SYNTHESIS OF TETRAETHYL (2-BENZYL-3-OXOISOINDOLYL-1,1-DIYL)BISPHOSPHONATE
1109
decanted from the residual sodium, and thereto was
added dropwise 2.9 ml (0.02 mol) of o-phthaloyl
dichloride with the stirring and cooling to –40°С. The
stirring was continued for 1–2 h, after which the reac-
tion mixture was heated to room temperature and then
was refluxed for 1–2 h to complete the reaction. Then
a small amount of hexane was added to the mixture for
sodium chloride coagulation. Sodium chloride was
filtered off, and the residue was washed twice with
ethyl acetate. The filtrate was evaporated under re-
duced pressure, the residue was crystallized from ethyl
acetate–hexane mixture (1:2) and dried in a vacuum.
Yield 3.20 g (40%). Bisphosphonate I was purified by
sublimation in a vacuum at 0.1 mm Hg at 100–120°C,
mp 90–91°C. IR spectrum (ССl4), ν, cm–1: 2988.57,
1781.74, 1262.43, 1022.40. 1Н NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.08 t (6Н, СН3, JPH 7), 1.27 t
(6Н, СН3, JPH 7), 3.91 m (2Н, ОСН2), 4,02 m (2Н,
ОСН2), 4.26 m (4Н, ОСН2), 7.55 d.d (1Н, Н5, JНH 6,
and dried by azeotropic distilling off water. The
residue was crystallized from ethyl acetate and dried.
Yield 0.12 g (82.9%), mp > 260°C. 1Н NMR spectrum
[(CD3)2SO], δ, ppm (J, Hz ): 7.57 d.d (1Н, Н5, JHH 7),
7.75 d.d (1Н, JHH 6), 7.80 d (2Н, H4, H7, JHH 7). 31Р
NMR spectrum (CDCl3): δР 8.02 ppm [7].
Tetraethyl (2-benzyl-3-oxoisoindolyl-1,1-diyl)bis-
phosphonate (IV). A mixture of 1.2 g (0.003 mol) of
bisphosphonate I, 0.4 ml (0.0035 mol) of benzylamine,
and 0.4 ml (0.004 mol) of triethylamine in 12 ml of
toluene was boiled with simultaneous water removal
for 3–4 h. The reaction mixture was evaporated, and
the residue was crystallized from anhydrous diethyl
ether. Yield 0.6 g (41.0%), mp 170–172°С. IR spec-
trum (KBr), ν, cm–1: 2984.27, 1764.34, 1259.33,
1232.87, 1064.61. 1Н NMR spectrum (CDCl3), δ, ppm
(J, Hz ): 0.87 t (JНH 7), 1.06 t (JНH 7), 1.14 t (JНH 7)
(intensities ratio 2:2:3) (12Н, CH3), 3.50 m (2Н,
ОСН2), 3.69 m (2Н, ОСН2), 3.95 m (2Н, ОСН2), 4.06
m, 4.08, 4.11 (intensities ratio 3:2:2, 2Н, СН2О), 7.31
m (3Н, С6Н5N), 7.47 d.d (1Н, JНH 6, JНH 7), 7.50 m
(2Н, С6Н5N), 7.62 d.d (1Н, Н6, JНH 6, JНH 7), 7.83 d
(1Н, H7, JPH 7), 7.86 d (1Н, Н4, JHH 6). 13C NMR
spectrum (CDCl3), δC, ppm (J, Hz ): 16.3 (CH3), 16.6
(CH3), 43.2 (CH2N), 62.8 (OCH2, J 7), 64.6 d (OCH2,
J 7), 86.1 d.d (CP2, J 147, J 150), 125.14, 128.3,
128.67, 128.76, 129.2, 133.8, 134.14 (CAr), 170.58
(C=O). 31Р NMR spectrum (CDCl3): δР 6.36 ppm.
Found P, %: 12.45. C23H31NO7P2. Calculated P, %:
12.50.
J
НH 8,), 7.69 d.d (1Н, Н6, JНH 6, JНH 8), 7.88 d (2Н, Н4,
Н7, JНH 6). 13C NMR spectrum (CDCl3), δC, ppm
(J, Hz): 16.09 (СН3), 16.32 (СН3), 64.82 (ОСН2),
65.14 (ОСН2), 83.26 t (РС, JPС 155.9), 124.85 d (С9,
JPС 3), 124.95 (С7), 125.84 (С4), 130.04 (С5), 134.33
31
(С6), 143.73 (С8), 169.14 с (С=О). Р NMR spectrum
(CDCl3): δР 10.28 ppm. Mass spectrum (APCI), m/z:
407 [M + 1] (calculated М 406). Found, %: C 47.30; H
5.85; P 14.92. С16Н24O8P2. Calculated, %: C 47.30; H
5.95; P 15.25.
2-(Diethoxyphosphorylcarbonyl)benzoic acid (II).
A mixture of 0.20 g (0.05 mol) of bisphosphonate I
and 0.2 g (0.015 mol) of K2CO3 in 2 ml of water was
boiled for 0.5 h until the end of carbon dioxide release.
The solution was cooled, acidified with dilute sulfuric
acid to pH 2–3 under cooling with ice water. The
solution was filtered from the precipitated o-phthalic
acid and the filtrate was extracted with ethyl acetate.
The organic layer was washed with brine, dried over
sodium sulfate, and evaporated under reduced pres-
2-Benzyl-3-oxoisoindoline-1,1-diylbisphosphonic
acid (V). A mixture of 1.20 g (0.003 mol) of bisphos-
phonate I and 12 ml of concentrated hydrochloric acid
was refluxed for 3 h, then 8 ml of the acid was added
and the mixture was refluxed for 1 h to the end of ethyl
chloride release. The solution was evaporated under
reduced pressure, and the residue was dried in a
vacuum and crystallized from 95% ethanol. Yield
0.80 g (87%), mp 240–242°С. IR spectrum (KBr), ν,
1
sure. Yield 0.12 g, mp 181–185°С. Н NMR spectrum
[(CD3)2CO], δ, ppm (J, Hz ): 1.21 t (6Н, CH3), 3.97 d.
q (4Н, ОСН2, JPH 7, J HH 7), 6.64 s (1Н, СО2Н), 7.63 t
(1Н, Н5, JHH 6), 7.69 d.d (1Н, JHH 6), 7.76 d (2Н, H4,
H7, JHH 6). 31Р NMR spectrum (CDCl3): δР 1.19 ppm.
1
cm–1: 3033.11, 1778.33, 1289.33, 1199.82, 956.46. Н
NMR spectrum [(CD3)2SO], δ, ppm (J, Hz ): 4.00 s
(2Н, СН2N), 7.40–7.56 m (7Н, Н5, Н6, С6Н5), 7.74 d
(1Н, Н7, JНH 6), 7.78 d (1Н, Н4, JНH 8). 13C NMR
spectrum [(CD3)2SO], δC, ppm (J, Hz ): 42.78 (СН2N),
86.63 t (PC, JPC 139.59), 124.67, 125.45, 125.63,
128.43, 128.82, 129.07, 129.35, 133.41, 134.60,
148.86 (СAr), 171.41 (С=О). 31Р NMR spectrum
(D2O), δР, ppm: 8.44, 8.32. Found, %: N 3.68; P 16.16.
C15H15NO7P2. Calculated, %: N 3.65; P 16.16.
3-Oxo-1,3-dihydroisobenzofuran-1,1-diyldiphos-
phonic acid (III). A mixture of 0.20 g (0.0005 mol) of
bisphosphonate I and 1 ml of concentrated hydro-
chloric acid was refluxed for 3–4 h till the end of ethyl
chloride release, adding 1 ml of acid every hour. The
obtained solution was cooled, evaporated in a vacuum,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 6 2011