Synthesis of 9-[1-(1-hydroxyethyl)-3-(phosphonomethoxy)propyl] adenine and prodrug as possible antiviral agents

Article abstract of DOI:10.1080/15257770500265612

□ The appropriately protected C-1′-hydroxyethyl-3-hydroxypropyl- N⁹-adenine nucleoside was prepared from 1-pivaloyloxy-5-tert- butyldiphenylsilyloxy-3-pentanol and adenine through the Mitsunobu reaction. One of the terminal hydroxyls was conver

Full text of DOI:10.1080/15257770500265612

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Synthesis of 9-[1-(1-Hydroxyethyl)-3-
(Phosphonomethoxy)Propyl] Adenine and Prodrug as
Possible Antiviral Agents
Ajit Ghosh a , Pooran Chand a , Yahya El-Kattan a , Minwan Wu a , Tsu-Hsing Lin a , Satish
Vadlakonda a , Pravin L. Kotian a & Yarlagadda S. Babu a
a BioCryst Pharmaceuticals, Inc. , Birmingham, Alabama, USA
Published online: 16 Aug 2006.
To cite this article: Ajit Ghosh , Pooran Chand , Yahya El-Kattan , Minwan Wu , Tsu-Hsing Lin , Satish Vadlakonda , Pravin L.
Kotian & Yarlagadda S. Babu (2005) Synthesis of 9-[1-(1-Hydroxyethyl)-3-(Phosphonomethoxy)Propyl] Adenine and Prodrug as
Possible Antiviral Agents, Nucleosides, Nucleotides and Nucleic Acids, 24:10-12, 1587-1595, DOI: 10.1080/15257770500265612
To link to this article: http://dx.doi.org/10.1080/15257770500265612
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Nucleosides, Nucleotides, and Nucleic Acids, 24:1587–1595, 2005
c
Copyright ꢀ Taylor & Francis Group, LLC
ISSN: 1525-7770 print/1532-2335 online
DOI: 10.1080/15257770500265612
SYNTHESIS OF
9-[1-(1-HYDROXYETHYL)-3-(PHOSPHONOMETHOXY)PROPYL]
ADENINE AND PRODRUG AS POSSIBLE ANTIVIRAL AGENTS
Ajit Ghosh, Yahya El-Kattan, Minwan Wu, Tsu-Hsing Lin, Satish Vadlakonda,
ᮀ
Pravin L. Kotian, Yarlagadda S. Babu, and Pooran Chand
BioCryst Pharma-
ceuticals, Inc., Birmingham, Alabama, USA
The appropriately protected C-1ꢀ-hydroxyethyl-3-hydroxypropyl-N9-adenine nucleoside was
prepared from 1-pivaloyloxy-5-tert-butyldiphenylsilyloxy-3-pentanol and adenine through the
Mitsunobu reaction. One of the terminal hydroxyls was converted to the phosphonomethoxy
derivative and the prodrug.
ᮀ
Keywords Acyclic nucleosides; Prodrugs; Antiviral
INTRODUCTION
Since the discovery of phosphonomethyl ether functionality as an im-
portant replacement of phosphoric acid ester, a lot of work has been done
on acyclic nucleosides.[1,2] As a result, a number of adenine derivatives
(Chart 1), PMEA (1a), PMPA (1c), HPMPA (1e), and FPMPA (1f); 2,6-
diaminopurine derivatives, PMEDAP (1g) and HPMPDAP (1h); and gua-
nine derivatives, PMEG (2a), PMPG (2b), and HPMPG (2c) have been ex-
tensively studied.[3–6] Prodrugs of two phosphonomethyl adenine deriva-
tives, adefovir dipivoxil (1b) and tenofovir disoproxil (1d), were approved
by FDA for HBV and HIV infections, respectively.
Most of these compounds have no substitution on the acyclic moiety or
have substitutions such as methyl, hydroxymethyl and fluoromethyl coming
from the C-2ꢁ position of the acyclic moiety. There are only a few reports
Dedicated to the memory of John A. Montgomery.
Received 19 January 2005; accepted 4 April 2005.
The authors thank Drs. Charlie Bugg and Claude Bennett for their encouragement throughout
this work. The authors also express appreciation to Linda Kay First for preparation of this manuscript.
Address correspondence to Pooran Chand, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake
Drive, Birmingham, AL 35244; Fax: (205)444-4640; E-mail: pchand@biocryst.com.
1587

1588
A. Ghosh et al.
CHART 1
on C-1ꢁ position substitutions, and most of those reports describe only
the acyclic nucleosides.[7–10] Phosphonomethyl ether derivatives have not
been prepared for the compounds branching from the C-1ꢁ position except
when substitution is methyl. In our preceding papers we have disclosed
the compounds substituted at the C-1ꢁ position keeping the number of
spacer atoms between the phosphorus of the phosphonomethyl group and
joining nitrogen of adenine as 5 in one case and 4 in other case. In
one of the papers, when we have 5 spacer atoms, the substitutions from
the C-1ꢁ position are methyl derivatives, such as methyl, hydroxymethyl,
fluoromethyl, amino methyl, azidomethyl, methoxymethyl, etc. In another
paper, we have 4 spacer atoms and the substitutions from the C-1ꢁ position
are ethyl, hydroxyethyl, aminoethyl, azidoethyl, and methoxyethyl.
The compounds in this report have the number of spacer atoms between
the adenine nitrogen and phosphorus as 5 while the substituent, hydrox-
yethyl is coming from the C-1ꢁ position of the acyclic moiety. The synthesis
of the corresponding nucleoside, phosphonomethyl ether derivative, and
the prodrug will be described.
RESULTS AND DISCUSSION
All synthesized compounds are racemic mixtures. The synthesis started
from known racemic 3,5-isopropylidene-1,3,5-pentanetriol (3, Scheme 1).[11]
The hydroxyl group of 3 was protected with the pivaloyl group by the re-
action of pivaloyl chloride in pyridine and the isopropylidene was removed
from the resultant 4 with 80% acetic acid. The primary hydroxyl group of di-
hydroxy compound 5 was selectively protected with the tert-butyldiphenylsilyl

Synthesis of Possible Antiviral Agents
1589
SCHEME 1 Reagents: i) Pivaloyl chloride, pyridine; ii) 80% aq. AcOH; iii) TBDPS-Cl, imidazole;
iv) Adenine, Ph3P, DEAD; v) NaOMe, MeOH; vi) Tr-Cl, pyridine; vii) N(n-Bu)4•F, THF; viii) NaH,
TSO-CH2-P(O)(O-iPr)2; ix) TMSI, Et3N; x) ClCH2OC(O)C(CH3)3, Et3N; xi) HCl.
(TBDPS) group on reaction with TBDPS-Cl and the secondary hydroxyl of
resultant 6 underwent the Mitsunobu reaction with adenine, triphenylphos-
phine and diethylazodicarboxylate (DEAD) in dioxane to give compound
7. The product obtained was identified as the N9 derivative based upon the
literature reports[12] and UV spectrum at different pH, which did not show
any shift in the absorption.[13] We then had to remove one of the protecting
groups from the hydroxyls to prepare the phosphonomethyl ether deriva-
tives. We chose to remove the pivaloyl because we had to prepare prodrugs
which are base sensitive and the pivaloyl group could not have been re-
moved at the end in the presence of the prodrug. Removal of the pivaloyl
group from 7 with sodium methoxide in methanol gave 8. From our previ-
ous experience, it was necessary: a) to protect the amino of adenine for the
preparation of the phosphonomethyl ether derivative, and b) not to have

1590
A. Ghosh et al.
the TBDPS group as the protecting group on the hydroxyl. Therefore, we
chose to protect both the amino and the free hydroxyl with a group which
could easily come off under very mild acidic conditions. We decided to pro-
tect both groups with the trityl group and the tritylation of compound 8 was
achieved with trityl chloride in pyridine at 70◦C in several days after adding
a lot of excess of the reagent and also triethylamine base. Compound 9 was
obtained although in low yield. The TBDPS group of 9 was removed with
tetrabutylammonium fluoride (TBAF) and the resultant compound 10 was
taken for the reaction with p-toluenesulfonyloxymethyl phosphonate in the
presence of sodium hydride to give the desired compound 11 and also 12,
which was the mono-isopropoxy derivative. Both could be easily separated
by silica gel column chromatography. Phosphonomethyl derivative 13 was
obtained from 11 and 12 with a TMS-iodide reaction in the presence of
triethylamine to avoid the deprotection of trityl, because of the acid gen-
erated from TMS-iodide alone. The formation of the prodrug of 13 with
chloromethylpivalate in the presence of triethylamine as base occurred over
several days and the resultant 14 was finally deprotected under mild acidic
conditions (HCl) to give the desired target 15.
BIOLOGICAL ACTIVITY
These compounds showed poor activity against HCV virus in replicon
assay.[14]
EXPERIMENTAL
All reagents and solvents were purchased from Aldrich and used as re-
ceived. 1H NMR and 13C NMR were recorded on a Bruker 300 MHz instru-
ment. Chemical shifts ( ) are reported in parts per million (ppm) refer-
enced to TMS at 0.00 or the respective deuterated solvent peak. 31P NMR
chemical shifts are reported with respect to D3PO4 in D2O as the exter-
nal standard. Coupling constants (J) are reported in hertz. IR spectra were
obtained from films on NaCl plates for oils or KBr pellets for solids with
a scan range of 4000–500 cm−1 on a FT-IR spectrometer (BioRad FTS-
3500GX). Mass spectra data were acquired on a Waters ZMD mass spec-
trometer coupled with a Waters System 2695 for loading of the samples in
ES positive or negative mode. HRMS data were recorded on Bruker Bioapex
4.7E. UV spectroscopy was carried out on an Agilent 8453 spectrophotome-
ter. The elemental analysis (C, H, and N) were performed by Atlantic Mi-
crolab in Norcross, Georgia, USA. The TLC solvent system CMA-80 and
CMA-50 refers to chloroform:methanol:conc. NH4OH (80:18:2) and chlo-
roform:methanol:conc. NH4OH (50:40:10), respectively. The non-UV ac-
tive compounds were visualized by charring the TLC plate sprayed with an
ammonium molybdate/cesium sulfate spray prepared by dissolving conc.

Synthesis of Possible Antiviral Agents
1591
H2SO4 (22.4 mL), CeSO4 (45 mg), (NH4)6Mo7O24 4 H2O (7 g) in 100 mL
water. The olefin compounds were visualized by using a KMnO4 spray.
( )-1-Pivaloyl-3,5-isopropylidenepentan-1,3,5-triol (4). To a solution of
3,5-isopropylidenepentan-1,3,5-triol[11]3 (6.2 g, 38.69 mmol) in pyridine
(125 mL) was added pivaloyl chloride (5.7 mL, 46.43 mmol) and the
resulting reaction mixture was stirred at room temperature for 17 h. After
evaporation of most of the solvent, water (200 mL) was added and then
extracted with EtOAc (2 100 mL). The combined organic extracts were
washed with water, dried over MgSO4, filtered, and concentrated to dryness
1
to give 9.35 g of 4 (98%) as an oil: HNMR (CDCl3): 4.13–4.17 (m, 2H),
3.92–4.04 (m, 2H), 3.80–3.89 (m, 1H), 1.74–1.81 (m, 2H), 1.54–1.72 (m,
2H), 1.43 (s, 3H), 1.37 (s, 3H) and 1.19 (s, 9H). IR (CHCl3, cm−1): 2959,
2918, 2872, 1726, 1458, and 1369.
( )-5-Pivaloylpentan-1,3,5-triol (5). A mixture of 4 (10 g, 40.92 mmol)
and 80% aqueous acetic acid (125 mL) was heated at 50–55◦C for 15 h.
The reaction mixture was evaporated to dryness under vacuum and then
co-evaporated with toluene (3 35 mL) to give 8.0 g (96%) of 5 as an oil:
1HNMR (DMSO-d6): 4.48 (d, J = 5.65 Hz, 1H), 4.34 (t, J = 5.08 Hz, 1H),
4.0–4.12 (m, 2H), 3.60–3.71 (m, 1H), 3.45–3.51 (m, 2H), 1.43–1.72 (m, 4H)
and 1.12 (s, 9H). IR (KBr, cm−1): 3405, 2963, 1722, 1477, 1288, 1166, and
1057.
( )-1-tert-Butyldiphenylsilyl-5-pivaloylpentan-1,3,5-triol (6). To a solu-
tion of 5 (8.0 g, 39.16) and imidazole (3.0 g, 43.07 mmol) in CH2Cl2 (170
mL) was added TBDPS-chloride (11.20 mL, 39.16 mmol) over a period of
1 h at room temperature. After stirring for 1 more h, the solvent was re-
moved and the residue was purified on a silica gel column using ethyl ac-
etate:hexanes as eluent to provide 13 g (75%) of 6, as a colorless oil: 1HNMR
(DMSO-d6): 7.57–7.67 (m, 4H), 7.36–7.47 (m, 6H), 4.55 (d, J = 5.8 Hz, 1H),
4.06–4.11 (m, 2H), 3.66–3.85 (m, 3H), 1.53–1.73 (m, 4H), 1.11 (s, 9H), and
0.97 (s, 9H). IR (KBr, cm−1): 3514, 2959, 2858, 1726, 1473, and 1428. HRMS
calcd for C26H38O4Si (M+H)+ 443.2617. Found 443.2598.
( )-9-[(1-tert-Butyldiphenylsilyloxyethyl)(3-pivaloyloxy)propyl]adenine
(7). To a stirring mixture of 6 (10.0 g, 22.59 mmol), triphenylphosphine
(11.85 g, 45.18 mmol), and adenine (6.1 g, 45.18 mmol) in anhydrous
dioxane (250 mL) was added a solution of DEAD (7.15 mL, 45.18 mmol) in
dioxane (50 mL) over a period of 3 h at room temperature. The reaction
mixture was further stirred for 19 h, then filtered through a short pad of
Celite and the filtrate concentrated. The residue was purified on a silica
gel column using chloroform:methanol (100:0 to 99:2) as eluent to give the

1592
A. Ghosh et al.
desired product 7, but it was contaminated with tri-phenylphosphine oxide
and the DEAD derivative. Two more purifications on silica gel gave 8.8 g of
1
pure 7 (70%), as a white solid, mp 137–139◦C: HNMR (DMSO-d6): 8.13
(s, 1H), 8.09 (s, 1H), 7.22–7.66 (m, 10H), 7.21 (br, 2H, exchangeable with
D2O), 4.92 (m, 1H), 3.64–3.98 (m, 2H), 3.24–3.58 (m, 2H), 2.06–2.46 (m,
4H), 1.05 (s, 9H), 0.9 (s, 9H). IR (KBr, cm−1): 3313, 3153, 2962, 1711, 1667,
1601, and 1472. MS (ES+) 560.31 (M+H). Anal. calcd for C31H41N5O3Si:
C, 66.51; H, 7.38; N, 12.51. Found: C, 66.26; H, 7.37; N, 12.70.
( )-9-[(1-tert-Butyldiphenylsilyloxyethyl)(3-hydroxy)propyl]adenine
(8). To a solution of 7 (7.6 g, 13.57 mmol) in anhydrous MeOH (300 mL)
was added NaOMe (5.4 M solution in MeOH, 5.0 mL, 27.15 mmol), and
then the reaction mixture was stirred at room temperature for 17 h. The
mixture was neutralized to pH 7.0 with acetic acid and concentrated. The
residue was purified on a silica gel column eluting with chloroform:methanol
(100:0 to 95:5) to provide 4.2 g (65%) of 8 as a white solid, mp 144–147◦C:
1HNMR (DMSO-d6): 8.09 (s, 1H), 8.07 (s, 1H), 7.24–7.56 (m, 10H), 7.19
(br, 2H, exchangeable with D2O), 4.85 (m, 1H), 4.55 (t, J = 4.7 Hz, 1H
exchangeable with D2O), 3.42–3.56 (m, 1H), 3.1–3.42 (m, 3H), 2.30–2.46
(m, 1H), 1.92–2.44 (m, 3H), 0.89 (s, 9H). IR (KBr, cm−1): 3341, 3185, 2929,
2854, 1668, 1607, 1412, and 1317. MS (ES+) 476.33 (M+H). Anal. calcd for
C26H33N5O2Si 0.5 H2O: C, 64.43; H, 7.07; N, 14.44. Found: C, 64.52; H,
7.14; N, 14.16.
( )-9-[(1-tert-Butyldiphenylsilyloxyethyl)(3-trityloxy)propyl]-N6 -trityl-
adenine (9). To a solution of 8 (1.9 g, 3.99 mmol) and DMAP (180 mg)
in anhydrous pyridine (100 mL) was added tritylchloride (4.4 g, 15.97
mmol), and then the reaction mixture was heated at 65◦C for 16 h. More
tritylchloride (4.4 g) was added and heated another 8 h at 65◦C. Another
4.4 g of trityl chloride and triethyl amine (1.0 mL) was added and heated
for 17 h. The solvent was removed and the residue was purified on a silica
gel column eluting with hexanes:ethanol (100:0 to 70:30) to provide 2.1 g
(54%) of 9 as a white solid, mp 202–204◦C: 1HNMR (CDCl3): 7.90 (s, 1H),
7.14–7.62 (m, 41H), 6.88 (s, 1H), 4.95–5.12 (m, 1H), 3.55–3.66 (m, 1H),
3.26–3.37 (m, 1H), 3.04–3.14 (m, 1H), 2.63–2.74 (m, 1H), 2.29–2.51 (m,
2H), 2.0–2.24 (m, 2H), and 1.63 (s, 9H). IR (KBr, cm−1): 3417, 3055,
2855, 1602, 1469, and 1442. MS (ES+) 960.27 (M+H). Anal. calcd for
C64H61N5O2Si 0.5 H2O: C, 79.30; H, 6.44; N, 7.23. Found: C, 79.33; H, 6.39;
N, 7.25.
( )-9-[(1-Trityloxyethyl)(3-hydroxy)propyl]-N6-trityladenine (10). To a
solution of 9 (2 g, 2.08 mmol) in THF (80 mL) was added 1 M solution
of TBAF in THF (2.2 mL, 2.2 mmol) and then the reaction mixture was

Synthesis of Possible Antiviral Agents
1593
stirred at room temperature for 2 h. The reaction mixture was concentrated
and the residue was purified on a silica gel column eluting with chloro-
form:methanol (100:0 to 98:2) to provide 1.2 g (80%) of 10 as a white solid,
mp 160–170◦C: 1HNMR (DMSO-d6): 8.18 (s, 1H), 7.83 (s, 1H), 7.1–7.4 (m,
31H), 4.84 (m, 1H), 4.54 (t, J = 5.0 Hz, 1H) 3.1–3.4 (m, 2H), 2.62–2.88 (m,
2H), 1.88–2.44 (m, 4H). IR (KBr, cm−1): 3054, 2926, 1605, 1470, 1444, and
1216. HRMS calcd for C48H43N5O2 (M+H)+ 722.3495. Found 722.3528.
Anal. calcd for C48H43N5O2 0.2 CHCl3: C, 77.62; H, 5.83; N, 9.39. Found:
C, 77.32; H, 5.82; N, 9.34.
( )-9-[(1-Trityloxyethyl)(3-diisopropylphosphonomethoxy)propyl]-N6-
trityladenine (11) and ( )-9-[(1-Trityloxyethyl)(3-mono-isopropylphospho-
nomethoxy)propyl]-N6-trityladenine (12). To a solution of 10 (0.54 g, 0.748
mmol) in DMF (6 mL) was added NaH (120 mg, 60% dispersion in oil,
2.99 mmol) under N2 atmosphere. After stirring the mixture for 0.5 h at
room temperature, a solution of p-toluenesulfonyloxymethyl phosphonate
in DMF (1.0 mL) was added over a period of 5 min. The reaction mixture was
stirred at room temperature for 18 h and then neutralized slowly with acetic
acid at 0–5◦C. After removing most of the solvent, the mixture was extracted
with chloroform (60 mL), the organic layer washed with water (2 30 mL),
dried over MgSO4, filtered and concentrated. The residue was purified on a
silica gel column using ethyl acetate:hexanes:methanol (100:0:0 to 70:25:5)
as eluent to provide 0.204 g (30%) of 11 as a gum: 1HNMR (DMSO-d6): 8.18
(s, 1H), 7.8 (s, 1H), 7.13–7.33 (m, 31H), 4.84 (m, 1H), 4.46–4.59 (m, 2H),
3.62 (d, J = 7.9 Hz, 2H), 3.20–3.46 (m, 4H), 1.98–2.8 (m, 4H), 1.14–1.20
(m, 12H). IR (KBr, cm−1): 3417, 3057, 2976, 1605, 1471, and 1220. HRMS
calcd for C55H58N5O5P (M+H)+ 900.4254. Found 900.4269. Anal. calcd for
C55H58N5O5P 0.5 H2O: C, 72.66; H, 6.54; N, 7.70. Found: C, 72.55; H, 6.37;
N, 7.72. Further elution of the column with CMA-80 afforded 0.200 g (31%)
of 12 as a light yellow gum: MS (ES ) 856.04 (M H).
(
)-9-[(1-Trityloxyethyl)(3-phosphonomethoxy)propyl]-N6 -tritylade-
nine (13). To a solution of 11 (0.13 g, 0.144 mmol) and 12 (0.2 g, 0.233
mmol) in DMF (6.0 mL) were added Et3N (0.4 mL) and TMSI(1.07 mL,
7.54 mmol) and stirred at room temperature for 13 h (in the dark). To this
reaction mixture was added TEAB (35 mL), water (60 mL), and chloroform
(100 mL) and stirred at room temperature for 1.5 h. The chloroform layer
was separated and the water layer was re-extracted with chloroform (3 30
mL). Combined chloroform extracts were dried over MgSO4, filtered, and
the filtrate concentrated. The residue was purified on a silica gel column
eluting with chloroform:methanol:NH4OH (100:0:0 to 50:40:10) to provide
0.15 g (48%) of 13: 1HNMR (DMSO-d6): 8.22 (s, 1H), 7.8 (s, 1H), 7.06–7.35
(m, 31H), 4.74–4.84 (m, 1H), 3.0–3.6 (m, 6H), 2.56–2.84 (m, 2H), 1.95–2.2

1594
A. Ghosh et al.
(m, 2H). IR (KBr, cm−1): 3415, 3028, 2876, 1605, 1472, 1446, and 1219.
HRMS calcd for C49H46N5O5P (M+H)+ 816.3315. Found 816.3331.
( )-9-[(1-Trityloxyethyl)(3-di-tert -butylcarbonyloxymethylphosphono-
methoxy)propyl]-N6-trityladenine (14). To a solution of 13 (0.14 g, 0.17
mmol) in DMF (6 mL) were added Et3N (6.2 mL, 42.89 mmol) and
chloromethyl pivalate (3.1 mL, 21.45 mmol) under N2 atmosphere and the
reaction mixture stirred at room temperature for 4 days. The mixture was
diluted with water (40 mL) and then extracted with chloroform (3
30
mL). Combined chloroform extracts were dried over MgSO4, filtered, and
the filtrate concentrated. The residue was purified on a silica gel column
using ethyl acetate:hexanes:methanol (90:10:0 to 50:49:1) to provide 0.093 g
(52%) of 14 as a light yellow solid, mp 73–75◦C: 1HNMR (DMSO-d6): 8.16
(s, 1H), 7.82 (s, 1H), 7.12–7.33 (m, 31H), 5.60 (s, 2H), 5.56 (s, 2H), 4.72–
4.87 (m, 1H), 3.79 (d, J = 7.9 Hz, 2H), 3.15–3.48 (m, 4H), 1.95–3.0 (m,
4H), and 1.11 (bs, 18H). IR (KBr, cm−1): 3419, 3028, 2973, 1753, 1605,
1473, 1448, and 1280. HRMS calcd for C61H66N5O9P (M+H)+ 1044.4676.
Found 1044.4629. Anal. calcd for C61H66N5O9P 0.25 EtOAc: C, 69.84; H,
6.42; N, 6.56. Found: C, 69.61; H, 6.32; N, 6.47.
( )-9-[(1-Hydroxyethyl)(3-di-tert -butylcarbonyloxymethylphosphono-
methoxy)propyl]adenine (15). A mixture of 14 (0.16 g, 0.15 mmol), HCl
(2.0 N, 15 mL), and MeCN (15 mL) was stirred at room temperature for
15 h. The reaction mixture was neutralized with Et3N, and then diluted
with water (40 mL). After evaporating the organic volatiles, the residue
was extracted with chloroform (3
70 mL), dried (MgSO4), filtered,
and the filtrate evaporated to dryness. The residue was purified over a
silica gel column eluting with chloroform:methanol (100:0 to 96:4). First, a
compound (60 mg) (49%) with one trityl group still attached was obtained.
Further elution of the column gave 24 mg (28%) of the desired 15 as a gum:
1HNMR (CDCl3): 8.27 (s, 1H, aromatic), 7.89 (s, 1H, aromatic), 6.17 (brs,
2H, NH2), 5.58–5.79 (m, 4H, 2 OCH2O), 4.92 (m, 1H, NCH), 3.75 (d,
J = 7.9 Hz, 2H, OCH2P), 3.52–3.64 (m, 2H, CH2CH2O), 3.1–3.42 (m, 2H,
CH2OH), 2.11–2.56 (m, 4H, NCH(CH2)2), 1.22 (s, 18H, t-butyl). IR (KBr,
cm−1): 3341, 2974, 2876, 1752, 1646, 1611, 1479. MS (ES+) 582.43 (M+Na).
Anal. calcd for C23H38N5O9P 0.75 H2O: C, 48.20; H, 6.94; N, 12.22. Found:
C, 48.26; H, 7.04; N, 11.94.
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