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Tetraethyl ((4-amino-phenylsulfonylamino)methyl)-1,1-bisphosphonate 19: White solid, 77% yield.
1H NMR (500 MHz, CDCl3):
= 1.26–1.31 (m, 12H, CH3), 4.04–4.12 (m, 1H, PCHP), 4.13–4.20 (m, 8H,
δ
CH2), 5.05 (br, 1H, NH), 6.65 (dl, J = 8.81, 2H, aromatics), 7.65 (dl, J = 8.81, 2H, aromatics). MS (ESI):
m/z: 481[M + Na]+, 459[M + H]+; MS2(469): m/z (%): 156(100), 138(28), 108(50).
3.2.4. General Procedure for the Preparation of N-acylate Derivates
The opportune acyl chloride (1.1–2 mmol) and triethylamine (2 mmol) were added to the solution
of amino derivate (18 and 19) (1 mmol) in anhydrous THF. Stirring of the mixture occurred at room
temperature under inert atmosphere (N2 or Ar) for 3–12 h. After a given time, the mixture was dried
under vacuum and dissolved in EtOAc; the resulting solution was washed with NaHCO3 and then
with HCl 1N, NH4Cl ss, and brine. The organic phase was finally dried over anhydrous Na2SO4,
filtered, and the filtrate was evaporated in vacuo. The residue was purified by chromatography on
silica gel (eluent: CHCl3/MeOH 98: 2 v/v or AcOEt /MeOH 9: 1 v/v) or crystallized with AcOEt to give
the desired product.
Tetraethyl((3-benzamidophenylsulfonylamino)methyl)-1,1-bisphosphonate 6a:
White solid, 64% yield, (AcOEt). 1H NMR (500MHz, [D6] DMSO):
δ
= 1.11–1.88 (m, 12H, CH3),
3.87–4.03 (m, 8H, CH2), 4.11 (t, JHP = 23.00, 1H, PCHP), 7.50–7.61 (m, 5H, aromatics), 7.95–7.97 (m, 3H,
aromatics), 8.30 (s, 1H, aromatic), 8.80 (br, 1H, NH), 10.50 (s, 1H, NH). MS (ESI): m/z: 561[M
MS2: m/z (%): 288(54), 260(37), 134 (100), 106 (34). 563 [M + H]+.
−
H]−;
Tetraethyl((4-benzamidophenylsulfonylamino)methyl)-1,1-bisphosphonate 7a:
1
White solid, 65% yield (chromatography, eluent: CHCl3/MeOH 98: 2 v/v). H NMR (500 MHz, [D6]
DMSO):
δ = 1.13–1.17 (m, 12H, CH3), 3.89–4.05 (m, 8H, CH2), 4.14 (t, JHP = 23.00, 1H, PCHP), 7.52–7.62
(m, 3H, aromatics), 7.78 (d, J = 8.81, 2H, aromatics), 7.90–7.96 (m, 4H, aromatics), 8.63 (br, 1H, NH),
10.53 (s, 1H, NH). MS (ESI): m/z: 585[M + Na]+, 563[M + H]+; MS2(563): m/z (%): 351(22), 282(10),
261(20), 260(100), 196(50), 166(63), 138(74), 110(42).
Tetraethyl((4-(4-methylbenzamido)phenylsulfonylamino)methyl)-1,1-bisphosphonate 8a:
1
White solid, 79% yield (AcOEt). H NMR(500 MHz, CDCl3):
δ = 1.25–1.34 (m, 12H, CH3), 2.43 (s, 3H,
CH3), 4.06–4.20 (m, 8H, CH2), 4.23 (td, JHP = 22.00, J = 9.79, 1H, PCHP), 5.31 (br, 1H, NH), 7.30 (dl,
J = 7.83, 2H, aromatics), 7.78–7.88 (m, 6H, aromatics), 8.15 (bs, 1H, NH). MS (ESI): m/z: 599 [M + Na]+,
577[M + H]+; MS2(577): m/z (%): 393(18), 365(23), 291(21), 275(26), 274(100), 166(87), 138(74), 138(58),
119 (96), 110 (36). 575[M − H]−; MS2: m/z (%): 437(25), 302(16), 210(32), 134(100).
Tetraethyl((4-(4-bromobenzamido)phenylsulfonylamino)methyl)-1,1-bisphosphonate 9a:
1
White solid, 55% yield (AcOEt). H NMR(500 MHz, CDCl3):
δ = 1.14–1.18 (m, 12H, CH3), 3.94–4.04
(m, 8H, CH2), 4.14 (t, JHP = 23.00, 1H, PCHP), 7.74 (d, J = 8.32, 2H, aromatics), 7.79 (d, J = 8.81, 2H,
aromatics), 7.80–7.92 (m, 4H, aromatics), 8.55 (br, 1H, NH), 10.54 (s, 1H, NH). MS (ESI): m/z: 643[M + 2
+ H]+, 641[M + H]+; MS2(641): m/z (%): 458(18), 431(18), 340(59), 338(53), 276 (11), 274(15), 185(24),
183(32), 166(100), 138(82), 110(39).
Tetraethyl((4-(3-bromobenzamido)phenylsulfonylamino)methyl)-1,1-bisphosphonate 10a:
White solid, 73% yield (AcOEt). 1H NMR(500 MHz, [D6] DMSO):
δ = 1.13–1.96 (m, 12H, CH3),
3.97–4.05 (m, 8H, CH2), 4.14 (t, JHP = 23.00, 1H, PCHP), 7.51 (t, J = 8.08, 1H, aromatic), 7.80–7.82 (m, 3H,
aromatics), 7.89–7.96 (m, 3H, aromatics), 8.14 (t, J = 1.96, 1H, aromatic), 8.63 (br, 1H, NH), 10.62 (s, 1H,
NH). MS (ESI): m/z: 643[M + 2 + H]+, 641 [M + H]+; MS2: m/z (%): 459(12), 430(12), 340(70), 338(43),
276(20), 274(18), 185(18), 183 (42), 166(88), 138(100).
Tetraethyl((4-(4-nitrobenzamido)phenylsulfonylamino)methyl)-1,1-bisphosphonate 11a:
1
White solid, 57% yield (AcOEt). H NMR(500 MHz, [D6] DMSO):
δ
= 1.15–1.17 (m, 12H, CH3), 3.90–4.05
(m, 8H, CH2), 4.14 (t, JHP = 23.00, 1H, PCHP), 7.81 (d, J = 8.56, 2H, aromatics), 7.92 (d, J = 8.56, 2H,
aromatics), 8.17–8.20 (m, 2H, aromatics), 8.36–8.39 (m, 2H, aromatics), 8.66 (br, 1H, NH), 10.85 (s, 1H,