Efficient synthesis of D6-clenproperol and D6-cimaterol using deuterium isopropylamine as labelled precursor

Article abstract of DOI:10.1002/jlcr.3447

This report presents an efficient synthesis of D₆-clenproperol and D₆-cimaterol with 99.5% and 99.7% isotopic abundance in acceptable yields and excellent chemical purities with deuterium isopropylamine as labelled precursor. Their structures and the isotope-abundance were confirmed by proton nuclear magnetic resonance and liquid chromatography–mass spectrometry.

Full text of DOI:10.1002/jlcr.3447

Received: 6 July 2016
DOI 10.1002/jlcr.3447
Revised: 15 August 2016
Accepted: 30 August 2016
R E S E A R C H A R T I C L E
Efficient synthesis of D ‐clenproperol and D ‐cimaterol using
6
6
deuterium isopropylamine as labelled precursor
1
,2
2
2
2
2
2
Kai Sun | Chao Fang | Weicheng Yang | Zhongjie Xu | Haoran Wang | Wen Sun |
2
1
Yong Luo | Yi Xu
1
School of Chemical and Environmental
Engineering, Shanghai Institute of Technology,
Shanghai, China
This report presents an efficient synthesis of D ‐clenproperol and D ‐cimaterol with
6
6
99.5% and 99.7% isotopic abundance in acceptable yields and excellent chemical
purities with deuterium isopropylamine as labelled precursor. Their structures and
the isotope‐abundance were confirmed by proton nuclear magnetic resonance and
liquid chromatography–mass spectrometry.
2
Research and Development Center, Shanghai
Research Institute of Chemical Industry, Shanghai,
China
Correspondence
Yong Luo, Research and Development Center,
Shanghai Research Institute of Chemical Industry,
KEYWORDS
3
45 East Yunling Road, Shanghai 200062, China.
D ‐cimaterol, D ‐clenproperol, deuterium isopropylamine, labelled internal standards,
synthesis
6
6
Yi Xu, School of Chemical and Environmental
Engineering, Shanghai Institute of Technology, 100
Hai Quan Road, Shanghai 201418, China.
Email: real‐luoyong@hotmail.com; xuyi@sit.edu.cn
1
|
INTRODUCTION
spectrometry has been widely used in food safety analysis
because of the high precision, high accuracy, and simple
pretreatment for samples, which could effectively avoid the
β‐Agonistic drugs like clenproperol, clenbuterol, salbutamol,
and cimaterol were widely used in the treatment of bronchial
disease, which were also used in the feed of animals such as
pigs, cattle, and sheep because they could increase the protein
10,11
interference caused by external factors.
But the most
important for the detection is the labelled compounds of inter-
nal standards.
To the best of our knowledge, there were very few proce-
dures described in the literature for the synthesis of labelled
clenproperol and cimaterol. In this study, we would like to
1
–3
to fat ratio, resulting in a higher production efficiency.
However, β‐agonistic drugs can be remained in the animals,
the meat products obtained from treated animals may pose a
potential risk for human health, and the abundant misuse
raised serious concerns about a toxicological risk for the con-
sumer. Thus, these drugs have been prohibited as a growth
promoter of farm animals in several countries, such as the
European Union, Japan, and China, and the detection of β‐
agonistic residue has been strengthened in all countries of
describe an efficient synthesis of D
‐clenproperol and D ‐
6
6
cimaterol using deuterium isopropylamine as labelled
precursor. The target compounds, with excellent isotopic
and chemical purities, were synthesized in acceptable yield
and could be used as an internal standard in the determination
of β‐agonists in animal tissues.
4–6
the world.
In recent years, numerous methods have been developed
for the detection of clenproperol and other β‐agonists in ani-
mal tissues, such as gas chromatography–mass spectrometry
2 | RESULTS AND DISCUSSION
(
GC‐MS), high‐performance liquid chromatography, and liq-
Based on the previous work about the synthesis of (1,3‐D6)‐
2‐bromopropane before, the strategy of labelling deuterium
7–9
uid chromatography–mass spectrometry (LC‐MS).
But
12
all of these methods have the uniform drawback for determin-
ing the residue of β‐agonists because of matrix effects, which
may interfere with analysis and affect the accuracy of the
results significantly. Researchers have wanted to develop
more prominent and reliable analytical methods desperately.
Liquid chromatography isotope diluted tandem mass
on isopropyl group was designed. The 5‐step synthesis of
the labelled isopropylamine 6 started with commercially
available D ‐acetone as depicted in Scheme 1. First of all,
6
D ‐acetone 1 was reduced with the minimum amount of
6
LiAlH to (1,3‐D )‐propan‐2‐ol 2 with 99.8% atom D at
4
6
0°C (93.6% yield). The (1,3‐D )‐propan‐2‐ol 2 was then
6
5
52
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J Label Compd Radiopharm 2016; 59: 552–556

SUN ET AL.
553
SCHEME
1
Synthesis of deuterium labelled
isopropylamine. Reagents and conditions: (I)
LiAlH , diglyme, diethylene glycol, 0°C, 1 h,
4
a
b
9
3.6% , 99.8% atom D ; (II) PBr
3
, rt, overnight,
7
3.9%, 99.8% atom D; (III) potassium
phthalimidate, DMF, 120°C, 4 h, 94.5%, 99.7%
atom D; (IV) hydrazine hydrate, methanol, 80°C,
2
7
h, 79.1%, 99.7% atom D; (V) CaO, rt, 4 h,
a
5.2%, 99.7% atom D. Isolated yield based on
b
labelled materials. Calculated by gas chromatog-
raphy–mass spectrometry or mass spectra
converted to (1,3‐D )‐2‐bromopropane 3 with 99.8% atom D
mass spectrum (MS) of Figure 1 and the unlabelled
clenproperol its MS was shown in Figure 2. The sodium
borohydride was added twice to be able to ensure adequate
reduction.
6
(
73.9% yield) at room temperature in the presence of phos-
13
phorus tribromide. According to the Gabriel synthesis,
3
was reacted with potassium phthalimide at 120°C, received
D ‐N‐isopropylphthalimide 4 with 99.7% atom D (94.5%
For synthesis of D ‐cimaterol 15 that was obtained by
6
6
14
yield). (1,3‐D )‐Isopropylamine 6 (99.7% atom D, 75.2%
the modification of a known procedure as depicted in
Scheme 3, 1‐(4‐aminophenyl) ethan‐1‐one 11 was bromi-
nated with the equal amount of N‐bromobutanimide in
toluene with the temperature kept below 30°C, giving 1‐(4‐
amino‐3‐bromophenyl) ethan‐1‐one 12 (95.2% yield). Then
12 was reacted with copper cyanide at 160°C, and corre-
sponding intermediate 5‐acetyl‐2‐aminobenzonitrile 13 was
obtained with 66.6% yield. Subsequently, crude 13 was
brominated with cupric bromide at 70°C, giving 2‐amino‐5‐
(2‐bromoacetyl)benzonitrile 14 in 71.5% yield. Through
6
yield) was obtained via hydrazinolysis reaction of 4 with the
excess amount of hydrazine hydrate in the presence of
hydrochloric acid to get (1,3‐D )‐isopropylamine hydrochlo-
6
ride 5 (99.7% atom D, 79.1% yield); then, the hydrochloric
acid was removed by excess amount of calcium oxide.
For synthesis of D ‐clenproperol 10 as depicted in
6
Scheme 2, 1‐(4‐amino‐3,5‐dichlorophenyl)ethan‐1‐one 7
was reacted with cupric bromide at 70°C to get 4‐amino‐
3,5‐dichlorophenacylbromide 8 with 76.2% yield via further
crystallization in chloroform. Through the subsequent
the subsequent amination of the (1,3‐D )‐isopropylamine
6
amination of the (1,3‐D )‐isopropylamine, corresponding
labelled intermediate 9 was obtained with 99.6% atom D
and reduction with sodium borohydride gave 15 in 36.7%
yield, with 99.7% atom D according to its MS of
Figure 3 and the unlabelled cimaterol its MS was showed
in Figure 4.
6
(37.4% yield). Then reduction of 9 using sodium borohydride
gave 10 with 99.5% atom D (76.3% yield) according to its
SCHEME 2 Synthesis of D
6
‐clenproperol. Reagents and conditions: (VI) CuBr
2 3 3
, CHCl , ethyl acetate, ethanol, 70°C, 2 h, 76.2%; (VII) CHCl , 63°C, 5 h,
3
7.4%, 99.6% atom D; (VII) NaBH
4
, methanol, rt, overnight, 76.3%, 99.5% atom D
FIGURE 1 Mass spectrum of 10

5
54
SUN ET AL.
a HP‐5MS 30 m × 0.25 mm capillary apolar column (station-
ary phase: 5% diphenyldimethylpolysiloxane film, 0.25 μm).
3
.2 | (1,3‐D )‐Propan‐2‐ol (2)
6
To a stirred suspension of LiAlH4 (5 g, 132 mmol) in
diglyme (80 mL, dried over CaH ) under nitrogen at 0°C
2
was slowly added D ‐acetone 1 (99.96% atom D, 20.0 g,
6
3
12 mmol). The solution was stirred at 0°C for 1 hour, and
then diethylene glycol (70 mL) slowly added. The (1,3‐D6)‐
propan‐2‐ol was distilled from the reaction mixture, and the
fraction boiling between 80°C and 107°C was collected to
give 2 (19.27 g, 292 mmol, 93.6% yield, 99.8% atom D).
1
H NMR (500 MHz, CDCl ) δ ppm: 3.91 (brs, 1H). GC‐
3
MS: m/z 48.
FIGURE 2 Mass spectrum of clenproperol
3
.3 | (1,3‐D )‐2‐Bromopropane (3)
6
3
3
|
EXPERIMENT
To a suspension of 2 (18.8 g, 284 mmol) stirred 10 minutes,
at −10°C, was added dropwise phosphorus tribromide
(49.8 g, 184 mmol). After that the resulting solution was
.1 | Materials and instruments
stirred at room temperature overnight and the product 3 is
isolated by distillation, the fraction boiling 50°C to 62°C
D ‐Acetone (99.96% atom D) was purchased from J&K Chem-
ical and used as received. All other reagents and solvents were
commercially available and used without further purification.
Proton nuclear magnetic resonance ( H NMR) spectra were
6
was collected (27.07 g, 210 mmol, 73.9% yield, 99.8% atom
1
D). H NMR (500 MHz, CDCl ) δ ppm: 4.23 (s, 1H). GC‐
3
1
MS: m/z 128, 130.
recorded on a Bruker AC‐500 (500 MHz) spectrometer (Bruker
Daltonics Inc, Billerica, Massachusetts, USA) in CDCl3
3
.4 | (D )‐N‐Isopropylphthalimide (4)
6
(Tetramethylsilane (TMS) as internal standard). Mass spectra
were recorded on a Finnigan TSQ Quantum Access spec-
trometer (Thermo Fisher Scientific, Waltham, Massachusetts,
USA). Gas chromatography–mass spectra were recorded
using an Agilent Technologies 7890‐7000C instrument
A dry and nitrogen‐flushed 250 mL 3‐necked flask, was
charged with potassium phthalimidate (8.892 g, 48 mmol),
3
(5.16 g, 40 mmol), and N,N‐dimethylformamide
(12.5 mL) were mixed and refluxed with stirring at 120°C
for 4 hours. Then the mixture was cooling to 0°C, added with
(Agilent Technologies Inc, Palo Alto, California, USA) with
SCHEME 3 Synthesis of D
6
‐cimaterol. Reagents and conditions: (IX) NBS, toluene, 30°C, 15 min, 95.2%; (X) CuCN, DMF, 160°C, 6 h, 66.6%; (XI) CuBr
, ethanol, 0°C, 6 h, 36.7%, 99.7% atom D
2
,
CHCl , ethyl acetate, ethanol, 70°C, 2 h, 71.5%; (XII) NaBH
3
4
FIGURE 3 Mass spectrum of 15

SUN ET AL.
555
8
0 mmol), CuBr (35.741 g, 160 mmol), CHCl (150 mL),
2
3
and ethyl acetate (150 mL). The reaction mixture was stirred
for 30 minutes at 70°C, then ethanol (90 mL) was added
portionwise in 30 minutes. After completion of the addition,
the mixture was stirred for 2 hours, then filtered while hot and
the cake washed with 40 mL ethyl acetate. The filtrate was
washed with water (200 mL) and saturated sodium chloride
solution(3 × 150 mL); the organic layers dried over anhy-
drous magnesium sulfate and removed in vacuum, and crys-
tallized in chloroform to give 8 (17.248 g, 60.96 mmol,
1
7
2
6.2% yield). H NMR (500 MHz, CDCl ) δ ppm: 7.86 (s,
3
−
H), 5.06 (brs, 2H), 4.31 (s, 2H). LC‐MS: [M−H] m/z 282.
3
.8 | (D )‐1‐(4‐Amino‐3,5‐dichlorophenyl)‐2‐
6
(isopropylamino) ethan‐1‐one (9)
FIGURE 4 Mass spectrum of cimaterol
To a stirred solution of 8 (7.173 g, 25.35 mmol) in chloro-
form (40 mL) at 63°C in a 250 mL round bottom flask sealed
water (100 mL) and dichloromethane (100 mL). The organic
layer was washed with saturated sodium bicarbonate solution
with a rubber, (1,3‐D )‐isopropylamine 6 (1.1 g, 16.91 mmol)
6
was injected by syringe slowly. The mixture was stirred for
(
3 × 80 mL) and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuum to yield 4 (7.38 g,
7.8 mmol, 94.5% yield, 99.7% atom D). The crude 4 was
5
hours, during this time a white solid generated, and the
mixture was filtered, the solid washed with chloroform, and
the combined filtrate and washings evaporated to dryness to
3
1
used in the next step without further purification. H NMR
500 MHz, CDCl ) δ ppm: 7.82 to 7.80 (m, 2H), 7.70 to
yield 9 (1.69 g, 6.32 mmol, 37.4% yield, 99.6% atom D).
(
3
1
H NMR (500 MHz, D O) δ ppm: 7.81 (s, 2H), 4.53 (s,
H), 3.45 (s, 1H). LC‐MS: [M+H] m/z 267.
2
7.68 (m, 2H), 4.50 (s, 1H). GC‐MS: m/z 195, 177, 130.
+
2
3
.5 | (1,3‐D )‐Isopropylamine hydrochloride (5)
6
3
.9 | (D )‐Clenproperol (10)
6
To the 4 (5.08 g, 26 mmol) was added hydrazine hydrate
3.03 g, 60.5 mmol) in methanol (5.5 mL). The mixture
Sodium borohydride (0.256 g, 6.77 mmol) was added gradually
to a solution of 9 (1.432 g, 5.36 mmol) and methanol (15 mL) in
water (5 mL) at 0°C. The reaction mixture was stirred at room
temperature for 2 hours then neutralized with 6 mol/L
hydrochloric acid to form a colorless liquid (pH = 3‐5). The
reaction mixture was further stirred at room temperature for
(
was heated at 80°C for 1 hour and white solid separated dur-
ing this time. Then addition of water (18 mL) and 12 mol/L
hydrochloric acid (16 mL) and the mixture were reacted for
1
hour again at 80°C. After that the mixture was cooled to
room temperature, phthalhydrazide was removed by filtra-
tion, and the filtrate were concentrated under reduced
12 hours; then, the sodium borohydride (0.256 g, 6.77 mmol)
was added gradually again. The reaction mixture was neutral-
ized with 6 mol/L hydrochloric acid to weak acidic (pH = 3‐
5) after stirring at room temperature for 2 hours. The mixture
was filtered, and the filtrate was added aqueous ammonia until
weak alkaline (pH = 8‐10). The mixture was filtered, and the fil-
pressure to give 5 (2.09 g, 20.6 mmol, 79.1% yield, 99.7%
1
atom D). H NMR (500 MHz, D O) δ ppm: 3.24 (s, 1H).
2
+
LC‐MS: [M+H] m/z 67.
3
.6 | (1,3‐D )‐Isopropylamine (6)
6
ter cake was dried to yield 10 (1.1 g, 4.1 mmol, yield 76.3%,
1
Calcium oxide (2.668 g, 47.57 mmol) and (1,3‐D6)‐
isopropylamine hydrochloride 5 (2.0 g, 19.69 mmol) were
mixed and stirred for 4 hours at the room temperature, then
distilled under atmospheric pressure. The product 6 is iso-
lated by distillation; the fraction boiling 30°C to 34°C was
collected (0.964 g, 14.8 mmol, 75.2% yield, 99.7% atom D)
99.5% atom D). H NMR (500 MHz, CDCl ) δ 7.78 to 7.75
3
(m, 2H), 4.64 (d, J = 8.5 Hz, 1H), 4.49 (s, 1H), 2.88 (s, 2H).
+
LC‐MS: [M+H] m/z 269.
3
.10 | 1‐(4‐Amino‐3‐bromophenyl)ethan‐1‐one (12)
1
To a stirred solution of 1‐(4‐aminophenyl) ethan‐1‐one 11
(4.055 g, 30 mmol) in toluene (50 mL) was added N‐
bromosuccinimide (5.34 g, 30 mmol) in portions over
in a flask cooled with liquid nitrogen. H NMR (500 MHz,
+
CDCl ) δ ppm: 3.31 (s, 1H). LC‐MS: [M+H] m/z 67.
3
1
3
5 minutes; then, the mixture was stirred for 15 minutes at
0°C. After that the reaction mixture was washed with water
3.7 | 4‐Amino‐3,5‐dichlorophenacylbromide (8)
A dry and nitrogen‐flushed 500 mL 3‐necked flask, equipped
with a nitrogen inlet and a dropping funnel, was charged with
(3 × 100 mL), dried with anhydrous magnesium sulfate, and
evaporated in vacuum, giving a dark brown oil. The crude
dark brown oil dissolved in ethanol (30 mL) and then water
1‐(4‐amino‐3,5‐dichlorophenyl) ethan‐1‐one 7 (16.325 g,

5
56
SUN ET AL.
(
700 mL) added to precipitate the solid product, the filter
vacuum to yield 15 (1.4 g, 6.2 mmol, yield 36.7%, 99.7% atom
1
cake was collected by filtration to get 12 (6.11 g, 28.56 mmol,
yield 95.2%). H NMR (500 MHz, CDCl ) δ 8.07 (d,
J = 2.5 Hz, 1H), 7.74 (dd, J = 2.5, 2.5 Hz, 1H), 6.74 (d,
J = 10.5 Hz, 1H), 4.57 (brs, 2H), 2.51 (s, 3H). LC‐MS: [M
D). H NMR (500 MHz, CDCl ) δ 7.39 (d, J = 1.5 Hz, 1H),
3
1
7.33 (dd, J = 1.5, 1.5 Hz, 1H), 6.72 (d, J = 7 Hz, 1H), 4.49
to 4.51 (m, 1H), 4.37 (s, 2H), 2.81 to 2.89 (m, 2H), 2.53 to
3
+
2.57 (m, 1H). LC‐MS: [M+H] m/z 226.
−
−
H] m/z 212.
4
|
CONCLUSIONS
3
.11 | 5‐Acetyl‐2‐aminobenzonitrile (13)
A mixture of 12 (3.56 g, 16.63 mmol), cuprous cyanide
1.79 g, 20 mmol), and N,N‐dimethylformamide (20 mL)
In summary, D ‐clenproperol and D ‐cimaterol were pre-
pared with 99.5% and 99.7% isotopic abundance, respec-
tively. The structure was confirmed by H‐NMR and LC‐MS.
6
6
(
1
was stirred at 160°C under nitrogen for 6 hours. After cooling
to room temperature, the mixture was treated with a solution
of ferric chloride (prepared from 6.6 g of ferric chloride,
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1
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3
1
.13 | (D )‐Cimaterol (15)
6
1
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4 (2.026 g, 8.5 mmol) was dissolved in ethanol (25 mL). The
solution was stirred for 0.5 hour at 0°C, and 6 (1.1 g,
6.91 mmol) was injected by syringe slowly. The reaction mix-
ture was stirred for 2 hours at room temperature, then cooled to
°C, and the sodium borohydride (0.512 g, 13.53 mmol) was
1
How to cite this article: Sun, K., Fang, C., Yang, W.,
Xu, Z., Wang, H., Sun, W., Luo, Y., and Xu, Y. (2016)
Efficient synthesis of D ‐clenproperol and D ‐
0
added slowly. After the completion of addition, the reaction
mixture was stirred for 4 hours at room temperature and then
added 30 mL of water and 40 mL of ethyl acetate. The com-
bined organic layers were separated, washed with water, dried
over anhydrous magnesium sulfate, and concentrated in
6
6
cimaterol using deuterium isopropylamine as labelled
precursor. J Label Compd Radiopharm, doi: 10.1002/
jlcr.3447