An efficient synthesis of dexlansoprazole employing asymmetric oxidation strategy

Article abstract of DOI:10.1016/j.tetlet.2011.08.033

An alternative and scalable synthesis of dexlansoprazole ((R)-(+)-1); the (R)-enantiomer of Lansoprazole with an enantiomeric excess of >99.8% is presented.

Full text of DOI:10.1016/j.tetlet.2011.08.033

Tetrahedron Letters 52 (2011) 5464–5466
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An efficient synthesis of dexlansoprazole employing asymmetric
oxidation strategy q
Manne Naga Raju a, Neelam Uday Kumar a, Baddam Sudhakar Reddy a, Naredla Anitha a,
Gangula Srinivas a, Apurba Bhattacharya a, Kagga Mukkanti b, Naveenkumar Kolla a,
,
⇑
Rakeshwar Bandichhor a,
⇑
a Research and Development, API, Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupally, Qutubullapur 500 090, R.R. Dist., A.P., India
b Center for Environment, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 085, A.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
An alternative and scalable synthesis of dexlansoprazole ((R)-(+)-1); the (R)-enantiomer of Lansoprazole
with an enantiomeric excess of >99.8% is presented.
Received 26 June 2011
Revised 3 August 2011
Accepted 6 August 2011
Available online 19 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Introduction
utilized by TAP’s group to synthesize the compound of present
interest (Scheme 1).7
Enantiopure sulfoxide derivatives belong to the family of sev-
eral biologically active compounds and there are many candidates
of this class which got approved by various regulatory authorities.1
Likewise, dexlansoprazole ((R)-(+)-1), (R)-enantiomer of lansopraz-
ole, is a new proton pump inhibitor (PPI) specifically developed for
anti ulcer activity by TAP pharmaceuticals Ltd employing new
modified-release technology (Fig. 1).2
Dexlansoprazole ((R)-(+)-1) was first approved by United States
of Food and Drug Administration (USFDA) in the form of 30 and
60 mg capsules for the management of patients with erosive
oesophagitis and non-erosive reflux disease (GERD or GORD), un-
der the brand name of DEXILANT.3 Extensive research work has
been directed/published by various groups on asymmetric sulfox-
idation with excellent results, in particular, the oxaziridine medi-
ated asymmetric oxidation4l is the recent advancement that has
been documented in this area.4
Nevertheless, an asymmetric sulfoxidation of prochiral sulfides
is one of the most straight forward and convenient approaches to
obtain corresponding chiral sulfoxides. In this class, Astra’s ap-
proach that allows the synthesis of Esomeprazole via modification
of Kagan’s asymmetric oxidation method is assumed to be one of
the best strategies to our knowledge.5 The detailed mechanistic
studies towards present asymmetric sulfoxidation were also re-
ported by the same group in collaboration with Stockholm Univer-
sity research group.6 Thereafter, the same methodology has been
In order to develop an alternative, robust and scalable process,
we embarked our studies towards asymmetric sulfoxidation of
the related prochiral nitrosulfide analogue 3 that has been utilized
later for dexlansoprazole ((R)-(+)-1) synthesis.8 Herein, we wish to
disclose our approach based on the understanding of the physical
properties of the prochiral nitrosulfide 3 hydrates specifically sol-
ubility profile under asymmetric oxidation reaction conditions
and influence of water on enantioselectivity of R-(+)-4 to establish
a robust and highly reproducible large-scale synthetic process for
dexlansoprazole with >99.8% ee and ICH quality of final API.
Results and discussion
Our approach began with enantioselective oxidation of the pro-
chiral nitrosulfide intermediate 3 under modified Kagan’s selective
oxidation conditions to obtain either enantiopure or enantiomeri-
cally enriched nitrosulfoxide intermediate (R)-(+)-4 that can easily
be converted to Dexlansoprazole ((R)-(+)-1) in the subsequent step
as shown in Scheme 2. The optimized route consists of two steps
involving asymmetric oxidation of 3 with cumene hydroperoxide9
(CHP) in presence of titanium derived chiral complex prepared
in situ from L-(+)-Diethyl tartarate (L
-(+)-DET), Ti-(OiPr)4 and water
applied in the molar ratio of 2.2:1.1:0.6 to obtain (R)-(+)-4 with
OCH2CF3
O
S
N
N
N
H
q
DRL-IPD Communication number: IPDO-IPM-00236
⇑
(R)-(+)-1
Corresponding authors. Tel.: +91 4044346117; fax: +91 40446285.
E-mail addresses: naveenk@drreddys.com (N. Kolla), rakeshwarb@drreddys.com
Figure 1. Structure of dexlansoprazole.
(R. Bandichhor).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.033

M. N. Raju et al. / Tetrahedron Letters 52 (2011) 5464–5466
5465
Ti(OiPr)4
isolation) were thoroughly optimized and the resulting process has
been successfully implemented on the large-scale (85 kg batch
size) with predetermined yield and quality. The screening and
optimization results are summarized in Table 2 (see Supplemen-
tary data). The systematic approach to the optimization led us to
arrive at optimal reaction conditions. Our efforts are detailed in
the experimental section (see Supplementary data).
OCH2CF3
O
OCH2CF3
(R, R)-DET; H2O
N
N
S
(iPr)2NEt
PhC(CH3)2OOH
S
N
N
N
H
1
N
H
2
(R)-(+)-
Scheme 1. TAP’s approach on dexlansoprazole synthesis.
Crystallization to wash the (S)-(À)-4, undesired enantiomer
followed by nucleophilic substitution reaction to introduce
2,2,2-triflouroethoxy group on enantiomerically purified (R)-
(+)-4
>90% ee. The enantiomerically enriched (R)-(+)-4 was subjected to
acetone mediated preferential crystallization to yield enantiopure
(R)-(+)-4 (>97% ee) which on treatment with potassium salt of
2,2,2-triflouroethanol in dimethylformamide (DMF) yielded Dex-
lansoprazole (after necessary aqueous work up) with ICH quality
having >99.8% ee. The detailed experimental study carried out to
arrive at the above two step process is discussed in length here
in this account.
Crystallization method has been developed to remove unde-
sired (S)-(À)-4 from enantiomerically enriched (R)-(+)-4. The unde-
sired (S)-(À)-4 precipitates out as racemic compound (RS)-( )-4
under reaction conditions leaving pure (R)-(+)-4 into the filtrate.
Solubility profile of the individual isomers ((R)-(+)-4 and (S)-(À)-
4) versus Racemic (RS)-( )-4 and solvent screening studies led us
to the conclusion that acetone is the best solvent system for effec-
tive removal of S-(À)-4 by attaining maximum yield and >97% ee as
shown in Table 3 (see Supplementarydata). Acetone quantity, crys-
tallization/isolation time and temperature also played a dramatic
role to attain desired chiral purity with substantial yield as
mentioned in the Table 4 (see Supplementary data). The optimum
solvent quantity was found to be 22 times with respect to input
(R)-(+)-4 as per the brief process described here: Enantiomerically
enriched (R)-(+)-4 was suspended in a desired amount of acetone
and heated to 45–50 °C for 15–20 min to get the clear solution.
Changes in reaction mass description were observed if the solution
is kept at 45–50 °C for more than 25 min. The resulting clear solu-
tion was cooled to 25–35 °C and then À5 to 0 °C thereby stirred at
same temperature for 60–90 min. During the course of operation,
(RS)-( )-4 was thrown out as a solid in the reaction mass leaving
pure (R)-(+)-4 into the filtrate. The precipitated (RS)-( )-4 has been
separated by filtration and then filtrate has been subjected to evap-
oration under vacuum to obtain enantiopure (R)-(+)-4 in ꢀ80%
yield [purity: 98.6% (HPLC); chiral purity: 95.2% (HPLC) (>90%
ee)]. The resulting enantiopure (R)-(+)-4 has directly been used
in the next step of –NO2 substitution reaction. The structure of
(R)-(+)-4 has been unambiguously confirmed by single crystal
analysis (Fig. 3, see Supplementary data).
Finally, the resulting enantiopure (R)-(+)-4 has been subjected
to nucleophilic substitution reaction conditions using potassium
salt of 2,2,2-triflouroethanol generated in situ to afford the com-
pound of present interest with ICH (International Conference on
Harmonization) quality in ꢀ59% yield [purity: 99.64% (HPLC); chi-
ral purity: 99.98% (HPLC)]. DMF is found to be an excellent choice
of solvent and reaction temperature (85–90 °C) is somewhat criti-
cal in controlling impurity formation. Furthermore, extensive opti-
mization of work-up conditions (viz., solvent screening, quantity,
pH range, isolation time and temperature etc) helped us to wash-
out carryover impurities specifically sulfone and undesired (S)-
(À)-1 to the desired limit (<0.15% by HPLC). Other variables of
Enantioselective oxidation of prochiral nitrosulfide
intermediate 3 under modified Kagan’s conditions
Despite the lack of consistency in the initial laboratory asym-
metric oxidation experiments that vary from one lot to another
lot of 3, we decided to continue our efforts to make the process
highly consistent and robust. As the project progresses, it was
understood that nitrosulfide 3 exists in two different hydrate forms
viz., hemihydrates and monohydrate (Fig. 2). Moreover, the
solubility profile of each was found to play dramatic role in the
presence of a chiral moiety in the initial chiral complex formation
step.
Reaction profile was excellent only with hemihydrate compared
to other hydrate and anhydrous forms mainly due to its high solu-
bility during reaction. Reaction profile with anhydrous 3 was found
to be heterogeneous that did not go to completion even after intro-
ducing equivalent amount of water into the reaction system. Since
we did not have good control over consistency of nitrosulfide 3
hydrates, an azeotropic distillation (ꢀ110 °C under atmospheric
condition) was incorporated at the beginning of the process (reac-
tion components: nitrosulfide 3 + Toluene) before introducing the
chiral moiety into the reaction system. At this particular stage,
after ensuring total water removal, reaction temperature was
brought down to 70 °C and added desired amount of water (i.e.,
slightly excess to hemihydrate equivalent—0.6 equiv or ꢀ3.6% with
respect to input 3) before introducing the chiral moiety into the
reaction system. With this change, reaction profile was found to
be consistent ending up with 90–95% ee (95–98% chiral purity).
The quantity of water has been thoroughly studied and validated
afterwards by monitoring enantiomeric excess of (R)-(+)-4 (chiral
HPLC) along with the mole equivalents optimization of L-(+)-DET,
and Ti-(OiPr)4 used for in situ chiral complex generation (Table 1,
see Supplementary data).
The other reaction parameters such as mole equivalents of base,
oxidizing agent, addition time & temperature, reaction mainte-
nance time, temperature and other work-up conditions (including
NO2
N
NO2
N
OCH2CF3
(II), (III)
(I)
O
S
O
N
N
N
S
S
N
N
H
N
H
N
H
3
(R)-(+)-4
(R)-(+)-1
Scheme 2. Dexlansoprazole synthesis via nitrosulfide 3 asymmetric oxidation. Reagents and conditions: (i) Ti(O-iPr)4/(R,R)-DET/H2O, PhCH3, (iPr)2NET, PhC(CH3)2OOH; 0–
5 °C, 4–5 h, aq NH3 and piperidine, acetonitrile, acetic acid; (ii) acetone, 45–50 °C; (iii) K2CO3, DMF, CF3CH2OH, acetonitrile, acetic acid, water.

5466
M. N. Raju et al. / Tetrahedron Letters 52 (2011) 5464–5466
Figure 2. pXRD data for various hydrate forms of the prochiral nitrosulfide derivative 3.
2. (a) TAP Pharmaceutical Products Inc. Announces Phase 3 TAK-390MR data
demonstrating higher overall healing versus Lansoprazole in patients with
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http://www.allbusiness.com/medicine-health/diseases-disorders/14048741-
1.html.
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references cited therein..
the reaction conditions involved in overall process were thor-
oughly optimized and implemented as a single step process in
the commercial scale.
Conclusion
An efficient and alternative synthetic protocol for Dexlansop-
razole ((R)-(+)-1) was developed with thorough understanding
over solubility profile of the prochiral sulfide hydrates and influ-
ence of water on Ti-derived chiral complex preparation that has
been used in the asymmetric oxidation step. This optimized pro-
cess has successfully been implemented in the commercial scale
with zero failure obtaining predetermined yield and quality.
Apparently, the present method has potential to serve as an alter-
native synthetic protocol for other enantiopure prazole compounds
viz., Omeprazole, Pantoprazole, Rabeprazole etc.
5. Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Sorensen, H.; Unge, S. V. Tetrahedron:
Asymmmetry 2000, 1, 3819–3825.
Acknowledgements
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7. Fujishima, A.; Aoki, I.; Kamiyama, K. US 6462058 B1, 2002.
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Vishwasrao, P. S.; Kumar, T. A.; Reddy, P. S.; Gulabrao, S. S.; Ashok, S.; Varma, M.
S. PCT 114789 A1, 2009.
We thank the management of IPDO-API, Dr. Reddy’s laborato-
ries Ltd for supporting this work. Support from the colleagues at
analytical research and development team is highly appreciated.
Supplementary data
9. The commercially available ꢀ75% cumenehydroperoxide (CHP) has been used
for present asymmetric oxidation.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.033.
References and notes
1. (a) Tomaszewski, J.; Rumore, M. M. Drug Dev. Ind. Pharm. 1994, 20, 119; (b)
Pellissier, H. Tetrahedron 2006, 62, 5559–5601.