The present invention relates to an improved and industrially advantageous process for the preparation of highly pure Vonoprazan and its pharmaceutically acceptable salts thereof by using purified intermediate namely 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde. In particular, the present invention provides various processes to prepare highly Vonoprazan fumarate and intermediates thereof.
BACKGROUD OF INVENTION:
Vonoprazan fumarate (TAK-438, Formula I) is one of the primary members of potassium-competitive acid blocker for the treatment of drug induced peptic ulcers and in the prevention of many acid- related diseases like reflux esophagitis, rebleeding after endoscopic hemostasis, is chemically known asl-[5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3-yl]-N-methyl methanamine fumarate.

Formula -1
Vonoprazan has high solubility and stability over a broad pH range, with more potency and long-lasting acid suppression effect than the conventional proton pump inhibitors (Wis)..
Vonoprazan or salt thereof and its preparation was first time disclosed in US patent 7,977,488. According to this patent, vonoprazan fumarate has been prepared by the method as disclosed in Scheme 1. One of the key intermediate, 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde involved in the formation of Vonoprazan fumarate is prepared from 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde

and pyridine-3-sulfonyl chloride hydrochloride in the presence of sodium hydride and crown ether. The resulting aldehyde compound has been purified using silica gel column chromatography followed by crystallization from di-isopropyl ether-ethyl acetate.
The major disadvantages of the above-mentioned method is that silica gel column chromatography is used to purify the aldehyde intermediate or vonoprazan, The use of column chromatography is very cumbersome at industrial scale, so process is not suitable for scale up.
According to one another synthetic process, disclosed in US 8,048,909B2 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde, key intermediate in the formation of vonoprazan fumarate is prepared from ethyl 5-(2-fluorophenyl)-lH-pyrrole-3-carboxylate and purified by silica gel column chromatography.

CuBra, EtOAc, reflux

o
NC,
VONO-003
1) KJCOJ, VONO-003, 45 °C
2) Acetone, VONO-002, 45 °C

F O
VONO-OD1

F O
VONO-002

F O ON
VONO-OD4
quant over 2 steps

4M HCI in EtOAc, r.t.

10% Pd/C H2, EtOH, r.t.

1 5M DIBAL-H in Toluene. THF. -78 °C

— OH VONO-007

TRAP. MMMO. MeCM 4A Molecular sieves, r.t.

VONO-008 50%. over 2 steps

J ■ HCI
VONO-009
1) NaH, VONU-OD8. THF, r.t.
2) 15-Crown-5: VOHO-OQ9 r.t.
82%

VONO-010

1) 40% MeNH2 MeOH. r.t
2) NaBH4, MeOH. r.t
3) 1M HCI, H20

Vonoprazan


—OH o VOMO-OI-I
MeOH. EtOAc. r.t.

Vonoprazan Fumarate TAa/a over 2 steps [912 mg obtained]

Scheme 1
US 8,822,694 discloses synthesis of vonoprazan fumarate starting from the preparation of 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (3) which was then reacted with pyridine-3-sulfonyl chloride to give 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde, followed by a reductive amination with methylamine to provide the free base, which was subsequently treated with fumaric acid to give compound (1) as given in Scheme 2. In the above disclosure, key intermediate 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde is purified successively using acetonitrile /water and then with water. Vonoprazan was not purified and converted to vonoprazan fumarate. The patent is silent about the purity of 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde and vonoprazan.

Scheme 2
Another synthetic process has been disclosed in CN 105085484 for the synthesis of vonoprazan fumarate from 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde, but in this process Boc. Protected intermediates were used as shown in Scheme 3, the key intermediate 5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrole-3-carbaldehyde was not prepared.

-I j 40% MeNH2, MeOH
25 to 35 °C
2) NaBH4, O to 20 to 30 °C ^==v^->'—~^cC ' ' ~7? Boc20, MeCN, O to 5 °C


VONO-OOS VOIMO-013
Ti
VOMO-OI 5
1> NaH. Crown ether
VOMO-O-14, THF. O °C r-»"^a -^^ft^- ^ 1 > "TFA. DCM. 25 to 30 °C
2> THF, VONO-Q15. O °C lo r.t.^ <^~~\K Z 2) 2Q% NaaCQ3
93.5%
IM
N.
VONO-014
voMO-oie



O VONO-011
MeOH. 25 to 30 to 50 °C

i-O

Vonoprazan Vonoprazan Fumarate
[20.7" g obtained]
Scheme 3
US patent 10,538,506 specifically discloses a crystal form of Vonoprazan fumarate by using alcohols with different solvents such as water or ethyl acetate. This patent also reports its Stability and methods for preparing its dosage forms.
A Chinese patent CN105315258 discloses Form A, Form B & another crystalline form and methods of their preparation. The crystal form A is prepared by dissolving Vonoprazan fumarate free alkali in ethyl acetate, adding fumaric acid solution in Methanol, stirring for reaction at room temperature, filtering, and drying the filtered cake. Crystal form B is prepared by dissolving the crystal form A in Ci-4 alkyl alcohol, (methanol, ethanol, etc.) aqueous solution or aqueous solution of ketone (acetone), heating, stirring for dissolution, cooling under stirring, filtering, and drying the filter cake.
Another Chinese patent CN106892900 discloses preparation of crystalline form of Vonoprazan fumarate by dissolving crude product into the mixture of acetonitrile/tetramethyl ethylenediamine under heating and stirring, decolorizing with active charcoal, filtering, cooling the filtrate to 0°C, drop adding isopropyl alcohol., cooling, crystallizing, vacuum filtering, washing and drying to obtain white crystal powder.
In view of the above, most of the prior art processes either involves use of silica gel column chromatography or toxic solvent like acetonitrile to purify key aldehyde

intermediate or vonoprazan. The disclosures are silent about the purity of intermediates and vonoprazan so there is an urgent need in the art to provide a process wherein column chromatography is avoided for purification, as it is not attractive option to use at industrial scale. The present invention aims to provide an efficient process to obtain pure vonoprazan or salt thereof, which is unique with respect to simplicity, cost effectiveness and convenient to operate on industrial scale.
OBJECT OF THE INVENTION
The main object of the present invention is to provide improved &efficient processes for the preparation of pure Vonoprazan fumarate.
Another object of the present invention is to provide a novel process for purification of Vonoprazan.
Another object of the present invention is to provide an improved, efficient, safe process for the preparation of the Vonoprazan free from impurities.
Yet another object of the present invention is to provide an efficient process for purification of key aldehyde intermediate.
Yet another object of the present invention is to prepare pure Vonoprazan fumarate using pure key aldehyde intermediate.
SUMMARY OF INVENTION:
Accordingly, the present invention provides an improved and industrially advantageous process for the preparation of vonoprazan fumarate of formula I wherein step of purification of key aldehyde intermediate is involved.
According to one embodiment, the present invention provides a novel process for the preparation and purification of Vonoprazan Fumarate of formula I,


which comprises steps of:
i. providing a solution of 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde of formula II

Formula II
in an aliphatic (C1-C4) alcohol at ambient temperature.,
ii. cooling the reaction mass to a temperature of 0-10°C with stirring,
iii. filtering the product,
iv. isolating highly pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde,
v. converting the highly pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde obtained in step iv to Vonoprazan Fumarate
According to the second embodiment of the present invention provides an improved process for the preparation of pure Vonoprazan of formula III, comprises the steps of:

NH CH3 Formula III
dissolving the pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde of formula II in aliphatic (C1-C4) alcohol at a temperature range of
20-30°C,
cooling the reaction mass to a temperature of -10 to 0°C.
adding methylamine solution (25%) to the reaction mass with stirring.
adding sodium borohydride to the above solution at -10 to 0°C
stirring, till reaction completion
adjusting pH to 3-6 with hydrochloric acid at 20-30°C,
adding potassium carbonate to the reaction mass with stirring,
extracting the product using a suitable halogenated solvent,
concentrating the organic layer to obtain Vonoprazan of formula III,
dissolving the Vonoprazan of formula III in an aliphatic straight or branched chain amide at 40-45°C,
adjusting the pH to 8-9 using dilute hydrochloric acid at 20-30°C
cooling the reaction mass to 0-10°C to crystallize the product,
isolating pure Vonoprazan .

According to the third embodiment of the present invention, a novel process of Vonoprazan is provided which comprises:
i. providing a solution of Vonoprazan in an aliphatic C1-C4 alcohol at temperature of40-70°C.
ii. adding a suitable cyclic or acyclic aliphatic hydrocarbon to the solution of step i) at a temperature of 50-60°C.
iii. cooling the reaction mixture to below 30°C with stirring to crystallize the product,
iv. isolating the resulting product.
According to the fourth embodiment of the present invention, provides a process for the preparation of crystalline Vonoprazan Fumarate which comprises:
i. dissolving pure Vonoprazan of Formula III in a halogenated hydrocarbon selected from methylene dichloride, chloroform or mixture thereof & water
ii. adding ammonia solution,
iii. separating the layers
iv. extracting aqueous layer with solvent of step i)
v. performing complete solvent recovery to get residue
vi. dissolving residue of step iv) in aliphatic C1-C4 alcohol, at temperature of 60-
70°C,
vii. adding Deionized water ,
viii. Cooling the reaction mixture to ambient temperature,
ix. adding fumaric acid to the reaction mass
x. heating the reaction to 60-70°Ctill reaction completion,
xi. cooling the reaction mass to 0-10°C to crystallize the product,

xii. isolating the product obtained in step x,
xiii. dissolving the wet cake obtained in step xii in aqueous solution of methanol or methanol-ethyl acetate at 60-70°C.
xiv. cooling the reaction mass to 0-10°C,
xv. isolating highly pure crystalline Vonoprazan Fumarate.with XRD as per Figure 1.
According to the Fifth embodiment of the present invention, provides a process for the preparation of crystalline Vonoprazan Fumarate which comprises:
i. dissolving Vonoprazan in aliphatic C1-C4 alcohol, at temperature of 60-70°C,
ii. adding deionized water
iii. Cooling the reaction mixture to ambient temperature,
iv. adding fumaric acid to the reaction mass
v. heating the reaction to 60-70°Ctill reaction completion,
vi. cooling the reaction mass to 0-10°C to crystallize the product
vii. isolating the product obtained in step x,
viii. dissolving the wet cake obtained in step xi in aqueous solution of methanol or methanol-ethyl acetate at 60-70°C.
ix. cooling the reaction mass to 0-10°C,
x. isolating highly pure crystalline Vonoprazan Fumarate having PXRD as per Figure 1.
According to the Sixth embodiment of the present invention, an improved process of preparing crystalline vonoprazan fumarate is provided which comprises

i. dissolving vonoprazan fumarate in aqueous solution of an aliphatic ketone, aliphatic nitriles, or aliphatic esters or aliphatic alcohols monoethylene glycol, diethylene glycol etc or mixture thereof at 60-70°C,
ii. cooling the reaction mass to 0-10°C to crystallize the product,
iii. isolating crystalline Vonoprazan Fumarate having XRD pattern as presented in Figures 2-4.
According to the Seventh embodiment of the present invention, an improved process for the preparation of crystalline Vonoprazan Fumarate is provided which comprises:
i. dissolving any form of vonoprazan fumarate in a suitable aqueous solvent mixture of aliphatic alcohol, monoethylene glycol or diethylene glycol at ambient temperature,
ii. fine filtrating the solution to use it as feed stock / solution in spray dryer
iii. spray drying of vonoprazan fumarate using JISL Mini Spray-drier LSD-48 (Make),
iv. isolating the pure crystalline vonoprazan fumarate in powdered form having XRD as per Figure 5.
According to another aspect of current invention, an improved process for the preparation of Vonoprazan is disclosed wherein the pure 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde (as obtained by purification in aliphatic alcohol) is converted to Vonoprazan Base as per prior art followed by its crystallization in an aliphatic straight or branched chain amide such as N,N-Dimethylformamide (DMF) and water. This Vonoprazan base (which has better purity then prior art process due to initial purification) is further purified by Novel purification/process using aliphatic Cl-C4 alcohol such as methanol, ethanol, 1-propanol, 2-propanol or butanol or a mixture thereof as solvent and cyclic or acyclic aliphatic hydrocarbon selected from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or a mixture thereof as antisolvent.

As per another aspect of current invention, the Vonoprazan Fumarate is crystallized/purified by a novel/improved process, in solvent system which comprises a mixture of water & aliphatic C1-C4 alcohol such as methanol, ethanol, 1-propanol, 2-propanol or butanol or water, aliphatic C1-C4 alcohol such as methanol, ethanol, 1-propanol, 2-propanol or butanol & aliphatic ester such as Ethyl acetate or a mixture thereof. The API, Vonoprazan Fumarate thus obtained is highly pure.
As per yet another aspect of current invention, various improved processes for the preparation of Crystalline Form of Vonoprazan Fumarate are disclosed. It involves preparation of crystalline Form using two new solvent system and by using spray drying process.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 - PXRD of Crystalline Vonoprazan Fumarate prepared using Aqueous Methanol or Aqueous Methanol-Ethyl acetate solvent system.
Figure 2 - PXRD of Crystalline Vonoprazan Fumarate prepared in Acetone-Water solvent system.
Figure 3- PXRD of Crystalline Vonoprazan Fumarate prepared in Acetonitrile-Water solvent system.
Figure 4 - PXRD of Crystalline Vonoprazan Fumarate prepared in Methanol-Ethyl Acetate-Water solvent system.
Figure 5 - PXRD of Crystalline Vonoprazan Fumarate prepared using Spray Drier.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention provides an improved and industrially advantageous process for the preparation of pure vonoprazan fumarate by using highly pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-lH-pyrrole-3-carbaldehyde of formula 2, prepared by using the purification process of present invention.

As used herein, the term 'highly pure' represents a compound having purity greater than 99.5% w/w by HPLC and any individual impurity present in an amount of less than 0.1%w/wbyHPLC.
As used herein, the term 'ambient temperature' represents a temperature 25°C+5°C.
The compound 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-lH-pyrrole-3-
carbaldehyde of formula II can be prepared by the process known in literature or by the process of the present invention. In particular, the carbaldehyde compound of formula II can be prepared by using the process of present invention from 5-(2-Fluorophenyl)-lH-pyrrole-3-carbaldehyde of formula IV.

O Formula IV
The process comprises of the step of reacting the compound of formula IV with pyridine-3-sulfonyl chloride hydrochloride in the presence of a suitable non nucleophilic base in a suitable solvent to obtain carbaldehyde compound of formula II. The suitable non nucleophilic base used can be selected from iV.JV-diisopropylethyl amine, 1,8-diazabicycloundec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN) and the like.
The solvent used herein includes but not limited to methanol, ethanol, 1-propanal, 2-propanol and butanol and alike.
The reaction can be accomplished at a temperature of 10-40°C, preferably at a temperature of 15- 30°C, for sufficient time till completion of reaction. After completion of reaction, the reaction mixture can be quenched with a suitable solvent such as water. Then reaction mixture can be cooled to a temperature of 0-10°C and stirred for 1-2 hours to induce crystallization. The resulting can be isolated by any method known in the art such as filtration. The compound obtained have a purity of around 98% and is

brownish in colour. An unknown impurity is found to be present at RRT 1.95 in an amount of about 1-2% and other impurities which are very difficult to remove in the next stages. It is advantageous to purify the compound at this stage itself, so that final compound can be obtained in high purity.
The crude compound of formula III can be purified by using a suitable solvent selected from C1-C4 alcohols, and mixture with water. Specifically solvent can be selected from methanol, ethanol, 1-propanal, 2-propanol andbutanol.
Specifically, the compound can be taken in a solvent methanol or ethanol at ambient temperature, stirred for few minutes to few hours. Thereafter the reaction mixture can be
cooled at the temperature below 10 °C and stirred for 1-2 hours followed by filtration followed by washing with the chilled same solvent as used for purification. The resulting compound can be dried at a temperature of 40-50°C to obtain the highly pure 5-(2-fluorophenyl)-1 -(pyridine-3-ylsulphonyl)-1 -H-pyrrole-3 -carbaldehyde compound of formula II, having purity of greater than 99.5%, more preferably 99.8%. The brown colour, the impurity at RRT 1.95 and other impurities have also been removed.
The purification of carbaldehyde compound of formula II using C1-C4 alcohols, selected from methanol, ethanol, 1-propanal, 2-propanol and butanolis an novel and inventive part of the invention.
Thereafter, highly pure 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde of formula III obtained by process of present invention can be converted to vonoprazan or salt thereof.
Specifically carbaldehyde compound of formula III is reacted with methylamine in the presence of a suitable reducing agent selected from sodium borohydride or lithium aluminum hydride in a suitable solvent. The reaction can be carried out at ambient temperature for few minutes to few hours. The suitable solvent can be selected from selected from methanol, ethanol, 1-propanal, 2-propanol and butanol. After the completion of the reaction, hydrochloric acid the pH of the reaction mixture is adjusted

in the range of 3-6 using a suitable acid at temperature of 10-30 °C. The suitable acid can be selected from hydrochloric acid.
Thereafter, the reaction mixture can be washed with a suitable solvent, preferably methylene dichloride. The aqueous layer may be basified with a suitable base such as potassium carbonate, sodium hydroxide and alike. The product can be extracted from aqueous layer using a suitable solvent such as methylene dichloride. The resulting organic later can be washed with water. The organic layer can be charcolized at a suitable temperature and the resulting filtrate can be concentrated under vacuum to obtain the residue.
The residue obtained can be dissolved in a suitable solvent such as N,N-dimethylformamide (DMF) at 40-45°C and pH can be adjusted to 8.0-9.0 with a suitable acid such as hydrochloric acid. The reaction mixture can be stirred at ambient temperature for few minutes to few hours. Thereafter the reaction mass can be cooled at the temperature below 10 °C and stirred for 2-5 hours in order to allow to form crystals of the product. The product can be isolated by filtration followed by drying at 40-50 °C to get Vonoprazan having purity greater than 97.80% w/w by HPLC. Vonoprazan obtained have an impurity at RRT 2.1 at a level of 1%, along with other impurities which are difficult to remove in the final stage. Therefore, a purification method has been developed, so that the impurity at RRT 2.1 can be reduced at a level of 0.3%. The purification can be performed using any suitable methods, such as crystallization, solvent-antisolvent purification, acid base treatment, extractions, charcoalization etc.
Specifically, crude Vonoprazan can be dissolved in a suitable solvent selected from the family of alcohol which includes methanol, ethanol, 1-propanol, 2-propanol or butanol. The suspension formed due to the addition of the solvent was heated at a temperature range of 40-70 °C and preferably 50-60°C to get clear solution, thereafter a suitable anti-solvent can be added, the antisolvent can be selected from hydrocarbon which may include but not limited to cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane. The reaction mixture is cooled at a temperature range of 20-30°C. Additionally the mixture is further cooled at a temperature below 10 °C and stirred for another 1-5 hours.

The product obtained is filtered and washed with one of the hydrocarbons mentioned above. The product is dried at a temperature range of 40-50°C to obtain the highly pure Vonoprazan having purity greater than 98.50%, preferably > 98.90 % w/w as determined by the HPLC.
Furthermore, the highly pure Vonoprazan can be converted to Vonoprazan Fumarate by treating with fumaric acid in a suitable solvent at 60-70°C. The suitable solvent can be selected from methanol, ethanol, propanol, Isopropyl alcohol the reaction mixture can be cooled and the resulting compound can be isolated by filtration followed by drying.
Vonoprazan Fumarate can be purified or crystallized using a suitable solvent to get the highly pure crystalline form in consistent manner. The suitable solvent can be selected from aqueous, methanol or its mixture of aqueous, methanol with ethyl acetate. In one another specific embodiment, Vonoprazan Fumarate can be crystallized using spray drying technique. Vonoprazan Fumarate obtained by using the process of present invention is highly pure and purity of greater than 99.7%, preferably >99.8% and more preferably >99.9% w/w by HPLC.
Major advantages realized in the present invention is that all intermediates i.e carbaldehyde compound of formula II, Vonoprazan of formula III are purified to remove the impurities at individual stage, to obtain highly pure Vonoprazan fumarate. None the less by the use of these particular purification process as set out in disclosure, Vonoprazan fumarate may be conveniently obtained in high purity having acceptable limits of impurities that is suitable for use in medicament.
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Process for the preparation of 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde

To a solution of 5-(2-fluorophenyl)-lH-pyrrole-3-carbaldehyde (100g) in acetonitrile (500ml), pyridine-3-sulfonyl chloride hydrochloride Q30g) and N,N-diisopropylethylamine (150 ml) were added at ambient temperature and the reaction mixture was stirred. After reaction completion, Deionized water was added with stirring. The resulting mass was further cooled to 0-10°C. The product was filtered, washed with Deionized water (100ml). The resulting wet cake was added in methanol at ambient temperature, cooled to 0-10°C and stirred for 1 hr. The product was filtered, washed with chilled methanol and dried at 40-50°C to obtain 120g of highly pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde having HPLC purity = 98.77%w/w.
Example 2: Process for the preparation of Vonoprazan
To 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde (100g), methanol (700ml) was added at ambient temperature and the reaction mixture was stirred. The resulting reaction mixture was cooled to -10 to 0°C followed by addition of methylamine solution (25%) with stirring for 20-30 minutes. Sodium borohydride (6g) was added to reaction mixture and resulting mixture was stirred at -10 to 0°C for 3hrs. After reaction completion, aqueous hydrochloric acid solution (70ml) was added to adjust pH 3-6 at 10-30°C and mixture was washed with methylene dichloride twice (2><300ml). The combined aqueous layer was basified using aqueous potassium carbonate solution, mixture was extracted with methylene dichloride (2x300ml) twice. The combined organic layer was washed with Deionized water. The organic layer was treated with activated carbon, heated at 30-40°C with stirring and filtered through a hyflo filter. The filtrate was concentrated under vacuum to get the residue. jV,jV-Dimethylformamide (80 ml) was added to the residue, heated to 40-45°C and stirred to get clear solution followed by addition of aqueous hydrochloric acid solution to adjust pH 8.0-9.0. The reaction mixture was stirred at ambient temperature. The resulting mass was further cooled to 0-10°C with stirring for 2-5 hours for complete crystallization. The product was filtered, washed with Deionized water (100 ml) and dried at 40-50°C to get crude Vonoprazan (HPLC purity-97.95%).

Example 3: Process for the Purification of Vonoprazan
A suspension of lOOg of crude Vonoprazan in ethanol (100ml) was heated at 50-60°C to get clarity followed by addition of hexanes (500 ml). The reaction mixture was cooled to 20-30°C with stirring for 20-30 minutes. The reaction mass was further cooled to 0-10°C with stirring for 1-3 hrs. The product was filtered, washed with hexanes and dried at 40-50°C to obtain highly pure Vonoprazan having HPLC purity 98.99%.
Example 4: Process for the preparation of Vonoprazan Fumarate
To a suspension of lOOg of Vonoprazan (HPLC purity 99.08%) in methylene dichloride (500ml), Deionized water (300ml) was added at 10-30°C followed by addition of ammonia solution (200ml) with stirring. The layers were separated, and the aqueous layer was extracted with methylene dichloride (200ml). The combined organic layer was concentrated to get the residue. The residue was dissolved in methanol, heated to 60-70°C followed by addition of activated carbon with stirring. The reaction mixture was filtered through a hyflo filter. Deionized water was added to the filtrate and reaction mixture was cooled to ambient temperature followed by addition of fumaric acid (28 g). The resulting reaction mixture was heated at 60-70°C and stirred for 40-60 minutes. The resulting mass was cooled to 0-10°C with stirring for 1-3 hrs. The product was filtered, washed with a methanol. The resulting wet cake was dissolved in a mixture of methanol and Deionized water (1: 0.25), heated at 60-70°C to get clarity. The resulting mass was cooled to 0-10°C and stirred for 1-3 hours, the mixture was filtered and washed with chilled methanol (50 mL). The solid was dried at under vacuum 40-50° C to obtain 90g of highly pure Vonoprazan Fumarate having XRD as per Figure 1. (FtPLC purity99.87%)
Example 5: Process for the preparation of Vonoprazan Fumarate
To a suspension of lOOg of Vonoprazan (FtPLC purity 99.08%) in methylene dichloride (500ml), deionized Water (300ml) was added at 10-30°C followed by addition of ammonia solution (200ml). The layers were separated, and the aqueous layer was

extracted with methylene dichloride (200ml). The combined organic layer was concentrated to get the residue.
The residue was dissolved in methanol, heated at 60-70°C followed by addition of activated carbon with stirring. The reaction mixture was filtered through a hyflo filter. Deionized Water was added to the filtrate and reaction mixture was cooled to ambient temperature followed by addition of fumaric acid (28 g). The resulting reaction mixture was heated at 60-70°C and stirred for 40-60 minutes. The resulting mass was cooled to 0-10°C with stirring for 1-3 hrs. The product was filtered, washed with a methanol. The resulting wet cake was dissolved in a mixture of methanol, deionized water and ethyl acetate (1:0.25:0.25), heated at 60-70°C to get clarity. The resulting mass was cooled to 0-10°C and stirred for 1-3 hours, the mixture was filtered and washed chilled with methanol (50 mL). The solid was dried at under vacuum 40-50° C to obtain 90g of highly pure Vonoprazan Fumarate. (HPLC purity99.92%) having XRD as per Figure 1.
Example 6: Process for the preparation of Crystalline Vonoprazan Fumarate
A solution of Vonoprazan Fumarate (100 g) in acetone (1500 ml) & water (500ml) was heated to 60-70°C with stirring. The reaction mass was stirred for 1-2 hours at 60-70°C. After the clarity was obtained, the reaction mixture was cooled to 0-10°C with stirring. The reaction mass was further stirred for 1-2 hours at 0-10°C to ensure proper crystallization. The product was filtered, washed with acetone (100 ml) and dried at 40-50°C for 4-6 hours to obtain highly pure crystalline Vonoprazan fumarate having FtPLC purity 99.90% and XRD as per Figure 2.
Example 7: Process for the preparation of Crystalline Vonoprazan Fumarate
A solution of Vonoprazan Fumarate (100 g) in acetonitrile (1000 ml) & water (500ml) was stirred and heated to 60-70°C. The reaction mass is stirred for 1-2 hours at 60-70°C. After the clarity is obtained, the reaction mixture was cooled to 0-10°C with stirring. The reaction mass was further stirred for 1-2 hrs at 0-10°C. The product was filtered, washed with ACN (100 ml) and dried at 40-50°C for 4-6 hours to obtain highly pure crystalline Vonoprazan fumarate having FIPLC purity99.89% and XRD as per Figure 3.

Example 8: Process for the preparation of Crystalline Vonoprazan Fumarate
A solution of Vonoprazan Fumarate (100 g) in methanol (500 ml), ethyl acetate (500 ml) & water (500ml) was heated to 60-70°C and stirred for 1-2 hours. Thereafter, the reaction mixture was cooled to 0-10°C. and further stirred for 1-2 hrs at 0-10°C. The product was filtered, washed with methanol (100 ml) and dried at 40-50°C for 4-6 hours to obtain highly pure crystalline Vonoprazan fumarate having FtPLC purity99.93% and XRD pattern as per Figure 4.
Example 9: Process for the preparation of Crystalline Vonoprazan Fumarate by spray drying
Vonoprazan Fumarate (25g ) was added in a mixture of methanol-water (10:3). The reaction mass was stirred for 30min at 25 to 35°C to get clear solution. After fine filtration, solution was followed by Spray drying under below conditions.

S.No. Parameter Conditions
a) Feed Pump Rate 30 rpm
b) Inlet Temperature 60°C
c) Outlet Temperature 30-40°C
d) Aspiration Rate 34 to 44 rpm
e) Vacuum 60-80 mm of Hg
f) Hot Air Supply 2 Kg/cm2
After completion of feeding, the product was collected from the cyclone and dried for 15-30 hrs at 50-60°C. The obtained solid (10.Og) was crystalline Vonoprazan fumarate as shown by X-Ray Diffraction pattern as per Fig 5 and FIPLC Purity = 99.88%

WE CLAIM:

1. A novel process for the preparation and purification of 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde or Formula II, which comprises:
i. dissolving 5-(2-Fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde of formula II in an aliphatic (C1-C4) alcohol at 25-30°C.

Formula II ii. cooling the reaction mass to a temperature of 0-10°C with stirring,
iii. filtering the product,
iv. isolating highly pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde
2. An improved process for the preparation of pure Vonoprazan of formula III, which comprises:

Formula III
i. dissolving pure 5-(2-fluorophenyl)-l-(pyridine-3-ylsulphonyl)-l-H-pyrrole-3-carbaldehyde of formula II in aliphatic (C1-C4) alcohol at a temperature range of 20-
30°C
ii. cooling the reaction mass to a temperature of -10 to 0°C. iii. adding methylamine solution (25%) to the reaction mass with stirring.

iv. adding sodium borohydride to the above solution at -10 to 0°C
v. stirring, till reaction completion
vi. adjusting pH to 3-6 with hydrochloric acid at 20-30°C
vii. adding potassium carbonate to the reaction mass with stirring
viii. extracting the product using a suitable halogenated solvent
ix. concentrating the organic layer to obtain Vonoprazan of formula III
x. dissolving the Vonoprazan of formula III in an aliphatic straight or branched chain amide at 40-45 °C
xi. adjusting the pH to 8-9 using dilute hydrochloric acid at 20-30°C
xii. cooling the reaction mass to 0-10°C to crystallize the product,
xiii. isolating pure Vonoprazan.
3. A novel process of Vonoprazan is provided which comprises:
i. dissolving Vonoprazan in an aliphatic C1-C4 alcohol at temperature of 40-70°C.
ii. adding a suitable cyclic or acyclic aliphatic hydrocarbon to the solution of step i) at a temperature of 50-60°C.
iii. cooling the reaction mixture to below 30°C with stirring to crystallize the product,
iv. isolating the resulting pure Vonoprazan as product by filtration & drying.
4. An improved process for the preparation of crystalline Vonoprazan Fumarate which comprises:
i. dissolving pure Vonoprazan of Formula III in a halogenated hydrocarbon selected from methylene dichloride, chloroform or mixture thereof & water
ii. adding ammonia solution,

separating the layers
extracting aqueous layer with solvent of step i)
performing complete solvent recovery to get residue
dissolving residue of step iv) in aliphatic C1-C4 alcohol, at temperature of 60-70°C,
adding Deionized water,
Cooling the reaction mixture to ambient temperature,
adding fumaric acid to the reaction mass
heating the reaction to 60-70°C till reaction completion,
cooling the reaction mass to 0-10°C to crystallize the product,
isolating the product obtained in step x,
dissolving the wet cake obtained in step xii in aqueous solution of methanol or methanol-ethyl acetate at 60-70°C.
cooling the reaction mass to 0-10°C,
isolating highly pure crystalline Vonoprazan Fumarate with XRD as per Figure 1 by filtration and drying.
process for the preparation of crystalline Vonoprazan Fumarate which comprises: dissolving Vonoprazan in aliphatic C1-C4 alcohol, at temperature of 60-70°C, adding deionized water
Cooling the reaction mixture to ambient temperature, adding fumaric acid to the reaction mass heating the reaction to 60-70°Ctill reaction completion, cooling the reaction mass to 0-10°C to crystallize the product

vii. isolating the product obtained in step x,
viii. dissolving the wet cake obtained in step xi in aqueous solution of methanol or methanol-ethyl acetate at 60-70°C.
ix. cooling the reaction mass to 0-10°C,
x. isolating highly pure crystalline Vonoprazan Fumarate having PXRD as per Figure 1.
6. An improved process of preparing crystalline Vonoprazan fumarate is provided which
comprises:
i. dissolving Vonoprazan Fumarate in aqueous solution of an aliphatic ketone, aliphatic nitriles, or aliphatic esters or aliphatic alcohols monoethylene glycol, diethylene glycol etc or mixture thereof at 60-70°C,
ii. cooling the reaction mass to 0-10°C to crystallize the product,
iii. isolating crystalline Vonoprazan Fumarate having XRD pattern as presented in Figures 2-4 by filtration and drying.
7. An improved process for the preparation of crystalline Vonoprazan Fumarate is provided
which comprises:
i. dissolving any form of Vonoprazan Fumarate in a suitable aqueous solvent mixture of aliphatic alcohol, monoethylene glycol or diethylene glycol at ambient temperature,
ii. fine filtrating the solution to use it as feed stock / solution in spray dryer
iii. spray drying of Vonoprazan Fumarate using JISL Mini Spray-drier LSD-48 (Make),
iv. isolating the pure crystalline Vonoprazan Fumarate in powdered form having XRD as per Figure 5 after filtration and drying.

8. A process claim 1-6, where the aliphatic alcohol used in claim l(i), 2 (i), 3(i), 4(vi), 5(i), 6(i) and 7(i) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol & diethylene glycol or a mixture thereof.
9. A process claim 2(viii) & 4(i) where the halogenated hydrocarbon is selected from methylene dichloride, chloroform, carbon tetrachloride or mixture thereof.
10. A process claim 2(x) where the aliphatic straight or branched chain amide is selected
from N,N-dimethyl formamide (DMF), N-butylformamide, N,N-dimethylmethanamide, N,N-
dimethy ethanamide, dimethylsulphoxide.
11. A process of claim 3(ii) where the cyclic or acyclic aliphatic hydrocarbon is selected
from cyclopentane, cyclohexane, cycloheptane, cycloctane, n-hexane, n-heptane, octane or a
mixture thereof.
12. A process of claim 6(i) where aliphatic ketone is selected from acetone, ethyl methyl
ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or mixture thereof,
aliphatic nitrile is selected from acetonitrile, propionitrile or mixture thereof.