CONVENIENT SYNTHESIS OF AMINODIPHOSPHONIC ACID DERIVATIVES
821
2
Hz, 2H, CH2), 5.02 (d, JHP = 16.0 Hz, 1H, CH), 8.16–9.06 (m, 4H, CHarom). 13C NMR
(D2O, 50 MHz): δ 47.7 (dd, 1JCP = 127.0 Hz, 3JCP = 4.9 Hz, CH2), 64.1 (dd, 1JCP = 121.7
3
2
3
Hz, JCP = 5.9 Hz CH), 127.0 (CHarom), 132.7(d, JCP = 3,4 Hz, Cqarom), 140.3 (d, JCP
= 3.9 Hz, CHarom), 150.8 (CHarom), 151.4 (d, 3JCP = 5,2 Hz, CHarom). 31P NMR (D2O, 80
MHz): δ 6.40, 6.51. Anal. Calcd for C7H13ClN2O6P2 . H2O: C, 23.71; H, 4.83%. Found:
C, 24.11; H, 4.86%.
{[(Furan-2-yl)(phosphono)methyl]amino}methylphosphonic Acid (1d).
The residue was dissolved in MeOH (5 mL), and toluene (50 mL) was added. Then
the solvent was evaporated, and the residue was co-evaporated with toluene (50 mL). The
residue was dissolved in MeCN (70 mL), and NaI (10.50 g, 70 mmol) was added. The mix-
ture was stirred and cooled to 0–5◦C and under nitrogen, and chlorotrimethylsilane (7.60
g, 70 mmol) was added over a period of 5 min. Stirring was continued for 24 h at rt. The
mixture was filtered, then the filtrate was treated with MeOH (20 mL) and evaporated. The
residue was dissolved in water and extracted with CH2Cl2 (3 × 50 mL). The water phase
was evaporated, and the residue was dissolved in cold (–20◦C) conc. HCl (aq) solution
(22 mL) and left at this temperature for 1 h. The precipitate of NaCl was filtrated off, and
hydrochloric acid was evaporated under reduced pressure (0.5 mm Hg). The residue was
washed with acetone (5 mL) then dissolved in water (50 mL). Activated carbon was added,
and the mixture was stirred at rt for 1 h. The mixture was filtered, and the filtrate was
evaporated to give the product as a white solid. 1H NMR (D2O, 80 MHz): δ 3.26 (d, 2JHP
= 12.8 Hz, 2H, CH2), 4.88 (d, 2JHP = 17.1 Hz, 1H, CH), 6.57–7.71 (m, 3H, CHarom). 13
C
NMR (D2O, 50 MHz): δ 44.7 (dd, 1JCP = 138.7 Hz, 3JCP = 5.0 Hz, CH2), 56.9 (dd, 1JCP
= 139.1 Hz, 3JCP = 5.8 Hz CH), 113.7 (CHarom), 116.5 (d, 3JCP = 5.1 Hz, CHarom), 145.6
(d, 3JCP = 5.0 Hz, Cqarom), 147.6 (CHarom). 31P NMR (D2O, 80 MHz): δ 5.87, 8.66. Anal.
Calcd for C6H11NO7P2: C, 26.58; H, 4.09%. Found: C, 26.45; H, 3.96%.
2-{[(3-Chlorophenyl)(phosphono)methyl]amino}ethylphosphonic Acid
(1e). The residue was treated in the same way as in the case of 1b. After evaporation
of hydrochloric acid, the residue was crystallized from water/acetone (1:5) to give the
product as colorless crystals. 1H NMR (D2O/NaOD, 250 MHz): δ 1.69–1.93 (m, 2H, CH2),
2
3.02–3.16 (m, 2H, CH2), 4.23 (d, JHP = 15.8 Hz, 1H, CH), 7.28–7.46 (m, 4H, CHarom).
13C NMR (D2O/NaOD, 20 MHz): δ 26.9 (d, 1JCP = 125.1 Hz, C-1), 45.9 (dd, 2JCP = 6.1
3
1
Hz, JCP = 2.5 Hz, C-2), 63.2(d, JCP = 125.1 Hz, 122.7, CH), 128.9 (d, JCP = 4.3 Hz,
CHarom), 130.1 (d, JCP = 1.8 Hz, CHarom), 130.4 (d, JCP = 4.9 Hz, CHarom), 132.0 (d, JCP
=
1.2 Hz, CHarom), 135.5 (d, JCP = 1.8 Hz, Cqarom), 137.4 (d, JCP = 4.3 Hz, Cqarom). 31P
.
NMR (D2O/NaOD, 101 MHz): δ 8.91, 19.09. Anal. Calcd for C9H14ClNO6P2 H2O: C,
31.10; H, 4.64%. Found: C, 30.55; H, 4.42%.
2-[(3-Hydroxy-3,3-bisphosphonopropylamino)phosphonomethyl]benzoic
Acid (1f). The residue was treated with water solution of NaOH (1 mol/L, 60 mL)
and evaporated. The residue was dissolved in conc. HCl (aq) solution (50 mL) and
refluxed for 2 h. After evaporation of hydrochloric acid, the residue was crystallized from
1
water/acetone (1:2) to give the product as colorless crystals. H NMR (D2O/NaOD, 250
2
MHz): δ 2.13–2.43 (m, 2H, CH2), 3.85–4.17 (m, 2H, CH2), 4.90 (d, JHP = 17.0 Hz,
1H, CH), 7.33–7.71 (m, 4H, CHarom). 13C NMR (D2O/NaOD, 63 MHz): δ 29.5 (CH2)
36.2 (CH2), 58.7 (d, 1JCP = 139.0 Hz, CH), 70.6 (t, 1JCP = 140.3 Hz, C[PO3H2]2), 121.0
(CHarom), 122.2 (CHarom), 126.4 (CHarom), 128.9 (Cqarom), 130.3 (CHarom), 139.9 (Cqarom),
169.2 (COOH). 31P NMR (D2O/NaOD, 101 MHz): δ 11.70 (s, 1P), 18.66 (s, 2P). Anal.
Calcd for C11H18NO12P3: C, 29.41; H, 4.04%. Found: C, 29.28; H, 4.01%.