Synthesis and characterization of potential impurities of carvedilol, an antihypertensive drug

Article abstract of DOI:10.1080/00397910903531839

Carvedilol (Coreg) is a nonselective -adrenergic blocking agent with vasodilating activity. It is used for the treatment of congestive heart failure and hypertension. During the bulk synthesis of carvedilol, we have observed six impurities: Imp-I, Imp-II, Imp-III, Imp-IV, Imp-V, and Imp-VI. The present work describes the synthesis and characterization of these impurities. Copyright

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Synthesis and Characterization of
Potential Impurities of Carvedilol, an
Antihypertensive Drug
Somisetti Narender Rao a , Devarasetty Sitaramaiah a , Kema
Srimannarayana a , Challa Nageswar Rao a , Peddi Srinivasa Rao a
K. Sudhakar Babu b
&
a Research and Development, Srini Pharmaceuticals Ltd.,
Hyderabad, India
b Department of Chemistry, Sri Krishna Devaraya University,
Anantapur, India
Version of record first published: 14 Dec 2010.
To cite this article: Somisetti Narender Rao, Devarasetty Sitaramaiah, Kema Srimannarayana, Challa
Nageswar Rao, Peddi Srinivasa Rao & K. Sudhakar Babu (2010): Synthesis and Characterization
of Potential Impurities of Carvedilol, an Antihypertensive Drug, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:1, 85-93
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Synthetic Communications1, 41: 85–93, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531839
SYNTHESIS AND CHARACTERIZATION OF
POTENTIAL IMPURITIES OF CARVEDILOL,
AN ANTIHYPERTENSIVE DRUG
Somisetti Narender Rao,1 Devarasetty Sitaramaiah,1
Kema Srimannarayana,1 Challa Nageswar Rao,1
Peddi Srinivasa Rao,1 and K. Sudhakar Babu2
1Research and Development, Srini Pharmaceuticals Ltd., Hyderabad, India
2Department of Chemistry, Sri Krishna Devaraya University,
Anantapur, India
Carvedilol (Coreg) is a nonselective b-adrenergic blocking agent with vasodilating activity.
It is used for the treatment of congestive heart failure and hypertension. During the bulk
synthesis of carvedilol, we have observed six impurities: Imp-I, Imp-II, Imp-III, Imp-IV,
Imp-V, and Imp-VI. The present work describes the synthesis and characterization of these
impurities.
Keywords: Carvedilol; impurities; spectral characterization; synthesis
INTRODUCTION
The carbazolyl-(4)-oxypropanolamine compound and its pharmaceutical
compositions are indicated for the treatment of prophylaxis of circulatory and
cardiac diseases (e.g., hypertension and angina pectoris). Carvedilol is the generic
1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol.[1–3]
Carvedilol is multiple-action drug, and its b-blocking activity affects the response to
certain nerve impulses in parts of the body.[4,5] As a result, b-clockers decrease the
heart’s need for blood and oxygen by reducing its workload. Carvedilol is also
known to be vasodilator, resulting primarily from a-adrenoceptor blocade.[6] The
multiple actions of carvedilol are responsible for the antihypertensive efficacy of
the drug and its effectiveness in managing congestive heart failure.[7]
The presence of impurities in an active pharmaceutical ingredient (API) can
have a significant impact on the quality and safety of the drug products. Therefore,
it is necessary to study the impurity profile of the API to be used in the manu-
facturing of the drug product. International Conference on Harmonization (ICH)
Received September 5, 2009.
Address correspondence to K. Sudhakar Babu, Research and Development, Srini Pharmaceuticals
Ltd., Plot No. 10 & 11, Type C, Road No. 8, Film Nagar, Jublee Hills, Hyderabad, 500033, A.P., India.
E-mail: ksbabusku@rediffmail.com
85

86
S. N. RAO ET AL.
guidelines recommends identifying and characterizing all impurities that are present
at level of ꢀ0.10%.[8]
In this context, a comprehensive study was undertaken to synthesize and
characterize the following six impurities: 4-oxiranylmethoxy-9H-carbazole (Imp-I),
1,1-[[2-(2-methoxyphenoxy)ethyl]nitrilo]bis[3-(9H-carbazol-4-yloxy)propan-2-ol-
(Imp-II), 1-[[9-[2-hydroxy-3-[[2-(2-methoxyphenoxy)ethyl] aminopropyl]-9H-carba-
zol-4-yl]oxy]-3-[[2-(2-methoxyphenoxy)ethyl]amino]propan-2-ol (Imp-III), (2RS)1-
[benzyl[2(2-methoxyphenoxy)ethyl]amino]-3-(9H-carbazol-4-yloxy)propan-2-ol
(Imp-IV), 1-{bis-{2-(2-methoxyphenoxy)ethyl}amino}-3-(9H-carbazol-4-yloxy)propan-
2-ol (Imp-V), and salicylic acid (Imp-VI).
Several analytical methods have been reported for the determination of
carvedilol in biological fluids and pharmaceutical formulations.[9,10] The syntheses
of three of the carvedilol impurities, Imp-I,[11] Imp-III,[12] and Imp-IV,[13] are
reported in the literature, and Imp-II, Imp-III, and Imp-IV are listed impurities of
the European Pharmacopia (EP).[14] The syntheses of Imp-II and Imp-V are not
reported anywhere. Imp-V is a new impurity reported here for the first time. One
degradation impurity (Imp-VI) is identified, and it was isolated and structurally con-
firmed as salicylic acid.
RESULTS AND DISCUSSION
Carvedilol 10 has been synthesized (Fig. 1) by the reaction of 4-oxiranyl-
methoxy-9H-carbazole 8 with 2-(2-methoxy-phenoxy)-ethylamine 9 in monoglyme,
and compound 8 was produced by the condensation of 4-hydroxy carbazole 6 with
epichlorohydrin 7 in the presence of sodium hydroxide in dimethyl sulfoxide
(DMSO) medium.
Imp-II was prepared by the reaction of 4-oxiranylmethoxy-9H-carbazole (8)
with 2-(2-methoxy-phenoxy)-ethylamine (9) by taking an equimolar ratio in mono-
glyme (Fig. 2). In this reaction, Imp-II was formed as the major product when
Figure 1. Synthesis of carvedilol.

SYNTHESIS OF CARVEDILOL IMPURITIES
87
Figure 2. Synthesis of Imp-II.
compound 9 was taken as 0.65 mol equivalents. This mixture was purified by column
chromatography to obtain pure Imp-II.
Synthesis of Imp-III
The N-alkylation on compound 8 with compound 7 using sodium hydroxide as
a base in DMSO affords disubstituted compound 4-oxiranylmethoxy-9-oxiranyl-
methyl-9H-carbazole (11), which on further reaction with compound 9 in mono-
glyme furnishes Imp-III (Fig. 3).
Synthesis of Imp-IV
The condensation of compound 9 with benzyl bromide in the presence of
potassium carbonate in dimethylformamide (DMF) gives benzyl-[2-(2-methoxy-
phenoxy)-ethyl]-amine (13), which on further reaction with compound 8 in
monoglyme affords Imp-IV (Fig. 4).
Figure 3. Synthesis of Imp-III.

88
S. N. RAO ET AL.
Figure 4. Synthesis of Imp-IV.
Synthesis of Imp-V
2-Methoxy phenol was treated with 1,2-dibromoethane using potassium
carbonate as a base in acetone medium to afford 1-(2-bromo-ethoxy)-2-methoxy-
benzene (15), which on condensation with compound 9 gives [2-(2-methoxy-
phenoxy)-ethyl]-[3-(3-methoxy-phenyl)-propyl]-amine (16), and this was further
reacted with compound 8 in monoglyme to furnish Imp-V (Fig. 5).
Along with these impurities, one degradation impurity was observed in the
carvedilol crude compound; it formed ꢁ0.5% and was observed as ꢁ 3% at stage
II of the carvedilol preparation (Fig. 1). The mother liquers at the crude stage were
concentrated, and the degradation impurity was isolated by column chromatography
and confirmed as salicylic acid (Imp-VI) based on the spectral data. This was form-
ing mainly as a result of the acidic degradation of compound 8 during carvedilol
preparation (Fig. 6).
IR (KBr, cmꢂ1): 3524 (O-H stretching in acid), 3238 (O-H stretching in acid),
=
3006 (C-H aromatic), 1655 (C O stretching), 1579, 1484 (aromatic C C), 758, 697
=
1
(Ar-H aromatic bending); HNMR (DMSO-d6, 300 MHz, d ppm): 14.0–10.0 (s, br,
1H), 7.86–7.81 (dd, J ¼ 9 Hz, J ¼ 3 Hz, 1H), 7.57–7.49 (dt, J ꢂ 12 Hz, J ¼ 3 Hz, 1H),
Figure 5. Synthesis of Imp-V.

SYNTHESIS OF CARVEDILOL IMPURITIES
89
Figure 6. Degradation of compound 8.
6.98 (d, J ¼ 9 Hz, 1H), 6.93 (d, J ¼ 9 Hz, 1H); 13CNMR (DMSO-d6, 300 MHz, d
ppm): 172, 161.2, 135.7, 130.3, 119.2, 117.1, 112.9; mass (MþþH) 136.9.
CONCLUSION
Information about the different possible impurities and synthetic routes is pre-
requisite for a thorough understanding of the impurity-formation pathway of the
antihypertensive drug carvedilol. Keeping in view the regulatory importance of car-
vedilol impurities, the process-related impurities in bulk carvedilol were identified,
synthesized, and characterized using mass, infrared (IR), and NMR techniques.
EXPERIMENTAL
1
The HNMR spectral data where recorded at 300 MHz on a Varian instru-
ment; the chemical shifts were reported in d ppm relative to tetramenthylsilane
(TMS) as an internal standard. The IR spectra were obtained using a Perkin-Elmer
Fourier transform–infrared (FT-IR) spectrometer. The mass analysis was performed
on an Agilent 1100 Q-trap LC-MS=MS mass spectrometer. Solvent removal was
accomplished by a rotary evaporator operating at house vacuum (40–50 Torr).
The solvents and reagents were used without further purification.
4-Oxiranylmethoxy-9h-carbazole (Imp-I, 8)
Compound 6 (50 g, 0.27 mol) followed by DMSO (75 mL) were added to a sol-
ution of sodium hydroxide (12 g, 0.3 mole) in water (150 mL). Epichlorohydrin
(37.85 g, 0.41 mol) was added to the reaction mass slowly during 2 h below 25 ꢃC
and warmed to 45 ꢃC. The contents were maintained at 45 ꢃC for 10 h. The reaction
mass was diluted by adding water (250 mL) and stirred for 1 h at room temperature.
The compound was filtered and washed with water, and the wet compound was
purified by recrystallizing it from isopropanol (150 mL) to afford pale brown
4-oxiranylmethoxy-9H-carbazole (8). Yield: 49 g, 75%. IR (KBr, cmꢂ1): 3295 (N-H
=
stretching), 2927 (C-H aliphatic), 1509, 1586, 1609 (aromatic C C), 1098 (C-O
arylalkylether), 725 (Ar-H aromatic bending); 1HNMR (CDCl3, 300 MHz, d
ppm): 8.16 (d, J ¼ 7.8 Hz, 1H), 8.04 (s, br), 7.42 (d, J ¼ 8.1 Hz, 1H), 7.31 (dt,
J ¼ 8.1 Hz, J ¼ 0.9 Hz, 1H), 7.16(d, J ¼ 7.8 Hz, 1H), 7.11 (d, J ¼ 7.2 Hz,1H), 6.92

90
S. N. RAO ET AL.
(d, J ¼ 8.1 Hz,1H), 6.58 (d, J ¼ 7.8 Hz,1H), 4.44 (dd, J ¼ 10.8 Hz, J ¼ 3 Hz,1H), 4.22
(dd, J ¼ 11.1 Hz, J ¼ 5.7 Hz,1H), 3.56–3.51 (m,1H), 2.99–2.85 (m, 2H); 13C NMR
(CDCl3, 300 MHz, d ppm): 154.8, 140.9, 138.6, 126.5, 125.0, 123.1, 122.4, 119.9,
112.7, 109.9, 104.0, 101.2, 68.7, 50.3, 44.8; mass (MþþH) 240.1.
1-[[2-(2-Methoxyphenoxy)ethyl]nitrilo]bis[3-(9h-carbazol-
4-yloxy)propan-2-ol (Imp-II)
Compound 9 (4.54 g, 0.027 mol) was added to a solution of compound 8 (10 g,
0.041 mol) in monoglyme (20 mL), heated to 65 ꢃC, and maintained for 2 h at the
same temperature. The solvent was distilled off completely under reduced pressure,
and the obtained residue was purified by column chromatography to obtain 1-[[2-(2-
methoxyphenoxy)ethyl]nitrilo]bis[3-(9H-carbazol-4-yloxy)propan-2-ol (Imp-II) as
an off-white solid. Yield: 10.4 g, 38.5%;
IR (KBr, cmꢂ1): 3403 (N-H stretching), 3530, 3461 (O-H stretching), 2938,
=
2917, 2870 (C-H aliphatic), 1604, 1589, 1506 (aromatic C C), 1252 (C-N stretching),
1104, 1124 (C-O stretching), 717, 752, 735 (Ar-H aromatic bending);1HNMR
(CDCl3, 300 MHz, d ppm): 8.15 (s, br, 1H exchanged with D2O), 8.1 (s, br, 1H,
exchanged with D2O), 8.4–8.2 (m, 2H), 7.45–7.35 (m, 6H), 7.2–7.0 (m, 4H),
6.7–6.6 (m, 2H), 6.95–6.85 (m, 4H), 4.4–4.2 (m, 7H), 3.2–3.0 (m, 6H), 3.84 (s, 3H),
3.82 (m, 1H); mass (MþþH) 646.7.
4-Oxiranylmethoxy-9-oxiranylmethyl-9h-carbazole (11)
Potassium bicarbonate (22.6 g, 0.163 mol) was added to a solution of com-
pound 8 (10 g, 0.054 mol) in DMF (30 mL) and stirred for 10 min. Epichlorohydrin
(7.57 g, 0.082 mol) was added slowly at 25 ꢃC, maintained for 1 h at 25ꢃC, and heated
to 55 ꢃC. The reaction mixture was maintained at 55 ꢃC for 8 h. The reaction mass
was cooled to 25 ꢃC, water (150 mL), was added, and it was extracted in ethyl acetate
(200 þ 100 mL). The organic layer was separated, dried over sodium sulfate, and
distilled off completely to obtain 5 g of 4-oxiranylmethoxy-9-oxiranylmethyl-
9H-carbazole (11) as a brown reside.
1-[[9-[2-Hydroxy-3-[[2-(2-methoxyphenoxy)ethyl]aminopropyl]-
9h-carbazol-4-yl]oxy]-3-[[2-(2-methoxyphenoxy)ethyl]-
amino]propan-2-ol (Imp-III)
A solution of compound 9 (11.31 g, 0.067 mol) in monoglyme (15 mL) was
heated to 75 ꢃC. A solution of compound 11 (5 g, 0.069 mol) in monoglyme
(15 mL)was added slowly and maintained at 80 ꢃC for 5 h. The solvent was distilled
off completely under reduced pressure below 60 ꢃC. The obtained residue was dis-
solved in ethyl acetate (25 mL) and heated to reflux to get clear dissolution. The con-
tents were slowly cooled to 30 ꢃC, than to 0 ꢃC. The precipitated product was filtered
and washed with precooled ethyl acetate (5 mL) to obtain 1-[[9-[2-hydroxy-3-[[2-(2-
methoxyphenoxy)ethyl]aminopropyl]-9H-carbazol-4-yl]oxy]-3-[[2-(2-methoxyphenoxy)-
ethyl]amino] propan-2-ol (Imp-III) as a pale green solid. Yield 4.8 g, 45%; IR (KBr,
cmꢂ1): 3281 (N-H stretching), 2833, 2835 (C-H aliphatic), 1593, 1505 (aromatic

SYNTHESIS OF CARVEDILOL IMPURITIES
91
=
C C), 1253 (C-N stretching), 1124, 1053 (C-O stretching), 743, 715 (Ar-H aromatic
1
bending); HNMR (CDCl3, 300 MHz, d ppm): 8.3 (d, 1H), 7.5 (t, 1H), 7.4 (t, 1H),
7.35 (d, 1H), 7.2 (t, 1H), 6.8–7 (m, 4H), 6.7 (d, 1H), 4.4 (t, 2H), 4.3 (t, 2H), 4.25
(t, 2H), 4.17 (t, 2H), 3.81 (s, 3H), 3.05 (m, 1H), 3.0 (t, 2H), 2.85 (m, 1H); 13CNMR
(CDCl3, 300 MHz, d ppm): 149, 148.1, 142.3, 140.1, 26.5, 124.8, 122.9, 122.1, 121.6,
20.8, 119.4, 111.8, 14.2, 114.0, 108.5, 102.4, 77.3, 68.9, 55.8, 52.5, 51.9, 48.7, 48.4
mass (MþþH) 630.6.
Benzyl-[2-(2-methoxy-phenoxy)ethyl]amine (13)
Triethylamine (6.05 g, 0.06 mol) was added to a solution of benzyl bromide
(4.09 g, 0.024 mol) in toluene (15 mL) and cooled to 0 ꢃC. A solution of compound 9
(5 g, 0.03 mol) in toluene (10 mL) was added slowly at the same temperature and
allowed to reach 25 ꢃC. The reaction mixture was maintained at room temperature
for 8 h. Water (25 mL) was added to the reaction mass and stirred for 15 min. The
layers were separated, and the organic layer was washed with water (15 mL) and dried
over sodium sulfate. The solvent was distilled off completely under reduced pressure
to obtain benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amine 13 as residue. Yield: 3.2 g.
(2RS)1-[Benzyl[2(2-methoxyphenoxy)ethylamino]-3-(9H-carbazol-
4-yloxy)propan-2-ol (Imp-IV)
Compound 8 (1.5, 0.006 mol) was added to a solution of compound 13 (3.2 g,
0.012 mol) in monoglyme (3 mL), and the contents were heated to 75 ꢃC. The reac-
tion mixture was maintained at 75 ꢃC for 6 h. The solvent was distilled off completely
under reduced pressure below 65 ꢃC to obtain the residue, which was solidified by
triturating with ethyl acetate (10 mL). The compound was filtered and washed with
ethyl acetate to afford (2RS)-1-[benzyl [2(2-methoxyphenoxy)ethyl]amino]-3-
(9H-carbazol-4-yloxy)propan-2-ol (Imp-IV) as an off-white solid. Yield: 2.63 g,
85%;IR (KBr, cmꢂ1): 3404 (O-H stretching), 2836, 2873 (C-H aliphatic), 1589,
=
1506 (aromatic C C), 1254 (C-N stretching), 1123, 1102, 1026 (C-O stretching),
1
741, 726 (Ar-H Aromatic bending); HNMR (CDCl3, 300 MHz, d ppm): 8.21 (d,
J ¼ 7.8 Hz, 1H), 8.09 (s, br, 1H exchanged with D2O), 7.4–7.3 (m, 3H), 7.3–7.2 (m,
3H), 6.89–6.87 (m, 1H), 6.86–6.84 (m, 1H), 6.82 (d, J ¼ 2.4, 1H), 6.59 (d, J ¼ 7.8 Hz,
1H), 4.3–4.2 (m, 1H), 4.1 (t, 5.4 Hz, 2H), 4.1 (s, 2H), 3.92 (d, J ¼ 13.5 Hz, 2H), 3.80
(s, 3H),3.74 (d, J ¼ 10.5 Hz, 2H), 3.15 (t, J ¼ 6 Hz, 2H); 13CNMR (CDCl3, 300 MHz,
d ppm): 155.2, 149.5, 148.2, 140.9, 138.7, 128.9, 128.4, 127.2, 126.6, 124.8, 122.9,
122.5, 120.7, 119.6, 113.2, 112.6, 111.6, 109.9, 103.6, 101.1, 70.2, 67.2, 67.1, 59.7,
57.9, 55.7, 53.2; mass (Mþ þH) 497.3.
1-(2-Bromo-ethoxy)-2-methoxy-benzene 15
Potassium carbonate (83.5 g, 0.6 mol) was added to a solution of 2-methoxy
phenol (25 g, 0.2 mol) in acetone (125 mL) and stirred at room temperature for
15 min. 1,2-Dibromoethane (189.2 g, 1.0 mol) was added, and the contents were
heated to 55 ꢃC and maintained at the same temperature for 10 h. The solvent was
distilled off completely under reduced pressure. The residue was partitioned between

92
S. N. RAO ET AL.
water (75 mL) and ethyl acetate (150 mL). The organic layer was separated, washed
with water (50 mL), and dried over sodium sulfate. The solvent was evaporated to
yield 1-(2-bromo-ethoxy)-2-methoxy-benzene 15 (30 g) as residue.
[2-(2-Methoxy-phenoxy)ethyl]-[3-(3-methoxy-phenyl)-
propyl]amine 16
Compound 9 and triethylamine (26.3 g, 0.26 mol) were added to a solution of
compound 15 (30 g, 0.13 mol) in tetrahydrofuron (150 mL) at room temperature. The
reaction mixture was heated to 65 ꢃC and maintained at the same temperature for
5 h. The solvent was distilled off completely under reduced pressure, and the residue
was partitioned between water (60 mL) and ethyl acetate (150 mL). The organic layer
was separated and dried over sodium sulfate. The solvent was distilled off completely
to obtain [2-(2-methoxy-phenoxy)-ethyl]-[3-(3-methoxy-phenyl)-propyl]-amine 16
(18 g) as an oily residue.
1-{Bis-{2-(2-methoxyphenoxy)ethyl}amino}-3-(9h-carbazol-
4-yloxy)propan-2-ol (Imp-V)
A solution of compound 16 (18 g, 0.056 mol) in monoglyme was heated to
75 ꢃC, and compound 8 (13.4 g, 0.056 mol) was added. The resultant reaction mixture
was maintained at 75 ꢃC for 7 h. The solvent was distilled completely, dissolved in
water (50 mL), and extracted into ethyl acetate (100 mL). The organic layer was sepa-
rated and dried over sodium sulfate. The evaporation of solvent yielded a residue,
which was purified by passing through a silica-gel coloumn using ethyl acetate and
n-hexane as eluent. The pure fraction was collected and evaporated to obtain an
off-white solid. Yield: 8.5 g, 27%.
IR (KBr, cmꢂ1): 3384 (O-H stretching), 3442 (N-H stretching), 2953 (C-H ali-
=
phatic), 1591, 1508 (aromatic C C), 1255.9 (C-N stretching), 1124, 1099, 1051 (C-O
stretching), 743.7, 728.2 (Ar-H aromatic bending); 1HNMR (DMSO-d6, 300 MHz, d
ppm): 8.2 (d, 1H), 7.3–7.1 (m, 4H), 7.1–6.9 (m, 4H), 6.9–6.7 (m, 2H), 6.7–6.5 (m,
4H), 6.0 (s, br, exchanged in D2O, 1H), 4.4–4.0 (m, 4H), 3.8 (s, 3H), 3.7 (s, 3H),
3.7–3.3 (m, 6H), 3.3–3.0 (m, 1H), 2.0 (s, br, exchanged in D2O, 1H); 13CNMR
(DMSO-d6, 300 MHz, d ppm): 175.6, 164.1, 155.5, 149.3, 148, 147, 146, 140, 138,
126, 124, 122, 121, 120, 119, 114, 113, 112, 111, 109, 103, 100, 69, 67, 66, 60, 58,
55; mass (Mþ þH) 557.4.
ACKNOWLEDGMENTS
The authors are grateful to colleagues in the Analytical Research and Develop-
ment department and the management of Srini Pharmaceuticals Ltd. for providing
the necessary support.
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