New insights into bromination process: Effective preparation of Ambroxol

Article abstract of DOI:10.1515/chempap-2015-0077

Ambroxol used as an expectorant in treating respiratory diseases was effectively prepared with a total yield of 62 %, with o-toluidine as the feedstock via successive procedures of electrophilic bromination, acetylation, radical benzylic bromination, N-alkylation and hydrolysis processes. The addition of aqueous hydrogen peroxide could enhance the utilisation of liquid bromine in the electrophilic bromination of o-toluidine, avoiding the hazardous HBr generated as a by-product. In addition, liquid bromine promoted by MnO₂ was used efficiently for the radical benzylic bromination of N-acetyl-N-(2,4-dibromo-6-methylphenyl)acetamide under mild conditions.

Full text of DOI:10.1515/chempap-2015-0077

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Chemical Papers 69 (5) 722–728 (2015)
DOI: 10.1515/chempap-2015-0077
ORIGINAL PAPER
New insights into bromination process: effective preparation
of Ambroxol
Jun-Hui Xu, Yan-Qiong Ma, Jian-Ping Wei, Fang-Mei Li, Xin-Hua Peng*
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China
Received 12 June 2014; Revised 8 October 2014; Accepted 8 October 2014
Ambroxol used as an expectorant in treating respiratory diseases was effectively prepared with
a total yield of 62 %, with o-toluidine as the feedstock via successive procedures of electrophilic
bromination, acetylation, radical benzylic bromination, N-alkylation and hydrolysis processes. The
addition of aqueous hydrogen peroxide could enhance the utilisation of liquid bromine in the elec-
trophilic bromination of o-toluidine, avoiding the hazardous HBr generated as a by-product. In
addition, liquid bromine promoted by MnO2 was used efficiently for the radical benzylic bromina-
tion of N-acetyl-N-(2,4-dibromo-6-methylphenyl)acetamide under mild conditions.
c
ꢀ 2014 Institute of Chemistry, Slovak Academy of Sciences
Keywords: Ambroxol, electrophilic bromination, radical benzylic bromination, total synthesis
Introduction
lation, condensation with trans-4-aminocyclohexanol
and reduction to afford the title compound (Yu et
al., 1996). In addition, o-aminobenzaldehyde under-
went bromination on the aromatic ring, condensation
with trans-4-aminocyclohexanol and finally reduction
to the target compound (Ratz et al., 1991; Latli et
al., 2010; Romeo et al., 1986; Liebenow & Grafe,
1985). However, both of the above entailed conden-
sation and reduction processes, which produced large
amounts of by-products and bore high costs. In the
present study, a modified and efficient way for the
synthesis of Ambroxol with a total yield of 62 % was
conducted towards an industrial application, using
o-toluidine as the feedstock with various organic units
involving electrophilic bromination, acetylation, radi-
cal benzylic bromination, N-alkylation and hydrolysa-
tion (Fig. 1).
Ambroxol, chemically described as trans-4-[(2-
amino-3,5-dibromobenzyl)-amino]-cyclohexanol, is a
potent mucolytic agent used in the treatment of res-
piratory disorders associated with abnormal mucus
secretion and impaired mucus transport (Malerba &
Ragnoli, 2008; Weiser, 2008). It is an active ingre-
dient with a long history of use that affects the pa-
rameters considered as the basis for the physiological
production and transport of bronchial mucus (Olivieri
et al., 1987). Furthermore, Ambroxol exhibits anti-
inflammatory and antioxidant properties that are ben-
eficial in balancing inflammatory reactions to alleviate
the symptoms of coughs and colds (Beeh, 2008). It
also exerts a local anaesthetic effect, which serves to
relieve pain in acute sore throats. Given Ambroxol’s
multi-factorial properties, it is highly significant to in-
vestigate the synthesis and technology of Ambroxol
preparation.
Experimental
The research published to date on Ambroxol prepa-
ration has varied according to the starting mate-
rials. In general, methyl o-aminobenzoate was used
as the starting material, which subsequently under-
went bromination, hydrazinolysis, methyl sulphony-
General
All chemical reagents and solvents (analytical
grade) were used as supplied (Aladdin, China) unless
otherwise stated. All experiments were monitored by
*Corresponding author, e-mail: xhpeng@mail.njust.edu.cn
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 5/18/15 3:07 PM

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
J. H. Xu et al./Chemical Papers 69 (5) 722–728 (2015)
723
Fig. 1. Synthetic route to Ambroxol: i) H2O2 (2.0 eq.)/Br2 (1.0 eq.), r.t., CH2Cl2/H2O, 8 h, 90 %; ii) acetic anhydride, reflux,
H2SO4 (96 %; cat.), 6 h, 96 %; iii) MnO2 (2.0 eq.)/Br2 (1.0 eq.), r.t., CH2Cl2, 1.5 h, 86 %; iv) trans-4-aminocyclohexanol
(3.0 eq.), KOH (cat.), reflux, ethanol, 5 h, 94 %; v)H2SO4 (0.5 M), refluxing, ethanol, 20 h, 89 %.
thin-layer chromatography (TLC). The spots on the
TLC plates were made visible by exposure to ultravi-
olet light (254 nm). Column chromatography was car-
ried out using silica gel (45–75 m). HPLC analysis
was performed using an Agilent 1200 (USA) equipped
with a 250 mm × 4.6 mm capillary column (ZORBAX
Eclipse XDB-C18, 5 m; solvent system MeOH/H2O
(ϕr = 9 : 1); flow-rate 1 mL min−1; λ = 254 nm).
1H NMR spectra were recorded on a Bruker Avance
III 500 MHz Digital NMR Spectrometer (Germany)
at 500 MHz using CDCl3 or DMSO-d6 as solvents.
The coupling constants are reported in hertz (Hz) and
the chemical shifts in δ relative to internal standard
(TMS). Melting points were determined using a Buchi
535 (Switzerland) melting point apparatus and are
uncorrected. All MALDI-TOF mass spectra analyses
were obtained using a Bruker Microflex LRF instru-
ment and Agilent 1100 series liquid chromatography-
mass spectrometer (LC-MS) by the ESI method of
ionisation.
dropwise. The reaction mixture was then stirred at
ambient temperature and the progress of the reac-
tion was monitored by TLC. At the end of the re-
action (6–8 h), the mixture was transferred into a
separating funnel and a solution of 5 mM NaHSO3
(10 mL) was added. The crude product was then ex-
tracted using dichloromethane (10 mL) and the or-
ganic phases washed with water (2 × 10 mL). The
mixture was dried over anhydrous Na2SO4. The sol-
vent was evaporated under reduced pressure and the
crude reaction mixture isolated by column chromatog-
raphy (hexane/EtOAc, ϕr = 5 : 1) and the pure prod-
uct was identified by comparison with data in the lit-
erature (Bagmanov, 2009).
2,4-Dibromo-6-methylbenzenamine (Ia)
White needle crystals; yield 90 % (1.18 g), m.p.
1
47.4–48.0◦C; H NMR (CDCl3, 500 MHz), δ: 2.20 (s,
3H, -CH3), 4.03 (bs 2H, -NH2), 7.13 (d, J = 1.9 Hz,
1H, -ArH), 7.43 (d, J = 1.9 Hz, 1H, -ArH); 13C NMR
(CDCl3, 125 MHz), δ: 18.2, 109.1, 109.4, 124.9, 131.9,
132.0, 141.4. MS (m/z, ESI): 264.501 [M + H]+ (calc.
for C7H8Br2N, 264.503).
Typical example procedure for o-toluidine
bromination with H O -Br system
o-Toluidine (5.0 mmol) was dissolved in dichloro-
methane (15 mL) and water (15 mL). Liquid bromine
(800 mg, 5.0 mmol) in dichloromethane (5 mL) was
added dropwise over a period of 2 h under vigorous
agitation. At the same time, a 30 mass % aqueous so-
lution of H2O2 (mass fraction, 10.0 mmol) was added
Typical example procedure procedure for pro-
tection of amino group in Ia
Ia (5.0 mmol) was dissolved in acetic anhydride
(15 mL), catalytic amounts of concentrated sulphuric
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 5/18/15 3:07 PM

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
724
J. H. Xu et al./Chemical Papers 69 (5) 722–728 (2015)
acid (two drops) was added with stirring. The mixture
was heated to reflux. The reaction progress was moni-
tored by TLC and on completion (5–6 h) the mixture
was quenched by the addition of 100 g cracked ice.
The white solid precipitate (1.73 g, yield of 98 %)
formed was filtered and washed with water (100 mL)
and purified by recrystallisation from petroleum ether
(15 mL).
Typical example procedure for N-alkylation
with trans-4-aminocyclohexanol
Trans-4-aminocyclohexanol (3.0 mmol) and aque-
ous 10 mass % potassium hydroxide (5.0 mmol) in
10 mL of ethanol was vigorously agitated. Next, III
(1.0 mmol) in ethanol (15 mL) was added over a pe-
riod of 1 h. The mixture was refluxed gently until
completion monitored by TLC (4–5 h), then the mix-
ture was poured into water and kept in a refrigerator
overnight. The crude product thus formed was quan-
titatively analysed by HPLC (Table 1S). The pure
product was isolated using column chromatography
(hexane/EtOAc, ϕr = 8 : 1).
N-acetyl-N-(2,4-dibromo-6-methylphenyl)
acetamide (IIa)
White needle crystals; yield 1.67 g (96 %), m.p.
1
88.4–89.0◦C; H NMR (CDCl3, 500 MHz), δ: 2.20 (s,
3H, -CH3), 2.29 (s, 6H, 2 × -COCH3), 7.45 (d, J =
1.8 Hz, 1H, -ArH), 7.71 (d, J = 1.8 Hz, 1H, -ArH);
13C NMR (CDCl3, 125 MHz), δ: 18.4, 26.1, 123.4,
124.6, 123.3, 133.6, 136.8, 140.1, 171.5. MS (m/z, ESI):
349.788 [M + H]+ (calc. for C11H12Br2NO2, 349.781).
Elemental analysis calculation for C11H11Br2NO2: C,
37.69; H, 3.09; N, 4.12; found: C, 37.85; H, 3.18; N,
4.01.
Trans-4-(2-acetylamino-3,5-dibromobenzyl)
aminocyclohexanol (IVa)
Light yellow needle crystals; yield 3.37 g (80 %),
m.p. 128.3–129.1◦C, 1H NMR (CDCl3, 500 MHz),
δ: 1.39–1.48 (m, 2H, -CH2), 1.64 (bs, 3H,-CHOH, -
NH), 1.70–1.76 (m, 4H,-CH2), 2.10–2.14 (m, 2H, -
CH2), 2.26 (s, 3H, -COCH3), 3.60–3.68 (m, 2H, -
CH,-NH), 4.33 (s, 2H,-CH2NH), 6.94 (d, J = 2.1 Hz,
1H, -ArH), 7.55 (d, J = 2.1 Hz, 1H, -ArH); 13C
NMR (CDCl3, 125 MHz), δ: 26.4, 27.5, 30.9, 33.7,
34.3, 60.9, 123.6, 125.43, 133.8, 136.3, 136.5, 139.1,
171.9. MS (m/z, ESI): 420.981 [M + H]+ (calc. for
C15H21Br2N2O2, 420.987). Elemental analysis calcu-
lation for C15H20Br2N2O2, C, 42.93; H, 4.90; N, 6.58;
found: C, 42.88; H, 4.80; N, 6.67.
Typical example procedure for radical reaction
on bromination of N-acetyl-N-(2,4-dibromo-6-
methylphenyl)acetamide with MnO /Br
IIa (1.0 mmol) was dissolved in dichloromethane
(10 mL). Commercially available non-activated MnO2
(2.0 mmol) was added first and then liquid bromine
(1.0 mmol) in 5 mL dichloromethane was added drop-
wise over a period of 2 h under vigorous agitation
at ambient temperature using an ambient temper-
ature water bath. The entire progress of the reac-
tion was monitored by TLC. After 1 h the reac-
tion was quenched by the addition of water (20 mL)
and the precipitated MnO2 was filtered and washed
with dichloromethane (10 mL). The combined organic
phase was washed to neutral reaction and dried over
anhydrous Na2SO4. The solvent was evaporated un-
der reduced pressure and a brown solid was formed.
The crude product (3.50 g, yield of 92 %) was purified
by recrystallisation from hexane (30 mL) and white
needles were obtained.
Typical example procedure procedure
for preparation of title compound by hydrolysis
IVa (1.0 mmol) in aqueous H2SO4 (0.5 mol L−1
;
10 mL) and ethanol (10 mL) were mixed together. The
mixture was refluxed until completion monitored by
TLC (20 h). Once cooled, a saturated aqueous solution
of Na2CO3 (≈ 30 mL) was added slowly to adjust the
pH of the solution to 12. Next, the organic phase was
extracted using dichloromethane (20 mL) and washed
with water (30 mL). The organic phase was dried over
anhydrous Na2SO4 and concentrated, purified by re-
crystallisation using ethanol (15 mL) and identified by
comparison with the data in the literature (Larsson et
al., 1997).
N-acetyl-N-(2,4-dibromo-6-(bromomethyl)-
phenyl)-acetamide (III)
White needle crystals; yield 3.67 g (86 %), m.p.
Ambroxol
1
118.2–119.4◦C; H NMR (CDCl3, 500 MHz), δ: 2.38
(s, 6H, 2 × -COCH3), 4.26 (s, 2H, -CH2Br), 7.67 (d, J
= 2.1 Hz, 1H, -ArH), 7.84 (d, J = 2.1 Hz, 1H, -ArH);
13C NMR (CDCl3, 125 MHz), δ: 26.4, 27.5, 123.6,
125.5, 133.8, 136.3, 136.6, 139.1, 171.9. MS (m/z, ESI):
427.490 [M + H]+ (calc. for C11H11Br3NO2, 427.493).
Elemental analysis calculation for C11H10Br3NO2, C,
30.87; H, 2.36; N, 3.27; found: C, 31.00; H, 2.45; N,
3.15.
White needle crystals; yield 3.37 g (89 %) m.p.
92.0–93.1◦C (lit. 92.4◦C); 1H NMR (CDCl3,
500 MHz), δ: 1.11–1.19 (m, 2H, -CH2), 1.27–1.61
(bs and m, 5H, -OH, -NH, -CH2), 1.85–1.74 (m,
1H, -CH2), 1.99–2.00 (m, 4H, -CH2), 2.44–2.50 (m,
1H, -CHN), 3.60–3.66 (m, 1H, -CH), 3.80 (s, 2H,
-ArCH2N), 5.31 (bs, 2H, -ArNH2), 7.10 (d, 1H, J
= 2.1 Hz, -ArH), 7.48 (d, 1H, J = 2.1 Hz, -ArH).
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 5/18/15 3:07 PM

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
J. H. Xu et al./Chemical Papers 69 (5) 722–728 (2015)
Table 1. Effect of reaction conditions on synthesis of 2,4-dibromo-6-methylbenzenamine
725
Yieldc/%
Entry
Reaction conditionsa
Conversionb/%
Ia
Ib
1
2
3
4
5
2NBS-H2Od(1NBS-H2O)
2NBS-CCld4(1NBS-CCl4)
2NBS-EtOAcd(1NBS-EtOAc)
2NBS-CH2Cld2(1NBS-CH2Cl2)
2NBS-EtOHd(1NBS-EtOH)
2Br2-H2O(1Br2-H2O)
2Br2-ClCH2CH2Cl
99.0 (79.0)
94.5 (77.5)
86.3 (77.9)
93.1 (71.7)
85.2 (70.1)
85.1 (52.1)
86.3
87.0 (30.5)
83.4 (11.8)
76.0 (12.9)
80.8 (3.8)
74.7 (8.1)
59.7 (15.7)
48.9
– (8.5)
– (46.0)
– (48.4)
– (61.5)
– (50.1)
8.1 (17.1)
35.0
6
7
8
2Br2-EtOH
75.4
45.3
29.1
9
2Br2-EtOAc
77.6
46.0
27.3
10
11
12
13
14
15e
16f
2Br2-CH2Cl2(1Br2-CH2Cl2)
2Br2-CH2Cl2-H2O
2Br2-ClCH2CH2Cl-H2O
2Br2-EtOH-H2O
87.2 (54.1)
96.5
50.3 (16.3)
89.4
34.1 (18.1)
–
93.4
78.7
90.2
92.5
84.1
66.3
81.2
89.8
–
4.1
3.0
–
2Br2-EtOAc-H2O
2H2O2-1Br2− CH2Cl2-H2O
4H2O2-2HBr CH2Cl2-H2O
90.0
88.2
–
−
a) The number preceding the chemical reagent denotes the mole equivalent to the substrate, a suspension of 2-toluidine (5.0 mmol)
in 30 mL of solvent and the volume ratio was controlled to 1 : 1 for the mixed solvent, r.t.; the values in parenthesis means another
bromination conditions and corresponding results; b) determined by gas chromatographic analysis; c) isolated yields after column
chromatography; d) 3.0 % of 2-amino-3,5-dibromobenzaldehyde was also formed; e) molecular bromine (800 mg, 5.0 mmol) in 5 mL
dichloromethane followed by 30 % aqueous hydrogen peroxide (10.0 mmol) were added dropwise to o-toluidine (5.0 mmol) in 15 mL
of dichloromethane and 15 mL of water under vigorous agitation at ambient temperature; f ) 10 mass % aqueous hydrogen bromide
10.0 mmol) followed by 30 % aqueous hydrogen peroxide (20.0 mmol) were added dropwise to o-toluidine (5.0 mmol) in 15 mL of
dichloromethane and 15 mL of water under vigorous agitation.
MS (m/z, ESI): 378.713 [M + H]+ (calculated for
C13H19Br2N2O 378.717).
Although the liquid bromine activity in the reac-
tion was lower than the activity of NBS, the use of
liquid bromine is very common in industry and aca-
demic research. Similarly, solvents affected the forma-
tion of Ia with 50.3 % yields in dichloromethane while
achieving 59.7 % yields in water (Table 1, Entries 6–
10) and a mole ratio of bromine to substrate of 1 : 1
exhibited poor selectivity for Ia and Ib. However, an
excellent selectivity for Ia with over 80 % yields in the
organic-water double phase system was achieved with
prospects of efficient industrial preparation by using
twice the amount of liquid bromine (Table 1, Entries
11–14,). As the HBr, evolved by mono-bromination,
combined with the amino group on the aromatic ring
to its protonated NH3+ form, which led to a weak
π-electron density on the aromatic ring, discouraged
further bromination resulting in the formation of Ia,
the moisture readily promoted a functional hydrolysis
in which the free amino group was released to fur-
ther afford a dibrominated product. In addition, wa-
ter with a high dipole moment and dielectric constant
could favour the heterolysis of liquid bromine. Bromi-
nation using molecular bromine exhibits 50 % atom
utilisation in terms of stoichiometry. Accordingly, hy-
drogen peroxide was successfully employed to reduce
Results and discussion
o-Toluidine was a typical electron-rich feedstock
which occurred readily by electrophilic aromatic sub-
stitution in the benzene ring including bromination.
First, N-bromosuccinimide (NBS) was employed in the
preparation of Ia for ease of handling and high se-
lectivity. Water was used as the reaction medium for
its environmentally benign properties (Sheldon, 2005).
Other organic solvents, such as ethyl acetate, halo-
hydrocarbons and ethanol, failed to achieve the se-
lectivity of Ia (Table 1, Entries 1–5,). Ia was formed
with good yields accompanied by small amounts
of an oxidation by-product of 2-amino-3,5-dibromo-
benzaldehyde in water (Table 1, Entry 1). Similar re-
sults were reported for the oxidative ability of NBS
(Krishnaveni et al., 2004; Mayhoub et al., 2010).
Meanwhile, over 50 % 4-bromo-2-methylbenzenamine
(Ib) was isolated in various media using the mole ratio
of o-toluidine/NBS of 1 : 1. It was found that water
improved the selectivity of Ia as compared with other
organic solvents.
Brought to you by | New York University Bobst Library Technical Services
Authenticated
Download Date | 5/18/15 3:07 PM