213 Chapter-V

CHAPTER-V

New Synthetic Methodology and Study the Key

Parameters of the Synthesis of Esomeprazole & its

Premix; a Proton Pump Inhibitor

214 Chapter-V

SECTION-A

5.1 INTRODUCTION

Mg salt of esomeprazole 1 is a first proton pump inhibitor (PPI) (brand

name, Nexium) developed by AstraZeneca.1 Nexium was approved by US

FDA for the treatment of heartburn and other symptoms accompanying

with gastro esophageal reflux disease (GERD).2

Figure-5.1. Structure of Mg salt of esomeprazole 1

Esomeprazole 1 is prepared from omeprazole which is a racemic

mixture of the R- and S- isomers of omeprazole. Out of both the isomers,

only S-isomer has the therapeutic activity. Esomeprazole comprises only

S-isomer. Esomeprazole is the third highest selling drug, has the total

sales around 6 $ billion.3

5.1.1. Biological activity

Esomeprazole also used for the treatment of Zollinger – Ellison

syndrome, peptic ulcers and dyspepsia.4 Esomeprazole furnishes

improved clinical efficacy, better acid control than current racemic PPI‟s,

pantoprazole, lansoprazole and omeprazole. It has a propitious

pharmacokinetic profile corresponding to omeprazole.

Around 3 crores adult persons have the practical acquaintance of

heartburns, swallowing problems and sour taste in mouth daily. These

215 Chapter-V

symptoms are connected to harsh stomach acid which is backing up to

the esophagus. If this acid reflux harms the lining of esophagus, it may

convert to a more dangerous condition named as erosive esophagitis.

5.1.2. Mechanism of Action

Esomeprazole reduces the secretion of gastric acid by inhibiting the

H+/K+ ATPase in gastric parietal cells. It prevents the production of

gastric acid by inhibiting the role of this enzyme. The R and S-isomers of

racemic omeprazole converts by protonation in the acidic zone of the

parietal cell generates the active inhibitor, achiral sulphenamide.

Esomeprazole blocks the decisive step in the acid production by acting

particularly on the proton pump, as a result, reduces the gastric acidity.

5.1.3. Pharmacology: Proton pump inhibitor

PPI‟s are a class of drugs their principal action is prominent and long

standing minimization of the production of gastric acid. PPI‟s are the

eminent inhibitors of the gastric acid secretion procurable in present

days. These PPI‟s are the most popularly used drugs in the world

because of their remarkable remedy and safety. Structurally most of

these drugs are benzimidazole derivatives.

5.1.4. Clinical results

Esomeprazole heals significantly more patients with reflux

esophagitis than omeprazole pantoprazole and lansoprazole and at both

216 Chapter-V

4 and 8 weeks. Provides sustained resolution of heartburn faster and in

significantly more patients with reflux esophagitis than lansoprazole or

omeprazole.5 It is favorably effective in resolving symptoms in patients

with GERD. Daily treatment with esomeprazole furnishes extremely

effective and well-tolerated long-term management to prevent relapse of

healed esophagitis, maintaining most of the patients in long-term

remission, and is significantly superior to lansoprazole and pantoprazole

in this regard. The high efficacy of Nexium® enables a symptom-driven

approach to the long period of time management of GERD in patients

with confirmed endoscopy-negative reflux condition. It provides effective

resolution of heartburn and acid regurgitation associated with the use of

NSAIDs, including COX-2 selective NSAIDs.

Esomeprazole is the first and only PPI documented for use with COX-

2 selective NSAIDs as well as non-selective NSAIDs. Esomeprazole is

available in an intravenous (i.v.) formulation, which can be administered

as an injection or infusion in patients with GERD who are unable to take

oral therapy. The efficacy and safety profile of Nexium® i.v. is similar to

that of oral Nexium® in the management of reflux esophagitis, so the two

formulations can be regarded as interchangeable. The results show that

Nexium® raises the standard in the management of acid-related

diseases, improving both the quality of patient care and the efficient use

of resources. The raised standard of clinical efficacy set by Nexium®,

217 Chapter-V

coupled with its good tolerability, make it the rational first-line therapy

in acid-related diseases such as GERD.

5.1.5. Side Effects

Side effects comprise stomach pain, gas, headache, nausea,

constipation, diarrhea and dry mouth.

5.1.6. Pantoprazole

Pantoprazole 2 (brand name is protonix) is a PPI drug was discovered

by Altana pharma, which is used for impermanent treatment of erosion

and ulceration belongs to the esophagus provoked by gastroesophageal

reflux disease.6 preliminary treatment is normally of 8 weeks duration,

thereafter additional 8 week duration of treatment could be considered if

it is required.

Figure-5.2. Structures of pantoprazole 2 and (S)-pantoprazole 3

Pantoprazole is proportionately less of drug interactions; Even though

it may change the absorption of the different medications which depend

on the acid quantity present in the in stomach, such as digoxin or

ketoconazole. Single isomer of pantoprazole (S-pantoprazole 3) is yet to be

launched.

218 Chapter-V

5.1.7 Product information.

Name of the drug : Esomeprazole Mg

Innovator : Astra Zeneca

Therapeutic category : proton pump inhibitor

Product patent filed : 1994 (estimated expiry in 2014)

M.F : (C17H18N3O3S)2 Mg

M.Wt. :713.13

Description : white colored crystalline powder

Dosage : 20 mg and 40 mg

Structure:

5.2. REVIEW OF LITERATURE

Chiral sulfoxides are useful synthons for the construction of many

chemically and pharmaceutically significant molecules.7 The traditional

approach to the preparation of optically active sulfoxides involves either

optical resolution of racemates8 or asymmetric oxidation of the prochiral

sulfides.9 Prazoles are a class of active pharmaceutical ingredients which

contain a chiral sulfoxide group as an active component. Prazoles are

known as proton pump inhibitors, which inhibit gastric acid secretion

219 Chapter-V

and are thus used as anti-ulcer agents.10 Nexium®, the magnesium salt

of esomeprazole 1, was one such prazole developed by AstraZeneca and

used for the treatment of acid-related diseases.1

5.3. PRESENT WORK

Earlier we have reported a resolution process for the synthesis of

magnesium salt of esomeprazole 1 through a transition metal complex

using a combination of D-(-)-diethyl tartrate, Ti(OiPr)4 and L-(+)-mandelic

acid as resolving agents.11 In this chapter we reported the systematic

investigation on the significant role of water, temperature and the mole

ratio of the resolving agents in the resolution of omeprazole sodium 4

and applied this methodology to resolve the Pantoprazole 2. Though the

influence of water and temperature in asymmetric sulfoxidation is well

precedent in the literature,12 the effect of these parameters on the

resolution of sulfoxides is not yet explored.

In one of our earlier experiments, we observed that no resolution

occurred when racemic omeprazole base 5 was exposed to a resolving

agent such as a mixture of Ti(OiPr)4, D-(-)-diethyl tartrate, L-(+)-mandelic

acid and triethylamine. Later, this resolution process was developed

using the sodium salt of racemic omeprazole 4 (Scheme 5.1). Although

this process gave esomeprazole 1 in >99% ee, some inconsistency was

observed as some of the scale up batches were failed in plant. This

prompted us to investigate the influence of various factors that affect the

220 Chapter-V

resolution process such as water content, temperature and mole ratio of

the resolving agents.

Scheme 5.1: Resolution of omeprazole sodium 4

In order to investigate the role of water in the resolution process, we

examined the water content of the omeprazole sodium 4 in both failed

and successful batches. It revealed that the water content of 4 in failed

batch was 0.5 mol (hemi-hydrate) whereas in the successful batch was 1-

2 mol. These observations encouraged us to explore this resolution

process further by altering the composition of water content present in

the reaction.

A systematic investigation on the influence of water in the resolution

of 4 at 35-40 °C showed an interesting phenomenon for the combination

of Ti(OiPr)4/D-(-)-DET/L-(+)-mandelicacid/Et3N/H2O (mole ratio 0.5:1:1:3

:x) where x ranged from 0 to 6. The maximum separation of enantiomers

(>99 % ee of 1)13 was achieved when x ranges from 1-2. No resolution

observed when x = 0 and x = 6. When x = 6, some precipitation occurred

(presumably TiO2). Figure 5.3 shows the effect of water on the resolution

of omeprazole sodium 4.

221 Chapter-V

0

20

40

60

80

100

0.25 0.5 1 1.5 2 2.5 3

water (mole %)

ee %

Fig 5.3: Influence of water on resolution of omeprazole sodium 4

Moreover the reaction temperature played a key role in chiral

discrimination. No resolution was observed at 0 °C and the best

selectivity(>99% ee) was obtained at 35-40 °C. Some product degradation

occurred above 40 °C, which led to the formation of many impurities.

Interestingly, an increase in temperature above 40 °C didn‟t affect the ee

of the product.

0

25

50

75

100

0 10 20 30 40 50 60

temp (°C)

ee %

Fig 5.4: Influence of temperature on resolution of omeprazole sodium 4

Figure 5.4 explains the influence of temperature in the resolution of

omeprazole sodium 4 (with water content 1-2 mol).

We also extended our studies toward the effect of mole ratio of the

resolving agents, base and solvents. Table 5.1 illustrate how the

222 Chapter-V

resolution of 4 (with water content 1-2 mol) was influenced by altering

the ratio of Ti(OiPr)4 and D-(-)-DET. The optimal mol ratio of Ti(OiPr)4 and

D-(-)-DET was found to be 0.5:1.

Table 5.1: Influence of mol ratio of Ti(OiPr)4 and D-(-)-DET

Ti (OiPr)4

(eq)

D-(-)-DET

(eq.)

ee (S)

(%)

0.25 0.5 25

0.5 0.5 28

0.5 1.0 >99

1.0 1.0 76

1.0 1.5 81

1.0 2.0 78

Although mol ratio of triethylamine had minimal influence on the

resolution, satisfactory results were obtained by using 3 eq. of

triethylamine with respect to 4. Solvents such as ethyl acetate, methanol,

acetonitrile and acetone were screened for this process and it was found

that the resolution occurred only when acetone was used as a solvent.

Resolution in other solvents led to racemic omeprazole.

Another interesting observation is, that the order of addition of the

reagents also played a significant role in resolution. The best results were

obtained by adding D-(-)-DET first followed by Ti(OiPr)4, triethylamine

and finally L-(+)-mandelic acid. If Ti(OiPr)4 was added before D-(-)-DET,

precipitation (presumably TiO2) occurred. If triethylamine was added

before D-(-)-DET and Ti(OiPr)4, no resolution observed. Since

223 Chapter-V

Esomeprazole 1 is sensitive towards acids, L-(+)-mandelic acid should be

added after the addition of triethyl amine.

We also executed these standard conditions to resolve omeprazole

base 5 and pantoprazole 2 by adding 1.5 eq. of water to the reaction

mixture. Surprisingly, both (5 & 214) were resolved with >99% ee using

acetone and EtOAc as solvents respectively (Scheme 2). No Resolution

observed without the addition of water in each case (5 & 2). In the case

of omeprazole, the yield of the product esomeprazole 1 was inferior

(36.5% on the basis of racemate) when compared to the Nexium

process,1b which involves asymmetric sulfoxidation, but the enantiomeric

excess of the product in our resolution technique was excellent (>99% ee)

and the process appears to be robust. Strategies towards converting

unwanted R-1 isomer to racemic 1 are currently under investigation.

Scheme 5.2: Resolution of omeprazole 5 and pantoprazole 2

224 Chapter-V

5.4. CONCLUSION

We have extensively examined the effects of various factors that

influence the resolution of omeprazole sodium 4. The optimized

resolution conditions were successfully extended to omeprazole base 5

and other prazoles such as pantoprazole 2.

225 Chapter-V

SECTION-B

SCALABLE PROCESS FOR THE PREMIX OF ESOMEPRAZOLE

5.5. INTRODUCTION

Prazoles are known as proton pump inhibitors (PPI) that

mechanistically inhibit gastric acid secretion and are thus used as anti-

ulcer agents.7,10 The new PPI, esomeprazole Mg (Nexium®), developed by

AstraZeneca is the S-isomer of omeprazole, the first PPI developed as a

single enantiomer used for the treatment of acid-related diseases.1

Figure 5.5: Structure of esomeprazole 1

Esomeprazole 1 as shown in Figure 5.5 is found to be highly effective

PPI than omeprazole15 due to the fact that it has superior

pharmacokinetic properties and less variability in effectiveness as

compared to omeprazole. Esomeprazole shares a similar mechanism of

action, side-effect profile, and precautions to currently available proton-

pump inhibitors. The better efficacy of esomeprazole may be attributed to

the active moiety that is enantiomerically pure (S)-isomer of omeprazole.

Earlier we have reported a resolution process for the synthesis of

magnesium salt of esomeprazole through a transition metal complex

using a combination of D-(-)-diethyl tartrate, Ti(OiPr)4 and L-(+)-mandelic

acid as resolving agents.11 In continuation to our work, we opted to

226 Chapter-V

stabilize unstable form of esomeprazole base to achieve pharmaceutically

acceptable formulation.

Certain pharmaceutically active ingredients are acid-labile thus they

create myriad of problems during in vivo absorption therefore formulating

such an acid-labile compounds in the oral pharmaceutical dosage forms

to make them compatible to the acidic environment of the stomach

imposes a great challenge. For example, few substituted benzimidazole

derivatives have poor stability. In particular, these compounds intend to

decompose rapidly and acquire color under moist or acidic to neutral

conditions. When these compounds are formulated for oral

administration, they require specific coating to avoid exposure to the

gastric acid of the stomach. In order to achieve effective enteric coating,

granulation or pellet formation techniques are practiced that prohibits

the active pharmaceutical ingredient (API) to become soluble in water

under acidic or neutral conditions and soluble in alkaline conditions.

Nevertheless, the ingredient used in enteric coatings is frequently acidic,

which can be a reason for the decomposition of the acid-labile

compounds. That decomposition happens even at the time of the enteric

coating process, which results in the coloration of the surface of the core.

In order to avoid such problem, an inert sub coating, which is not acidic,

is often required between the core and enteric coating, which brings the

intricacy and adds the cost of the formulation in the manufacturing

process of acid-labile compounds.

227 Chapter-V

For drug substances which are labile in the acidic medium, but

contains good stability in alkaline to neutral media, it is often beneficial

to add base as the inactive ingredient in order to enhance the stability of

the drug substance in the period of synthesis and storage.

Benzimidazole derivatives such as esomeprazole and omeprazole are

highly unstable in acidic medium and also in the neutral conditions. As a

result, to enhance the storage stability, an alkaline base such as sodium

bicarbonate is often being used during the formulation. Also substituted

benzimidazole derivatives are converted to their alkaline salts, which are

usually more stable than the free base species. It is familiar that such

alkaline base has side effects on patients who suffer from heart failure

and hypertension etc.

5.6. REVIEW OF LITERATURE

Various stabilizing agents are disclosed for benzimidazole derivatives

in the core tablets.16 The findings also show that such compounds are

stable in the presence of basic inorganic salts of magnesium, calcium,

potassium and sodium. The stability is further consolidated by

separating the acid labile prazoles from the acidic components of the

enteric coat by an intermediate coating (sub coating).

At our end, we have unsuccessfully attempted to formulate the

amorphous form of the free base of 1 by employing the basic, or neutral

or acidic coating or sub coating excipients. This observation prompted

228 Chapter-V

us to embark studies on preparation of premix to stabilize the

amorphous form of 1.

Premix is a well defined mixture of API and a set of additives that

help in retaining the stability of formulated drug product. Premix

process of esomeprazole base is not yet reported. Herein, we describe an

efficient scalable unprecedented process for the premix of unstable

esomeprazole base by understanding the role of water which was not

studied in detail in earlier disclosure16h and employing organic base and

neutral components that allows us to stabilize the esomeprazole base 1.

5.7. PRESENT WORK

During formulation, it was found that esomeprazole base can

undergo degradation due to its unstable nature at ambient conditions as

well as at lower temperatures. To overcome this problem, we decided to

make the API more stable at 2-8 °C, by mixing it with additives like

mannitol 6 and meglumine 7 (Fig-5.6) in the preparation of esomeprazole

1 premix.

Figure 5.6: Structures of mannitol 6, meglumine 7

This innovative approach provides a stabilized premix for the

pharmaceutical formulations of acid-labile APIs. Esomeprazole base 1 as

229 Chapter-V

oily residue prepared by following the novel resolution process published

earlier by us11 as shown in Scheme 5.3

Scheme 5.3: Synthesis of esomeprazole 1 starting from omeprazole 5

Esomeprazole 1 generates many impurities under acidic conditions.

In our early attempts, we prepared the esomeprazole base 1 as a solid

amorphous polymorph from its oily residue employing acetone and water

(1:2). In this experiment the chiral purity was enhanced from 97% to

99.8%. However, we encountered difficulty in drying the wet solid at less

than 30 °C, as the compound started changing its color from off white to

cream and simultaneously the material also changes its morphological

behavior as it turned out to be sticky mass instead of free flowing

powder.

In order to prepare premix, we have screened different

pharmaceutically acceptable water-soluble sugar derivatives, like

mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates,

dextrins, lactitol and we found that the sugar derivative alone is not

230 Chapter-V

sufficient to get the stable premix (Table 5.2). In fact ingredients (6 and

7) with other additives were employed in the formulation of

commercialized batches of omeprazole tablets.17 Thus, 6 and 7 were

considered to be non-toxic and clinically safe to use in our premix

preparation of 1.

Considering the first principle of acid base reaction it can be

visualized that the use of base may enhance the stability therefore we

screened different pharmaceutically acceptable water-soluble bases, like

meglumine, lysine, N,N′-dibenzylethylenediamine, chloroprocain, choline,

diethanolamine, ethylenediamine, procaine (except meglumine 7; results

with other bases are not included) along with mannitol 6 as the

structures are shown in Table 5.2.

Interestingly, stable esomeprazole premix was obtained with

meglumine base along with mannitol in appropriate solvents. We have

tried different combinations of meglumine and mannitol along with

esomeprazole to get the stable premix. Noticeably, 50:47:3 ratio of

esomeprazole, mannitol and meglumine offered stable premix.

Interestingly, it was observed that the dry esomeprazole base is

fragile under the conditions that we applied for the preparation of premix

of 1. However, in presence water we were able to isolate stable premix of

1. This observation prompted us to investigate the role of water in the

premix formation event.

231 Chapter-V

Table 5.2: Different ratios of 1, 6, 7 and various solvents used for premix

preparation

Esomeprazole

1 (%)

Mannitol

6 (%)

Meglumine

7 (%) Solvent Result

15 85 -- Acetone &

cyclohexane

Unstable premix

HPLC purity failed

25 75 -- Acetone &

cyclohexane

Unstable premix

HPLC purity failed

50 50 -- Acetone &

cyclohexane

Unstable premix

HPLC purity failed

61.5 30 8.5 Acetone &

cyclohexane

Unstable premix

HPLC purity failed

75 25 -- Acetone &

cyclohexane

Unstable premix

HPLC purity failed

97 -- 3 Acetone &

cyclohexane

Unstable premix

HPLC purity failed

50 47 3 Methanol &

cyclohexane Sticky material

50 47 3 MDC &

cyclohexane Sticky material

50 47 3 EtOAc &

cyclohexane Sticky material

50 47 3 Acetone &

cyclohexane

Free flow powder

Stable premix

50 47 3 Acetone Sticky material

50 47 3 Methanol Sticky material

50 47 3 EtOAc Sticky material

50 47 3 MDC Sticky material

50 47 3 cyclohexane Sticky material

232 Chapter-V

At first, we attempted the preparation of premix by using dried

material (dried under vacuum at 25-30 °C) 1 at lower temperatures

(10-20 °C) which afforded only degradation by products. In other

experiments, water was removed by extracting the product in

dichloromethane followed by evaporation of solvent and eventually the

base 1 was subjected to premix preparation that afforded sticky mass.

Considering the aforementioned observations, we proceeded to

prepare the premix with wet solid and surprisingly we obtained

esomeprazole premix as a free flowing solid. As a result, we anticipate the

hydrogen bonding between additives 6, 7 and 1 up to great extent. The

typical procedure involves the dissolution of around 75% (water) wet 1 in

acetone followed by addition of additives, distillation of solvent up to

around 60 - 70% and co distillation with cyclohexane afforded the

material as a free flowing powder of premix of 1 (Table 5.2).

5.7.1. Polymorphism studies

During the synthesis, we observed that amorphous nature of the

esomeprazole base was retained. Interestingly the impression of 3% of

meglumine in the premix was not detected in the PXRD. However, the

mannitol XRD remained unchanged. The X-ray powder diffraction results

have been obtained on a Rigaku D/Max-2200 model diffractometer

equipped with horizontal goniometer in /2 geometry. The Cu-Kα (1 =

233 Chapter-V

1.5418 Å) radiation was used and the samples were scanned between 3-

45° 2.

5.7.2. Stability studies

Stability studies of esomeprazole premix were conducted at following

different stability conditions: 1) Accelerated stability conditions at 40 °C

+ 2 °C & Relative Humidity (RH): 75% + 5%, 2) Intermediate stability

conditions at 30 °C + 2 °C & RH : 60% + 5%, 3) Long term stability

conditions at 25 °C + 2 °C & RH : 60% + 5% 4) Cold storage stability

conditions at 2 °C to 8 °C. We have observed that esomeprazole premix

was stable at cold storage stability conditions (condition 4).

Table 5.3: Assessment of the stability of premix of 1.

Time

duration

Colour

description

HPLC

purity

(%)

Esomeprazole

base content

in premix (%)

XRD

Initial day Light yellow

colour solid

99.82 49.2 Amorphous

1st month No change 99.86 47.1 Amorphous

2nd month No change 99.85 47.3 Amorphous

3rd month No change 99.80 47.6 Amorphous

6th month No change 99.82 47.9 Amorphous

9th month No change 99.83 47.6 Amorphous

12th month No change 99.82 47.7 Amorphous

18th month No change 99.81 47.4 Amorphous

24th month No change 99.78 47.0 Amorphous

234 Chapter-V

The stability was judged by color description, HPLC purity,

esomeprazole base content in the premix and XRD. The details are

summarized in Table 5.3. The level of water content during the first

month of stability test was found to be slightly higher (1.73%) than the

initial content (1. 61% w/w). This amount of moisture intake did not

affect the nature of sample since no extra peak in XRD has been detected

indicating that the esomeprazole base in premix of 1 is amorphous in

nature at least for two years.

5.8. CONCLUSION

We have developed a robust and scalable process for the preparation

of stable premix of esomeprazole 1 and successfully demonstrated with

concurrent pilot plant scale. Polymorphic study was performed to

generate irrefutable evidence for amorphous nature of the premix of 1

identical to its free base. We have also conducted the stability studies to

document the storage conditions for the premix of 1, which was found to

have better stability profile over 1 (free base) and it helped us to

formulate premix of 1 as tablets with wide range of excipients.

235 Chapter-V

5.9. EXPERIMENTAL SECTION

Solvents and regents were used for all the reactions as received. The

1H spectra were recorded in CDCl3 using Varian Gemini 200 MHz or 400

MHz FT NMR spectrometer; the chemical shifts are reported in ppm

relative to tetramethylsilane TMS (0 ppm). The FT-IR spectra were

recorded in the solid state as KBR dispersion using Perkin-Elmer 1650

FT-IR spectrophotometer. Mass spectra were obtained on a low

resonance Q-trap machine in electron spray mode. Optical rotations were

recorded on Perkin Elmer model 341 polarimeter.

Preparation of Esomeprazole (1) by resolution of omeprazole sodium (4)

To a suspension of omeprazole sodium 4 (50.0 kg, 136.2 mol) [with 7.2%

water content (200.0 mol)] in acetone (600 L) was added D-(-)-diethyl

tartrate (28.1 kg, 136.2 mol) followed by titanium (IV) isopropoxide (19.4

kg, 68.1 mol) and triethylamine (41.3 kg, 408.7 mol) at 35-40 °C. The

reaction was maintained at the same temperature till it became

homogeneous. L-(+)-mandelic acid (20.7 kg, 136.2 mol) was added to the

reaction mixture and stirring was continued for additional 2 h. The

separated solid was filtered and washed with acetone (350 L). It was

suspended in CH2Cl2 (200 L) and treated with 5% aq. sodium bicarbonate

solution (200 L) for 30 min. The organic phase was separated, dried over

anhydrous sodium sulfate and subjected to distillation under reduced

pressure to afford esomeprazole 1 as an oily residue. Yield 18.3.kg (78%

with respect to the single isomer); 99.92% ee (by HPLC)13; []D20 = – 157.0

236 Chapter-V

(c = 0.5 in CHCl3) {lit.10 []D20 = – 155.0 (c = 0.5 in CHCl3)}; IR (KBr, cm-1):

3369 (NH), 2948 (C-H), 1155 (C-O), 1000 (S=O); 1H NMR18 (400 MHz,

CDCl3) δ 2.13 (s, 3H), 2.21 (s, 3H), 3.61 (s, 3H), 3.83 (s, 3H), 4.74 (s, 2H),

6.93 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 7.52 (bs, 1H), 8.20 (s,

1H), 12.11 (bs, 1H); MS (ESI): m/z calcd for C17H19N3O3S (M+H): 346.11,

found (M + H):=346.3 (Fig. 5.7 – 5.9)

Preparation of esomeprazole (1) by resolution of racemic

Omeprazole (5)

To a suspension of racemic omeprazole 5 (1.0 kg, 2.9 mol) in acetone

(12 L) was added water (78.2 mL, 4.3 mol), D-(-)-diethyl tartrate (597.6 g,

2.9 mol) followed by titanium (IV) isopropoxide (412.1 g, 1.5 mol) and

triethylamine (878.1 g, 8.7 mol) at 35-40 °C. The reaction was

maintained at same temperature till it became homogeneous. L-(+)-

mandelic acid (441.1 g, 2.9 mol) was added to the reaction mixture and

stirring was continued for an additional 2 h. The separated solid was

filtered and washed with acetone (7 L). It was suspended in CH2Cl2 (4 L)

and treated with 5% sodium bicarbonate solution (4 L) for 30 min. The

organic phase was separated, dried over anhydrous sodium sulfate and

subjected to distillation under reduced pressure to afford esomeprazole 1

as an oily residue. Yield 365.0 g (73% with respect to the single isomer);

99.76% ee (by HPLC).13

237 Chapter-V

Preparation of S-pantoprazole (3) by resolution of racemic

pantoprazole (2)

To a suspension of racemic pantoprazole 2 (20.0 gm, 0.052 mol) in

ethyl acetate (200 mL) was added water (1.4 ml, 0.078 mol), D-(-)-diethyl

tartrate (10.72 g, 0.052 mol) followed by titanium (IV) isopropoxide (7.39

g, 0.026 mol) and triethylamine (15.75 g, 0.156 mol) at 40-45 °C. The

reaction was maintained at same temperature till it became

homogeneous. L-(+)-mandelic acid (7.91 g, 0.052 mol) was added to the

reaction mixture and stirring was continued for additional 2 h. The

separated solid was filtered and washed with ethyl acetate (140 mL). It

was suspended in EtOAc (80 mL) and treated with 5% sodium

bicarbonate solution (80 mL) for 30 min. The organic phase was

separated, dried over anhydrous sodium sulfate and subjected to

distillation under reduced pressure to afford S-pantoprazole 3 as an oily

residue. Yield 5.51 g (55% with respect to the single isomer); 99.99% ee

(by HPLC)13; 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 3.89 (s, 3H), 4.72

and 4.80 (AB q, J = 13.1 Hz, 2H), 6.57 (t, JH-F = 74.3 Hz, 1H), 6.82 (d, J =

5.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.40 (bs,

1H), 7.62 (bd, J = 8.0 Hz, 1H), 8.18 (d, 1H); MS (ESI): m/z calcd for

C16H15F2N3O4S (M + H): 384.08, found (M + H): 384.20 (Fig. 5.10 – 5.12)

238 Chapter-V

Preparation of esomeprazole base wet solid (1) (50-80% water

content)

To a solution of esomeprazole residue 1 (10 kg, 28.9 mol) in acetone

(50 L) was added DM water (100 L) and stirred for 30 min. The pH of the

mass was adjusted to 12-13 with 40% caustic lye solution (1.2 L) at

25-30 °C and stirred for 30 min. Thereafter, activated carbon (1 kg) was

charged and solution stirred for 30 min. and the reaction mass was

filtered through leaf-filter having celite bed. Moreover, leaf filter was

washed with a solution of acetone (13 L) and demineralized water (25 L).

Subsequently pH was adjusted slowly to 7.0-8.0 with acetic acid and the

mass was cooled to 0-5 °C. After stirring for 2 h at 0-5 °C, solid material

was separated, filtered, washed with de-mineralized (DM) water (50 L),

spin dried for 4 h and the wet solid [15 kg; 99.9% (HPLC)]13 was used

immediately for next step.

Preparation of esomeprazole (1) premixed with mannitol (6) and

meglumine (7)

To a solution of esomeprazole base wet solid 1 (15 kg, 70% water

content) in acetone (22.5 L) was added activated carbon (0.5 kg). After

stirring for 30 min., the mass was filtered through sparkler and on-line

cartridge filters and the filter bed was washed with acetone (13.5 L).

Thereafter mannitol 6 (3.88 kg) and meglumine 7 (0.27 kg) were added.

After stirring for 30 min, cyclohexane (54 L) was added and distilled up

to 60-70% at 20-30 °C under vacuum. Subsequently, cyclohexane (45 L)

239 Chapter-V

was charged and distilled again at 20-30 °C under vacuum followed by

further addition of cyclohexane (27 L) and stirred for 30 min. at 20-30°C.

A free flowing material suspended in cyclohexane was filtered and

washed with another lot of cyclohexane (13.5 L), dried at 30-35 °C under

vacuum to afford esomeprazole 1 premix in 90% (over all 35%) yield (7.15

kg) and 99.85% purity (HPLC);19 [water content: 1.0%, esomeprazole base

content: ~ 49 % (that corresponds to 90% yield), ~48% of 6 and ~3.0% of

7].

5.10. REFERENCES

1. Baker, D. E. Rev. Gastroenterol. Disord. 2001, 1, 32 (b) Cotton, H.;

Elebring, T.; Larsson, E. M.; Li, L.; Sörensen, H.; Unge, S, V. Tetrahedron

Asymmetry 2000, 11, 3819 (c) Larsson, E. M.; Stenhede, U. J.; Sörensen,

H.; Unge, S, V.; Cotton, H. EP 0773940 B1, 1997 (d) Federsel, H. J.;

Larsson, E. M. in Asymmetric Catalysis on Industrial Scale: Challenges,

Approaches and Solutions; Blaser, H. U.; Schmidt, E., Eds.; Wiley-VCH,

Weinheim, 2004; p 413.

2. Lindberg, P.; Weidolf, L. US patent 5,877,192, 1997

3. http://www.reference.com/browse/wiki/Esomeprazole

4. Lindberg, P.; Keeling, D.; Fryklund, J.; Andersson, T.; Lundborg, P.;

Carlsson. Alimentary Pharmacology & Therapeutics, 2003, 17, 481

5. (a) Miner, P.; Katz, P.; Chen, Y.; Sostek, M. Am J Gastroenterol 2003,

98, 2616. (b) Röhss, K.; Lind, T.; Wilder-Smith, C. Eur J Clin Pharmacol

240 Chapter-V

2004, 60, 531. (c) Röhss, K.; Wilder-Smith, C.; Nauclér, E.; Jansson, L.

Clin Drug Invest 2004, 24, 1. (d) Kahrilas, P.; Falk, G.; Johnson, D.;

Schmitt, C.; Collins, D.; Whipple, J. Aliment Pharmacol Ther 2000, 14,

1249 (e) Richter, J.; Kahrilas, P.; Johanson, J.; Maton, P.; Breiter, J.;

Hwang, C. Am J Gastroenterol 2001, 96, 656 (f) Vakil, N.; Shaker, R.;

Johnson, D.; Kovacs, T.; Baerg, R.; Hwang, C. Aliment Pharmacol Ther

2001, 15, 927.

6.(a) Corinaldesi, R.; Valentini, M.; Belaiche, J.; Colin, R.; Geldof, H.;

Maier, C. Alimentary Pharmacology & Therapeutics 2007, 9, 667.(b)

Moosner, J.; Holscher, A. H.; Herz, R.; Schneider, A. Alimentary

Pharmacology & Therapeutics 2007, 9, 321. (c) Rehner, M.; Rohnner

H.G.; Schepp, W. 2007, 9, 411.

7. For reviews, see: (a) Pellissier, H. Tetrahedron 2006, 62, 5559 (b)

Bentley, R. Chem. Soc. Rev. 2005, 34, 609 (c) Fernandez, I.; Khiar, N.

Chem. Rev. 2003, 103, 3651 (d) Legros, J.; Dehli, J. R.; Bolm, C. Adv.

Synth. Catal. 2005, 347, 19.

8. (a) Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. J. Org. Chem.

2004, 69, 8500 (b) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Medici, A.;

Pedrini, P. Chem. Commun. 2000, 5, 365 (c) Serreqi, A. N.; Kazlauskas,

R. J. Can. J. Chem. 1995, 73, 1357 (d) Komatsu, N.; Hashizume, M.;

Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 7624 (e) Davis, F. A.;

Billmers, J. M. J. Org. Chem. 1983, 48, 2672.

241 Chapter-V

9. (a) Kagan, H. B. in Catalytic Asymmetric Synthesis; Ojima, I., Ed; VCH:

New York 1993; p 203 (b) Bolm, C.; Muniz, K.; Hildebrand, J. P. In

Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,

Yamammoto, H., Eds.; Springer: Berlin, 1999; p 697

10. For reviews, see: (a) Sachs, G.; Shin, J. M.; Howden, C. W. Aliment

Pharmacol. Ther. 2006, 23, 2 (b) Tonini, M.; Giorgio, R, D.; Ponti, F. D.

Expert Opin. Ther: Patents 2003, 13, 639.

11. Raju, S. V. N.; Purandhar, K.; Reddy, P. P.; Reddy, G. M.; Reddy, L.

A.; Reddy, K. S.; Sreenath, K.; Mukkanti, K.; Reddy. G. S. Org. Proc. Res.

Dev. 2006, 10, 33.

12. Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan H. B. J. Am. Chem.

Soc.1984, 106, 8188.

13. HPLC data: Chiral pack AD 50 mm x 4.6 mm or equivalent, flow rate

0.5 mL/min with a UV detector at 280 nm, load 20 μL, runtime 30 min

at 25-30 °C.

14. HPLC Data: HI-CHROM TBB, flow rate 1.0 ml/min with a UV

detector at 280 nm, load 22 μL, runtime 50 min at 25-30 °C.

15. (a) Rabasseda, X., Cole, P; Drugs Today 2001, 37, 767 (b) Graul, A., Castaner, R.,

Castaner, J. Drugs Fut. 1999, 24, 1178.

16. (a) Nohara, A.; Maki, Y.; U.S. Patent 4,628,098, 1986 (b) Lovgren, K.

I.; Pilbrant, A. G.; Yasumura, M.; Morigaki, S.; Oda, M.; Ohishi, N.; U.S.

Pat. 4,786,505, 1998 (c) Lovgren, K. I.; Pilbrant, A. G.; Yasumura, M.;

Morigaki, S.; Oda, M.; Ohishi, N.; U.S. Pat. 4,853,230, 1989 (d) Makino,

242 Chapter-V

T.; Tabata, T.; Hirai, S.; U.S. Pat. 5,045,321, 1991 (e) Makino, T.;

Tabata, T.; Hirai, S.; U.S. Pat. 5,093,132, 1992 (f) Makino, T.; Tabata, T.;

Hirai, S.; U.S. Pat. 5,433,959, 1995 (g) Kolhe, U. D.; Krishna, D. M.;

Dixit, A. A.; Deshmukh, A. M.; Rajput, N. D.; Mohan, M. S.; Reddy, M.

S.; Kumar, M. K.; Purender, K.; Reddy, A. S. WO 2004/093875 A1,

2004.

17. Lundberg, P. J.; Lovgren, K.; U.S. Pat. 6,013,281, 2000.

18. Lindberg, P. L.; Unge, S. V. EP 0652872 B1, 1994.

19. HPLC Data: HI-CHROM TBB, flow rate 1.0 ml/min with a UV

detector at 280 nm, load 22 μL, run time 50 min at 25-30 °C.

5.11 SPECTRAS

243 Chapter-IV

Figure-5.7: 1H NMR spectrum of compound 1 in CDCl3 (Esomeprazole)

244

Figure-5.8: +ve ESI mass spectrum of compound 1

245

Figure-5.9: IR spectrum of compound 1

246

Figure-5.10: 1H NMR spectrum of compound 3 in CDCl3 (S-Pantoprazole)

247

Figure-5.11: 1H NMR spectrum of compound 3 in CDCl3 (S-Pantoprazole) (zoomed at δ 6.4 – 8.2)

248

Figure-5.12: +ve ESI mass spectrum of compound 3