Contemporary Drug Synthesis Esomeprazole 2

Contemporary Drug Synthesis. Jie-Jack Li, Douglas S. Johnson, Drago R. Sliskovic, Bruce D.
Roth
Copyright 0 2004 John Wiley & Sons, Inc.
ISBN: 0-47 1 -2 1480-9
Chapter 3. H'K-ATPase Inhibitors: Esomeprazole (Nexium") 21
Chapter 3. H+/K+-ATPaseInhibitors: Esomeprazole (Nexium@)
USAN: Omeprazole USAN. Esomeprazole

Trade Name. Prilosec@ Trade Name Nexium@
AstraZeneca AstraZeneca
Launched:1985 Launched: 2001
M.W. 345 21 M.W. 713.13
$3.1 Introduction
Hydrochloric acid (HCl), as the gastric acid, is a major constituent of the
secretions of the gastrointestinal tract. It is essential to the food digestion process.
However, excessive secretion of HCl will damage the mucosa and subsequently the
submucosa, producing ulceration of the gastrointestinal tract, especially the stomach and
duodenum. Thus maintaining the equilibrium between HCl and the acid-neutralizing
mucus is important for the gastnc system. Two types of drugs are utilized for
neutralizing the excess acid produced in the GI tract: the first type are antacid salts, such
as CaC03, NaHC03, and Alp04 whose mode of action is a simple acid-base
neutralization; while the second type are inhibitors of acid production. The latter is
evidently superior to the former due to lesser side effects. The inhibitor approach has
produced many block-buster drugs that have revolutionized the pharmaceutical industry.
Examples include Hz-blockers such as cimetidine (3) and ranitidine (4).
3 4
Fig. 1. Cimetidine (3) and ranitidine (4).

22 Contemporary Drug Synthesis
Omeprazole (I), introduced in 1988, was the first H‘/K+-ATPase inhibitor, also
known as a proton pump inhibitor (PPI), which was marketed as a treatment for gastric
ulcers. It functions by preventing acid production in the mucosa. Omeprazole was the
best-selling drug for several years until its patent expiration in 2001. The mechanism of
action of omeprazole (l), the “omeprazole cycle”, is shown in Scheme l.132
Consequently, protonation of 1 takes place slowly when it encounters the acidic medium
in the gastric chamber. The protonated intermediate 5 then undergoes an intramolecular
nucleophilic cyclization in a 5-exo-digfashion where the pyridine moiety serves as the
nucleophile to furnish benzoimidazoline 6. A reversible ring opening of 6 then delivers
sulfenic acid 7, which serves as an electrophile in a 6-exo-trig ring-closure to afford the
reactive intermediate 8 after dehydration. The pyndinium sulfydryl 8 is a very good
electrophile, and is readily attacked by the cysteine residue of the enzyme H‘/K+-ATPase.
Therefore, omeprazole (1) behaves more like a pro-drug because pyridinium sulfydryl 8
is the actual inhibitory species.
s:
H,SOEnzyme Enzyme
f
Scheme 1. Bioactivation of omeprazole - the “omeprazole cycle”.

Chapter 3. H'/K'-ATPase Inhibitors: Esomeprazole (Nexium@) 23
Esomeprazole (2) is the (S)-enantiomer of racemic omeprazole (1). The former

has better pharmacokinetics and pharmacodynamics than the latter and therefore
possesses higher efficacy in controlling acid secretion and has a more ideal therapeutic
profile.
$3.2 Synthesis of Esomeprazole
The synthesis of esomeprazole (2) is illustrated below.
10 11
Pyridylmethyl chlonde 11 was obtained by direct chlorination of alcohol 10 using

thionyl chloride3-' The hydroxymethyl-pyndine 10, in turn, was synthesized from 3 3 -
dimethylpyndine in 6 steps utilizing a Boekelheide reaction6 that transformed the 2-
methylpyridine-N-oxide to the corresponding h ydrox ymethyl-pyridine 10.
13 reflux, 2 h, 70%
12
Methoxyphenylene diamine 12 was treated with potassium ethylxanthate to afford

benzimidazole-thiol 13. The coupling of thiol 13 and chloromethyl-pyridine 11 was then
facilitated by treatment with NaOH in refluxing EtOWH20. Subsequently, the oxidation

of resulting sulfide 14 was easily camed out using m-CPBA in CHClj to deliver
omeprazole (1).
An improved transformation of 14 to 1 was patented in 1991.7 The invention
involved carrying out the m-CPBA oxidation of 1 in CHZC12 at a substantially higher pH
of 8.0 to 8.6 using KHC03 as the buffer. The reaction mixture was subsequently
extracted with aqueous NaOH. The separated aqueous phase was then treated with an
alkyl formate (e.g. methylformate), maintaining the pH > 9, allowing omeprazole (1) to
crystallize. Another improved sulfide oxidation was patented in 2000 using EtOAc as the
solvent.8
$3.2.1 Separation using HPLC
The small-scale synthesis of esomeprazole (2) was conveniently accomplished via

an HPLC separation of the omeprazole (1) enantiomer~.~
For large-scale separations, it
can be achieved by a reverse phase HPLC of the two stereoisomers of a diastereomeric
mixture of an alkylated omeprazole where the alkyl group serves as a chiral
In order to install the requisite chiral auxiliary, a “handle” was required for tethering.
This was easily installed by treating 1 with formaldehyde, followed by chlorination with
thionyl chloride to afford chloromethylbenzimidazole 15. Subsequently, treatment of 15
with (R)-(-)-mandelic acid (16) in the presence of NaOH under phase transfer catalysis
conditions gave ester 17 as a mixture of two &astereomers. The pair of diastereomers
was then separated by reverse phase HPLC to render the pure diastereomer 17a.
Removal of the (R)-(-)-mandelic acid chiral auxiliary was achieved by a brief exposure
of ester 17a to a NaOH solution. Finally, magnesium salt formation using MgC12 then
delivered esomeprazole (2).
1
1. CH20
2. soc12
*
H3C-o a)- r c L .,
C
H
3.&!&g
15 CH3
CH, Ho%Ph
OH
NaOH, Bu4NHS04
16
CHC13/H20, reflux, 38%

*
Chapter 3. H'W-ATPase Inhibitors: Esomeprazole (Nexium') 25
U
.. - u '
CH3 17a CH3
17
1. NaOH, MeOH/H20, rt, 10 rnin, 77%
2. MgClp, H20,86%
H3C, 0
2
$4::; CH3
2
Mg2+
§3.2.2 Asymmetric oxidation of the sulfide
The advent of asymmetric synthesis methodology has had a tremendous impact

on both academia and industry. For example, the Sharpless epoxidation has become a
staple in the construction of chlral building blocks. In this particular case,'2313
asymmetnc oxidation of the sulfide 14 was accomplished by employing a catalytic
amount of chiral ligand, D-(-)-&ethyl tartrate to fashion sulfoxide 18 in 99.99% ee.
Conversion of 18 to the corresponding magnesium salt 2 was then easily accomplished
by treatment with MgC12. This method was apparently more advantageous than the
HPLC separation method which involves the use of one equivalent of chiral auxiliary.
The asymmetric oxidation approach is also more amenable to the large-scale process.
J9pqCH3
1.2 equiv cumene peroxide
10 mol% D-(-)-diethy1 tartrate
14 L H3C,~ O'CH3
5 rnol% Ti(O/-Pr)4, HN(/-Pr)2
18 CH3
5OoC, 74%, > 99.9% ee
$3.2.3 Biooxidation
Oxidation of the sulfide 14 can also be carried out via bio~xidation,'~as

biotransformations have become recognized as a viable method for chemical
transformations due to their environmentally friendly conditions. Thus, sulfide 14 was
incubated with a variety of microorganisms in 50 mM Na2HP04 buffer, pH 7.6 with 5-10
g/L dry cell weight and a substrate concentration of 1 g L The cells were incubated with
the sulfide 14 on a rotary shaker at 28OC for 18-20 h. The screening process gave
enantiomencally enriched 18 with ee from 56-99%. In particular, Penicillium
frequentans BPFC 386, Penicillium frequentans BPFC 585 and Brevibacterium
paraffinophagus ATCC 21494 all resulted in > 99% ee.
Penicrllium
frequentans
* 18
H3L0 BPFC 386
CH3
14
Similarly, sulfides 19 and 21 were biooxidized to the corresponding

enantiomencally enriched sulfoxides, (-)-pantoprazole 20 and (-)-lansoprazole 22,
respectively. These biotransformation processes are still at the exploratory stage. The
concentration of the substrate is generally minute - in the ppm range. As a result, this
method I S not suitable for large-scale processes.
Chapter 3. H+IK+-ATPaseInhibitors: Esomeprazole (Yexiurn@) 27
03.3 References
1. Lindberg, P.; Branstrom, A.; Wallmark, B.; Mattsson, H.; Rikner, L.; Hoffman, K.-J.
Med. Res. Rev. 1990,10, 1-54.
2. Lindberg, P.; Nordberg, P.; Alminger, T.; Branstrom, A.; Wallmark, B. J. Med.
Chem. 1986,29, 1327-1329.
3. Junggren, U. K.; Sjostrand, S. E. EP 0005129 (1979).
4. Kohl, B.; Sturn, E.; Senn-Bilfinger, J.; er al. J. Med. Chem. 1992,35, 1049-1053.
5 . Winterfeld, K.; Flick, K. Arch. Pharm. 1956,26,448-452.
6. Li, J. J. Name Reactions Springer: Berlin, 2002, 39.
7. Brandstron, A. E. WO 9118895 (1991).
8. Hafner, M.; Jereb, D. WO 0002876 (2000).
9. Erlandsson, P.; Isaksson, R.; Lorentzon, P.; Lindberg, P. J. Chromatography 1990,
532,305-3 19.
10. WO 9208716 (1992).
11. Lindberg, P. L.; Von Unge, S. WO 9427988 (1994).
12. Lindberg, P. L.; Von Unge, S. US 5714504 (1998).
13. Cotton, H.; Krostrom, A.; Mattson, A.; Moller, E. WO 9854171 (1998).
14. Holte, R.; Lindberg, P.; Reeve, C.; Taylor, S. WO 9617076 (1996).

Contemporary Drug Synthesis Esomeprazole 2

Uploaded by

Copyright:

Available Formats

Contemporary Drug Synthesis Esomeprazole 2

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Contemporary Drug Synthesis Esomeprazole 2

Uploaded by

Copyright:

Available Formats

Contemporary Drug Synthesis. Jie-Jack Li, Douglas S. Johnson, Drago R. Sliskovic, Bruce D.

Chapter 3. H'K-ATPase Inhibitors: Esomeprazole (Nexium") 21

Chapter 3. H+/K+-ATPaseInhibitors: Esomeprazole (Nexium@)

USAN: Omeprazole USAN. Esomeprazole

Fig. 1. Cimetidine (3) and ranitidine (4).

Scheme 1. Bioactivation of omeprazole - the “omeprazole cycle”.

Esomeprazole (2) is the (S)-enantiomer of racemic omeprazole (1). The former

$3.2 Synthesis of Esomeprazole

The synthesis of esomeprazole (2) is illustrated below.

Pyridylmethyl chlonde 11 was obtained by direct chlorination of alcohol 10 using

Methoxyphenylene diamine 12 was treated with potassium ethylxanthate to afford

facilitated by treatment with NaOH in refluxing EtOWH20. Subsequently, the oxidation

$3.2.1 Separation using HPLC

The small-scale synthesis of esomeprazole (2) was conveniently accomplished via

CHC13/H20, reflux, 38%

1. NaOH, MeOH/H20, rt, 10 rnin, 77%

§3.2.2 Asymmetric oxidation of the sulfide

The advent of asymmetric synthesis methodology has had a tremendous impact

Oxidation of the sulfide 14 can also be carried out via bio~xidation,'~as

Similarly, sulfides 19 and 21 were biooxidized to the corresponding

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.