M. Vohra et al.
1
material and monitored by LC-MS (UV detection). The unlabeled product
3
H NMR (CDCl ) ς 8.02 (1H, bs, NH), 7.17–7.13 (2H, m), 7.05 (1H, d,
(
R
3′) showed retention time (R
= 18.52 min. It was then brought at room temperature and diluted with
acetonitrile (50 ml) and filtered. The filtrate was concentrated in vacuo (2H, t, J = 8.0 Hz).
t
) of 18.12 min and dimer (11) showed J = 8.5 Hz), 6.97 (1H, dd, J = 7.0, 2.0 Hz), 6.54 (1H, dd, J = 8.0, 2.5 Hz), 6.33
t
(1H, d, J = 2.5 Hz), 3.08 (4H, bs), 2.90 (2H, t, J = 8.0 Hz), 2.66 (4H, bs), 2.62
and chromatographed on silica to furnish the desired product 3 as
19 8 2 3 2
ESI for C23H D Cl N O : 456.3 (M + 1), 458.3 (M + 3), 459.3 (M + 4).
yellowish thick oil (1.0 g, 32.1% based on 2).
LC-MS UV detector purity: 99.93%.
1
H NMR (CDCl
.05 (1H, NH).
3
) ς 7.34–7.42 (4H, Ar), 7.18–7.32 (5H, Ar), 4.22 (1H, CH),
2
Electrospray ionization (ESI) for C17
H
11
D
8
ClN : 294 (M), 295 (M + 1).
2
Results and discussion
Large-scale synthesis of non-deuterated hydroxyzine and its
2
-(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}ethoxy)
12,13
4
intermediates
and Aripiprazole has been reported previously.
ethanoldihydrochloride-d
8
(5)
However, we developed an efficient and economically feasible
8 8
About 1.0 g (3.4 mmol) of 3 was dissolved in acetonitrile (50 ml), followed method of synthesizing hydroxyzine-d and aripiprazole-d to
by the addition of potassium carbonate (0.93 g, 6.73 mmol) and 2-(2- act as an internal standard.
chloroethoxy)ethanol (4) (0.72 g, 5.78 mmol). The resulting reaction
mixture was heated at 85°C and stirred overnight. TLC in methanol and
dichloromethane (1:9) showed the desired product (Rf = 0.55). The
reaction was also monitored by LC-MS (UV detection). The desired
For the purposes of preparing an effective standard, several
deuterium atoms were introduced to prevent any discrepancies
during mass spectrophotometry analysis. In the case of halogen
containing compounds similar to hydroxyzine and aripiprazole, a
minimum of five and six deuterium atoms are necessary. Mass
increases below the M + 5 and M + 6 ranges may result in
interference from the natural form of the compound and make
t
product (5) showed R of 11.90 min. The reaction was brought at room
temperature and filtered. The filtrate was concentrated in vacuo and
was chromatographed using 1–5% methanol in ethyl acetate. The pure
oily compound obtained after concentration was dissolved in ether
9
it significantly more difficult to quantify drug levels.
(
150 ml) and then treated with 2N ethereal HCl (20 ml). The resulting
white suspension was stirred for 20 min and filtered. The cake was
washed with hexane and dried to furnish 5 (dihydrochloride salt) as steps using piperazine-d
white solid (0.61 g, 39%, 98% D enrichment).
The synthesis of hydroxyzine-d
2. The use of any other deuterated
(5) was accomplished in two
8
8
materials was avoided because the addition of deuterium atoms
to any alternative location on hydroxyzine would entail a greater
number of steps and introduce a higher cost to the production
process. In the first step, piperazine-d8 (2.5 equivalents) was
directly reacted with 1 in a sealed reaction flask capable of
accommodating the vapor pressure of acetonitrile at 85°C.
Intermediate 3 was purified via column chromatography and
afforded a 32.1% yield based on the labeled piperazine.
1
H NMR (CD
.32–7.27(1H, m, Ar), 4.89 (1H, bs, CH), 3.81 (2H, t, J = 10 Hz), 3.69 (2H, t,
J = 8 Hz), 3.59 (2H, t, J = 8 Hz), 3.41 (2H, t, J = 10 Hz).
ESI for C21 ClN : 382 (M), 383(M + 1).
3
OD):ς 7.60–7.50 (4H, m, Ar), 7.40–7.32 (4H, m, Ar),
7
H
19
D
8
2 2
O
LC-MS UV detector purity: 99.5%.
7
-(4-Bromobutoxy)-3,4-dihydro-2-(1H)-quinolinone-d (8)
8
8
Hydroxyzine-d was synthesized after coupling 3 with 2-(2-
chloroethoxy) ethanol to account for an overall yield of 11.7%
A mixture of 7-hydroxy-3,4-dihydro-2(1H)-quinolinone (6) (0.65 g, 3.98 mmol),
potassium carbonate (1.1 g, 7.98 mmol), and 1,4-dibromobutane-d (7) (5 g,
2.32 mmol, 99% D enrichment) in methyl ethyl ketone (MEK) (20 ml) was
heated at 75°C in a 50-ml sealed flask overnight. TLC in ethyl acetate/
8
yield based on 2 following purification.
2
12
In a previous report, the synthesis of non-isotopic hydroxyzine
hexanes (1:1) showed complete conversion to desired product (Rf = 0.75). was accomplished using multiple equivalents of piperazine in
The reaction was optimized using unlabeled material and monitored by
LC-MS (UV detection). The product (8′) showed R
t
= 8.21 min and dimer
(
12) showed R = 14.34 min. Potassium carbonate was removed by filtration
t
Table 1. Optimization of intermediate 3
and concentrated to produce a crude oil (7 g), which was subsequently
purified by silica gel column chromatography. The non-polar fractions from
hexanes recovered pure 1,4-dibromobutane-d (7) (3.53 g). In the reaction,
8
only 1.47 g (1.7 equivalents) of 7 was consumed. The desired product 8
was obtained as a white solid (0.97 g, 46.6%, calculated on the basis of 7
Equivalents of
Equivalents of 4-chlorobenzehydryl
Equivalents of
potassium
carbonate
Percent
dimer (11)
a
piperazine-d
8
chloride
formation (%)
1.1
2.5
5
1
1
1
1
1
1
38.3
15.9
7.6
consumed) with ethyl acetate/hexanes (1:4).
1
3
H NMR (CDCl ): ς 8.32 (1H, bs, NH), 7.05 (1H, d, J = 8 Hz), 6.53 (1H, dd,
J = 8.5, 2 Hz), 6.35 (1H, d, J = 2.5 Hz), 2.91 (2H, t, J = 8 Hz), 2.63 (2H, t, J = 7 Hz).
ESI for C13 BrNO : 306 (M), 308 (M + 2), 613 (2M + 1).
H
8
D
8
2
a
Percent dimer formation was determined via LC-MS.
7-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy}-3,4-
dihydroquinolinone-2(1H)-one-d (10)
8
Table 2. Optimization of intermediate 8
A mixture of 7-(4-bromobutoxy)-3,4-dihydro-2-(1H)-quinolinone-d
8
8
Equivalents of
7-hydrxy-3,4- Equivalents
,4-dibromobutane- dihydro-2(1H)- of potassium
(
(
0.96 g, 3.13 mmol), 1-(2,3-dichlorophenyl)piperazine hydrochloride (9)
1 g, 3.76 mmol), and powdered sodium carbonate (797 mg, 7.52 mmol)
Equivalents of
1
Percent
dimer (12)
in ethanol (15 ml) was heated at 80°C in a sealed reaction flask overnight.
The reaction was monitored by LC-MS (UV detection). The desired
a
d
8
quinolinone
carbonate
formation (%)
product (10) showed R
t
= 15.21 min. Ethanol was evaporated, and the
1
3
5.6
1
1
1
2
2
2
23
18
0
solid mass was partitioned between ethyl acetate and water. The ethyl
acetate layer was separated and washed with water and brine, dried over
sodium sulfate and chromatographed. The final crude product was
eluted with 1–5% methanol in ethyl acetate to afford the desired
compound (1.02 g, 72%, 99% D enrichment) as a white solid.
a
Percent dimer formation was determined via LC-MS.
J. Label Compd. Radiopharm 2015, 58 304–307
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