purity, 5.4 mL, 39 mmol) and tetra-
n-butylammonium fluoride (1.0 M in THF, 38.4 mL, 38.4 mmol) in THF following the method of Takaya [
35]. Care was taken to ensure the diazide was not subjected to shock or heat. The diazide
4 was obtained as a light brown oil which was purified by flash chromatography (20: 1 DCM/MeOH) to afford a cream-colored solid (4.09 g, 74%). δ
H (CDCl
3) 1.40–1.85 (complex, 6H), 1.59 (s, 9H), 2.02 (m, 2H), 2.42 (t,
J = 7.2 Hz, 2H), 3.26 (t,
J = 6.6 Hz, 2H), 3.50 (t,
J = 6.6 Hz, 2H), 4.02 (t,
J = 5.8 Hz, 2H), 7.05 (dd,
J = 3.2, 9.2 Hz, 1H), 7.44 (d,
J = 3.2 Hz, 1H), 8.60 (d,
J = 9.2 Hz, 1H), 10.92 (br s, 1H); δ
C (CDCl
3) 25.0, 26.3, 28.1, 28.6, 28.7, 38.2, 48.1, 51.2, 64.9, 82.6, 116.2, 117.6, 120.2, 121.8, 135.4, 153.2, 167.2, 171.3;
m/z (ESI
+, 50 eV):
m/z (%): 454.6 (15) [M + Na]
+, 432.7 (100) [M + H]
+.
2-(6-Azidohexanamido)-5-(3-azidopropoxy)benzoic acid (5)
To a solution of 4 (1.31 g, 3.05 mmol) in dry DCM (10 mL) was added TFA (10 mL) dropwise. After stirring the reaction mixture at RT for 4 h it was poured into water (20 mL) and extracted with DCM (2 × 10 mL). The organic phase was dried, and concentrated in vacuo to yield the title compound as a solid (1.14 g, 99%). δH (CDCl3) 1.43–1.87 (complex, 6H), 2.05 (m, 2H), 2.48 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 6.6 Hz, 2H), 3.52 (t, J = 6.4 Hz, 2H), 4.06 (t, J = 5.8 Hz, 2H), 7.16 (dd, J = 3.0, 9.2 Hz, 1H), 7.61 (d, J = 3.0 Hz, 1H), 8.64 (d, J = 9.2 Hz, 1H), 10.86 (br s, 1H); δC (CDCl3) 25.1, 26.2, 28.5, 28.7, 38.1, 48.1, 51.2, 65.0, 116.0, 116.6, 121.6, 122.1, 172.2, 135.3, 153.7, 170.9; m/z (ESI+, 50 eV): m/z (%): 398.6 (100) [M + Na]+, 376.5 (70) [M + H]+.
6-Azido-N-(4-(3-azidopropoxy)-2-(4-benzhydrylpiperazine-1-carbonyl)phenyl)hexanamide (6a)
The title compound was prepared following an amidation procedure used by Marquez and Shpiro [
36]. To a solution of the diazide
5 (120 mg, 0.33 mmol) in anhydrous THF and DMF (1:1, 3.2 mL) was added DCC (100 mg, 0.49 mmol). After the reaction mixture was stirred at RT for 15 min, HOBt (70 mg, 0.49 mmol) and 4-DMAP (8 mg, 0.06 mmol) were added. After 1.5 h, 1-benzhydrylpiperazine (170 mg, 0.65 mmol) and DIPEA (0.17 mL, 0.98 mmol) were sequentially added. After stirring at RT for 24 h, the mixture was filtered, the precipitate washed with DCM and solvent was removed
in vacuo. Purification by flash chromatography (3:1 PET spirit 40–60/ethyl acetate) gave the title compound
6a as a solid (130 mg, 66%); δ
H (CDCl
3) 1.40–1.80 (complex, 6H), 2.01 (m, 2H), 2.32 (t,
J = 7.2 Hz, 2H), 2.40 (br s, 4H), 3.30 (t,
J = 6.6 Hz, 2H), 3.48 (t,
J = 6.6 Hz, 2H), 3.71 (br s, 4H), 3.98 (t,
J = 6.0 Hz, 2H), 4.26 (s, 1H), 6.70 (d,
J = 2.8 Hz, 1H), 6.89 (dd,
J = 3.0, 9.0 Hz, 1H), 7.15–7.43 (m, 10H), 8.01 (d,
J = 8.0 Hz, 1H), 8.49 (br s, 1H); δ
C (CDCl
3) 25.1, 26.3, 28.6, 28.7, 37.3, 48.1, 51.2, 51.9 (br), 52.1 (br), 65.0, 75.9, 113.4, 116.0, 125.0, 126.5, 127.2, 127.8, 128.6, 129.6, 141.9, 154.4, 168.3, 171.1;
m/z (ESI
+, 50 eV):
m/z (%): 632.3 (10) [M + Na]
+, 610.3 (50) [M + H]
+.
6-Azido-N-(4-(3-azidopropoxy)-2-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)phenyl)hexanamide (6b)
The title compound 6b was prepared from 5 and 1-(bis(4-fluorophenyl)methyl)piperazine according to the procedure used to prepare 6a, except that the reaction mixture was stirred at RT for 56 h. Purification by flash chromatography (2:1 PET spirit 40–60/ethyl acetate) gave 6b (140 mg, 85%). δH (CDCl3) 1.39–1.79 (m, 6H), 2.01 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.36 (br s, 4H), 3.29 (t, J = 6.8 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.73 (br s, 4H), 3.98 (t, J = 6.0 Hz, 2H), 4.24 (s, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.89 (dd, J = 2.8, 9.0 Hz, 1H), 6.92–7.02 (m, 4H), 7.29–7.36 (m, 4H,), 7.95 (d, J = 9.0 Hz, 1H), 8.50 (br s, 1H); δC (CDCl3) 25.1, 26.3, 28.6, 28.7, 37.2, 48.1, 51.2, 51.7 (br), 65.0, 74.2, 113.4, 115.6 (d, J = 21.6 Hz), 116.0, 125.3, 126.8, 129.1, 129.2 (d, J = 7.9 Hz), 137.4 (d, J = 3.0 Hz), 154.5, 161.9 (d, J = 246.5 Hz), 168.4, 171.2; m/z (ESI+, 50 eV): m/z (%): 668.3 (10) [M + Na]+, 646.3 (35) [M + H]+.
6-Azido-N-(4-(3-azidopropoxy)-2-(4-phenylpiperidine-1-carbonyl)phenyl)hexanamide (6c)
The title compound 6c was prepared from 5 and 4-phenylpiperidine according to the procedure used to prepare 6a. Purification by flash chromatography (1:1 PET spirit 40–60/ethyl acetate) gave 6c (190 mg, 93%); δH (CDCl3) 1.37–2.00 (methylene envelope, 10H), 2.02 (m, 2H), 2.32 (t, J = 6.0 Hz, 2H), 2.78 (m, 1H), 3.00 (br s, 2H), 3.25 (t, J = 6.0 Hz, 2H), 3.49 (t, J = 6.0 Hz, 2H), 4.01 (t, J = 6.0 Hz, 2H), 4.80 (br s, 2H), 6.76 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 2.0, 6.0 Hz, 1H), 7.17–7.32 (m, 5H), 7.90 (d, J = 8.0 Hz, 1H), 8.63 (s, 1H); δC (CDCl3) 24.8, 25.0, 26.2, 28.5, 28.6, 33.3 (br), 33.8, 37.0, 42.3, 48.0, 51.1, 64.9, 113.0, 115.8, 125.4, 126.5, 127.6, 128.5, 129.1, 144.6, 154.6, 168.4, 171.1; m/z (ESI+, 50 eV): m/z (%): 541.3 (100) [M + Na]+, 519.3 (20) [M + H]+.
6-Azido-N-(4-(3-azidopropoxy)-2-(4-((3a,7a-dihydrobenzo[d][1,3]dioxol-5-yl)methyl)piperazine-1-carbonyl)phenyl)hexanamide (6d)
The title compound 6d was prepared from 5 and 1-piperonylpiperazine according to the procedure used to prepare 5. Purification by flash chromatography (5:1 PET spirit 40–60/ethyl acetate) gave 6d (200 mg, 54%); δH (400 MHz, CDCl3) 1.43 (m, 2H), 1.59–1.74 (methylene envelope, 4H), 2.02 (m, 2H), 2.30 (t, J= 7.6 Hz, 2H), 2.41 (br s, 2H), 2.47 (br s, 2H), 3.27 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.49 (t, J = 6.8Hz, 2H), 3.75 (br s, 4H), 4.00 (t, J = 6.0 Hz, 2H), 5.92 (s, 2H), 6.70–6.72 (m, 3H), 6.83 (s, 1H), 6.89 (dd, J = 2.8, 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 8.52 (s, 1H); δC (100 MHz, CDCl3) 25.1, 26.3, 28.6, 28.7, 37.2, 48.1, 51.2, 52.6 (br), 53.0 (br), 62.4, 65.0, 101.0, 108.0, 109.4, 113.3, 116.1, 122.3, 125.4, 127.0, 129.4, 130.9, 146.9, 147.8, 154.6, 168.4, 171.2; HRMS (ES+) [M + H]+ calcd for C28H36N9O5 578.2839 found 578.2829.
6-Amino-N-(4-(3-aminopropoxy)-2-(4-benzhydrylpiperazine-1-carbonyl)phenyl)hexanamide (7a)
A solution of 6a (140 mg, 0.22 mmol) in methanol (4.5 mL) was treated sequentially with dithiothreitol (20 mg, 1.3 mmol) and TEA (0.1 mL, 0.9 mmol). After the reaction mixture was stirred at room temperature for 20 h, the solvent was removed in vacuo. Purification by reverse phase chromatography [elution with methanol/water (90:10, 60 mL), followed by methanol (75 mL) and then acetonitrile (30 mL)] gave 7a (60 mg, 52%); δH (methanol-d4) 1.35–1.60 (complex, 4H), 1.69 (m, 2H), 1.91 (m, 2H), 2.33 (complex, 4H), 2.45 (m, 2H), 2.67 (br t, J = 6.8 Hz, 2H), 2.82 (br t, J = 6.9 Hz, 2H), 3.38 (br s, 2H), 3.71 (br s, 2H), 4.04 (br t, J = 6.2 Hz, 2H), 4.30 (s, 1H), 6.82 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 2.8, 8.8 Hz, 1H), 7.18–7.29 (m, 7H,), 7.43 (d, J = 6.9 Hz, 4H); δC (methanol-d4) 26.8, 27.6, 33.2, 33.3, 37.2, 39.6, 42.3, 43.2, 49.9, 52.6, 53.1, 67.5, 77.2, 114.1, 117.2, 128.3, 129.0, 129.1, 129.7, 133.9, 143.7, 158.3, 170.0, 171.2; m/z (ESI+, 50 eV): m/z (%): 558.3 (100) [M + H]+, 570.3 (30) [M + Na]+. HRMS (ESI+) [M + H]+ calcd for C33H44N5O3 558.3444 found 558.3460.
6-Amino-N-(4-(3-aminopropoxy)-2-(4-(bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)phenyl)hexanamide (7b)
The diamine 7b was prepared from 6b according to the procedure used to prepare 7a. The product was isolated as an oil (90 mg, 75%). δH (methanol-d4) 1.36–1.75 (methylene envelope, 6H), 1.91 (m, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.42 (br s, 4H), 2.66 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 3.38 (br s, 2H), 3.70 (br s, 2H), 4.03 (t, J = 6.0 Hz, 2H), 4.35 (s, 1H), 6.81 (d, J = 2.6 Hz, 1H), 6.94–7.05 (m, 5H), 7.26 (d, J = 8.8 Hz, 1H), 7.38–7.45 (m, 4H); δC (methanol-d4) 26.7, 27.5, 32.9, 33.0, 37.1, 39.5, 42.1, 43.1, 52.4, 52.7, 67.5, 75.2, 114.1, 116.3 (d, J = 21.5 Hz), 117.0, 129.0, 130.7 (d, J = 7.9 Hz), 133.7, 139.4 (d, J = 3.1 Hz), 158.2, 163.3 (d, J = 244.3 Hz), 169.9, 175.0; m/z (ESI+, 50 eV): m/z (%): 594.3 (100) [M + H]+. HRMS (ESI+) [M + H]+ calcd for C33H42N5O3F2 (M + H)+ 594.3256 found 594.3259.
6-Amino-N-(4-(3-aminopropoxy)-2-(4-phenylpiperidine-1-carbonyl)phenyl)hexanamide (7c)
The diamine 7c was prepared from 6c according to the procedure used to prepare 7a. Purification by reverse phase chromatography [elution with methanol/water (80:20)] gave 7c as an oil (120 mg, 99%); δH (400 MHz, methanol-d4) 1.39–1.60 (methylene envelope, 4H), 1.72 (m, 4H), 1.95 (m, 2H), 2.37 (m, 2H), 2.68 (m, 2H), 2.80–2.91 (complex, 5H), 3.17 (br s, 2), 3.76 (br d, J = 13.2 Hz, 1H), 4.07 (t, J = 6.0 Hz, 2H), 4.74 (d, J = 12.0 Hz, 1H), 6.90 (s, 1H), 7.01 (dd, J = 2.4, 8.4 Hz, 1H),7.18–7.43 (m, 6H); δC (methanol-d4) 25.3, 26.1, 31.1, 31.4, 32.7, 33.3, 35.7, 38.1, 40.6, 42.2, 66.1, 112.5, 115.5, 126.1, 126.4, 126.8, 127.7, 128.2, 132.8, 145.3, 156.9, 168.5, 173.6; m/z (ESI+, 50 eV): m/z (%): 467.3 (100) [M + H]+, 489.3 (55) [M + Na]+.
6-Amino-N-(4-(3-aminopropoxy)-2-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazine-1-carbonyl)phenyl)hexanamide (7d)
The diamine 7d was prepared from 6d according to the procedure used to prepare 7a. The product was isolated as an oil (90 mg, 61%); δH (methanol-d4) 1.37–1.76 (methylene envelope, 6H), 1.94 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.39 (br s, 2H), 2.50 (br s, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 3.36 (br s, 2H), 3.47 (s, 2H), 3.70 (br s, 2H), 4.06 (t, J = 6.0 Hz, 2H), 5.91 (s, 2H), 6.75 (br s, 2H), 6.82 (br s, 2H), 7.00 (dd, J = 2.8, 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H); δC (methanol-d4) 25.3, 26.1, 31.2, 31.5, 35.7, 38.1, 40.6, 41.4, 52.0, 52.3, 62.0, 66.1, 100.9, 107.4, 109.2, 112.6, 115.7, 122.4, 126.8, 127.7, 130.8, 132.4, 147.0, 147.8, 156.9, 168.5, 173.7; m/z (ESI+, 50 eV): m/z (%): 526.4 (20) [M + Na]+, 477.3 (30) [M + H]+. HRMS (ES+) [M + H]+ calcd for C28H39N5O5 526.3029 found 526.3018.
N-2(4-Benzhydrylpiperazine-1-carbonyl)-4-(3-guanidinopropoxy)phenyl-6-guanidinohexanamide dihydrochloride (8a)
The diguanidinium compound
8a was prepared following the general procedure of Bernatowitcz
et al. [
21]. To the amine
7a (50 mg, 0.09 mmol) in DMF (0.2 mL) was added 1
H-pyrazole-carboxamidine hydrochloride (30 mg, 0.17 mmol) and DIPEA (0.03 mL, 0.17 mmol) and the reaction mixture was stirred at RT for 68 h. The solvent was then removed
in vacuo and the residue triturated with diethyl ether to give a solid that was recrystallized from ether/methanol to afford
8a as a glassy semisolid (45 mg, 74%); δ
H (methanol-
d4) 1.49 (m, 2H), 1.67 (m, 4H), 2.04 (m, 2H), 2.32–2.46 (complex, 6H), 3.18-3.42 (methylene envelope, 6H), 3.71 (br s, 2H), 4.07 (t,
J = 5.6 Hz, 2H), 4.32 (s, 1H), 6.86 (d,
J = 2.6 Hz, 1H), 7.02 (dd,
J = 2.8, 8.8 Hz, 1H), 7.11–7.33 (m, 8H), 7.43 (br d,
J = 7.0 Hz, 3H); δ
C (methanol-
d4) 26.4, 27.2, 29.6, 36.9, 39.6, 42.4, 43.2, 52.6, 53.0, 66.6, 77.2, 114.3, 117.2, 121.4, 128.3, 128.5, 129.0, 129.7, 133.9, 143.7, 158.1, 158.7, 158.8, 170.0, 175.0;
m/z (ESI
+, 50 eV):
m/z (%): 642.5 (100) [M + H]
+. HRMS (ESI
+) [M + H]
+ calcd for C
35H
48N
9O
3 642.3880 found 642.3885.
N-2-(4-(Bis(4-fluorophenyl)methyl)piperazine-1-carbonyl)-(4-(3-guanidinopropoxy)phenyl)guanidinohexanamide dihydrochloride (8b)
The diguanidinium compound 8b was prepared from the diamine 7b according to the method used to prepare 8a. The product 8b was obtained as a semiglassy solid (90 mg, 84%); δH (methanol-d4) 1.40–1.55 (methylene envelope, 2H) 1.55–1.80 (methylene envelope, 4H), 2.04 (t, J = 6.0 Hz, 2H), 2.25–2.45 (methylene envelope, 6H), 3.20 (t, J = 6.0 Hz, 2H), 3.30–3.42 (methylene envelope, 6H), 3.70 (br s, 2H), 4.06 (t, J = 6.0 Hz, 2H), 4.38 (br s, 1H), 6.86 (d, J = 4.0 Hz, 1H), 7.01 (m, 5H), 7.26 (d, J = 10.0 Hz, 1H), 7.39–7.46 (m, 5H); δC (methanol-d4) 25.0, 25.8, 28.2, 35.5, 38.1, 40.9, 41.8, 51.0, 51.3, 65.2, 73.7, 113.0, 114.9 (d, J = 21.6 Hz), 115.8, 127.0, 127.6, 129.3 (d, J = 8.0 Hz), 132.4, 137.9 (d, J = 3.0 Hz), 156.6, 157.2, 157.4, 161.9 (d, J = 244.5 Hz), 168.5, 173.6; m/z (ESI+, 50 eV): m/z (%): 714.4 (10) [M + HCl]+, 678.4 (50) [M + H]+. HRMS (ESI+) [M + 2H + Cl]+ calcd for C35H47N9O3F2Cl 714.3458 found 714.3462; HRMS (ESI+) [M + H]+ calcd for C35H46N9O3F2 678.3692 found 678.3685.
6-Guanidino-N-(4-(3-guanidinopropoxy)-2-(4-phenylpiperidine-1-carbonyl)phenyl)hexanamide dihydrochloride (8c)
The diguanidinium compound 8c was prepared from the diamine 7c according to the method used to prepare 8a. The product 8c was obtained as a semiglassy solid (45 mg, 56%); δH (methanol-d4) 1.47 (m, 2H), 1.62 (m, 2H), 1.73 (methylene envelope, 4H), 1.96 (m, 1H), 2.07 (m, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.83–2.91 (complex, 2H), 3.19 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 3.49 (m, 1H), 3.75 (br d, J=12.8 Hz, 1H), 4.11 (t, J = 5.6 Hz, 2H), 4.73 (br d, J = 11.6 Hz, 1H), 6.94 (s, 1H), 7.05 (dd, J = 2.8, 8.8 Hz, 1H), 7.16–7.33 (complex, 6H); δC (methanol-d4) 26.3, 27.1, 29.54, 29.58, 33.9, 34.6, 36.7, 39.4, 42.2, 43.5, 66.4, 114.0, 116.9, 127.4, 127.7, 128.3, 129.0, 129.4, 134.1, 146.6, 158.0, 158.5, 158.6, 169.8, 174.9; m/z (ESI+, 50 eV): m/z (%): 551.5 (30) [M + H]+ HRMS (ES+) [M + H]+ calcd for C29H43N8O3 551.3458 found 551.3431.
N-(2-(4-(Benzo[d][1,3]dioxol-5-yl)methyl)piperazine-1-carbonyl)-4-(3-guanidinopropoxy)phenyl-6-guanidinohexanamide dihydrochloride (8d)
The diguanidinium compound 8d was prepared from the diamine 7d according to the method used to prepare 8a. The product 8d was obtained as a glassy semisolid (50 mg, 93%); δH (methanol-d4) 1.40–1.55 (methylene envelope, 2H), 1.55–1.74 (methylene envelope, 4H), 2.06 (m, 2H), 2.35 (t, J = 7.2 Hz, 2H), 2.43 (br s, 2H), 2.53 (br s, 2H), 3.17–3.26 (br t, J = 6.7 Hz, 2H), 3.34–3.43 (complex, 4H), 3.50 (s, 2H), 3.71 (br s, 2H), 4.08 (m, 2H), 5.92 (s, 2H), 6.76 (br s, 2H), 6.86 (br s, 1H), 6.88 (d, J = 2.7 Hz, 1H), 7.04 (dd, J = 2.6, 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H); δC (methanol-d4) 26.4, 27.2, 29.6, 36.9, 39.6, 42.4, 53.2, 53.4, 63.1, 66.6, 102.5, 109.0, 110.9, 114.3, 117.3, 124.3, 128.5, 129.0, 131.0, 133.6, 148.7, 149.3, 158.1, 170.0, 174.9; m/z (ESI+, 50 eV): m/z (%): 610.5 (20) [M + H]+. HRMS (ES+) [M + H]+ calcd for C30H44N9O5 610.34 65 found 610.3474.