Synthesis of the impurity F of salbutamol

Article abstract of DOI:10.1080/10286020.2020.1771700

First synthesis of the diastereomeric mixture of salbutamol impurity F is described in seven steps by using 4-hydroxyacetophenone as starting material, with 15.2percent total yield. The synthesis provides access to multi-gram quantities of impurity F with good purity for reference supplies and further analytical and toxicology investigations. (Figure presented.).

Full text of DOI:10.1080/10286020.2020.1771700

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
Synthesis of the impurity F of salbutamol
Shu-Lian Song, Cheng-Xi Lian, Li-Ping Chen & Long-Liang Huang
To cite this article: Shu-Lian Song, Cheng-Xi Lian, Li-Ping Chen & Long-Liang Huang (2020):
Synthesis of the impurity F of salbutamol, Journal of Asian Natural Products Research
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1771700
Synthesis of the impurity F of salbutamol
Shu-Lian Song, Cheng-Xi Lian, Li-Ping Chen and Long-Liang Huang
State Key Laboratory Base for Eco-Chemical Engineering, College of Chemical Engineering, Qingdao
University of Science and Technology, Qingdao 266042, China
ABSTRACT
ARTICLE HISTORY
Received 10 March 2020
Accepted 14 May 2020
First synthesis of the diastereomeric mixture of salbutamol impur-
ity F is described in seven steps by using 4-hydroxyacetophenone
as starting material, with 15.2% total yield. The synthesis provides
access to multi-gram quantities of impurity F with good purity for
reference supplies and further analytical and toxicology
investigations.
KEYWORDS
Salbutamol; impurity
F; synthesis
1. Introduction
Sulbutamol sulfate (Figure 1) as a derivative of adrenaline, an important natural
human hormone, can be used as a bronchodilator for the treatment of asthma, as
well as prevention and relief of bronchospasm induced by exercise [1,2].
It is known that there are several different process impurities associated with the
manufacture of sulbutamol sulfate. Ten of the known specified impurities have been
mentioned in European Pharmacopoeia 6.0. Their structures and names are showed
in Table 1.
According to European Pharmacopoeia 6.0, individual impurity should be <0.3%
and total impurity <1.0%. In the British Pharmacopoeia, the maximum contents of
the related impurities are specified to be 0.5%. The United States pharmacopoeia
requires that total impurity should not be >2.0%. In recent years, new quantitative
CONTACT Long-Liang Huang
huanglj@qust.edu.cn
State Key Laboratory Base for Eco-Chemical Engineering,
College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
S.-L. SONG ET AL.
Figure 1. The chemical structure of salbutamol sulfate.
Table 1. The structures and chemical names of the specified impurities in EP 6.0.
Specified impurities
A
Chemical names
Structures
4-(2-tert-butylamino-1-methoxy-
ethyl)-2-hydroxymethyl-phenol
B
C
4-(2-tert-butylamino-1-hydroxy-
ethyl)-phenol
4-[2-(benzyl-tert-butyl-amino)-1-
hydroxy-ethyl]-2-
hydroxymethyl-phenol
D
E
5-(2-tert-butylamino-1-hydroxy-
ethyl)-2-hydroxy-benzaldehyde
4-[2-(benzyl-tert-butyl-amino)-1-
hydroxy-ethyl]-2-
hydroxymethyl-phenol
F
1,1-[oxybis[methylene(4-hydroxy-1,3-
phenylene)]]bis[2-[(1,1-
dimethylethyl)amino]ethanol]
G
2-(benzyl-tert-butyl-amino)-1-(4-
hydroxy-3-hydroxymethyl-
phenyl)-ethanone
H
I
4-(2-tert-butylamino-ethyl)-2-
methyl-phenol
1-(4-benzyloxy-3-hydroxymethyl-
phenyl)-2-tert-butylamino-ethanol
(continued)

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Table 1. Continued.
Specified impurities
J
Chemical names
Structures
2-tert-Butylamino-1-(4-hydroxy-3-
hydroxymethyl-phenyl)-ethanone
Figure 2. The chemical structure of impurity F and deoxygenated dimer of salbutamol. Reagents
and conditions: (a) ꢀ37% HCHO, conc. HCl, 50 ꢀC, 75%; (b) BnCl, K2CO3, CH3CN, reflux, 97%; (c)
Ph3P, CBr4, DCM, 0 C-rt, 92%; (d) t-BuOK, THF, 0 ꢀC-rt, 63%; (e) NBS, TsOH, CH3CN, 50 ꢀC, 93%; (f)
NaBH4, MeOH, DCM, 0 ꢀC, 98%; (g) tert-butylamine, i-PrOH, reflux, 48%; (h) Pd/C, THF, rt, 76%.
determination of salbutamol sulfate impurities using achiral supercritical fluid chro-
matography was developed [3]. All of these analyses require impurity references of
sulbutamol. Therefore, it is very important to develop convenient synthetic methods
of these references.
In 2011, Sharma et al. [4] firstly produced impurity F accompanied with other two
impurities by heating salbutamol base with NaOH in MeOH and got it by preparative
HPLC with 87.93% purity. However, there are some confusion in their spectral data espe-
cially for the carbon of position 13 (C-13) in their structure’s determination (Figure 2).
The chemical shift of C-13 was assigned to be 58 ppm, which is very inconsistent with
the chemical shift of carbon connected with oxygen of benzyl ether (about 70 ppm) [5].
In order to get unambiguous structure of impurity F reported by Sharma et al.
and also provide an easy access to this compound for further analytical and toxicol-
ogy investigations, we describe the first total synthesis of impurity F of salbutamol.
The synthesis provides multi-gram quantities of impurity F with good purity for ref-
erence supplies. The structures of intermediate and impurity F were confirmed by
1H, 13C NMR and HRMS.
2. Results and discussion
In 2002, Nizar Haddad et al. [6] first synthesized deoxygenated “side-by-side” dimer
of salbutamol (Figure 2) by using 4-bromophenol as starting material. In their pro-
cess, tributylvinyltin was coupled with bromide to introduce the vinyl group, which
can subsequently be functionalized to the key part 2-(tert-butylamino)ethan-1-ol of
salbutamol. However, as very toxic and dangerous compounds, tributylvinyltin should
be avoided to use in the synthesis process as much as possible. It should be feasible

4
S.-L. SONG ET AL.
Scheme 1. Synthetic route of the impurity F. Reaction conditions:(i) i-PrOH, reflux, 7 h.
to use safer and commercial unavailable vinyl boric acid and its esters instead of trib-
utylvinyltin or avoid the vinyl intermediate.
The impurity F of salbutamol is the diastereomeric O-dimer mixture of salbutamol
and symmetric without considering the chiral center. With avoiding using vinyl inter-
mediate in mind, the total synthetic route was designed by using 1-(4-hydroxypheny-
l)ethan-1-one as starting material containing the carbonyl group which can be easily
transformed to the key part 2-(tert-butylamino)ethan-1-ol of salbutamol and the syn-
thetic route is showed in Scheme 1.
According to the method reported by Chris Meier et al. [7], 1-(4-hydroxy-3-
(hydroxyl methyl)phenyl)ethan-1-one 2 was obtained in 75% yield by reaction of 1-
(4-hydroxy phenyl)ethan-1-one 1 with 37% formaldehyde solution and concentrated
HCl at 50 ꢀC for 5 h and subsequent hydroxylation with CaCO3 in the mixture of
THF/water. Selective protection of phenolic hydroxyl group of 2 by benzyl group
afforded compound 3 in 97% yield. Bromination of hydroxyl group of benzyl alcohol
3 by Appel reaction [8] afforded bromide 4 in 92% yield.
2.1. The synthesis of compound 5
In our synthetic route of impurity F, the key step is the synthesis of compound 5 by
using classic Williamson ether reaction which normally works under alkaline condi-
tion. In the structures of intermediates 3 and 4, the carbonyl group easily condensed
by aldol condensation under Williamson ether condition. In order to avoid the pos-
sible aldol reaction, the reaction condition was optimized.
The anhydrous solvents were used to avoid the hydroxylation of bromide 4 under
alkaline condition. The effects of different solvents and bases on the reaction were
studied, and the results were showed in Table 2. The addition sequence of starting
materials especially the base had a significant influence on the yield of the product,
and the result indicated that it is better to add base to the mixture of compounds 3

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Table 2. Optimization of the reaction conditions on synthesizing compound 5.
Entry
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
t-BuOKa
t-BuOKa
t-BuOKa
t-BuOKa
NaHa
DMF
PhF
Dioxane
THF
THF
THF
THF
DMF
THF
58
48
53
63
54
32
48
35
15
20
CH3ONaa
DBUa
NaHa
9
10
NaHb
t-BuOKb
THF
Reaction condition:
aAlcohol 3 and bromide 4 were mixed in the solvent, base was added in small portions at 0 ꢀC.
bAlcohol 3 and base were mixed and bromide 4 was added in small portions.
Scheme 2. The reaction of 7 with t-BuNH2.
and 4 (Table 2, entry 4, 10 and 5, 9). The yield was 63% when using t-BuOK in THF
(entry 4); the yield was a little lower when using DMF (N,N-Dimethylformamide) as
solvent (Table 2, entry 1); treatment of 4 with t-BuOK in PhF and dioxane respect-
ively gave 5 in 28% and 53% (Table 2, entry 2, 3). Using other bases such as NaH,
CH3ONa and DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) in THF also gave lower yield
(Table 2, entry 5, 6, 7).
The bromination at a position of carbonyl group in compound 5 by using NBS in
the presence of TsOH to afford compound 6 in 93% yield. Reduction of the carbonyl
group of compound 6 with NaBH4 in the mixture solvent of DCM/MeOH afforded
compound 7 in quantitative yield.
2.2. The synthesis of compound 8
As shown in Scheme 2, interestingly, when compound 7 reacted with t-BuNH2, two
compounds 8 and by-product 10 were obtained in the ratio of 6:4, the structure of
by-product 10 was confirmed by the 1D NMR (1H, 13C and DEPT), 2D NMR
(1H-1H COSY and HMQC) (all of the original spectrum are supplied in Supporting
Information) and HRMS, and the results indicated that the formation of 10 is pos-
sible through epoxy intermediate which easily formed under the alkaline condition in
the reaction, and then the ring of epoxy was open by t-BuNH2 to afford compound 8
and compound 10. The possible mechanism of reaction of compound 7 with t-
BuNH2 shown in Scheme 3 was verified by reaction of compound 11 with t-BuNH2.
Compound 11 was obtained by reacting compound 7 with strong base NaH in DMF

6
S.-L. SONG ET AL.
Scheme 3. The possible mechanism of the formation of 10.
and the ring of epoxy of compound 11 was opened by t-BuNH2 to afford compounds
8 and 10 in similar ratio as the reaction of 7 with t-BuNH2.
Removal of benzyl group of compound 8 by palladium catalytic hydrogenation in
the solvent of THF afforded the product 9 in 76% yield.
2.3. Conclusion
The impurity F of salbutamol was firstly synthesized in seven steps by using 4-
hydroxyacetophenone as starting material with 15.2% total yield. The synthesis pro-
vides multi-gram quantities of impurity F with good purity for reference supplies and
further analytical and toxicology investigations.
3. Experimental
3.1. General experimental procedures
1H-NMR and 13C-NMR spectra were recorded on Bruker 500 MHz and 125 MHz
1
instruments (Bruker, Rheinstetten, Germany) except compound 10. H-NMR, 13C-
NMR, DEPT and 2D NMR spectra of compound 10 were recorded on Bruker
600 MHz instruments (Bruker, Rheinstetten, Germany). Chemical shifts are reported
relative to tetramethylsilane as internal standard. Mass spectra were performed on an
XEVO g2-XS (Waters Corporation, Worcester, MA, USA) equipped with an ESI
source. Reagents were all purchased from commercial suppliers without further puri-
fication and anhydrous solvents were dried by the standard procedures before using.
Column chromatography was performed with silica gel (200–300 mesh), and analyt-
ical thin-layer chromatography (TLC) used 60-GF254.
3.2. Synthesis of 4-acetylsalicyl alcohol (2)
A mixture of 4-hydroxyacetophenone (20.0 g, 14.7 mmol), formaldehyde solution
(37%, 50 ml, 66.2 mmol) and concentrated hydrochloric acid (150 ml) was stirred at
50 ꢀC for 5 h. The resulting suspension was cooled to room temperature and filtered,
the filter cake was dissolved in THF (250 ml), water (200 ml) and calcium carbonate
(20.6 g, 20.6 mmol) was added. The reaction mixture was stirred at room temperature

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
for 24 h. Concentrated hydrochloric acid was added dropwise to adjust the pH to <7,
and the phases were separated with ethyl acetate. The aqueous layer was extracted
with ethyl acetate twice, and the combined organic layers were dried with magnesium
sulfate. The desired product 2 was obtained by column chromatography (PE/EtOAc
1
¼ 3:1) as a colorless solid (18.0 g, 75%). H NMR(500 MHz, DMSO-d6): d 10.35 (s,
1H), 7.95 (s, 1H), 7.72 (dd, J ¼ 8.5, 2.0 Hz, 1H), 6.85 (d, J ¼ 8.5 Hz, 1H), 5.13 (t,
1
J ¼ 5.5 Hz, 1H), 4.49 (d, J ¼ 5.5 Hz, 2H), 2.47 (s, 3H). 13Cf Hg NMR(125 MHz,
DMSO-d6): d 196.2, 158.8, 128.79, 128.72, 128.4, 127.9, 114.2, 57.8, 26.2. HRESIMS:
m/z 167.0607 [M þ H]þ (calcd for C9H11O3, 167.0608).
3.3. Synthesis of (2-benzyloxy-5-isopropenyl-phenyl)-methanol (3)
To a solution of compound 2 (2.0 g, 12.0 mmol) in acetonitrile (30 ml), benzyl chlor-
ide (1.5 g, 12.3 mmol) and potassium carbonate (2.5 g, 18.1 mmol) were added, and
the reaction mixture was heated under reflux for 4 h. After being cooled to room
temperature, water (40 ml) was added, and the mixture was extracted with EtOAc
(2 ꢁ 10 ml). The combined organic layers were dried over MgSO4, filtered, and con-
centrated under vacuum. The crude product was purified by flash chromatography
1
on silica gel to afford desired product 3 (3.0 g, 97%). HNMR (500 MHz, CDCl3): d
7.19 (s, 1H), 7.85 (dd, J ¼ 8.5, 2.0 Hz, 1H), 7.35–7.29 (m, 5H), 6.93 (d, J ¼ 8.5 Hz,
1
1H), 5.13 (s, 2H), 4.72 (s, 2H), 2.51 (s, 3H). 13C f Hg NMR (125 MHz, CDCl3): d
195.9 (1C), 159.1 (1C), 134.9 (1C), 129.4 (1C), 129.0 (1C), 128.6 (1C), 128.0 (1C),
127.8 (2C), 127.4 (1C), 126.3 (2C), 110.1(1C), 69.3 (1C), 60.3 (1C), 25.4 (1C).
HRESIMS: m/z 257.1179 [M þ H]þ (calcd for C16H17O3, 257.1178).
3.4. Synthesis of 1-(4-benzyloxy-3-bromomethyl-phenyl)-ethanone (4)
A solution of compound 3 (2.0 g, 7.8 mmol) in dry dichloromethane (20 ml) was
treated with triphenylphosphine (2.7 g, 10.3 mmol) and carbon tetrabromide (3.4 g,
10.2 mmol) at 0 ꢀC. The reaction mixture was stirred at 0 ꢀC for 30 min, then satu-
rated aqueous sodium bicarbonate (20 ml) was added. The organic layer was washed
with brine, dried over magnesium sulfate, and concentrated under vacuum. The resi-
due was purified by silica gel column chromatography (PE/EA ¼ 3:1) to afford com-
1
pound 4 as white solid (2.3 g, 92%). H NMR (500 MHz, CDCl3): d 7.93 (s, 1H), 7.84
(dd, J ¼ 8.5, 2.0 Hz, 1H), 7.43–7.28 (m, 5H), 6.90 (d, J ¼ 8.5 Hz, 1H), 5.18 (s, 2H),
1
4.55 (s, 2H), 2.50 (s, 3H). 13Cf Hg NMR (125 MHz, CDCl3): d 192.2 (1C), 159.2
(1C), 134.9 (1C), 130.4 (1C), 130.1 (1C), 129.4 (1C), 127.7 (2C), 127.2 (1C), 126.1
(2C), 125.7 (1C), 110.7 (1C), 69.4 (1C), 27.1 (1C), 25.2 (1C). HRESIMS: m/z 319.0340
[M þ H]þ (calcd for C16H16BrO2, 319.0334).
3.5. Synthesis of 1-f3-[2-(2-acetyl-5-benzyloxy-phenyl)-ethoxymethyl]-4-
benzyloxy-phenylg-ethanone (5)
To a solution of compound 3 (5.0 g, 19.5 mmol) and compound 4 (6.9 g, 21.5 mmol)
in anhydrous THF (150 ml) at 0 ꢀC, was added t-BuOK (2.4 g, 21.5 mmol) slowly in
small portions over 0.5 h. The resulting reaction mixture was allowed to warm to

8
S.-L. SONG ET AL.
room temperature and stirred at room temperature overnight. Water (60 ml) and
EtOAc (50 ml) were added, the organic layer was separated, and the water phase was
extracted with EtOAc (2 ꢁ 30 ml). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude prod-
uct was purified by flash chromatography on silica gel using PE/EA/DCM (4:1:0.5) as
1
eluent to afford desired product 5 as white solid (6.35 g, 63%). H NMR (500 MHz,
CDCl3): d 8.06 (s, 2H), 7.84 (dd, J ¼ 8.6, 2.0 Hz, 2H), 7.32–7.25 (m, 10H), 6.90 (d,
1
J ¼ 8.6 Hz, 2H), 5.09 (s, 4H), 4.69 (s, 4H), 2.48 (s, 6H). 13Cf Hg NMR (125 MHz,
CDCl3): d 195.9 (2C), 158.9 (2C), 135.2 (2C), 129.3 (2C), 128.7 (2C), 128.5 (2C),
127.6 (4C), 127.1 (2C), 126.2 (2C), 126.0 (4C), 110.0 (2C), 69.1 (2C), 66.4 (2C), 25.3
(2C). HRESIMS: m/z 517.1991 [M þ Na]þ (calcd for C32H30O5Na, 517.1991).
3.6. Synthesis of 1-(4-benzyloxy-3-f2-[5-benzyloxy-2-(2-bromoacetyl) phenyl]-
ethoxymethylg-phenyl)-2-bromo-ethanone (6)
To a solution of compound 5 (2.0 g, 4.0 mmol) in acetonitrile (20 ml), were added
NBS (N-bromosuccinimide) (1.5 g, 8.2 mmol) and p-toluene sulfonic acid monohy-
drate (1.6 g, 8.2 mmol). Then the reaction mixture was stirred at 50 ꢀC overnight.
Water (40 ml) and EtOAc (20 ml) were added, the organic layer was separated, and
the water phase was extracted with EtOAc (2 ꢁ 10 ml). The combined organic layers
were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum.
The crude product was purified by flash chromatography on silica gel using DCM/PE
1
(1:1) as eluent to afford desired product 6 (2.4 g, 93%). H NMR(500 MHz, CDCl3): d
8.13 (s, 2H), 7.94 (d, J ¼ 8.6 Hz, 2H), 7.37–7.33 (m, 10H), 6.98 (d, J ¼ 8.6 Hz, 2H),
1
5.16 (s, 4H), 4.76 (s, 4H), 4.39 (s, 4H). 13Cf Hg NMR (125 MHz, CDCl3): d 190.1
(2C), 160.5 (2C), 136.0 (2C), 130.6 (2C), 129.8 (2C), 128.7 (4C), 128.3 (2C), 127.7
(2C), 127.1 (4C), 126.9 (2C), 111.3 (2C), 70.3 (2C), 67.4 (2C), 30.8 (2C). HRESIMS:
m/z 673.0198 [M þ Na]þ (calcd for C32H28O5Br2Na, 673.0201).
3.7. Synthesis of 1-(4-benzyloxy-3-f2-[5-benzyloxy-2-(2-bromo-1-hydroxyethyl)-
phe nyl]-ethoxymethylg-phenyl)-2-bromoethanol (7)
To a solution of compound 6 (2.0 g, 3.1 mmol) in CH2Cl2/MeOH (1:1, 20 ml) at 0 ꢀC,
was added NaBH4 (0.24 g, 6.2 mmol), and the reaction mixture was stirred at room
temperature for 1 h. Water (50 ml) and CH2Cl2 (20 ml) were added, the organic layer
was separated, and the water phase was extracted with CH2Cl2 (2 ꢁ 20 ml). The com-
bined organic layers were washed with water (2 ꢁ 20 ml), dried over MgSO4, filtered,
and concentrated under vacuum to afford the crude product 7 (1.96 g, 98%), which
1
was used for next step without further purification. H NMR (500 MHz, CDCl3): d
7.47 (s, 2H), 7.39–7.29 (m, 12H), 6.90 (d, J ¼ 8.4 Hz, 2H), 5.08 (s, 4H), 4.84 (m, 2H),
1
4.73 (s, 4H), 3.58–3.54 (m, 2H), 3.52–3.48 (m, 2H). 13C f Hg NMR (125 MHz,
CDCl3): d 155.1 (2C), 135.9 (2C), 131.6 (2C), 127.5 (4C), 126.9 (2C), 126.7 (2C),
126.1 (4C), 125.7 (2C), 125.1 (2C), 110.7 (2C), 72.5 (2C), 69.0 (2C), 66.6 (2C), 39.1
(2C). HRESIMS: m/z 677.0518 [M þ Na]þ (calcd for C32H32O5Br2Na, 677.0514).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
9
3.8. Synthesis of 1-f4-benzyloxy-3-[2-benzyloxy-5-(2-tert-butylamino-1-
hydroxyethyl)-benzyloxymethyl]-phenylg-2-tert-butylamino-ethanol (8) and
its isomer (10)
A solution of compound 7 (2.0 g, 4.0 mmol) in tert-butylamine/i-PrOH (1:1, 40 ml)
was heated to reflux for 7 h. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography on silica gel by using DCM/
MEOH/NH3ꢂH2O (10:1:0.1) as eluent to afford desired product solid 8 (0.94 g) as
pale yellow solid and a sticky compound 10 (0.62 g). Compound 8: 1H NMR
(500 MHz, CDCl3): d 7.46 (s, 2H), 7.40–7.24 (m, 12H), 6.88 (d, J ¼ 8.5 Hz, 2H), 5.07
(s, 4H), 4.74 (s, 4H), 4.54 (m, 2H), 2.83 (m, 2H), 2.57 (m, 2H), 1.07 (s, 18H).
1
13Cf Hg NMR(125 MHz, CDCl3): d 155.6 (2C), 137.3 (2C), 135.2 (2C), 128.5 (4C),
127.7 (2C), 127.4 (2C), 127.1 (4C), 126.8 (2C), 125.9 (2C), 111.7 (2C), 72.1 (2C), 70.1
(2C), 67.77 (2C), 50.30 (2C), 50.33 (2C), 29.2 (6C). HRESIMS: m/z 641.3955
[M þ H]þ (calcd for C40H53N2O5, 641.3954).
1
Compound 10: H NMR (600 MHz, CDCl3): d 7.50 (d, J ¼ 5.4 Hz, 1H), 7.39–7.25
(m, 12H), 7.13 (d, J ¼ 7.8 Hz, 1H), 6.89 (d, J ¼ 8.4 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz, 1H),
5.07 (s, 2H), 5.05 (s, 2H), 4.75–4.70 (m, 4H), 4.60 (d, J ¼ 7.2 Hz, 1H), 3.81 (m, 1H),
3.50 (m, 1H), 3.26 (m, 1H), 2.85 (m, 1H), 2.61 (m, 1H), 1.10 (s, 9H), 1.01 (s, 9H).
1
13Cf Hg NMR(150 MHz, CDCl3): d 155.5 (1C), 155.2 (1C), 137.2 (1C), 136.1 (1C),
136.0 (1C), 135.0 (1C), 128.5 (2C), 127.7 (1C), 127.65 (1C), 127.63 (1C), 127.33 (1C),
127.31 (1C), 127.02 (1C), 126.97 (1C), 126.93 (1C), 126.6 (1C), 126.54 (1C), 126.50
(1C), 125.86 (1C), 125.83 (1C), 111.6 (1C), 111.5 (1C), 71.9 (1C), 70.01 (1C), 69.99
(1C), 67.7 (1C), 67.6 (1C), 66.8 (1C), 58.0 (1C), 51.32 (1C), 51.30 (1C), 50.7 (1C),
50.3 (1C), 30.4 (3C), 28.9 (3C). HRESIMS: m/z 641.3956 [M þ H]þ (calcd for
C40H53N2O5, 641.3954).
3.9. Synthesis of 1,1-[oxybis[methylene(4-hydroxy-1,3-phenylene)]]bis [2-[(1,1-
dimethylethyl)amino]ethanol] (9)
A mixture of compound 8 (2.0 g, 3.1 mmol) and 10% palladium on carbon (0.1 g) in
THF (10 ml) was stirred under hydrogen at room temperature overnight. The catalyst
was filtered and washed with THF, and the combined filtrate was removed under
reduced pressure. The crude product was purified by flash chromatography on silica
gel using DCM/MeOH/NH3ꢂH2O (10:1:0.1) as eluent to afford desired product 9 as
1
white solid (1.1 g, 76%). H NMR (500 MHz, DMSO-d6): d 7.25 (s, 2H), 7.05 (d,
J ¼ 7.95 Hz, 2H), 6.75 (d, J ¼ 8.2 Hz, 2H), 4.49 (s, 6H), 2.60 (d, J ¼ 8.3 Hz, 4H), 2.47
1
(d, J ¼ 1.45 Hz, 2H), 1.04 (s, 18H). 13Cf Hg (125 MHz, DMSO-d6) d 153.9 (2C), 134.1
(2C), 126.4 (2C), 125.8 (2C), 124.2 (2C), 114.5 (2C), 71.4 (2C), 67.0 (2C), 51.0 (2C),
50.1 (2C), 27.9 (6C). HRESIMS: m/z 461.3015 [M þ H]þ (calcd for
C26H41N2O5, 461.3015).
Acknowledgments
The authors acknowledge Dr. PeiCheng Zhang and Qunqun Guo for useful discussion and Dr.
Yan Wu for assistance in the NMR.

10
S.-L. SONG ET AL.
Disclosure statement
No potential conflict of interest was reported by the authors.
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