An improved process for the production of lansoprazole: Investigation of key parameters that influence the water content in final API

Article abstract of DOI:10.1021/op900258b

An improved large-scale synthesis of lansoprazole 1 an anti-ulcer drug is described. The synthesis commences with condensation of 2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl4-(2,2, 2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a solvent to yield thioether 4. Subsequently, 4 was selectively oxidized to 1 by using sodium hypochlorite, a mild, economic, and eco- friendly oxidizing agent. A systematic investigation of crystallization parameters in the final stage, which enabled us to control the water content in the final API to <0.10%, were also discussed. (As recommended by USP 28 monograph (The United States Pharmacopeia: USP 28: NF 23, 28th rev. of The Pharmacopeia of the U.S., 23rd ed. of The National Formulary; United States Pharmacopeial Convention; Rockville, MD, 2005; p 1110.).

Full text of DOI:10.1021/op900258b

Organic Process Research & Development 2010, 14, 229–233
An Improved Process for the Production of Lansoprazole: Investigation of Key
Parameters That Influence the Water Content in Final API†
Srinivas Gangula,*,‡ Chandrasekhar R. Elati,‡ Anitha Neredla,‡ Sudhakar R. Baddam,‡ Uday Kumar Neelam,‡
Rakeshwar Bandichhor,‡ and Ashok Dongamanti§
Product DeliVery Team, Integrated Product DeVelopment, InnoVation Plaza, Dr. Reddy’s Laboratories Ltd.,
Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India, and Department of Chemistry, Osmania UniVersity,
Hyderabad-5000007, Andhra Pradesh, India
Scheme 1. Previously reported approaches for lansoprazole
Abstract:
An improved large-scale synthesis of lansoprazole 1 an anti-ulcer
drug is described. The synthesis commences with condensation of
2-mercaptobenzimadazole 3 with 2-chloromethyl-3methyl-4-(2, 2,
2-trifluoro ethoxy) pyridine hydrochloride 2 using water as a
solvent to yield thioether 4. Subsequently, 4 was selectively oxidized
to 1 by using sodium hypochlorite, a mild, economic, and eco-
friendly oxidizing agent. A systematic investigation of crystalliza-
tion parameters in the final stage, which enabled us to control the
water content in the final API to <0.10%, were also discussed.
(As recommended by USP 28 monograph (The United States
Pharmacopeia: USP 28: NF 23, 28th rev. of The Pharmacopeia of
the U.S., 23rd ed. of The National Formulary; United States
Pharmacopeial Convention; Rockville, MD, 2005; p 1110.)
Introduction
Scheme 2. Our improved synthesis of lansoprazole
Proton pump inhibitors (PPIs) are a group of drugs that elicit
pronounced and long-lasting pharmacological effect by reducing
the gastric acid production. These drugs are among the most
widely marketed drugs in the world due to their outstanding
efficacy and safety. Lansoprazole (1) is one of benzimidazole
derivatives that act as gastric pump inhibitor and therefore used
to prevent ulcers.1,2 The most common approach for synthesis
of 1 involves coupling of 3 with 2 in presence of organic solvent
and base to afford thioether 4, oxidation of 4 with m-
chloroperbenzoic acid (m-CPBA) or hydrogen peroxide in
chlorinated solvents to furnish lansoprazole 1 (Scheme 1).2-4
These processes suffer with the following limitations (i) safety
and environmental concerns due to usage of either hydrogen
peroxide or m-CPBA, (ii) demands strict cryogenic conditions
(-30 to -20 °C) to control formation of sulfone (5) and
N-oxide (6) impurities, (iii) utilizes huge volumes of chlorinated
solvents and long processing times that are less attractive for
industrial scale, (iv) involves either chromatographic purifica-
tions or cumbersome workup/repeated crystallizations to meet
the ICH quality of the final active pharmaceutical ingredient
(API).5
In this report we wish to report our efforts in developing an
eco-friendly, easily scalable synthesis of 1 by addressing the
above drawbacks.
† Communication number: IPDO IPM - 00148.
* Corresponding author. Telephone: +91 40 44346430. Fax: +91 40
Results and Discussion
44346164. E-mail: sgangula@drreddys.com.
‡ Dr. Reddy’s Laboratories Ltd.
The first step of our synthesis commences with condensation
of 2-mercaptobenzimidazole 3 with 2-chloromethyl-3-methyl-
4-(2,2,2-trifluoroethoxy)pyridine hydrochloride 2 in the presence
of sodium hydroxide using water as a solvent to afford thioether
compound 4. The selection of water as a solvent not only
provided 4 as a solid in 97.5% yield and 99.5% purity but also
served as an eco-friendly media and thus avoided the use of
organic solvents, unlike prior reported procedures.6 On the basis
of our previous experience on process development of proton
§ Osmania University.
(1) (a) Prous, J. R. Drugs News Perspect. 1988, 1, 38. (b) Barradell, L. B.;
Faulds, D.; Mc Tavish, D. Drugs 1992, 44, 225. (c) Sachs, G.; Shin,
J. M.; Howden, C. W. A. Pharmacol Ther. 2006, 23, 2–8.
(2) For reviews, see: (a) Akira, N.; Yoshitaka, M. U.S. Patent 4,628,098,
1986. (b) Kohl, B.; Sturm, E.; Rainer, G. U.S. Patent 4,758,579, 1988.
¨
(3) (a) Unsal, S. WO/2003/062223, 2003. (b) Bra¨ndstrøm, A. E. WO/
1991/18895, 1991. (c) Cosme Gomez, A.; Fau de Casa-Juana Munoz,
M.; Gelpi Vintro, J. M.; Molina Ponce, A. WO/2001/004109, 2001.
(d) Ahm, K. H.; Kim, H.; Kim, J. R.; Jeong, S. C.; Kang, T. S.; Shin,
H. T.; Lim, G. J. Bull. Korean Chem. Soc. 2002, 23, 4.
10.1021/op900258b  2010 American Chemical Society
Published on Web 12/23/2009
Vol. 14, No. 1, 2010 / Organic Process Research & Development
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229

pump inhibitors,7 we were very certain that controlled oxidation
of 4 to 1 coupled with a facile workup procedure which
safeguards the process impurities is crucial to the success of
the synthesis of 1. Among the available oxidizing agents for
oxidation of 4 to 1, sodium hypochlorite8 (NaOCl) was found
to be an attractive choice in view of (a) mild reactivity, (b)
sole byproduct is sodium chloride, (c) low cost, (d) safety in
storage. Subsequently, our approach to understand this oxidation
step was carried out in the following selected solvents: water,
methanol, isopropanol, acetonitrile, ethyl acetate, and acetone
using mixtures of aq sodium hypochlorite: aq sodium hydroxide
(1.2 equiv each) at 20-25 °C.9 Among these, acetonitrile and
ethyl acetate were found to be good solvents of choice in terms
of complete reaction conversion (Table 1).
Figure 1. Graphical representation of experimental results.
drying conditions (<50 °C) ended always with >2.0% of water
content. Thus, we focused on finding a common purification
procedure to afford lansoprazole with >99.5% purity and
<0.10% of water content.
Table 1. Solvent screening for thio ether oxidation (4)
entry
solvent
water
methanol
1a
5a
4a
yield (%)
Purification for Control of Water Content and Impurities
in the Final API. In an early screening of the purification
procedure, crude product 1 was slurried in selected organic
solvents which included ethyl acetate, n-hexane, n-heptane,
cyclohexane, isopropyl alcohol (IPA), acetone, acetonitrile
(ACN), and tetrahydrofuran (THF) (Table 2). None of these
experiments was found to be fruitful in reducing the water
content to <0.10% even after drying with the use of various
drying techniques. Although we succeeded in achieving >99.5%
purity of 1 by subjecting crude 1 to an ethyl acetate slurry, the
required level of <0.10% water content in the sample was not
achieved even after prolonged drying (Table 2, entry 4). In the
next step, the recrystallization procedure was investigated by
using different solvent systems such as acetontrile:H2O, acetone:
H2O, and THF:H2O to address the water content. A fine
crystalline product with the desired physical properties was
obtained when a 1:2 ratio of THF:H2O was used by dissolving
the crude material in 8 volumes of THF followed by dropwise
addition of 16 volumes of water as antisolvent.11 This process
yielded 1 with <0.10% of water, whereas the target of >99.5%
purity was left undetermined (Table 3, entry 4). Thereafter, the
resultant product was suspended in ethyl acetate, and the
>99.5% pure solid with <0.10% water content was filtered. In
this way, the problems of purity and required water content
were addressed.
1
2
3
4
5
6
0.98
14.4
-
-
97.6
38.5
39.9
98.5
0.74
-
-
19.2
76.6
-
isopropyl alcohol 55.4
-
acetone
ethyl acetate
acetonitrile
0.5
96.6
97.5
-
1.96
0.03
67.0
85.0
a HPLC purity (%).
The reaction progress in acetone and water was almost
negligible. On the other hand reaction progress was found to
be very slow and undesirable impurity formation (at RRT 3.0,
3.8, and 4.0 unidentified) was observed in methanol and
isopropylalcohol. Finally, opting for acetonitrile as choice of
solvent, a systematic screening of the reaction conditions
(reaction temperature, reaction time, mole ratio of aq NaOCl/
NaOH) was carried out, and the optimum conditions were
identified to be 22.5 ( 2.5 °C, 1.5 h, 1.2 equiv (1:1 ratio).
Lansoprazole is thermally sensitive, and attempts to isolate the
compound through distillation at temperatures >45 °C or hot
crystallizations turn the material into pinkish colored product.
Thus, an isolation procedure was established which comprises
dilution of the reaction mass with water and subsequent pH
adjustment to 9.0-9.5 by using 10% acetic acid to afford 1 as
a filterable solid in 85% yield and 97.5% purity. An important
parameter was observed during establishment of the isolation
procedure, wherein a pH of 9.0-9.5 is essential in achieving
the good yield and purity of 1 (Figure 1). While the USP 28
monograph10a recommends a water content of <0.10% in the
final API, our attempt to dry the resultant crude 1 at various
Thus, the optimized procedure consists of the following:
crude lansoprazole 1 was dissolved in THF at 45-50 °C, cooled
to 25-30 °C, and water was added about 60-90 min. The
suspension was stirred at 5-10 °C for 45-60 min. The solid
material was slowly filtered on a pressure nutsche filter (PNF)
Table 2. Choice of solvent for purification of crude lansoprazole by the slurry method
quality of 1 before slurry
drying conditionsc
quality of 1 after slurry
entry
puritya
water contentb
solvents screened for slurries
time (h)
temp (°C)
puritya
water contentb
1
2
3
97.96
95.66
98.54
3.0
3.0
3.0
acetonitrile
acetone
IPA
12.0
8.0
50-55
50-55
50-55
50-55
50-55
50-55
50-55
50-55
97.13
99.33
98.87
99.64
99.02
98.10
98.35
97.20
0.81
0.15
1.72
0.30
0.28
1.14
0.85
1.72
8.0
12.0
24.0
7.0
7.0
8.0
4
93.39
3.0
ethyl acetate
5
6
7
98.09
98.31
95.66
3.7
4.2
1.7
n-hexane
n-heptane
THF
a Area (%) by HPLC. b Water content (w/w). c Slurried samples were dried in a vacuum tray drier (VTD).
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Table 3. Choice of solvent for purification of crude lansoprazole by recrystallization method
quality of 1 before recrystallization
drying conditionsc
quality of 1 after recrystallization
entry
puritya
water contentb
solvent:anti solvent
time (h)
temp (°C)
puritya
water contentb
1
2
3
97.96
97.96
92.50
3.0
3.0
3.0
acetonitrile:H2O
acetone:H2O
MeOH:H2O
12.0
8.0
50-55
50-55
50-55
50-55
50-55
97.13
97.34
94.2
0.85
0.14
1.72
0.09
0.08
8.0
8.0
15.0
98.8
4
98.30
3.0
THF:H2O
98.0
a Area (%) by HPLC. b Water content (w/w). c All slurried samples were dried in vacuum tray driers (VTD).
Table 4. Choice of solvent for purification of crude 1 by recrystallization (RC) followed by slurry method
quality of 1 before RC quality of 1 after RC in THF:H2O quality of 1 after EtOAc slurries
drying
filtration equipment Ad Be
entry
puritya
H2Ob
puritya
H2Ob
THFc
puritya
H2Ob
THFc
1
2
3
4
98.30
98.30
98.30
98.30
3.0
3.0
3.0
3.0
98.37
98.37
98.37
98.37
30.0
0.10
30.0
30.0
15,000
850.0
15,000
15,000
99.8
99.8
99.8
99.8
0.03
0.10
0.03
0.5
900
750
PNF
ND ND
PNF
D
D
D
D
320
PNF
centrifuge
ND
ND
1300
a Area (%) by HPLC. b Water content (w/w). c THF content in ppm (ICH limit: 720 ppm). d A: after RC in THF:H2O. e B: after EtOAc slurries; ND: not dried; D: Dried.
Table 5. Details of scaled up batches in the final purification step of lansoprazole (1)
content of residual solvents in 1a
HPLC purity (%)
entry
crude 1 (kg)
water content (w/w)
MeOH
ACN
EtOAc
THF
1
5
1
2
3
30.0
30.0
30.0
0.08
0.04
0.06
37
62
33
ND
29
26
136
113
124
230
452
319
99.75
99.76
99.80
0.10
0.09
0.01
a Residual solvent limits in ppm: MeOH NMT 3000, acetonitrile (ACN) NMT 410, EtOAc NMT 5000, and THF NMT 720.
and washed with water. The obtained wet solid was suspended
in ethyl acetate at 45-50 °C and stirred for 45-60 min. Then
the heterogeneous mass was allowed to cool to 5-10 °C for
2-3 h, the slurry was filtered and washed with ethyl acetate,
and the wet solid was suspended in ethyl acetate at 45-50 °C
and stirred for 45-60 min. Then the heterogeneous mass cooled
to 5-10 °C for 2-3 h. The resultant solid was filtered and
washed with ethyl acetate and dried to afford lansoprazole 1 in
>99.5% purity and <0.10% water content (Table 4, entry 3).
Here the choice of filtration equipment was found to be crucial
for filtration of the THF:H2O recrystallized product. Following
the above procedure it was noticed that utilization of a
centrifuge for filtration of the recrystallized solid gave a
hard cake and resulted in higher levels of THF (about 1300
ppm) and water (about 0.5%) in solid 1 and eventually
failed to meet the USP/ICH requirements even when
employing an ethyl acetate slurry and drying at higher
temperature (Table 4, entry 4).10,12 Presumably, under
centrifugation conditions the filtered cake turns hard and
leads to trapping of solvent and water in the crystal lattice.
In contrast, filtration of the recrystallized product in PNF
and subsequent slurring with ethyl acetate always resulted
in water content of <0.10%. To our curiosity, a micro-
scopic evaluation of the samples obtained through PNF
filtration process and centrifugation process revealed
significant differences in morphology (Figure 2).
(4) (a) Kato, M.; Yoshio, T.; Iwano, N. U.S. Patent 5,578,732, 1996. (b)
Avrutov, I.; Mendelovici, M. U.S. Pat. Appl. 2008/0091024 A1, 2008.
(5) (a) Arulmoli, T.; Rao, S. M.; Peraka, K. S.; Selvan, A. S. WO/2008/
035189, 2008. (b) Singer, C.; Liberman, A.; Veinberg, I.; Finkelstein,
N.; Nidam, T. U.S. Pat. Appl. 2005/0165060 A1, 2005. (c) Della
Greca, M.; Iesce, M. R.; Previtera, L.; Rubino, M.; Temussi, F.;
Brigante, M. Chemosphere 2006, 63, 1087–1093.
Finally, from the above studies, the recrystallized (THF:H2O)
product was filtered in PNF and subjected to ethyl acetate slurry
which always provides water <0.10% and purity >99.5%. The
results of some of the production batches are summarized in
(6) (a) Moon, Y.-H.; Lee, K.-I.; Lee, G.-S. U.S. Patent 6,423,846, 2002.
(b) Slemon, C.; Macel, B. U.S. Patent 5,374,730, 1994.
(7) For reviews, see: (a) Mathad, V. T.; Govindan, S.; Kolla, N. K.;
Maddipatla, M.; Sajja, E.; Sundaram, V. Org. Process Res. DeV. 2004,
8, 266–270. (b) Kotagiri, V. K.; Vankawala, P. J.; Neelam, U. K.;
Baddam, S. R.; Elati, R. R. C.; Kolla, N. K.; Dayabhai, J. L.; Pingili,
R. R.; Gangula, S.; Jonalagadda, V. R.; Thakur, P.; Neredla, A.;
Kammili, V. R. WO/2008/045777, 2008.
(8) (a) Available at the following: http://www.lenntech.com/processes/
disinfection/chemical/disinfectants-sodium-hypochlorite.htm. (b) Kow-
alski, P.; Mitkaa, K.; Ossowskab, K.; Kolarska, Z. Tetrahedron 2005,
61, 1933–1953. (c) Donohoe, T. J. Oxidation and Reduction in Organic
Synthesis; Oxford University Press: New York, 2000. (d) Xu, W. L. Z.;
Zhang, Q. S.; Zhu, H. S. Synthesis 2004, 227.
Figure 2. Microscopic pictures (50× magnification) of recrys-
tallized samples of lansoprazole in (A) THF:H2O/EtOAc (PNF
filtration); (B) THF:H2O/EtOAc (centrifuge filtration).
(9) For all these reactions, commercially available 12.0% aq sodium
hypochlorite was used.
Vol. 14, No. 1, 2010 / Organic Process Research & Development
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231

Table 6. Comparative results obtained with the use of a different oxidizing agentb
S. no.
4 (kg)
oxidizing agent
byproduct
solvent system
reaction time (h)/temp (°C)
yield %
1a
40.0
40.0
aq NaOCl
m-CPBA
NaCl
m-CBA
CH3CN/H2O (240 L: 5.4 L)
CHCl3 (1325 L)
2/25
8/-20
62.5
57.0
2b
a See reference 3a. b To evaluate the performance of NaOCl, it was compared with the m-CPBA oxidation system.
Table 5. This work has provided a great insight into how the
simple filtrations can significantly influence the quality of the
API.
IR spectrum was recorded on Perkin-Elmer model spec-
trum series FT-IR as KBr pellet. Thermal analysis was
carried out on DSC Q1000 of TA Instruments. Micro-
scopic picture study was performed with a Nikon Eclipse
50 ipol.
Conclusion
Synthesis of 2-[[{4-(2,2,2-Trifluoroethoxy)-3-methylpy-
ridine-2yl}methyl]thio]-1H-benzimidazole Intermediate (4).
To a solution of sodium hydroxide (45 kg, 1125 mol, in 300 L
water) solution, was added 2-Mercapto benzimidazole 3 (47.2
kg, 314.66 mol), and the mixture stirred at 30-40 °C for
homogeneous solution. To this mixture was added 2-chlorom-
ethyl-3methyl-4-(2, 2, 2-trifluoroethoxy)pyridine hydrochloride
2 (75.2 kg, 271.7 mol, in 450 L water) solution about 2.0-2.5
h and stirred at 25-30 °C for 2.0-2.5 h. The solid was filtered
and washed with water (40 L) to afford wet 4, subsequently
the wet solid 4 was suspended in water (375 L) at 50- 55 °C
and stirred for 30-45 min. Then the solid was filtered at 25-30
°C and dried under vacuum to obtain thio ether 4 as off-white
solid in 97.5% (94.12 kg) yield with 99.5% HPLC purity.131H
NMR (400 MHz): δ 12.6 (s, 1H), 8.3 (d, J ) 5.6, 1H), 7.4 (br,
2H), 7.1 (m, 3H), 4.8 (q, J ) 8.8, 2H), 4.7 (s, 2H), 2.2 (s, 3H);
Mass: Anal., Calc (C16H14 F3N3OS) (m/z): 353 and found (M
+ H) ) 354.
Synthesis of 2-[[4-(2,2,2-Trifluoroethoxy)pyrid-2-yl]eth-
ylsulfinyl]-1H-benzimidazoles (Crude Lansoprazole). To a
suspension of 2-[[{4-(2,2,2-trifluoroethoxy)-3-methylpyridine-
2yl}methyl]thio]-1H-benzimidazole 4 (40 kg, 113.31 mol) in
acetonitrile (240 L) was added sodium hypochlorite (94 kg, 132
mol)/sodium hydroxide/water (5.44 kg, 136 mol/16.8 L) mixture
at 20-25 °C about 60-120 min. After maintaining the reaction
mass at the same temperature, water (80 L) was added, and
the pH was adjusted to 9.0-9.5 by using 10% acetic acid
solution (90 L) at 0-10 °C. To this suspension was added water
(240 L) and was stirred for 2-3 h at 0-10 °C. The solid
material was filtered and washed with water (100 L) and dried
at 45-50 °C to constant weight to afford crude lansoprazole 1
in 85% yield (35.5 kg) with 97.5% HPLC purity.13
In conclusion, we have developed an improved process for
production of lansoprazole 1, anti-ulcer drug, by switching to
cheaply available eco-friendly NaOCl in place of expensive
m-CPBA for oxidation of thio ether 4 (see Table 6 for
comparative results). A systematic investigation of crystalliza-
tion parameters in the final stage enabled us to control the water
content in the final API to <0.10% (as recommended by USP
28 monograph10a).
Experimental Section
Materials and Instruments. All commercially available
materials and solvents were used as received without any
further purification. 1H and 13C NMR spectra were
recorded in DMSO-d6 at 400 and 50 MHz, respectively,
on a Varian Gemini 200 MHz spectrometer. The chemical
shift values were reported on δ scale in ppm with respect
to TMS (δ 0.00 ppm) and DMSO-d6 (δ 39.5 ppm) as
internal standards, respectively. The ESI mass spectrum
was recorded on 4000-Q-trap LC/MS spectrometer. FT-
(10) For reviews, see: (a) The United States Pharmacopeia: USP 28: NF
23, 28th rev. of The Pharmacopeia of the U.S., 23rd ed. of The
National Formulary; United States Pharmacopeial Convention; Rock-
ville, MD, 2005; Lansoprazole, p 1110. (b) http://www.usp.org. (c)
Robinson, D. Org. Process Res. DeV. 2007, 11 (5), 797–801. (d)
Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.; Gilmore,
A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W. Chem. ReV.
2006, 106, 3002–3027. (e) International Conference on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH) Q3C (R3): Impurities: Guidelines for Residual
SolVents; International Conference on Harmonisation, 1997.
(11) Ludescher, J.; Khan, R. A. R.; Das, T. C. WO/2007/017244 A2, 2007.
(12) Attempts were made to reduce water/THF levels with the following
input sample: water content 0.5% /THF 1300 ppm. Experimental
results: (a) Hot water slurry 1.0%/850 ppm. (b) THF slurry: 0.5%/
850 ppm. (c) Drying in rotavapor/air tray drier/vacuum tray drier at
50-55 °C for 20-25 h samples displayed ∼0.18-0.2%/750-800
ppm, respectively.
Purification of Crude 2-[[4-(2,2,2-Trifluoroethoxy)-
pyrid-2-yl]ethylsulfinyl]-1H-benzimidazoles (Lansopra-
zole). Crude lansoprazole 1 (30 kg) was dissolved in THF (270
L) at 45-50 °C and cooled to 25-30 °C; water (540 L) was
added in about 60-90 min. The suspension was stirred at 5-10
°C for 45-60 min. The solid material was slowly (about 60-90
min) filtered on PNF and washed with water (150 L). The thus
obtained wet solid was suspended in ethyl acetate (90 L) at
45-50 °C and stirred for 45-60 min. Then the heterogeneous
mass was allowed to cool to 5-10 °C for 2-3 h. Then the
solid compound was filtered and washed with ethyl acetate (30
L), the wet solid was suspended in ethyl acetate (90 L) at 45-50
°C and stirred for 45-60 min, and then the heterogeneous mass
was cooled to 5-10 °C for 2-3 h. The thus obtained solid
(13) Purity of compound 1 has been determined by RSHPLC analysis
[Column YMC-PAK ODS-A 100 mm × 4.6 mm, 3 µ or equivalent,
15 µL; flow rate 1.0 mL/min and injection load 15 µL with a UV
detector at 285 nm]. Mobile phase - A: water (100%); mobile phase - B:
acetonitrile/water/triethylamine, pH 7.0 [160:40:1 (v/v)]. Diluents prepara-
tion: acetonitrile/water/triethylamine, pH 10.5 by o-phosphoric acid
[40:60:1 (v/v)].
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was filtered and washed with ethyl acetate (90 L), and dried to
obtain lansoprazole 1 in 74.0% yield (22.2 kg, w/w) with 99.8%
HPLC13 purity. Water content was found by the Karl Fisher
method:14 0.06% (w/w). Residual solvents MeOH 73 ppm,
acetonitrile 29 ppm, THF 319 ppm, and EtOAc 124 ppm were
analyzed by gas chromatography.15 1H NMR (400 MHz): δ
13.3 (br, 1H), 8.30 (d, J ) 6.0, 1H), 7.65 (s, 1H), 7.30 (m,
2H), 7.65 (s, 1H), 7.1 (d, J ) 5.6, 1H), 4.9 (q, J ) 13.6, 2H),
4.8 (q, J ) 8.8, 2H), 2.18 (s, 3H); 13C NMR (100 MHz): δ
161.2, 154.1, 150.9, 148.1, 143.2, 134.8, 122.1, 123.0, 119.8,
112.6, 64.7, 60.0, 10.5; FT-IR (cm-1): 3235 (-N-H Stretch-
ing), 2984, 2930 (Aliphatic -C-H Stretching), 1580 (-CdC
Stretching), 1457, 1401 (Aliphatic -C-H Bending), 1173
(-C-N Stretching), 1267, 1039 (-C-O (alkyl ether) Stretch-
ing), 972, 750 (Aromatic -C-H Bending); DSC (V): 178.4 °C;
Mass: Anal. Calculated (m/z): 369.37, (C16 H14 F3 N3 O2 S),
found (M + H): 369.37; CHNS analysis: N ) 11.31, C ) 51.96,
S ) 9.31, H ) 3.80.
Acknowledgment
(14) Water content of 1 was analyzed by the Karl Fisher method as
mentioned in USP 2810a (2.0 gm of lansoprazole and pyridine/ethylene
glycol, 8:2 ratios).
We thank the management of Dr. Reddy’s Laboratories Ltd.
for supporting this work. In addition, we gratefully acknowledge
to K. R. Janardhan Sharma & CPEL team for providing
technical assistance, and AR&D and CRAAI division of IPDO
for their support.
(15) Residual solvent analysis of 1 was determined by gas chromatography.
[Column AT-Wax, 30 mm × 0.53 mm i.d., 1 µm film thickness,
injection volume: 1.0 µL, injector temperature 160 °C, and detector
temperature 260 °C, injection mode/ratio: split/1.5. Carrier gas flow
used 2.5 psi (Helium). Column initially held at 40 °C for 10 min,
then rose to 140 °C at a rate of 10 °C for 1 min, held for 10 min, and
then raised to 250 °C at a rate of 45 °C/min and held for 16 min.
Headspace conditions: oven temperature maintained at 80 °C, vial
equilibration kept for 30 min, loop temperature was 100 °C, and
transfer line temperature 110 °C, pressurization for 0.5 min].
Received for review October 2, 2009.
OP900258B
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