A new route for the synthesis of 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid

Article abstract of DOI:10.3184/174751916X14631433537513

1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid 8 was synthesised from tetraethylene glycol through a 7 step sequence including esterification, mesylation, azide substitution with subsequent reduction followed by hydrolysis. The structure of product 8 was

Full text of DOI:10.3184/174751916X14631433537513

368 RESEARCH PAPER
VOL. 40 JUNE, 368–370
JOURNAL OF CHEMICAL RESEARCH 2016
A new route for the synthesis of 1-amino-3,6,9,12-tetraoxapentadecan-15-oic
acid
Xuan Wua, Xi Zonga and Min Jib*
aSchool of Chemistry and Chemical Engineering, Southeast University, Nanjing, 210000, P.R. China
bSchool of Biological Science and Medical Engineering & Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University,
Suzhou, 215123, P.R. China
1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid 8 was synthesised from tetraethylene glycol through a 7 step sequence including
esterification, mesylation, azide substitution with subsequent reduction followed by hydrolysis. The structure of product 8 was identified
1
by H and 13C NMR spectroscopy, elemental analysis and electrospray ionisation mass spectrometry (ESI-MS). All reaction conditions
were optimised and easy to control. The key advantages of this process are the high yields of products and a new route to synthesise
1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid.
Keywords: PEG, linker, synthesis method, protecting group
Polyethylene glycol (PEG) is a composed of ethylene glycol
units and can range in molecular weight from a few hundred
to several tens of hundreds. It is a biocompatible water-soluble
polymer1 due to its low toxicity, low immunogenicity and good
solubility in both aqueous and organic solvents.2–5 It also can
be excreted through the kidney and will not be accumulated
in the body.6 More importantly, when PEG couples with
other modifications, its many attractive properties would be
transferred to the compounds.7–9 Therefore it is widely used as
a carrier system for biological proteins.10,11
Hybrid formation of bioactive materials with PEG is the
focus of many studies on drug delivery systems.12 Excellent
biocompatibility of PEG has resulted in its applications
in medicine and biotechnology, and some have received
FDA approval.13–17 In the past several years, a variety of
micromolecule PEG derivatives which contain both carboxyl
and amino functions have been used as linkers to connect sialyl
LewisX amine with protected spacer-equipped asparagines.18
Currently, PEGs are also widely used in the field of prodrug
research, because it can improve not only tumour uptake19 but
also excretion kinetics of 125I- and 18F-labeled c(RGDyK) and
64Cu-labeled E[c(RGDyK)]2.20–23
easily react with other compounds. Thus, the compound 8 is
attracting more and more attention and several methods for its
synthesis have been developed.24–26 In spite of their potential
utility, many of these reported syntheses have drawbacks such
as harsh reaction conditions, unsatisfactory yields, prolonged
reaction times, cumbersome product isolation procedures,
polar, volatile and hazardous organic solvents, which limit
their application. Therefore, there is continuous demand for
the development of a novel environmentally friendly synthetic
method. Herein, we report a simple and highly efficient method
for the preparation of compound 8. In our route, compound
8 and two useful intermediates (compounds 5 and 7) can be
easily obtained. Compared with other synthetic routes,24–26 the
yield from our approach is higher and the reaction conditions
are easier to control. More importantly all the materials are
readily available and cost effective.
Results and discussion
As shown in Scheme 1, the spacer amino acid was synthesised
from tetraethylene glycol and its base catalysed conjugate
addition to tert-butyl acrylate to yield 2. After mesylation to
afford 3, the latter was subjected to nucleophilic displacement
by treatment with sodium azide in DMF to give the azido ester 4
in good yield (65%) following chromatography. Hydrogenation
of the azido group in 4 furnished the spacer amino acid ester
5. Finally, 7 was obtained through hydrolysis of the carboxylic
ester following benzylation and protection of the amino group
These results indicate that PEG offers many interesting
opportunities in the development of novel drug-carrier systems
and has also been used in the synthesis of many compounds as a
linker. Compound 8 and PEG have the same fragment. Besides,
compound 8 contains carboxyl and amino functions which can
a
b
O
S
HO
OH
3
HO
O
3
O
O
O
3
O
O
O
O
O
O
O
1
2
3
c
d
e
H
N
H2N
O
3
O
N3
O
3
O
O
O
3
O
O
O
O
O
O
O
4
5
6
H
f
g
H2N
N
H
O
3
O
H
O
O
O
3
O
O
7
8
Scheme 1 Reagents and conditions: (a) Na, tert-butyl acrylate, THF, r.t., 24 h, 77%; (b) MeSO2Cl, Et3N, CH2Cl2, 0 °C, 15 h, 92%;
(c) NaN3, DMF, r.t., 2 d, 65%; (d) Raney nickel, H2, i-PrOH, r.t., 12 h, 93%; (e) BnBr, CH2Cl2, r.t., 18 h, 72%;
(f) LiOH (4 mol L–1), MeOH, reflux, 5 h, 93%; (g) Pd/C, H2, MeOH, r.t., 15 h, 94%.
* Correspondent. E-mail: zhiming@cczu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2016 369
chromatography (silica gel; 30% EtOAc–PE) to afford 4 as pale
yellow oil; 1.4 g, 65%; H NMR (300 MHz, CDCl3): 3.76–3.53 (m,
16H), 3.33 (t, J = 5.9 Hz, 2H), 2.44 (t, J = 6.1 Hz, 2H), 1.40 (s, 9H);
ESI-MS m/z: [M + H]+ 348.20899.
as in 6. Subsequent hydrogenolysis of the N-benzyl group
provided 8 in 94% yield. In our route, we can easily obtain
compound 8 and two useful intermediates (compounds 5
and 7). These two intermediates have a protecting group at
the carboxyl or amino function. PEG can be replaced by one
of compounds 5, 7, 8 according to the actual situation. The
reaction sequence is applicable to other chain lengths and
analogues of 1 to access other derivatives of compound 8.
The structure of 8 was confirmed on the basis of
1
tert-Butyl 1-amino-3,6,9,12-tetraoxapentadecan-15-oate (5)
To a solution of 4 (1.0 g, 2.88 mmol) in isopropanol (20 mL) freshly
prepared Raney nickel (0.7 g, pH 9) was given. Air was exchanged for
argon and then for hydrogen. After hydrogenation for 12 h, the catalyst
was filtered off through Hyflo and washed with isopropanol (50 mL).
The solvent was evaporated in vacuo to afford 5 as pale yellow oil;
0.86 g, 93%; 1H NMR (300 MHz, CDCl3): 3.69–3.53 (m, 14H), 3.45 (t,
J = 5.8 Hz, 2H), 2.64 (t, J = 5.8 Hz, 2H), 2.47 (t, J = 6.1 Hz, 2H), 1.42
(s, 9H); ESI-MS m/z: 322.21849 [M + 1]+.
1
spectroscopic data, particularly its H NMR and MS data. In
the 1H NMR spectrum of 8, the singlet signal at 11.21 ppm was
due to the –COOH proton. The singlet at 8.88 ppm was due to
NH2 function. Two triplets at 2.94 and 2.45 ppm correspond to
the N–CH2 and –CH2COO– protons respectively. In addition,
the signals in 13C NMR also proved the existence of –NH2CH2
and –COOH functions. In ESI-MS spectrum, the calculated
m/z [M + H]+ of 8 was 266.15254, and the m/z found was
266.15589.
tert-Butyl 1-phenyl-5,8,11,14-tetraoxa-2-azaheptadecan-17-oate (6)
To a solution of 5 (0.4 g, 1.22 mmol) in dry CH2Cl2 (15 mL) at 0 °C,
benzyl bromide (0.34 g, 2.0 mmol) was added dropwise within
10 min. After stirring for 18 h at r.t., the reaction mixture was then
quenched by the addition of saturated aqueous NaHCO3 (20 mL). The
resulting aqueous solution was extracted with CH2Cl2 (3 × 50 mL)
and the organic extracts were combined, and dried over Na2SO4. The
residue was purified by flash chromatography (silica gel; 20% EtOAc–
Conclusion
In conclusion, an efficient and simple method for the synthesis
of 1-amino-3,6,9,12-tetraoxapentadecan-15-oic acid 8 under
mild conditions was reported. The main advantages of this
method are the new route to synthesise 8 and the high yields
of products.
1
PE) to afford 6 as pale yellow oil; 0.36 g, 72%; H NMR (300 MHz,
CDCl3): 7.36–7.17 (m, 5H), 3.68–3.48 (m, 18H), 2.66 (t, J = 5.9 Hz,
2H), 2.45 (t, J = 6.4 Hz, 2H), 1.43 (s, 9H); ESI-MS m/z: [M + H]+
412.26544.
1-Phenyl-5,8,11,14-tetraoxa-2-azaheptadecan-17-oic acid (7)
Experimental
Compound 6 (0.3 g, 0.73 mmol) was added to an aqueous solution of
LiOH (4 mol/L, 0.4 mL) and THF (15 mL). The solution was heated
to reflux for 5 h. After concentration, the residue was partitioned
between EtOAc and water. The pH of the combined aqueous phase
was adjusted to 1 with 10% HCl, and then washed with EtOAc. The
EtOAc layer was washed with brine and then dried over anhydrous
Na2SO4 and concentrated to give product 7 as pale yellow oil; 0.24 g,
All chemicals were of analytical reagent grade and purchased from
commercial sources, which were used directly without further
purification. 1H and 13C NMR spectra were recorded in CDCl3
solutions on a Bruker Avance 300 spectrometer; chemical shifts (δ)
are reported in parts per million (ppm) relative to the internal standard
tetramethylsilane (TMS). Electrospray ionisation mass spectrometry
(ESI-MS) was obtained on a Finnigan MAT-95 Spectrometer.
1
93%; H NMR (300 MHz, CDCl3): 12.21 (s, 1H), 7.72–7.44 (m, 5H),
tert-Butyl 1-hydroxy-3,6,9,12-tetraoxapentadecan-15-oate (2)
3.59–3.43 (m, 18H), 3.01 (t, J = 5.9 Hz, 2H), 2.45 (t, J = 6.1 Hz, 2H);
ESI-MS m/z: [M + H]+ 356.20284.
To dry tetraethylene glycol (17.2 mL, 0.10 mol) in dry tetrahydrofuran
(100 mL), sodium (0.02 g, 0.87 mmol) was added. After 2 h, the
sodium had dissolved and tert-butyl acrylate (4.35 mL, 0.03 mol)
was added. The solution was stirred under exclusion of moisture for
24 h. After neutralisation with 1 M HCl (0.8 mL), the solvent was
evaporated under reduced pressure. The residue was dissolved in brine
(100 mL) and extracted three times with ethyl acetate (150 mL). The
combined organic layers were washed with water (50 mL) and dried
with MgSO4. The solvent was evaporated under reduced pressure to
afford 2 as clear, pale yellow liquid; 4.3 g, 77%; 1H NMR (300 MHz,
CDCl3): 3.77–3.52 (m, 18H), 3.06 (s, 1H), 2.41 (t, J = 5.8 Hz, 2H), 1.40
(s, 9H); ESI-MS m/z: [M + H]+ 323.20252.
1-Amino-3,6,9,12-tetraoxapentadecan-15-oic acid (8)
A mixture of compound 7 (200 mg, 0.56 mmol), 10% Pd–C catalyst
(64 mg, 0.06 mmol) in MeOH (10 mL) was stirred under a hydrogen
atmosphere at room temperature and atmospheric pressure until the
absorption of hydrogen ceased. After the Pd–C catalyst was filtered
off, the solvent was evaporated in vacuo to afford 8 as pale yellow oil;
140 mg, 94%; 1H NMR (300 MHz, CDCl3): 11.21 (s, 1H), 8.88 (s, 2H),
3.64–3.50 (m, 18H), 2.94 (t, J = 6.1 Hz, 2H), 2.45 (t, J = 6.0 Hz, 2H);
13C NMR (75 MHz, CDCl3): 172.80, 73.52, 70.59, 70.52, 70.33, 70.31,
66.88, 41.54, 34.81; ESI-MS m/z: [M + H]+ 266.15589; Anal. calcd for
C11H23NO6: C, 49.80; H, 8.74; N, 5.28; found: C, 49.50; H, 8.59; N,
5.31%.
tert-Butyl 1-mesyloxy-3,6,9,12-tetraoxapentadecan-15-oate (3)
To a solution of 2 (2.0 g, 6.2 mmol) in dry CH2Cl2 (30 mL) and Et3N
(2.1 mL, 15 mmol) of at 0 °C, methanesulfonyl chloride (1.0 mL,
13 mmol) was added dropwise within 15 min. After stirring for 15 h
at 0 °C, filtration through Hyflo and washing with water and brine,
the CH2Cl2 layer was dried with MgSO4, filtered, and concentrated in
vacuo to afford 3 as dark brown oil; 2.3 g, 92%; 1H NMR (300 MHz,
CDCl3): 3.69–3.52 (m, 18H), 3.14 (s, 3H), 2.44 (t, J = 6.1 Hz, 2H), 1.40
(s, 9H); ESI-MS m/z: [M + H]+ 401.18003.
This work was supported by National High-Tech Research
and Development Project (863 Project, 2013AA032205),
Industry Project of Jiangsu Science-Technology Support Plan
(BE2013840), Science and Technology Development Program
of Suzhou (ZXY201412).
Received 10 January 2016; accepted 6 April 2016
Paper 1603832 doi: 10.3184/174751916X14631433537513
Published online: 3 June 2016
tert-Butyl 1-azido-3,6,9,12-tetraoxapentadecan-15-oate (4)
Sodium azide (0.82 g, 12.5 mmol) was added to solution of the
mesylate 3 (2.5 g, 6.2 mmol) in DMF (30 mL). The mixture was
stirred under exclusion of moisture for 2 d at room temperature.
The reaction mixture was filtered and the residue was partitioned
between EtOAc and H2O, The aqueous phase was extracted with
EtOAc, and the combined organic phases were dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by flash
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