Development of a Scalable Process for α-Amino-ω-methoxyl-dodecaethylene Glycol

Article abstract of DOI:10.1021/acs.oprd.5b00270

We have developed a process for the efficient and scalable preparation of heterofunctionalized dodecaethylene glycol from the readily available tetraethylene glycol and its macrocyclic sulfate. By employing the benzyl group as both a protecting group and a separative tag, multiple chromatographic separations were avoided. With this method, α-amino-ω-methyl-dodecaethylene glycol was prepared on a 53 g scale with high purity and 61% overall yield in eight steps and one chromatographic separation.

Full text of DOI:10.1021/acs.oprd.5b00270

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Full Paper
Development of a Scalable Process for #-
Amino-#-methoxyl-dodecaethylene glycol
Guiquan Xia, Yu Li, Zhigang Yang, and Zhong-Xing Jiang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00270 • Publication Date (Web): 05 Oct 2015
Downloaded from http://pubs.acs.org on October 14, 2015
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Development of a Scalable Process for αꢀAminoꢀωꢀ
methoxylꢀdodecaethylene glycol
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Guiquan Xia,† Yu Li,† Zhigang Yang,*,†,§ Zhong-Xing Jiang*,†,‡,§
†School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
‡State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Dong Hua
University, Shanghai 201620, China
§Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study,
Hengyang 421001, China
Corresponding authors
Zhigang Yang, Email: zgyang@whu.edu.cn
ZhongꢀXing Jiang, Eꢀmail: zxjiang@whu.edu.cn
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ABSTRACT: We developed a process for the efficient and scalable preparation of
heterofunctionalized dodecaethylene glycol from the readily available tetraethylene glycol and
its macrocyclic sulfate. By employing the benzyl group as both a protective group and a
separative tag, multiple chromatographic separations were avoided. With this method, αꢀaminoꢀ
ωꢀmethylꢀdodecaethylene glycol was prepared on a 53ꢀg scale with high purity, 61% overall
yield in eight steps and one chromatography separation.
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Key words: Monodisperse polyethylene glycols, Macrocyclic sulfate, Heterofunctionalized,
Separative tag, Scalable preparation
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INTRODUCTION
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Polyethylene glycols (PEGs) are biocompatible polymers with a broad range of
applications. For example, PEGs are the most frequently used polymers in biopharmaceutics to
improve solubility and stability, reduce immunogenicity and dosing frequency, and prolong
blood circulation.1ꢀ4 However, the heterogeneity of PEGs dramatically complicates their
applications.5ꢀ8 To this end, monodisperse PEGs (MꢀPEGs) are highly valuable because they can
avoid the heterogeneity issue associated with regular PEGs.
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Even though MꢀPEGs are structurally simple molecules, preparing MꢀPEGs on a large
scale, especially in heterofunctionalized forms, is far from straightforward. Regular PEGs are
very complex mixtures of homologs as a result of polymerization. As such, it is nearly
impossible to obtain MꢀPEGs through accurately monitoring the polymerization process and
selectively isolating a specific component from regular PEGs. Unfortunately, the only
commercially available starting materials for MꢀPEGs synthesis are monodisperse building
blocks with one to four ethylene glycol units. Because of this, MꢀPEGs synthesis involves long
synthesis and tedious purification. Although many synthetic strategies have been developed for
MꢀPEGs since 1939,9ꢀ19 the application of MꢀPEGs is severely hampered by challenges in the
synthesis of long or heterofunctionalized MꢀPEGs, convenient purification of the intermediates
and products, and, especially, large scale preparation of MꢀPEGs. Thus, it is of great importance
to develop efficient and scalable processes for MꢀPEGs, especially fully functionalized MꢀPEGs
which can be directly used in biomedical research and development.
Recently, heterofunctionalized monodisperse dodecaethylene glycol 7 was employed as a
solubility enhancer and selfꢀassembly modulator in 19F magnetic resonance and fluorescence
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dual imaging agents in this group.20 Through the iteratively nucleophilic ringꢀopening of
macrocyclic sulfate 1, the amine 7 was efficiently prepared on a 43ꢀg scale with a 51% overall
yield in six steps (Scheme 1).20 The macrocyclic sulfate strategy highlighted the synthesis with
high efficacy by avoiding the application of protection and activation groups, as well as high
versatility in manipulating the functionalities and length of functionalized MꢀPEGs.19,20,21
However, chromatographic purification in each synthetic step severely increased the cost and
hampered the large scale preparation of amine 7. Therefore, a scalable synthesis of 7 without
using chromatography is of great importance. It is noteworthy that, besides amine 7, there are
numerous highly valuable functionalized MꢀPEGs with various lengths and ending groups, such
as thiol, alkynyl, carboxylic, etc. Because their synthesis share similar synthetic intermediates
and length extension strategies as amine 7, the synthesis for amine 7 can be easily expanded to
them.
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Scheme 1. Previous synthesis of heterofunctionalized MꢀPEGs 7.
To develop a scalable process for MꢀPEGs and their derivatives, the purification of
intermediates and products is the most challenging issue. PEGs are highly water soluble and
high polar oils (for low molecular weight oligoethylene glycols) or waxes (for high molecular
weight polyethylene glycols) that can hardly be purified by either crystallization or normal phase
silica gel purification. In order to purify MꢀPEGs and their synthetic intermediates, a few
methods have been developed, such as reverse phase chromatography, gel permission
chromatography, and precipitation.9ꢀ18 However, both reverse phase chromatography and gel
permission chromatography are very expensive and nonꢀscalable. Although precipitation is a
straightforward method, it is only fit for high molecular weight MꢀPEGs. In addition, it can
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hardly provide MꢀPEGs with high purity. In our previous macrocyclic sulfateꢀbased MꢀPEGs
synthesis, a convenient purification process was developed by removing most starting materials
and impurities through reverse extraction of the highly water soluble sulfate intermediates.19ꢀ21
But chromatography purification was still required to remove the remaining impurities. Herein,
we report an efficient and scalable process for heterofunctionalized MꢀPEGs through convenient
purification of MꢀPEGs and their synthetic intermediates.
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RESULTS AND DISCUSSION
Amine 7 was selected as a representative heterofunctionalized MꢀPEGs to illustrate the
synthetic efficacy with previous synthesis (Scheme 1) as a comparison. The synthesis started
with the macrocyclization of tetraethylene glycol 8 on multiꢀhundredꢀgram scales. Previously,
macrocyclic sulfate 1 was prepared on a 290ꢀg scale in a 55% yield with analytic grade solvents
and reagents (Table 1). Without purifying the macrocyclic sulfite intermediate, macrocyclic
sulfate 1 was isolated through recrystallization. To develop a costꢀeffective and green process
for 1, industrial grade solvents and reagents were used directly and environmentally unfriendly
carbon tetrachloride was replaced by dichloromethane. Lower yields of 1 were obtained with
industrial grade dichloromethane, acetonitrile, and diisopropylethylamine. During the oxidation,
higher yields of 1 were obtained with industrial grade dichloromethane as a coꢀsolvent when the
reaction was carried out with extended reaction time. Little difference was found when
diisopropylethylamine was replaced with much cheaper triethylamine. Dilution of 8 during the
macrocyclization could slightly improve the yield of 1. In terms of costꢀeffectiveness, the
preparation of 1 with industrial grade reagents and solvents at higher concentration (Table 1,
entry 4) is highly preferred.
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Table 1. Macrocyclization of tetraethylene glycol.
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Solvents and
reagentsa
Conc. of 8
(mol/L)
0.06
Yield
(%)
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1
(g)
1
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3
Analytic grade
Industrial grade
Industrial grade
290
288
190
0.06
37
0.06
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4b
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Industrial grade
Industrial grade
0.06
0.04
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a. Solvents and reagents are CH2Cl2, Et3N, DIPEA, CH3CN, and CCl4.
b. Et3N and CH2Cl2 were used instead of DIPEA and CCl4.
It is very interesting to point out that a small amount of a side product 9 (1ꢀ2% yields)
was isolated from the crystallization mother liquid of 1 when tetraethylene glycol 8 was
macrocyclized at 0.06 mol/L. Little difference in H/13C NMR between 1 and 9 was observed.
1
While, a mass peak, which is twice the molecular weight of 1, was found in the mass spectrum of
9. To illustrate the structure of 9, Xꢀray crystal structures of 1 and 9 were obtained.
Surprisingly, compound 9 is a 28ꢀmembered macrocyclic sulfate which is actually a monocyclic
dimer of 1 (Figure 1). No catenaneꢀlike side product was isolated, which is a common side
product in macrocyclization. It is noteworthy that 9 was not observed when 8 was
macrocyclized at 0.04 mol/L. Therefore, higher concentration for this macrocyclization actually
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promotes the formation of even larger ringꢀsized dimers instead of intermolecular catenaneꢀlike
side product.
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Figure 1. Singleꢀcrystal Xꢀray structures of macrocyclic sulfates 1 and 9
To avoid column chromatographic purification in the following synthetic steps, the
development of straightforward purification methods, like extraction and recrystallization, is of
great importance. Since MꢀPEGs and their synthetic intermediates are usually viscous oils or
waxes at room temperature, liquid phase extraction is the method of choice. Although most
impurities can be removed by selectively reverseꢀextraction of the sulfate intermediates, a
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column chromatography is used to remove aqueous soluble impurities after hydrolysis of the
sulfate intermediates. Another selective extraction of the products into organic phase while
leaving impurities in aqueous phase may be an alternative for column chromatography. To
improve the efficiency of extraction, some fine tunes on the chemical structures and thus the
partition of product and impurities between water and organic solvents are necessary.
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With these ideas in mind, benzyl group was then employed as both a separative tag and a
protective group. From benzyl alcohol, iterative nucleophilic ringꢀopening of the macrocyclic
sulfate 1 provided monobenzylated dodecaethylene glycol 12. In these synthetic steps, the
monobenzylated MꢀPEGs 10ꢀ12 were selectively extracted into diisopropyl ether or
dichloromethane while these highly aqueous soluble impurities were left in aqueous phase. As
expected, through a selective extraction of the sulfate intermediates into aqueous phase followed
by another selective extraction of the hydrolyzed products into organic phase, 10ꢀ12 were
conveniently purified without column chromatography. After methylation of 12 using
iodomethane, heterofunctionalized dodecaethylene glycol 13 with low polarity was conveniently
purified by flash chromatography on regular silica gel. Hydrogenolysis of the benzyl group
afforded monomethylated dodecaethylene glycol 4 without purification. After tosylation of 4,
nucleophilic substitution of tosylate 5 with sodium azide afforded azide 6 with high yields over
two steps. Because no side product was observed during these reactions, simple extraction
provided 5 and 6 with high purities. Reduction of azide 6 with triphenyl phosphine and water
afforded amine 7 which was conveniently purified by selectively extraction 7 into aqueous
phase. Finally, amine 7 was prepared from 1 on a 53ꢀg scale with a 61% overall yield in eight
steps. 1H/13C NMR and mass spectra indicated that high purities of amine 7 and its synthetic
intermediates were achieved by convenient extractions and one chromatography.
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NaH, 1, THF, rt, then
NaH, 1, THF, rt, then
H2SO4, H2O, rt
H2SO4, H2O, rt
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BnOH
BnO(CH2CH2O)4H
89%
95%
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1st chain extension
2nd chain extension
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NaH, 1, THF, rt, then
H2SO4, H2O, rt
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BnO(CH2CH2O)8H
BnO(CH2CH2O)12H
89%
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12
3rd chain extension
NaH, CH3I,
THF, 0 oC to rt
H2, Pd/C, CH3OH, rt
93%
BnO(CH2CH2O)12Me
4
99%
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Ph3P, H2O,
TosCl, NaOH(aq),
THF, 0 oC to rt
NaN3, DMF, 80 oC
98%
THF, rt-45 oC
6
5
7
97%
92%
Scheme 2. Modified synthesis of heterofunctionalized MꢀPEGs 7.
This modified synthesis of 7 provided a good example for preparing heterofunctionalized
MꢀPEGs on a large scale with high efficiency. In comparison with previous synthesis, most of
the column chromatographic purifications were successfully replaced with extractions, which
dramatically simplified the product purification. Although two additional synthetic steps on
benzyl group manipulations were introduced, the overall yield was improved from 51% to 61%.
Furthermore, the costꢀeffectiveness was significantly improved by the application of industrial
grade solvents and reagents and the replacement of environmentally unfriendly carbon
tetrachloride with dichloromethane during the preparation of macrocyclic sulfate.
CONCLUSION
In this work, we successfully demonstrated a scalable and efficient process for
heterofunctionalized MꢀPEGs which was highlighted by low cost, environmental friendliness
and convenient purification of the intermediates and product. As a class of highly valuable
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compounds with a broad range of applications, MꢀPEGs suffer from limited availability due to
their synthetic difficulties. This process may promote the scalable production of MꢀPEGs and
their derivatives and therefore wide applications of MꢀPEGs in biomedicine and beyond.
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EXPERIMENTAL SECTION
General information. Unless otherwise noted, solvents and reagents were purchased from
commercial suppliers and used as received. NMR spectra were recorded on a 400 MHz
instrument. Chemical shift values are reported in ppm. 1H NMR spectra were referenced to
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tetramethylsilane and C NMR spectra were referenced to the corresponding deuterated solvent
peak. Multiplicities are denoted as follows: s = singlet, t = triplet, m = multiplet. High
resolution mass spectra were recorded on a 4.7 Tesla FTMS.
General procedure for the preparation of Macrocyclic sulfate 1. A 50 L jacketed glass
reactor was charged with tetraethylene glycol (349.6 g, 1.8 mol), triethylamine (868.6 g, 8.6
o
mol), DMAP (11.0 g, 0.09 mol) and CH2Cl2 (45.0 L). To the stirring solution at 0 C was
added a solution of SOCl2 (428.3 g, 3.6 mol, in 2.0 L of CH2Cl2) over a period of 3 h. After
o
the addition, the reaction was warmed to 25 C and monitored by TLC until the complete
consumption of tetraethylene glycol. Water (5.0 L) was then added to quench the reaction.
The organic lay was collected, washed with water (10.0 L, three times) and concentrated
under reduced pressure to provide the macrocyclic sulfite intermediate (243.0 g) as brownish
oil. It is noteworthy that, when the reaction mixture volume was far more than 50 L, the
macrocyclization reaction was carried out in portions with a 50 L jacketed reactor. Then, to
a 50 L jacketed reactor was added the macrocyclic sulfite intermediate (243.0 g, 1.0 mol),
CH2Cl2 (2.0 L), CH3CN (2.0 L) and water (3.0 L). After cooled to 0 oC, NaIO4 (259.6 g, 1.2
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mol) and RuCl3 3H2O (1.3 g, 5.1 mmol) were added. The stirring reaction mixture was
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gradually warmed to 25 C and monitored by TLC. Upon the completely consumption of
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the macrocyclic sulfite, the reaction mixture was filtered through a pad of Celite and the
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solution was washed with water.
After removal of the solvent under vacuum,
recrystallization of the residue with methanol (0.8 L) at room temperature gave the
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macrocyclic sulfate 1 (210.0 g, 46%) as a white crystal. Macrocyclic sulfate 1: H NMR
(CDCl3, 400 MHz) δ 3.60ꢀ3.68 (m, 4H), 3.68ꢀ3.74 (m, 4H), 3.85 (t, J = 6.0 Hz, 4H), 4.48 (t,
J = 6.0 Hz, 4H).
Macrocyclic sulfate 9 was obtained as a byproduct with a yield of less than 2% when the
1
reaction was carried out at 0.06 mol/L. H NMR (CDCl3, 400 MHz) δ 3.58ꢀ3.75 (m, 16H),
3.78ꢀ3.90 (m, 8H), 4.40ꢀ4.48 (m, 8H); 13C NMR (CDCl3, 100 MHz) δ 68.3, 70.6, 70.3, 72.2;
HRMS (ESI) calcd for C16H32NaO14S2 ([M+Na]+) 535.1126, found 535.1136.
General procedure for nucleophilic ringꢀopening of the macrocyclic sulfate 1. 1ꢀ
Phenylꢀ2,5,8,11ꢀtetraoxatridecanꢀ13ꢀol (10). A suspension of NaH (31.2 g, 60% in
mineral oil, 0.8 mol) in anhydrous THF (0.5 L) was cooled to 0 oC and a solution of benzyl
alcohol (56.2 g, 0.5 mol) in anhydrous THF (1.0 L) was added slowly at 0 oC. After 30 min
o
of stirring at 0 C, a solution of macrocyclic sulfate 1 (200.0 g, 0.8 mol) in anhydrous THF
(0.5 L) was added slowly. The reaction mixture was stirred until no benzyl alcohol can be
detected by TLC and the reaction was quenched with water (0.1 L). After removal of
solvent under vacuum, the residue was dissolved in water (2.0 L) and washed with EtOAc
(0.5 L, three times). The aqueous layer was concentrated under vacuum. The residue was
dissolved in THF (1.5 L) and water (9.2 g, 0.5 mol) which was acidified to pH 3 with
o
concentrated sulfuric acid and stirred overnight at 25 C. The reaction mixture was
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neutralized with concentrated NaOH solution and concentrated under vacuum. The residue
was diluted with water (1.2 L) and extracted with diisopropyl ether (0.5 L, three times). The
combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum
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to yield 10 as clear oil (132.2 g, 89%). H NMR (CDCl3, 400 MHz) δ 3.56ꢀ3.74 (m, 16H),
4.55ꢀ4.58 (m, 2H), 7.24ꢀ7.38 (m, 5H).
Monobenzylated octaethylene glycol 11 was prepared from alcohol 10 by following the
general procedure for nucleophilic ringꢀopening of the macrocyclic sulfate 1 as clear oil
(101.0 g, 95%). 1H NMR (CDCl3, 400 MHz) δ 3.51ꢀ3.75 (m, 32H), 4.50ꢀ4.60 (m, 2H),
7.16ꢀ7.41 (m, 5H).
Monobenzylated dodecaethylene glycol 12 was prepared from alcohol 11 by following the
general procedure for nucleophilic ringꢀopening of the macrocyclic sulfate 1 as clear oil
(124.3 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 3.56ꢀ3.76 (m, 48H), 4.47ꢀ4.66 (m, 2H),
7.25ꢀ7.38 (m, 5H).
αꢀBenzylꢀωꢀmethylꢀdodecaethylene glycol 13.
Under an argon atmosphere, to a
suspension of NaH (10.8 g, 60% dispersed in mineral oil, 270.9 mmol) in anhydrous THF
o
(1.0 L) at 0 C was slowly added a solution of alcohol 12 (115.0 g, 180.6 mmol) in
anhydrous THF (0.3 L) and the resulting mixture was stirred for 30 min. Iodomethane (51.3
o
g, 361.2 mmol) was added and the reaction mixture was stirred overnight at 25 C. After
quenching the reaction with water (0.1 L), the reaction mixture was concentrated under
vacuum and the residue was dissolved in CH2Cl2 (0.8 L) and washed with water (0.5 L, three
times). The organic layer was concentrated under vacuum and purified by flash
chromatography on silica gel (MeOH/CH2Cl2 = 1/100) to give ether 13 as clear oil (117.5 g,
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99%). H NMR (CDCl3, 400 MHz) δ 3.30ꢀ3.45 (m, 3H), 3.52ꢀ3.58 (m, 2H), 3.60ꢀ3.71 (m,
46H), 3.54ꢀ3.60 (m, 2H), 7.24ꢀ7.39 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 59.0, 69.4,
70.5, 70.56, 70.64, 71.9, 73.2, 127.6, 127.8, 128.4, 138.2; HRMS (ESI) calcd for
C32H62NO13 ([M+NH4]+) 668.4216, found 668.4263.
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Monomethylated dodecaethylene glycol 4. To a 1 L autoclave was added ether 13 (117.5
g, 180.5 mmol) in MeOH (450 mL) and Pd/C (10% on carbon, 22.5 g) and the mixture was
stirred under an atmosphere of hydrogen (3.0 MPa) for 12 h at 25 oC. After filtration of the
mixture through a pad of Celite, the solution was concentrated under vacuum to give alcohol
4 as clear oil (94.1 g, 93%). 1H NMR (CDCl3, 400 MHz) δ 3.38 (s, 3H), 3.52ꢀ3.76 (m,
48H).
Tosylate 5. To a solution of alcohol 4 (60.0 g, 107.0 mmol) in THF (300 mL) was added a
o
solution of NaOH (14.9 g, 374.5 mmol) in water (45 mL). After cooled to 0 C, a solution
of pꢀtoluenesulfony chloride (24.5 g, 128.4 mmol) in THF (150 mL) was slowly added and
o
the resulting mixture was stirred overnight at 25 C. The reaction mixture was concentrated
under vacuum. The residue was dissolved in water (500 mL) and extracted with CH2Cl2
(200 mL, three times). The combined organic layer was dried over anhydrous Na2SO4,
1
concentrated under vacuum to give tosylate 5 as clear oil (74.4 g, 97%). H NMR (CDCl3,
400 MHz) δ 2.32ꢀ2.40 (m, 3H), 3.22ꢀ3.31 (m, 3H), 3.46ꢀ3.61 (m, 46H), 4.02ꢀ4.11 (m, 2H),
7.23ꢀ7.30 (m, 2H), 7.66ꢀ7.73 (m, 2H).
Azide 6. To a solution of tosylate 5 (74.4 g, 104.1 mmol) in DMF (350 mL) was added
o
NaN3 (13.5 g, 208.1 mmol) and the resulting mixture was stirred at 80 C for 4 h.
CAUTION: Because remaining NaN3 can be hazardous, removal of it with the following
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method before evaporating the solvent! To this end, the reaction mixture containing the
excess NaN3 was filtered through a pad of Celite, concentrated under vacuum, dissolved in
water (500 mL) and extracted with CH2Cl2 (300 mL, three times). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give azide 6 as
clear oil (59.6 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 2.55 (s, 2H), 3.36ꢀ3.44 (m, 5H),
3.52ꢀ3.58 (m, 2H), 3.61ꢀ3.71 (m, 42H).
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Amine 7. To a solution of azide 6 (59.6 g, 101.8 mmol) in THF (500 mL) was added
triphenyl phosphine (40.0 g, 152.6 mmol) and the resulting mixture was stirred at room
temperature for 30 min. Water (9.2 g, 508.8 mmol) was added and the mixture was stirred
o
overnight at 45 C. The reaction mixture was concentrated under vacuum, the residue was
dissolved in diethyl ether (500 mL) and washed with water (100 mL, three times). The
aqueous layers were combined and concentrated under vacuum to give amine 7 as clear oil
1
(52.6 g, 92%). H NMR (CDCl3, 400 MHz) δ 2.86 (t, J = 6.0 Hz, 2H), 3.38 (s, 3H), 3.49ꢀ
3.57 (m, 4H), 3.61ꢀ3.69 (m, 42H).
ASSOCIATE CONTENT
1
Supporting information with copies of H NMR, 13C NMR, and HRMS for 1, 4ꢀ7, 9ꢀ13 and
singleꢀcrystal Xꢀray of 1 and 9.
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This work was financially supported by the National Natural Science Foundation of China
(21372181, 21572168) and State Key Laboratory for Modification of Chemical Fibers and
Polymer Materials，Donghua University. We thank Miss Maggi Smith and Dr. Yihua Bruce Yu
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for their help with the manuscript preparation.
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