Syntheses of potential degradation products of phenylephrine in OTC products

Article abstract of DOI:10.1080/00397910802026188

Compound 1 and 2 are potential major degradants in over the counter (OTC) products containing phenylephrine HCl and dexbrompheniramine maleate or chlorpheniramine maleate. Compound 2 matches the unknown peak in the solution of stressed active and excipient and thus was identified as the correct degradation product. Whether the degradation product is racemic or chiral is not known. This article describes synthesis of both compounds. Compound 2 will be useful as an analytical standard for quantitative analysis of the major degradant in OTC products of phenylephrine HCl and dexbrompheniramine maleate or chlorpheniramine maleate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802026188

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Syntheses of Potential
Degradation Products of
Phenylephrine in OTC Products
T.-M. Chan a , Jianshe Kong a , Paul McNamara a
Jesse K. Wong a
&
a Schering-Plough Research Institute, Kenilworth,
New Jersey, USA
Version of record first published: 18 Aug 2008.
To cite this article: T.-M. Chan, Jianshe Kong, Paul McNamara & Jesse K.
Wong (2008): Syntheses of Potential Degradation Products of Phenylephrine in
OTC Products, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:13, 2252-2260
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Synthetic Communications1, 38: 2252–2260, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802026188
Syntheses of Potential Degradation Products of
Phenylephrine in OTC Products
T.-M. Chan, Jianshe Kong, Paul McNamara, and Jesse K. Wong
Schering-Plough Research Institute, Kenilworth, New Jersey, USA
Abstract: Compound 1 and 2 are potential major degradants in over the counter
(OTC) products containing phenylephrine HCl and dexbrompheniramine maleate
or chlorpheniramine maleate. Compound 2 matches the unknown peak in the sol-
ution of stressed active and excipient and thus was identified as the correct degra-
dation product. Whether the degradation product is racemic or chiral is not
known. This article describes synthesis of both compounds. Compound 2 will
be useful as an analytical standard for quantitative analysis of the major degra-
dant in OTC products of phenylephrine HCl and dexbrompheniramine maleate
or chlorpheniramine maleate.
Keywords: Chlorpheniramine; Degradants; Maleate; Michael addition;
Phenylephrine
INTRODUCTION
The decongestant phenylephrine is used in many over-the-counter (OTC)
products for treatment of the common cold. A novel degradation product
was isolated from pharmaceutical formulations containing phenylephrine
HCl and chlorpheniramine maleate and was assigned structure 1.[1] Com-
pound 1 is presumably formed by reaction of phenylephrine with maleic
acid with a hydroxyl group migration or with malic acid with a removal
of water. We observed a compound with the same molecular weight and
similar high pressure liquid chromatography (HPLC) retention time and
ultra violet (UV) spectrum in formulations containing phenylephrine
Received in the USA January 10, 2008.
Address correspondence to Jesse K. Wong, Schering-Plough Research Insti-
tute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail: jesse.wong@
spcorp.com
2252

Degradation Products of Phenylephrine
2253
HCl and dexbrompheniramine maleate. We synthesized compound 1 and
found the NMR spectrum to be different from that reported.[2] Reaction
of phenylephrine and maleic acid could also give structure 2. We synthe-
sized compound 2 and found this structure to be correct.[2]
RESULTS AND DISCUSSION
The synthesis of compound 1 is shown in Scheme 1. (R)-(ꢀ)-Phenyleph-
rine hydrochloride (3)[3] was treated with Boc2O in the presence of 1 N
NaOH to give compound 4. An attempt to protect both hydroxyl groups
of 4 with 2 equivalents of benzyl bromide and 2 equivalents of NaH in
N, N-dimethyl formamide (DMF) gave 5a[3b, 4] instead. [One equivalent
of NaH and 1 equivalent of benzyl bromide under the same condition
1
afforded 63% of compound 5a. H NMR (400 MHz, CDCl3) d 2.90 (s,
3H), .21 (dd, 1H, J ¼ 8.4, 8.8 Hz), 3.90 (t, 1H, J ¼ 8.8 Hz), 5.08 (s,
2H), 5.42 (t, 1H, J ¼ 8.0 Hz), 6.90–7.00 (m, 3H), 7.30–7.43 (m, 6H).
Scheme 1. Synthesis of compound 1: Reagents and conditions: (a) 1N
NaOH=THF (1:1), Boc2O, 1 h, 100%; (b) 2 eq. NaH, 2 eq. BnBr, DMF, rt,
18 h, 56%; (c) 2 eq. Cs2CO3, 2 eq. BnBr, 3 h, 100%; (d) 4N HCl in dioxne, 3 h,
76%; (e) 1N NaOH, 1 h, 100%; (f) 1 eq. Cs2CO3, 1 eq. BnBr, DMF, 3 h, 59%;
(g) DMF, 105ꢁC, 12 h, 34%; and (h) MeOH, Pd=C, H2, rt 18 h, 98%.

2254
T.-M. Chan et al.
MS, m=z284 (Mþ þ 1, 75%).] No product 5 was detected. Use of 2
equivalents of Cs2CO3 and 2 equivalents of benzyl bromide in DMF gave
5 in quantitative yield. Compound 5 was treated with 4 N HCl in dioxane
to remove the Boc protecting group. To our surprise, the benzyl group of
the secondary alcohol was also cleaved off to give 6 in 83% isolated yield.
The amino alcohol 7 was obtained quantitatively after basification of 6.
Compound 9[5] was prepared by reacting racemic compound 8 with ben-
zyl bromide in the presence of NaH in DMF. Following the procedure of
A. Khalaj,[6] heating a mixture of 7 and 9 in DMF at 103 to 105ꢁC for
12 h afforded compound 10 in 34% isolated yield. The benzyl protecting
group of 10 was removed by hydrogenolysis with H2 and Pd=C in MeOH
to give compound 1.
The synthesis of compound 2 is shown in Scheme 2. Maleic acid 11
was treated with benzyl bromide in the presence of Cs2CO3 in DMF at
60ꢁC to give a mixture of dibenzyl maleate and dibenzyl fumarate 12,
in a ratio of 2.5 to 1. Compound 7 reacted with the maleate–fumarate
mixture 12 in DMF at 45ꢁC for 65 h to give compound 13 in 20% isolated
yield. The low yield of 13 was caused by several factors. The major factor
was the competition between isomerization of dibenzyl maleate 14 to
dibenzyl fumarate 15 versus the desired Michael addition of 7 to dibenzyl
maleate. This competition was confirmed by reacting pure dibenzyl
Scheme 2. Synthesis of compound 2: Reagents and conditions: (a) DMF, 1 1=2 h,
20%; (b) 2 eq. Cs2CO3, 2 eq. BnBr, DMF, rt, 5 h, 80%; (c) MeoH, H2, rt 18 h,
96%; (d) DMF, 42ꢁC, 1 h, 16% of 13.

Degradation Products of Phenylephrine
2255
maleate 14 with amine 7 in the same fashion as described previously.
Dibenzyl fumarate 15 and compound 13 were isolated in 46% and
16% yield, respectively. It seems that amine 7 only reacted with dibenzyl
maleate 14. By-products 13a and 13b or 13c and starting material 7 were
identified from their Mþ þ 1 ions in the mass spectrum of the crude reac-
tion. These side reactions also contributed to the poor yield. Compound
2 was obtained after removal of all benzyl groups of 13 by hydrogenation
in MeOH with Pd=C in 90% yield.
CONCLUSION
Structures of compounds 1 and 2 were determined by two-dimensional
nuclear magnetic resonance (2D NMR) as described previously.[2] All pro-
tons and carbon resonances in the spectra were assigned, and the con-
nectivities between proton and carbon nuclei were confirmed by 2D NMR
techniques such as heteronuclear single-quantum correlation (HSQC),
heteronuclear single-quantum correlation total correlation spectroscopy
(HSQCTOCSY), and HMBC. The NMR spectrum of compound 1 is
more complicated than compound 2 because both diastereomers have
two rotomers. Therefore, four sets of peaks in the NMR spectrum were
observed for compound 1, and only two sets of peaks were observed for
compound 2. Compound 2 matches the major unknown peak in the
solution of stressed active and excepient, and compound 1 does not.[2]
Two new potential degradants were synthesized. These two com-
pounds were fully characterized by MS and NMR. Both compounds
are adducts of phenylephrine and maleic acid. The Michael addition pro-
duct, compound 2, is the correct structure of the degradation product
found in OTC pharmaceutical preparations. The stereochemistry of iso-
lated degradant is not known.[1]
EXPERIMENTAL
General
Starting materials, reagents, and solvents were purchased from commercial
suppliers and used without further purifications. Because compound 8 is
not available as a racemate from Aldrich, a 1:1 mixture of R and S is used.
Melting points were determined with a Thomas-Hoover Uni-Melt appar-
atus and are uncorrected. Column chromatography was performed on sil-
ica gel, 230–400 mesh. Chemical shifts (d) are reported in parts per million.
1
All H NMRs were recorded with a Varian 400-MHz spectrometer with
solvents indicated. Mass spectra were obtained with either Waters-ZQ

2256
T.-M. Chan et al.
mass spectrometer or JUL Mstation magnetic factor mass spectrometer.
Mass spectra were used only to detect mass ions. CHN analyses were per-
formed by QTI Technologies Inc., Whitehouse, New Jersey.
tert-Butyl[(2R)-2-hydroxy-2-(2-hydroxyphenyl)ethyl]carbamate (4)
To a stirred solution of (R)-(ꢀ)-phenylephrine hydrochloride 3 (10 g,
49.3 mmol) in 1 N NaOH and THF (1:1) (100 mL), Boc2O (10.75 g,
49.3 mmol) was added. The reaction mixture was stirred at rt for 1 h. Sol-
vents were removed, and the residue was dissolved in CH2Cl2 (100 mL)
and washed with water (50 mL). The aqueous was extracted again with
layer CH2Cl2 (100 mL). The combined CH2Cl2 phases was dried over
MgSO4, filtered, and concentrated to give 4 as a glassy foam (12 g,
97%): 1H NMR (CDCl3) of two rotamers with 3:2 ratio. d 6.7–7.3
(4 H), 4.8–4.9 (1 H), 3.3–3.6 (2 H), 2.8–2.9 (3 H), 1.4–1.5 (9 H); MS
m=z 290 (Mþ þ Na). [a]21 ¼ þ 25.2ꢁ (C ¼ 1.0 MeOH).
D
(5R)-5-[3-(Benzyloxy)phenyl]-3-methyl-1,3-oxazolidin-2-one (5a)
NaH (60%) (659 mg, 10 mmol) was added portionwise to a solution of 4
(2.0 g, 7.5 mmol) in DMF (20 mL). This was stirred at rt for 30 min or
until no gas evolution. To this was then added BnBr (3.76 g, 21.9 mmol)
via a syringe. The reaction was stirred at rt overnight. The reaction mix-
ture was diluted with water (50 mL) and extracted with Et2O
(2 ꢂ 200 mL). Et2O layer was washed with water (2 ꢂ 50 mL), dried over
MgSO4, filtered, and then concentrated. The crude mixture was purified
with a silica-gel column, eluted with 10 to 50% EtOAc in hexane to
afforded 5a (1.13 g, 53%) as white crystalline solid: mp 57–59ꢁC; MS
m=z 284 (Mþ þ H). Anal. calc. for C17H17NO3: C, 72.07; H, 6.05; N,
4.94. Found: C, 72.06; H, 6.07; N, 4.96.
tert-Butyl{(2R)-2-(benzyloxy)-2-[3-(benzyloxy)phenyl]ethyl}-
methylcarbamate (5)
Cs2CO3 (3.25 g, 10 mmol) was added to a solution of 4 (1.0 g, 3.74 mmol)
and BnBr (1.71 g, 10 mmol) in DMF (10 mL). The reaction was stirred at
rt for 3 h. The reaction was filtered, diluted with Et2O (100 mL), washed
with water (3 ꢂ 30 mL), dried over with MgSO4, and concentrated to give
1
5 (1.8 g > 100%) as a yellowish oil: H NMR (CDCl3) d 7.2–7.5 (11 H),
7.1 (1 H), 6.8–7.0 (2 H), 5.1 (s, 2 H), 4.9 (1 H), 4.5 (s, 2 H), 3.3–3.6 (br,
2 H), 2.8 (br, 3 H), 1.5 (s, 9 H); MS m=z 470 (Mþ þ Na).

Degradation Products of Phenylephrine
2257
(1R)-1-[3-(Benzyloxy)phenyl]-2-(methylamino)ethanol, hydrochloride (6)
HCl (4N) in dioxane (150 mL) was added to a solution of 5 (24 g,
53.6 mmol) in dioxane (100 mL) at rt. After stirring for 2 h, solvents were
removed, and the residue was triturated with Et2O (250 mL). The solids
1
were filtered to give 6 (12 g, 76%) as a white solid: H NMR (D2O) d
6.8–7.4 (9 H), 5.0 (s, 2 H), 4.8 (m, 1 H), 3.1 (m, 2 H), 2.6 (s, 3 H).
(1R)-1-[3-(Benzyloxy)phenyl]-2-(methylamino)ethanol (7)
NaOH (1N) (50 mL) was added to a solution of 6 (12 g, 41 mmol) in water
(55 mL). After stirring for 15 min, the reaction was diluted with water
(100 mL) and then extracted with CH2Cl2 (2 ꢂ 500 mL). CH2Cl2 phase
was washed with brine, dried over MgSO4, filtered, and ꢁthen concen-
1
trated to give 7 (10.5 g, 100%) as a white solid: mp 91–93 C; H NMR
(CDCl3) d 7.3–7.4 (m, 5 H), 7.2 (t, J ¼ 8 Hz, 1 H), 7.1 (s, 1 H),7.0 (dd,
J ¼ 8, 2 Hz, 1 H), 6.9 (dd, J ¼ 8, 2 Hz, 1 H), 5.1 (s, 2 H), 4.7 (m, 1 H),
2.6–2.9 (m, 2 H), 2.4 (s, 3 H); MS m=z 258 (Mþ þ H), 240 (M þ þ
H-H2O). Anal. calc. for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found:
C, 74.29; H, 7.49; N, 5.44.
2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid Benzyl Ester (9)
BnBr (15.7 g, 91.8 mmol) was added to a solution of 1:1 mixture of (R)
and (S) of 2.2, dimethyl-5-oxo-1,3-dioxolane-4-acetic acid 8 (16 g,
91.8 mmol) in DMF (100 mL). After stirring for 5 min, Cs2CO3 (30 g,
91.8 mmol) was added. The reaction was stirred at rt for 3 h and at
45ꢁC for 30 min. The reaction was filtered. The filtrate was diluted with
Et2O (500 mL, washed with water (3 ꢂ 300 mL) and brine (1 ꢂ 100 mL),
dried over MgSO4, and then filtered. Solvents were evaporated. The
crude product was chromatographed on a silica column, and eluted with
20ꢁ% EtOAc in hexane to give 9 (14.2 g, 59%) as a white solid: mp 42–
1
44 C; H NMR (CDCl3) d 7.4 (m, 5 H), 5.2 (m, 2 H), 4.7 (m, 1 H), 3.0
(dd, 4, 15 Hz, 1 H), 2.9 (dd, 8, 15 Hz, 1 H), 1.6 (s, 3 H), 1.5 (s, 3 H). Anal.
calc. for C14H16O5: C, 63.63; H, 6.10. Found: C, 63.44; H, 6.13.
Benzyl-4-[{(2R)-2-[3-(benzyloxy)phenyl]-2-hydroxyethyl}(methyl)amino]-
3-hydroxy-4-oxo-butanoate (10)
A solution of 7 (11 g, 42.8 mmol) and 9 (8.3 g, 31.4 mmol) in DMF
(150 mL) was heated at 104ꢁC for 12 h. DMF was evaporated, and the

2258
T.-M. Chan et al.
residue was diluted with EtOAc (500 mL), washed with water
(3 ꢂ 300 mL), dried over MgSO4, filtered, and then concentrated. The
crude product was chromatographed on a silica-gel column and eluted
with 30–60% of EtOAc in hexane to give 10 (5.0 g, 34%) as a yellowish
gum: 1H NMR (CDCl3) of 2 diastereomers and 2 rotamers with 3:1 ratio
d 6.9–7.5 (14 H), 5.2 (s, 2 H), 5.1 (s, 2H), 4.7–5.1 (2 H), 3.2–3.9 (2 H), 2.9–
3.1 (3 H), 2.5–2.8 (2 H); MS m=z 486 (Mþ þ Na), (FAB) m=z 464
(Mþ þ H), 446 (Mþ þ H–H2O).
3-Hydroxy-4-{[(2R)-2-hydroxy-2-(3-hydroxyphenyl)ethyl](methyl)amino}-
4-oxo-butanoic Acid (1)
Compound 10 was dissolved in MeOH (200 mL), and 10% Pd=C (1 g)
was added under an N2 atmosphere. The reaction was hydrogenated with
a balloon filled with H2 overnight. After purging with N2, catalyst was
removed by filtration, and solvents were removed under reduced pressure
to afford 1 (3.0 g, 98%) as a white gum: 1H NMR (CD3OD) of 2 diaster-
eomers and 2 rotamers d 7.2 (1 H), 6.9 (2 H), 6.7 (1 H), 4.8–5.0 (2 H), 3.4–
3.9 (2 H), 2.9–3.1 (4 s, 3 H), 2.4–2.9 (2 H); MS m=z 306 (Mþ þ Na), 284
(Mþ þ H), 266 (Mþ þ H–H2O). [a]22 ¼ ꢀ6.8ꢁ (C ¼ 1.0, MeOH).
D
Z and E But-2-enedioic acid Dibenzyl Ester (12)
Cs2CO3 (65 g, 200 mmol) was added to a solution of maleic acid 11 (11 g,
94.8 mmol) and BnBr (34 g, 199 mmol) in DMF (300 mL). The reaction
was stirred at 60ꢁC for 5 h and then stirred at rt overnight. Solids were
filtered, and the filtrate was evaporated on rota-evaporator. The residue
was dissolved in EtOAc (500 mL), washed with water (2 ꢂ 250 mL), dried
over MgSO4, filtered, and then concentrated to give 12 (22.3 g, 75%,
Z=E ¼ 2.5) as a brown oil. A portion of this mixture (15 g) was chroma-
tographed on a silica-gel column, eluted with 5 to 20% of EtOAc in hex-
ane to give E isomer 15 (4 g) as an off-white solid (less polar) and Z
1
isomer 14 (10 g) as a clear oil (more polar). 14: H NMR (CDCl3) d
1
7.38 (m, 10 H), 6.29 (s, 2 H), 5.15 (s, 4 H); 15: H NMR (CDCl3) d
7.39 (m, 10 H), 6.92 (s, 2 H), 5.22 (s, 4 H).
Dibenzyl-N-{(2R)-2-[3-(benzyloxy)phenyl]-2-hydroxyethyl}-N-
methylaspartate (13)
Compound 12 (1.5 g, 5.1 mmol) was added to a stirred solution of 7
(1.3 g, 5.1 mmol) in DMF (14 mL) at rt. The reaction was heated at

Degradation Products of Phenylephrine
2259
45ꢁC for 1.5 hours. The reaction was chilled in an ice bath and then
diluted with Et2O (100 mL), washed with water (2 ꢂ), dried over MgSO4,
filtered, and concentrated. The crude product was passed through a
silica-gel column and eluted with 10–30% EtOAc in hexane to provide
13 (540 mg, 20%) as a yellowish thick oil: 1H NMR (CDCl3) of 2 diaster-
eomers in the ratio 2.5 to 1, d 6.8–7.6 (19 H), 5.0–5.2 (6 H), 4.6–4.8 (1 H),
4.0 (1 H), 3.6–3.9 (br, 1 H), 2.5–3.0 (4 H), 2.4–2.5 (2 s, 3 H); MS m=z 554
(Mþ þ H).
N-{(2R)-2-Hydroxy-2-(3-hydroxyphenyl)ethyl]}-N-methylaspartic Acid (2)
Compound 13 (634 mg, 1.15 mmol) was dissolved in MeOH (50 mL), and
10% Pd=C (60 mg) was added under an N2 atmosphere. The reaction was
hydrogenated overnight with a balloon filled with H2. After purging with
N2, catalyst was removed by filtration. Solvents were removed under
1
reduced pressure to give 2 (335 mg, 96%) as a white glassy foam: H
NMR (D2O) of 2 diastereomers, d 6.7–7.2 (4 H), 5.0 (1 H), 4.2 (1 H),
3.2–3.4 (2 H), 3.2 and 2.8 (2 s, 3 H), 2.8 (2 H); MS m=z 284 Mþ þ H),
266 (Mþ þ H–H2O).
ACKNOWLEDGMENTS
We thank Birendra Pramanik, L.-K. Zhang, and Rebecca Osterman for
spectroscopic analyses, L. Wiseman for HPLC analysis, and H. Yun for
library research.
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