Description:FORM 2

THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULES 2003
(SECTION 10 AND RULE 13)

COMPLETE SPECIFICATION

“PREPARATION OF HIGHLY PURE VONOPRAZAN FUMARATE SUBSTANTIALLY FREE OF IMPURITIES”

SYMED LABS LIMITED
An Indian Company having its Office at
8-2-293/174/3, B.N. Reddy Colony,
Road No. 14, Banjara Hills,
Hyderabad-500 034,
Telangana, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES AND ASSERTAINS THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of highly pure Vonoprazan or a pharmaceutically acceptable salt thereof substantially free of impurities with high yield. The present invention further relates highly pure Vonoprazan or a pharmaceutically acceptable salt thereof substantially free of nitrosamine impurity.

BACKGROUND OF THE INVENTION
U.S. Patent No. 7,977,488B2 (hereinafter referred to as the US‘488 patent) discloses a variety of nitrogen containing heterocyclic compounds, salts, solvates and processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds exhibit a superior acid secretion inhibitory effect and showing an antiulcer activity and the like. Among them, Vonoprazan fumarate, chemically named 5-(2-Fluorophenyl)-N-methyl-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-methanamine 2-butenedioate is a selective potassium-competitive acid blocker indicated for the treatment of gastric ulcer, duodenal ulcer and reflux esophagitis. Vonoprazan Fumarate is represented by the following structural formula I(a):

Vonoprazan fumarate was originally developed by Takeda Pharmaceutical Company Ltd and first approved in Japan. Takeda has granted a license to Phathom Pharmaceuticals, Inc for the development and exclusive commercialization rights to Vonoprazan fumarate in the United States, Europe and Canada. Vonoprazan fumarate is orally administered as 10 mg and 20 mg tablets, and marketed under the brand names Takecab® in Japan and Voquezna® in the United States.
Various processes for the preparation and/or crystallization of Vonoprazan fumarate and its intermediates are described in U.S. Patent Nos. US7,977,488B2, US8,822,694B2, US9,487,485B2, US10,570,091B2; PCT Publication Nos. WO2019131695A1; Chinese patents or application Nos. CN104860923B, CN105085484B, CN108191829B, CN105646453A, CN 105294653B, CN105693693A, CN107759568A, CN104327051A, CN108689991B, CN115124506A; and Journal Articles Journal of Medicinal Chemistry 55 (9), 4446–4456, 2012;and Synthetic Communications 47 (12), 1169-1174, 2017.
The synthetic routes of Vonoprazan fumarate and its intermediates were first disclosed in the US7,977,488B2. The synthetic route of Vonoprazan fumarate disclosed in the US’488 patent is prepared by a process as depicted in Scheme 1:

As per the process exemplified in the US’488 patent (Reference Example 63 and Example 8), Vonoprazan fumarate is prepared by a process comprising the following steps: (i) 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde is reacted with pyridine-3-sulfonyl chloride hydrochloride in presence of Sodium hydride and 15-Crown-5 in tetrahydrofuran solvent to produce 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde as a residue, which is purified by silica gel column chromatography (eluent: hexane - ethyl acetate = 7:3 to 2:3) followed by crystallization from diisopropyl ether-ethyl acetate (4:1) to give 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde as colorless crystals; (ii) the resulting intermediate compound is reacted with 40% methylamine methanol solution and Sodium borohydride to produce a residue which was purified by basic silica gel column chromatography (eluent: ethyl acetate - methanol = 1:0 to 7:3) to produce Vonoprazan free base; and (iii) the Vonoprazan free base is treated with fumaric acid in ethyl acetate and methanol to produce Vonoprazan fumarate as colorless crystals (M.P. 201-203°C).
However, the above process for the preparation of Vonoprazan fumarate suffers from several drawbacks such as (i) the yields and purities of the product obtained are very low; (ii) large amount of impurities (10 to 20%) are formed during the reaction in the process steps 1 and 2; and (iii) the process requires the use of expensive and slow column chromatographic purifications; thereby increasing manufacturing cost and making the process commercially not feasible.
U.S. Patent No. US 8,822,694B2 (hereinafter referred to as the US’694 patent) describes a synthetic route of Vonoprazan fumarate comprising the following steps: (i) 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is reacted with pyridine-3-sulfonyl chloride in acetonitrile solvent in the presence of N,N-dimethylpyridin-4-amine and diisopropylethylamine to obtain 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde; (ii) the resulting intermediate is reacted 40% methylamine in methanol and sodium borohydride in N,N-dimethylacetamide under Nitrogen atmosphere to produce Vonoprazan free base; (iii) the resulting Vonoprazan free base is treated with fumaric acid to obtain Vonoprazan fumarate as a crude product; and (iv) the crude Vonoprazan fumarate is finally purified with a mixed solution (10 volumes) of methanol and water (7:3 or 1:1) to produce Vonoprazan fumarate as crystals (Melting point 203-205°C).
CN104327051A discloses the X-ray powder diffraction (XRPD) data of the prior art crystalline form A of Vonoprazan fumarate (as shown in Figure 1), which is characterized by an XRPD 2? peaks at about 5.1, 10.1, 11.4, 11.5, 12.2, 13.4, 13.9, 15.2, 16.1, 16.6, 16.9, 17.3, 17.8, 18.5, 19.1, 20.0, 20.3, 20.6, 21.0, 21.5, 22.4, 23.0, 23.5, 24.3, 25.1, 25.5, 26.0, 26.7, 27.6, 27.9, 28.8, 29.1 and 29.9 degrees; and a DSC thermogram showing an melting point at about 203°C (as shown in Figure 2).
The XRPD and DSC data of Vonoprazan fumarate crystalline form was also later disclosed in the US10538506B2. The present inventors have found that the XRPD data of the Vonoprazan fumarate produced according to the prior art crystallization processes exemplified in the US’488 and US’694 patents (examples 5 and 6) is exactly identical with that of the XRPD data of Vonoprazan fumarate crystalline forms reported in the CN104327051A and US10538506B2.
Chinse Patent No. CN 104860923 B (hereinafter referred to as the CN’923 patent) describes a process for preparation of Vonoprazan fumarate comprising the following steps: (i) 5-(2-fluorophenyl)-1H-pyrrole-3carbonitrile is reacted with 3-pyridine-sulfonyl chloride in the presence of 4-dimethylaminopyridine and N,N-diisopropylethylamine in acetonitrile solvent to produce 5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carbonitrile; (ii) the resulting intermediate is subject to catalytic hydrogenation in the presence of Raney Nickel in methanol to produce 3-amino-5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole; (iii) the resulting intermediate is reacted with sodium borohydride and paraformaldehyde to produce Vonoprazan; and (iv) the Vonoprazan is further treated with fumaric acid in isopropanol solvent to produce Vonoprazan fumarate.
Chinse Patent No. CN105085484B (hereinafter referred to as the CN’484 patent) describes a process for producing Vonoprazan fumarate comprising the following steps: (i) 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde is reacted with 40% methylamine in methanol and sodium borohydride to produce 1-[5-(2-Fluorophenyl)-1H-pyrrol-3-yl]-N-methylmethanamine; (ii) the resulting intermediate is reacted with Boc acid anhydride in acetonitrile to produce ((5-(2-fluorophenyl)-1H-pyrrol-3-yl)-N-methyl)methylcarbamate tert-butyl ester; (iii) the resulting intermediate is reacted with 3-pyridinesulfonyl chloride in anhydrous tetrahydrofuran solvent in the presence of sodium hydride to produce ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl) carbamic acid tert-butyl ester; (iv) the resulting intermediate is then deprotected by reacting with trifluoroacetic anhydride in dichloromethane solvent to produce Vonoprazan free base; and (v) the resulting Vonoprazan free base is further treated with fumaric acid in anhydrous methanol solvent to produce Vonoprazan fumarate.
Chinse Patent No. CN 108191829 B (hereinafter referred to as the CN’829patent) describes a process for producing Vonoprazan fumarate comprising the following steps: (i) N-methyl-5-(2-fluorophenyl)-1H-pyrrole-3-carboxamide is reacted with 3-pyridine-sulfonyl chloride in presence of sodium hydride and 15-crown-5 in tetrahydrofuran solvent to produce N-methyl-5-(2-fluorophenyl)-1-(pyridine-3-ylsulfonyl)-1H-pyrrole-3-carboxamide; (ii) the resulting compound obtained in step-(i) is reduced with sodium borohydride and Boron trifluoride or iodine in tetrahydrofuran to produce Vonoprazan free base; and (iii) Vonoprazan free base is treated with fumaric acid in dimethylformamide solvent to produce Vonoprazan fumarate.
Chinse Patent No. CN 105294653 B (hereinafter referred to as the CN’653B patent) discloses a process for producing Vonoprazan fumarate comprising the following reaction steps: (i) 5-(2-Fluorophenyl)-3-methyl-1H-pyrrole is reacted with 3-pyridine-sulfonylchloride in the presence of triethylamine in dichloromethane and toluene to produce 5-(2-Fluorophenyl)-3-methyl-1-(pyridine-3-ylsulfonyl)-1H-pyrrole; (ii) the resulting intermediate is reacted with N-bromosuccinimide in carbon tetrachloride in presence of benzoyl peroxide to produce 5-(2-Fluorophenyl)-3-bromomethyl-1-(pyridine-3ylsulfonyl)-1H-pyrrole; (iii) the resulting compound obtained in step-(ii) is reacted with methyl amine in presence of triethylamine and 1-butyl-3-methylimidazole bromide in toluene to produce Vonoprazan free base; and (iv) Vonoprazan free base is treated with fumaric acid in dimethylformamide to produce Vonoprazan fumarate.
Vonoprazan fumarate and its intermediates obtained by the processes described in the prior art references do not have satisfactory purity. Unacceptable amounts of impurities (including genotoxic impurities and nitrosamine impurity) are formed during the synthesis of Vonoprazan fumarate which are persistent and hence they cannot be removed at final stages of the process. The yields of Vonoprazan and/or Vonoprazan fumarate obtained according to the processes disclosed in the prior art are also very low.
It is known that synthetic compounds can contain impurities resulting from their synthesis or degradation or oxidation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, degradation or oxidation products. Impurities in Vonoprazan fumarate or any active pharmaceutical ingredient (API) are undesirable and might be harmful. At certain stages during processing of the active pharmaceutical ingredient, the product is analyzed for purity, typically, by HPLC, TLC, or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. Purity standards are set with the intention of ensuring that an API is free of impurities as possible, and thus, are safe as possible for clinical use. The USFDA guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.
Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity present in the lowest possible levels, even if structural determination is not possible.
Generally, impurities are identified spectroscopically and by other physical methods, and then the impurities are associated with a peak position in a HPLC chromatogram. Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the “retention time” (“Rt”). This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use “relative retention time” (“RRT”) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
Further, it is known that nitrosamine impurities are generally formed during the preparation, storage and/or processing of the active pharmaceutical ingredients (drug substances or APIs) having secondary amines such as Vonoprazan. The drug manufactures have been facing with the problem of controlling and/or preventing the formation of nitrosamine impurities and/or genotoxic impurities during the synthesis, storage and/or processing of APIs. Identification of nitrosamine impurities and genotoxic impurities in pharmaceuticals is traditionally a vital task in the drug development process. Although this task is complicated in nature by the fact that these impurities generally appear at a very low level, i.e., ppm (parts per million) or ppb (parts per billion) of mass fraction levels relative to the drug substance. LC-MS (or HPLC-MS), and in particular LC-MS/MS, is one technique that can be used for the selective, specific and sensitive identification of impurities, often with sensitivity enabling the detection of parts per billion levels. Among various types of LC-MS instruments, high resolution instruments enabling LC-MS/MS analysis are best suited for the detection of trace impurities.
The processes for the preparation of Vonoprazan fumarate as described in the prior art suffer from several drawbacks and disadvantages as follows: (a) the prior art processes have failed to produce the highly pure Vonoprazan fumarate substantially free of impurities; (b) the prior art processes suffer from several disadvantages such as lack of reproducibility, low purity and low quality of the product; (c) the prior art processes have failed to control the formation of nitrosamine impurity; and (d) the prior art processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolation /re-crystallizations.
A need still remains for novel, improved, commercially viable and industrially advantageous processes for the preparation of the highly pure Vonoprazan fumarate substantially free of impurities to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The object of the present invention is to provide a novel, commercially viable and industrially advantageous processes for the preparation of highly pure Vonoprazan or a pharmaceutically acceptable salt thereof, preferably Vonoprazan fumarate salt, substantially free of impurities, with high yield.
The present inventors have found that the following impurities are formed during the process for the preparation of Vonoprazan or a pharmaceutically acceptable salt:
1. N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine of formula A (hereinafter referred to as the Impurity-A or Nitrosamine impurity or Nitrosamine compound):

2. Bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine of formula B (hereinafter referred to as the Impurity-B or Dimer impurity or Dimer compound):

3. N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methylamine of formula C (hereinafter referred to as Impurity-C):

4. Pyridine-3-sulfonic acid of formula D (hereinafter referred to as the Impurity-D or PRDS acid impurity):

5. 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV (hereinafter referred to as the Impurity-E):

6. N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine of formula F (hereinafter referred to as the Impurity-F or Dimethyl Impurity or Dimethyl-Vonoprazan):

7. [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol of formula G (hereinafter referred to as the Impurity-G or alcohol impurity):

In one aspect, provided herein is an improved, commercially viable and industrially advantageous process for the preparation of highly pure Vonoprazan fumarate substantially free of at least one, or more, specifically all, of the impurities A, B, C, D, E, F and/or G.
In another aspect, provided herein is a highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G.
In another aspect, provided herein is a process for the preparation of highly pure Vonoprazan fumarate substantially free of nitrosamine impurity (Impurity-A).
In another aspect, provided herein is a highly pure Vonoprazan fumarate substantially free of nitrosamine impurity (Impurity-A).
In another aspect, provided herein is a highly pure Vonoprazan fumarate substantially free of dimer impurity (Impurity-B).
In another aspect, provided herein is a pharmaceutical composition comprising highly pure Vonoprazan fumarate substantially free of impurities made by the processes disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure Vonoprazan fumarate made by the process disclosed herein with one or more pharmaceutically acceptable excipients.
In another aspect, the highly pure Vonoprazan fumarate made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 350 microns, specifically about 5 microns to about 100 microns, and most specifically about 8 microns to about 60 microns.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of highly pure crystalline Form A of Vonoprazan fumarate.
Figure 2 is a characteristic infra-red (IR) spectrum of highly pure crystalline Form A of Vonoprazan fumarate.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of highly pure crystalline Form A of Vonoprazan fumarate.
Figure 4 is a characteristic Particle Size Distribution (PSD) Histogram of highly pure Vonoprazan Fumarate obtained in Example 3.
Figure 5 is a characteristic Particle Size Distribution (PSD) Histogram of highly pure Vonoprazan Fumarate obtained in Example 4.
Figure 6 is a characteristic Particle Size Distribution (PSD) Histogram of highly pure Vonoprazan Fumarate obtained in Example 5.
Figure 7 is a characteristic powder X-ray diffraction (XRPD) pattern of highly pure crystalline form of Vonoprazan hydrobromide.
Figure 8 is a characteristic infra-red (IR) spectrum of highly pure crystalline form of Vonoprazan hydrobromide.
Figure 9 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of highly pure crystalline form of Vonoprazan hydrobromide.

DETAILED DESCRIPTION OF THE INVENTION
Extensive research and experiments have been carried by the present inventors to control, reduce and/or prevent the formation of nitrosamine impurity (Impurity-A) and other process related impurities (Impurities B to G) during the synthesis of Vonoprazan or a pharmaceutically acceptable salt thereof.
As a result, it has been found that the use of purified water substantially free of the traces of nitrites and nitrates (instead of using normal water or DM water) in the processes for preparation of Vonoprazan or a pharmaceutically acceptable salt thereof (including the reaction, work-up, isolation, purification and/or recrystallization processes) either as a solvent, or as a mixture of solvents with an organic solvent, or as an anti-solvent, or as an aqueous solution of reagents, reactants, acids and/or bases) successfully controls, reduces and/or prevents the formation of nitrosamine impurity. The processes of the present invention also successfully control, prevent and/or reduce the formation of the process related impurities (Impurities B to G).
In one embodiment, the purified water used in the processes of the present invention contains the traces of nitrites in an amount of less than about 1 ppm, specifically less than about 0.5 ppm, more specifically less than about 0.05 ppm and most specifically less than about 0.01 ppm as measured by the methods known in the art.
In another embodiment, the purified water used in the processes of the present invention contains the traces of nitrates in an amount of less than about 10 ppm, specifically less than about 5 ppm, more specifically less than about 1 ppm and most specifically less than about 0.2 ppm in order to control and/or prevention of the formation of nitrosamine impurities as measured by the methods known in the art.

According to one aspect, there is provided a highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G, wherein the impurities are characterized having the following chemical names:
Impurity A: N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine;
Impurity B: Bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine;
Impurity C: N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methylamine;
Impurity D: Pyridine-3-sulfonic acid;
Impurity E: 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde;
Impurity F: N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine;
Impurity G: [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol.
The Impurity-A is detected and resolved from Vonoprazan by HPLC-MS/MS. The Impurities B, C, D, E, F and G are detected and resolved from Vonoprazan by HPLC with the RRTs 2.11, 0.50, 0.16, 1.98, 1.87 and 1.64 respectively.
As used herein, the term “highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G” or “highly pure Vonoprazan fumarate substantially free of impurities” refers to the Vonoprazan fumarate comprising the impurities B, C, D, E, F and/or G, each one, in an amount of less than 0.1%, specifically less than 0.05%, more specifically less than 0.02%, and most specifically less than 0.01% as measured by HPLC; and the Impurity-A in an amount of less than 0.3 ppm (300 ppb), specifically less than 0.2 ppm (200 ppb), more specifically less than 0.1 ppm (100 ppb); and most specifically less than 0.04 ppm (40 ppb) as measured by HPLC-MS/MS.
In one embodiment, the Vonoprazan or a fumarate salt thereof produced herein comprises the impurities B, C, D, E, F and/or G, each one, in an amount of less than 0.1%, specifically less than 0.05%, more specifically less than 0.02%, and most specifically less than 0.01% as measured by HPLC.
According to another aspect, there is provided a highly pure Vonoprazan fumarate substantially free of nitrosamine impurity (Impurity-A).
As used herein, the term “highly pure Vonoprazan fumarate substantially free of nitrosamine impurity (Impurity-A)” refers to Vonoprazan fumarate comprises the nitrosamine impurity (Impurity-A) in an amount of less than 0.3 ppm (300 ppb), specifically less than 0.2 ppm (200 ppb), more specifically less than 0.1 ppm (100 ppb); and most specifically less than 0.04 ppm (40 ppb) as measured by HPLC-MS/MS.
According to another aspect, there is provided a highly pure Vonoprazan fumarate comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.3 ppm (300 ppb), specifically less than 0.2 ppm (200 ppb), more specifically less than 0.1 ppm (100 ppb); and most specifically less than 0.04 ppm (40 ppb) as measured by HPLC-MS/MS.
The structure of the Vonoprazan nitrosamine (Impurity-A) chemically named “N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine” is deduced with the aid of 1H, 13C NMR, IR Spectroscopy and Mass Spectrometry.
According to another aspect, there is provided a process for the preparation of Vonoprazan nitrosamine compound, N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine, of formula A, which comprises reacting Vonoprazan free base with sodium nitrite in the presence of concentrated hydrochloric acid in a solvent medium comprising water and dichloromethane.
According to another aspect, there is provided a dimer compound, bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine, of formula B or a salt thereof.
The structure of the dimer compound of formula B chemically named “bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine” is deduced with the aid of 1H, 13C NMR, IR Spectroscopy and Mass Spectrometry.
According to another aspect, there is provided a highly pure Vonoprazan fumarate substantially free of dimer impurity-B.
According to another aspect, there is provided a process for the preparation of the dimer compound, bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine, of formula B or a salt thereof comprising reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde of formula II or a salt thereof with [5-(2-Fluoro phenyl)-1H-pyrrol-3-ylmethyl]-methylamine of formula C or a salt thereof in the presence of sodium borohydride and acetic acid in toluene solvent.
According to another aspect, there is provided a process for the preparation of the dimethyl-vonoprazan compound (Impurity-F), N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine, of formula F comprising reacting 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde of formula IV with sodium borohydride and dimethylamine in methanol solvent followed by the addition of fumaric acid.
According to another aspect, there is provided a process for the preparation of Vonoprazan alcohol compound (Impurity-G), [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol, of formula G comprising reacting 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde of formula IV with sodium borohydride using methanol solvent.
As used herein, the term “highly pure Vonoprazan fumarate” refers to the Vonoprazan fumarate having the chemical purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure Vonoprazan fumarate is about 99.8% to about 99.99% as measured by HPLC.
According to another aspect, there is provided a process for the preparation of highly pure Vonoprazan of formula (I):

or a pharmaceutically acceptable salt thereof, specifically fumarate salt, substantially free of the impurities A, B, C, D, E, F and/or G; which comprises:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde of formula II:

or a salt thereof with pyridine-3-sulfonyl chloride of formula III:

or a salt thereof, in the presence of an organic base and a catalyst in a ketone solvent to produce 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV:

(b) reacting the compound of formula IV with monomethylamine in an alcohol solvent to produce a reaction mass containing the intermediate compound, N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethylene]-methylamine, of formula V:

(c) combining the reaction mass containing the compound of formula V obtained in step-(b) with a suitable reducing agent to produce Vonoprazan free base of formula I;
(d) dissolving the Vonoprazan free base obtained in step-(c) in a suitable solvent and then adding aqueous hydrobromic acid solution to produce a reaction mass containing the Vonoprazan hydrobromide;
(e) isolating the crystalline form of Vonoprazan hydrobromide salt by cooling the reaction mass obtained in step-(d) to a temperature of below 15ºC;
(f) neutralizing the Vonoprazan hydrobromide salt obtained in step-(e) with a base in a suitable solvent while adjusting the pH of the resulting mass to above 9 to produce pure Vonoprazan free base;
(g) converting the Vonoprazan free base obtained in step-(f) into Vonoprazan fumarate salt by treating with fumaric acid in a suitable solvent or a mixture of suitable solvents; and
(h) purifying the Vonoprazan fumarate salt obtained in step-(g) with a suitable solvent or a mixture of suitable solvents to produce highly pure Vonoprazan fumarate substantially free of the impurities.
Unless otherwise specified, the term “salt” or “pharmaceutically acceptable salt” as used herein may include pharmaceutically acceptable acid addition salts.
Exemplary acid addition salts of the compounds prepared according to the present invention may include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, oxalic acid, fumaric acid, maleic acid and benzoic acid.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC, and specifically to a temperature of about 25ºC to about 30ºC.
Unless otherwise specified, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, an ether, an ester, an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon, a nitrile solvent, a ketone, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds prepared herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, 2-butanone, methyl isobutyl ketone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to inorganic bases such as carbonates, bicarbonates, hydroxides of alkali metals or alkaline earth metals; and organic bases such as alkoxides, acetates, amines and amides.
Exemplary inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof.
Exemplary organic bases include, but are not limited to alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, amines such dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine (DMAP), and mixtures thereof.
Unless otherwise specified, the term ‘acid’ as used herein is an inorganic acid or organic acid. Exemplary acids as used herein include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, succinic acid, citric acid, oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid and benzoic acid.
In one embodiment, the ketone solvent used in step-(a) is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof. A most specific solvent used in step-(a) is acetone.
In another embodiment, the organic base used in step-(a) is selected from the group consisting of diethylamine, diisopropyl amine, diisopropylethylamine, triethylamine, and mixtures thereof. A most specific organic base used in step-(a) is diisopropylethylamine.
In another embodiment, the catalyst used in step-(a) is selected from the group consisting of N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine (DMAP), hydroxybenzotriazole, and mixtures thereof. A most specific catalyst used in step-(a) is 4-dimethylaminopyridine.
In another embodiment, the reaction in step-(a) is carried out at a temperature of above about 25°C, specifically at a temperature of about 25°C to about 55°C, and most specifically at a temperature of about 30°C to about 40°C. In another embodiment, the reaction in step-(a) is carried out for about 5 hours to about 20 hours, and more specifically for about 10 hours to about 12 hours.
The reaction mass containing the 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV obtained in step-(a) may be subjected to usual work up methods such as washing, quenching, extraction, pH adjustment with an acid and/or a base, evaporation, layer separation, decolorization, carbon treatment, filtration, or a combination thereof. The reaction mass containing the compound of formula IV may be used directly (in situ) in the next step to produce the compound of formula V or the compound of formula IV may be isolated and/or recrystallized and then used in the next step.
In a preferred embodiment, the pH of the reaction mass obtained in step-(a) is adjusted to 4 to 5 with an acid and further adjusting the pH of the resulting mass to above 8 with an inorganic base to produce compound of formula IV with high purity and yield.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula IV obtained in step-(a) is selected from the group of solvents as described hereinabove. A most specific solvent used for work-up, isolation and/or purification of the compound of formula IV is selected from the group consisting of water, acetone and a mixture thereof.
The acid used for adjusting the pH of the reaction mass obtained in step-(a) is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, tartaric acid, acetic acid and mixtures thereof. A most specific acid used for adjusting the pH of the reaction mass is aqueous hydrochloric acid.
The inorganic base used for adjusting the pH of the resulting mass is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof. A most specific inorganic base used for adjusting the pH of the resulting mass is aqueous sodium bicarbonate solution.
In another embodiment, the compound of formula IV obtained in step-(a) is isolated and/or purified from a suitable solvent by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
Specifically, the monomethylamine used in step-(b) is in form of an aqueous monomethylamine or a solution of monomethylamine in an alcohol solvent; and most specifically, the monomethylamine used in step-(b) is a solution of monomethylamine in methanol.
In one embodiment, the alcohol solvent used in step-(b) is selected from the group methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, and mixtures thereof. A most specific solvent used in step-(b) is methanol. In another embodiment, the reaction in step-(b) is carried out at room temperature.
Exemplary reducing agents used in step-(c) include, but are not limited to, sodium borohydride, potassium borohydride sodium cyanoborohydride, sodium triacetoxy borohydride, nickel borohydride, zinc borohydride, lithium aluminium hydride, and the like. A most specific reducing agent used in step-(c) is sodium borohydride.
In another embodiment, the reaction in step-(c) is carried out at a temperature of below about 10°C, specifically at a temperature of about -10°C to about 10°C, and most specifically at a temperature of about -5°C to about 5°C. In another embodiment, the reaction in step-(a) is carried out for about 30 minutes to about 3 hours, and more specifically for about 1 hour to about 2 hours.
The reaction mass containing the Vonoprazan free base obtained in step-(c) may be subjected to usual work up methods such as washing, quenching, extraction, pH adjustment with an acid and/or a base, evaporation, layer separation, decolorization, carbon treatment, filtration, or a combination thereof. The reaction mass containing the Vonoprazan free base may be used directly in the next step to produce Vonoprazan hydrobromide salt or the Vonoprazan free base may be isolated and/or purified and then used in the next step.
In a preferred embodiment, the pH of the reaction mass obtained in step-(c) is adjusted to 1 to 2 with an acid and further adjusted the pH of the resulting mass to above 9 with an inorganic base to produce Vonoprazan free base.
In another embodiment, the solvent used for work-up, isolation and/or purification of the Vonoprazan free base obtained in step-(c) is selected from the group of solvents as described hereinabove. A most specific solvent used for work-up, isolation and/or purification of the Vonoprazan free base is selected from the group consisting of water, ethyl acetate and a mixture thereof.
The acid used for adjusting the pH of the reaction mass obtained in step-(c) is selected from the group of acids as described hereinabove. A most specific acid used for adjusting the pH of the reaction mass is dilute hydrochloric acid. The inorganic base used for adjusting the pH of the resulting mass is selected from the group of inorganic bases as described hereinabove. A most specific inorganic base used for adjusting the pH of the resulting mass is aqueous ammonia solution.
In another embodiment, the Vonoprazan free base obtained in step-(c) is isolated and/or purified from a suitable solvent by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
Exemplary solvents used for dissolving the Vonoprazan free base in step-(d) include, but are not limited to, water, an alcohol, a ketone, or a mixture thereof.
In one embodiment, the solvent used for dissolving the Vonoprazan free base in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, 2-butanone, methyl isobutyl ketone, and mixtures thereof. A most specific solvent used for dissolving the Vonoprazan free base in step-(d) is ethanol.
In another embodiment, the dissolution in step-(d) is carried out at a temperature of about 30ºC to about 50ºC, and most specifically at a temperature of about 35ºC to about 40ºC.
In another embodiment, the addition of aqueous hydrobromic acid solution to the solution of Vonoprazan free base in step-(d) is carried out slowly at a temperature of about 20°C to about 30°C. The addition of aqueous hydrobromic acid solution is, for example, carried out drop wise or in one portion or in more than one portion. After completion of the addition process, the resulting mass is stirred at a temperature of about 20°C to about 30°C for at least 10 minutes and specifically at a temperature of about 25°C to about 30°C for about 20 minutes to about 2 hours.
Specifically, the reaction mass in step-(e) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; more specifically to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; and most specifically to a temperature of about 0°C to about 6°C while stirring for about 2 hours to 3 hours.
The isolation of the pure crystalline form of Vonoprazan hydrobromide salt in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, drying, or a combination thereof.
In one embodiment, the neutralization in step-(f) is carried out at temperature of about 25ºC to about 35ºC and pH of the reaction mass is adjusted to above 9.5.
In another embodiment, the solvent used in step-(f) is selected from the group consisting of water, ethyl acetate, propyl acetate, butyl acetate, and a mixture thereof. Specifically, the solvent used in step-(f) is a mixture of water and ethyl acetate.
In another embodiment, the base used in step-(f) is an inorganic base selected from the group consisting of inorganic bases as described hereinabove. A most specific inorganic base used for adjusting the pH of the resulting mass is aqueous ammonia solution.
The reaction mass containing the Vonoprazan free base obtained in step-(f) may be subjected to usual work up methods as described hereinabove.
In another embodiment, the Vonoprazan free base obtained in step-(f) is isolated and/or purified from a suitable solvent by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, or a combination thereof.
Exemplary solvents used in step-(g) include, but are not limited to, an ester solvent, a polar aprotic solvent or a mixture thereof. In one embodiment, the solvent used in step-(g) is selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate, dimethylformamide, dimethylacetamide and mixtures thereof. A most specific solvent used in step-(g) is a mixture of ethyl acetate and dimethylacetamide.
In one embodiment, the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of above 35ºC, and specifically at a temperature of about 45ºC to about 55ºC.
In another embodiment, the Vonoprazan fumarate obtained in step-(g) is isolated as a solid by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
Specifically, the Vonoprazan fumarate obtained in step-(g) is isolated by cooling the resulting mass while stirring at a temperature of below 35ºC, and most specifically at a temperature of about 25-30ºC. The resulting wet material is collected by filtration, followed by drying the material under vacuum at 25-35ºC and then further drying the material at a temperature of about 45ºC to about 55ºC.
In one embodiment, the purification of Vonoprazan fumarate in step-(h) is carried out by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
In another embodiment, the solvent used for purification of Vonoprazan fumarate in step-(h) is selected from the group of solvents as described hereinabove. Specifically, the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and an alcohol solvent; and most specifically, the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and methanol.
Specifically, the purification of Vonoprazan fumarate in step-(h) is carried out by the methods of the present invention described hereinafter.
According to another aspect, there is provided a process for the preparation of highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G; which comprises:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II or a salt thereof, with pyridine-3-sulfonyl chloride of formula III or a salt thereof in the presence of an organic base and a catalyst in acetone solvent to produce a reaction mass, followed by adjusting the pH of the reaction mass to 4 to 5 with aqueous hydrochloric acid and further adjusting the pH of the resulting mass to above 8 with aqueous sodium bicarbonate solution to produce 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV;
(b) reacting the compound of formula IV obtained in step-(a) with monomethylamine in an alcohol solvent to produce a reaction mass containing the compound, N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethylene]-methylamine, of formula V;
(c) combining the reaction mass obtained in step-(b) with sodium borohydride to produce a reaction mass, followed by adjusting the pH of the reaction mass to 1 to 2 with an acid and further adjusting the pH of the resulting mass to above 9 with an inorganic base to produce Vonoprazan free base;
(d) dissolving the Vonoprazan free base obtained in step-(c) in a suitable solvent and then adding aqueous hydrobromic acid solution to produce a reaction mass containing the Vonoprazan hydrobromide;
(e) isolating the crystalline form of Vonoprazan hydrobromide salt by cooling the reaction mass obtained in step-(d) to a temperature of below 15ºC, wherein the crystalline form of Vonoprazan hydrobromide is characterized by an X-ray powder diffraction pattern having two or more 2-theta peaks at about 11.48, 13.94, 15.18, 15.58, 16.67, 18.45, 18.70, 19.67, 22.04, 23.14, 24.43 and 25.39 ± 0.2 degrees substantially in accordance with Figure 7;
(f) neutralizing the Vonoprazan hydrobromide salt obtained in step-(e) with a base in a suitable solvent while adjusting the pH of the resulting mass to above 9 to produce pure Vonoprazan free base;
(g) converting the Vonoprazan free base obtained in step-(f) into Vonoprazan fumarate salt by treating with fumaric acid in a suitable solvent or a mixture of suitable solvents; and
(h) purifying the Vonoprazan fumarate salt obtained in step-(g) with a suitable solvent or a mixture of suitable solvents to produce highly pure Vonoprazan fumarate substantially free of the impurities.
In one embodiment, the organic base used in step-(a) is selected from the group consisting of diethylamine, diisopropyl amine, diisopropylethylamine, triethylamine, and mixtures thereof. A most specific organic base used in step-(a) is diisopropylethylamine.
In another embodiment, the catalyst used in step-(a) is selected from the group of catalysts as described hereinabove. A most specific catalyst used in step-(a) is 4-dimethylaminopyridine.
In another embodiment, the reaction in step-(a) is carried out at a temperature of above about 25°C, specifically at a temperature of about 25°C to about 55°C, and most specifically at a temperature of about 30°C to about 40°C. In another embodiment, the reaction in step-(a) is carried out for about 5 hours to about 20 hours, and more specifically for about 10 hours to about 12 hours.
The reaction mass containing the 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV obtained in step-(a) may be subjected to usual work up methods as described hereinabove.
The reaction mass containing the compound of formula IV is isolated and/or recrystallized and then used in the next step.
In another embodiment, the compound of formula IV obtained in step-(a) is isolated and/or re-crystallized from a suitable solvent by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula IV obtained in step-(a) is selected from the group of solvents as described hereinabove. A most specific solvent used for work-up, isolation and/or purification of the compound of formula IV is selected from the group consisting of water, acetone and a mixture thereof.
Specifically, the monomethylamine used in step-(b) is in form of an aqueous monomethylamine or a solution of monomethylamine in an alcohol solvent; and most specifically, the monomethylamine used in step-(b) is a solution of monomethylamine in methanol.
In one embodiment, the alcohol solvent used in step-(b) is selected from the group methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, and mixtures thereof. A most specific solvent used in step-(b) is methanol. In another embodiment, the reaction in step-(b) is carried out at room temperature.
In another embodiment, the reaction in step-(c) is carried out at a temperature of below about 10°C, specifically at a temperature of about -10°C to about 10°C, and most specifically at a temperature of about -5°C to about 5°C. In another embodiment, the reaction in step-(a) is carried out for about 30 minutes to about 3 hours, and more specifically for about 1 hour to about 2 hours.
The reaction mass containing the Vonoprazan free base obtained in step-(c) may be subjected to usual work up methods as described hereinabove. The reaction mass containing the Vonoprazan free base is isolated and/or purified and then used in the next step.
In another embodiment, the solvent used for work-up, isolation and/or purification of the Vonoprazan free base obtained in step-(c) is selected from the group of solvents as described hereinabove. A most specific solvent used for work-up, isolation and/or purification of the Vonoprazan free base is selected from the group consisting of water, ethyl acetate and a mixture thereof.
The acid used for adjusting the pH of the reaction mass obtained in step-(c) is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, tartaric acid, acetic acid and mixtures thereof. A most specific acid used for adjusting the pH of the reaction mass is dilute hydrochloric acid. The inorganic base used for adjusting the pH of the resulting mass is selected from the group of inorganic bases as described hereinabove. A most specific inorganic base used for adjusting the pH of the resulting mass is aqueous ammonia solution.
In another embodiment, the Vonoprazan of formula I obtained in step-(c) is isolated and/or purified from a suitable solvent by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
In one embodiment, the solvent used for dissolving the Vonoprazan free base in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, 2-butanone, methyl isobutyl ketone, and mixtures thereof. A most specific solvent used for dissolving the Vonoprazan free base in step-(d) is ethanol.
In another embodiment, the dissolution in step-(d) is carried out at a temperature of about 30ºC to about 50ºC, and most specifically at a temperature of about 35ºC to about 40ºC.
In another embodiment, the addition of aqueous hydrobromic acid solution to the solution of Vonoprazan free in step-(d) is carried out slowly at a temperature of about 20°C to about 30°C. The addition is, for example, carried out drop wise or in one portion or in more than one portion. After completion of the addition process, the resulting mass is stirred at a temperature of about 20°C to about 30°C for at least 10 minutes and specifically at a temperature of about 25°C to about 30°C for about 20 minutes to about 2 hours.
Specifically, the reaction mass in step-(e) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; more specifically to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; and most specifically to a temperature of about 0°C to about 6°C while stirring for about 2 hours.
The isolation of the highly pure crystalline form of Vonoprazan hydrobromide salt in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, drying, or a combination thereof.
In one embodiment, the neutralization in step-(f) is carried out at temperature of about 25ºC to about 35ºC while adjusting the pH of the resulting mass is adjusted to above 9.5.
In another embodiment, the solvent used in step-(f) is selected from the group consisting of water, ethyl acetate, propyl acetate, butyl acetate, and a mixture thereof. Specifically, the solvent used in step-(f) is a mixture of water and ethyl acetate.
In another embodiment, the base used for adjusting the pH in step-(f) is an inorganic base selected from the group of consisting of inorganic bases as described hereinabove. A most specific inorganic base used for adjusting the pH of the resulting mass is aqueous ammonia solution.
The reaction mass containing the Vonoprazan free base obtained in step-(f) may be subjected to usual work up methods as described hereinabove.
In another embodiment, the Vonoprazan free base obtained in step-(f) is isolated and/or purified from a suitable solvent by the methods as described hereinabove.
Exemplary solvents used in step-(g) include, but are not limited to, an ester solvent, a polar aprotic solvent or a mixture thereof. In one embodiment, the solvent used in step-(g) is selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate, dimethylformamide, dimethylacetamide and mixtures thereof. A most specific solvent used in step-(g) is a mixture of ethyl acetate and dimethylacetamide.
In one embodiment, the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of above 35ºC, and specifically at a temperature of about 45ºC to about 55ºC.
In another embodiment, the Vonoprazan fumarate obtained in step-(g) is isolated as a solid by the methods as described hereinabove.
Specifically, the Vonoprazan fumarate obtained in step-(g) is isolated by cooling the resulting mass while stirring at a temperature of below 35ºC, and most specifically at a temperature of about 25-30ºC. The resulting wet material is collected by filtration, followed by drying the material under vacuum at 25-35ºC and then further drying the material at a temperature of about 45ºC to about 55ºC.
In one embodiment, the purification of Vonoprazan fumarate in step-(h) is carried out by the methods as described hereinabove.
In another embodiment, the solvent used for purification of Vonoprazan fumarate in step-(h) is selected from the group of solvents as described hereinabove. Specifically, the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and an alcohol solvent; and most specifically, the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and methanol.
According to another aspect, there is provided a process for the preparation of 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV with high yield and purity, comprising:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II or a salt thereof, with pyridine-3-sulfonyl chloride of formula III or salt thereof in the presence of diisopropylethylamine or triethylamine and a catalyst in acetone solvent to produce a reaction mass containing 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV;
(b) adjusting the temperature of the reaction mass obtained in step-(a) to 25-30°C followed by the addition of water;
(c) adjusting the pH of the reaction mass obtained in step-(b) to about 4 to 5 with a dilute hydrochloric acid solution followed by the addition of water and then stirring the mass at 25-30°C;
(d) cooling the mass obtained in the step-(c) further to below 10°C and then isolating the crude compound of formula IV;
(e) combining the crude compound obtained in step-(d) with an inorganic base and adjusting the pH of the resulting mass to above 8; and
(f) collecting the pure compound of formula IV obtained in step-(e).
In another embodiment, the catalyst used in step-(a) is selected from the group of catalysts as described hereinabove. A most specific catalyst used in step-(a) is 4-dimethylaminopyridine.
In another embodiment, the reaction in step-(a) is carried out at a temperature of above about 25°C, specifically at a temperature of about 25°C to about 55°C, and most specifically at a temperature of about 30°C to about 40°C. In another embodiment, the reaction in step-(a) is carried out for about 5 hours to about 20 hours, and more specifically for about 10 hours to about 12 hours.
The inorganic base used for adjusting the pH of the resulting mass in step-(f) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof. A most specific inorganic base used for adjusting the pH of the resulting mass in step-(f) is aqueous sodium bicarbonate solution.
The collection of the compound of formula IV in step-(f) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein is a crystalline form (designated as Form A) which is characterized by an X-ray powder diffraction pattern having 2-theta peaks at about 5.1, 10.2, 11.4, 11.7, 12.2, 13.5, 15.1, 15.3, 16.9, 20.4 and 22.4 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infrared absorption spectrum (IR) having two or more characteristic IR bands at about 3433±5, 3135±3, 3010±3, 2806±3, 2757±3, 2593±3, 2520±3, 1698±2, 1637±2, 1575±2, 1563±2, 1526±2, 1471±2, 1418±2, 1373±2, 1282±2, 1229±2, 1175±2, 1033±2, 1018±2, 996±2, 935±2, 903±2, 819±2, 758±2, 749±2 and 700±2 (cm-1) substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having an endotherm peak at about 209.86°C (± 3°C) with an onset temperature at about 206.53°C (±3°C) substantially in accordance with Figure 3.
In another embodiment, the highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein is an amorphous form.
According to another aspect, there is provided a purification process for the preparation of highly pure crystalline Form A of Vonoprazan fumarate, comprising:
a) providing a solution of Vonoprazan fumarate in a solvent medium comprising methanol and purified water at a temperature of about 45°C to about 65°C, wherein the quantity of solvent medium employed is about 15 volumes to about 35 volumes with respect to the quantity of Vonoprazan fumarate used;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment at reflux temperature to obtain a filtrate;
c) cooling the solution obtained in step-(a) or step-(b) at a temperature of below about 35°C to cause crystallization; and
d) collecting the highly pure crystalline Form A of Vonoprazan fumarate formed in step-(c).
In one embodiment, the amount of solvent medium employed in step-(a) is about 16 volumes to about 32 volumes, specifically about 18 volumes to about 28 volumes, and most specifically about 24 volumes to about 26 volumes, with respect to the quantity of Vonoprazan fumarate used.
In another embodiment, the quantity of methanol used in step-(a) is about 0.8 to 1.6 volumes, specifically about 1 to 1.2 volumes, with respect to the volume of purified water used.
Step-(a) of providing a solution of Vonoprazan fumarate includes dissolving Vonoprazan fumarate in the solvent medium at a temperature of about 45°C to about 65°C, or obtaining an existing solution from a previous processing step.
In one embodiment, the Vonoprazan fumarate is dissolved in the solvent medium at a temperature of about 50°C to about 60°C. After complete dissolution of Vonoprazan fumarate, the resulting solution is stirred at the temperature of about 50°C to about 60°C for at least 5 minutes, and specifically for about 10 minutes to about 30 minutes.
The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the temperature of about 50°C to about 60°C for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Vonoprazan fumarate by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the crystallization in step-(c) is accomplished by cooling the solution initially to a temperature of about 20°C to about 35°C while stirring for at least 10 minutes, and more specifically at a temperature of about 25°C to about 30°C for about 20 minutes to about 2 hours. The resulting mass is further cooled to a temperature of about -5°C to about 15°C while stirring for at least 10 minutes, and more specifically at a temperature of about 0°C to about 6°C for about 20 minutes to about 5 hours.
The collection of the highly pure Vonoprazan fumarate in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
According to another aspect, there is provided a highly pure crystalline form of Vonoprazan hydrobromide which is characterized by an X-ray powder diffraction pattern having two or more 2-theta peaks at about 11.48, 13.94, 15.18, 15.58, 16.67, 18.45, 18.70, 19.67, 22.04, 23.14, 24.43 and 25.39 ± 0.2 degrees substantially in accordance with Figure 7; and/or an infrared absorption spectrum (IR) having two or more characteristic IR bands at about 3433±5, 3142±3, 2980±3, 2919±3, 2870±3, 2738±3, 2700±3, 2560±3, 2447±3, 1584±2, 1525±2, 1470±2, 1429±2, 1385±2, 1309±2, 1205±2, 1105±2, 1064±2, 1025±2, 994±2, 821±2, 762±2, 743±2 and 699±2 (cm-1) substantially in accordance with Figure 8; and/or a Differential Scanning Calorimetric (DSC) thermogram having an endotherm peak at about 197.10°C (± 3°C) with an onset temperature at about 193.76°C (± 3°C) substantially in accordance with Figure 9.
According to another aspect, there is provided a process for the preparation of highly pure crystalline form of Vonoprazan hydrobromide, comprising:
a) providing a solution of Vonoprazan free base in ethanol solvent at a temperature of about 30°C to about 50°C;
b) cooling the solution obtained in step-(a) to a temperature of below 30°C;
c) combining the solution obtained in step-(b) with aqueous hydrobromic acid solution at a temperature of about 20°C to about 30°C to produce a reaction mass;
d) cooling the reaction mass obtained in step-(c) further to a temperature of below about 15ºC to cause crystallization; and
e) collecting the highly pure crystalline form of Vonoprazan hydrobromide obtained in step-(c); and optionally converting the Vonoprazan hydrobromide obtained into a highly pure Vonoprazan fumarate salt.
In one embodiment, the solution in step-(a) is prepared by dissolving Vonoprazan free base in ethanol at a temperature of about 30°C to about 40°C or obtaining an existing solution from a previous processing step.
Specifically, the solution in step-(b) is cooled to a temperature of about 20°C to about 30°C, and most specifically to a temperature of about 25°C to about 30°C.
Combining of the solution with aqueous hydrobromic acid solution in step-(c) is carried out by adding the aqueous hydrobromic acid solution (48%) slowly to the solution of Vonoprazan free base solution at a temperature of about 20°C to about 30°C. The addition is, for example, carried out drop wise or in one portion or in more than one portion. The addition is specifically carried out at a temperature of about 25°C to about 30°C. After completion of the addition process, the reaction mass is stirred at a temperature of about 20°C to about 30°C for at least 10 minutes and specifically at a temperature of about 25°C to about 30°C for about 20 minutes to about 3 hours.
Specifically, the reaction mass in step-(d) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; more specifically to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; and most specifically to a temperature of about 0°C to about 6°C while stirring for about 2 to 3 hours.
The collection of the highly pure crystalline form of Vonoprazan hydrobromide in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II used as a starting material in the processes of the present invention can be prepared by known methods described in the art, for example, as per the processes described in the following literature references: US7977488B2, US 10912769B2, US6559177B2 and US8,822,694B2.
The compound of formula IV, Vonoprazan free base, Vonoprazan hydrobromide and Vonoprazan fumarate prepared according to the processes described in the present invention are further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C, specifically at a temperature of about 35°C to about 65°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 15 minutes to 30 hours, more specifically for a period of about 30 minutes to about 12 hours.
Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed dryer, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art. The drying can be carried out in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure or at atmospheric pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
The highly pure Vonoprazan fumarate obtained by the processes disclosed herein has a purity of greater than about 99.8%, specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure Vonoprazan fumarate obtained by the processes disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
Further encompassed herein is the use of the highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier/excipient.
In another aspect, the highly pure Vonoprazan fumarate made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 350 microns, specifically about 5 microns to about 100 microns, and most specifically about 8 microns to about 60 microns.
In another aspect, the highly pure Vonoprazan fumarate made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 200 microns, specifically about 3 microns to about 40 microns, and most specifically about 4 microns to about 25 microns.
In another aspect, the highly pure Vonoprazan fumarate made by the processes disclosed herein for use in the pharmaceutical compositions, has the Specific Surface Area of greater than or equal to about 60 m2/kg, specifically about 350 m2/kg to about 1400 m2/kg, and most specifically about 400 m2/kg to about 1200 m2/kg.
In another embodiment, the particle sizes of the highly pure Vonoprazan fumarate obtained by the processes disclosed herein are accomplished by milling, grinding, micronizing, pulverizing to bring the solid-state form to the desired particle size range.
In another embodiment, the particle sizes of the highly pure Vonoprazan fumarate obtained by the processes disclosed herein are accomplished by the specific methods and conditions described the in Examples 3, 4, 5 and 6 of the present invention.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there is provided a highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of less than or equal to about 350 microns, D50 particle size of less than or equal to about 200 microns, and/or the Specific Surface Area of greater than or equal to about 60 m2/kg.
According to another aspect, there is provided a highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of about 5 microns to about 100 microns, D50 particle size of about 3 microns to about 40 microns, and/or the Specific Surface Area of about 350 m2/kg to about 1400 m2/kg.
According to another aspect, there is provided a highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of about 8 microns to about 60 microns, D50 particle size of about 4 microns to about 25 microns, and/or the Specific Surface Area of about 400 m2/kg to about 1200 m2/kg.
According to another aspect, there is provided a pharmaceutical composition comprising highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical composition comprising combining highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, and the like.
In one embodiment, the oral dosage form of highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes disclosed herein is a tablet with 10 mg and 20 mg strengths for use in the treatment for adults for the healing of all grades of Erosive Esophagitis, also known as Erosive GERD (gastroesophageal reflux disease), maintenance of healing of all grades of Erosive GERD, and relief of heartburn associated with Erosive GERD.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylenesorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 40 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 1.5 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a PerkinElmer spectrum-2 FT-IR spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 250°C.
Particle Size Method of Analysis (PSD):
Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern Mastersizer 3000 or its equivalent under the following conditions: Accessory Name = Hydro MV; Dispersant = Liquid paraffin Light; Dispersant Refractive Index = 1.468; Absorption = 0.01; Obscuration limit = 10% to 30%; Measurement time = 10 seconds; Background time = 10 seconds; Stirrer speed = 2000 rpm.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Column = XInertsil ODS 3V, (150 × 4.6) mm; 5µm; Detector wavelength = UV at 260 nm; Flow Rate = 1.0 ml/min; Injection volume = 10 µl; Column Oven temperature = 35°C; Run time = 65 minutes; Diluent = A mixture of water and acetonitrile in a ratio of 75:25, (v/v); Sample concentration: 0.5 mg/ml and Elution mode: Gradient. Mobile phase-A: a mixture of Buffer, Methanol and Acetonitrile in the ratio of 700:250:50, (v/v/v) and degas; Mobile phase-B: a mixture of Buffer and Acetonitrile in the ratio of 300:700, (v/v) and degas.
HPLC-MS/MS Instrument used for measuring the content of Nitrosamine Impurity:
Instrument: Thermo Scientific Vanquish UHPLC, TSQ ALTIS Triple Quadrupole
Column: Kromasil 100-5-C18, (150 × 4.6) mm, or Equivalent; Flow Rate: 0.5 mL/min; Injection Volume: 5 ?L; Run time: 18 min. Preparation of Buffer: Transfer 1.0 mL of Formic acid into a beaker containing 1000 mL water. Mix well and filter through 0.22 µm membrane filter paper and degas. Mobile phase-A: Buffer. Mobile phase-B: Methanol. Elution Program: Isocratic (Mobile phase-A and Mobile phase-B in the ratio of 30:70 (%v/v)). Diluent: Prepare a mixture of Methanol and Water in the ratio of 50:50 (% v/v).

The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde
Acetone (400 ml), 4-dimethylaminopyridine (13 g) and diisopropylethylamine (150 g) were added to 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (100 g) at room temperature and the temperature of the resulting mixture was adjusted to 20-25°C. To the resulting mass, a solution of pyridine-3-sulfonyl chloride (146 g) in acetone (100 ml) was added at 25-37°C and the resulting mixture was stirred for 10 to 11 hours at 33-37°C. After completion of the reaction, the resulting mass was cooled to 25-30°C and purified water (300 ml) was added, followed by adjusting the pH of the resulting mass to 4 to 5 with a solution of hydrochloric acid (24 g) in purified water (180 ml). To the resulting mass, purified water (600 ml) was added at 25-30°C and stirred for 25-35 minutes at the same temperature. The resulting mass was cooled 0-6°C and stirred for about 1 hour at the same temperature. The resulting mass was filtered and the bed was washed with pre-cooled aqueous acetone (50 ml of acetone in 100 ml of purified water). Further, the bed was washed with purified water (150 ml) and suck dried the bed till mother liquors expelled out completely. Sodium bicarbonate solution (0.35 g in 500 ml purified water) was added to the resulting wet material at 25-35°C and then stirred for 30 minutes at the same temperature. The pH of the resulting mass was adjusted to above 8. The reaction mass was filtered and washed the bed with purified water (200 ml). The resulting wet material was dried in a hot air oven at 25-35°C for about 2 hours and then further dried at 45-55°C for about 6 hours to produce 160g of 5-(2-Fluorophenyl)-1-pyridine-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde as a brown color powder [Purity by HPLC: 99.53%; Water content by KF: 0.08%w/w].
Content of known impurities: Pyridine-3-sulfonic acid: 0.13%; and 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde: 0.13%.

Example 2
Preparation of crude Vonoprazan fumarate
Step-1: Preparation of Vonoprazan Hydrobromide salt
Monomethyl amine (~ 25% in methanol) (45.12 g) was added to methanol (800 ml) at room temperature, followed by the addition of 5-(2-Fluorophenyl)-1-pyridine-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (100 g) at the same temperature and then stirring for 30 minutes. The resulting mass was cooled to 0-5°C, sodium borohydride (4.58 g) was added (portion-wise) at -5 to 5°C and then stirred for about 1 hour at the same temperature. After completion of the reaction, the pH of the reaction mass was adjusted to 1 to 2 with dilute hydrochloric acid solution (60 g of HCl in 600 ml of purified water).The temperature of the resulting mass was adjusted to 15-20°C and then stirred for 30 minutes at the same temperature, followed by adjusting the pH of the resulting mass to above 9 with dilute ammonia solution (200 ml of ammonia in 200 ml of purified water). To the resulting mass, purified water (500 ml) and ethyl acetate (1000 ml) were added at room temperature, stirred the resulting mass for 30 minutes and then settled the reaction mass for 30 minutes at the same temperature. The upper organic layer and the bottom aqueous layer were separated. Purified water (700 ml) and ethyl acetate (600 ml) were added to the aqueous layer and then stirred for 30 minutes at 25-35°C, followed by separation of the layers. The organic layers were combined, followed by the addition of a solution of sodium chloride (30 g) in purified water (600 ml) and then stirring for 30 minutes at 25-35°C. The layers were separated and then distilled off the solvent completely from the resulting organic layer under vacuum at 45-50°C. The organic layer was cooled to 35-40°C, followed by the addition of ethanol (600 ml) at the same temperature and then stirring the mass for 10 minutes at the same temperature. The resulting mass was further cooled to 25-30°C, 48% hydrobromic acid solution (54 g) was slowly added and then stirred for about 40-50 minutes at the same temperature. The resulting mass was cooled to 0-5°C and then stirred for 2 hours at the same temperature. The separated solid was filtered and the bed was washed with pre-cooled ethanol (200 ml) and then suck dried thoroughly till the mother liquors expelled out completely. The resulting wet material was dried at 47-53°C for about 4 hours to produce Vonoprazan hydrobromide [Content of Nitrosamine Impurity: 0.725ppm].
Step-2: Preparation of crude Vonoprazan Fumarate
To the resulting dried compound, purified water (350 ml) and ethyl acetate (500 ml) were added, followed by adjusting the pH of the reaction mass to above 9.5 with aqueous ammonia solution (about 110 ml) at 25-35°C and then stirring for 30 minutes at the same temperature. The layers were separated and the organic layer was kept aside. Ethyl acetate (500 ml) was added to the aqueous layer and the resulting mixture was stirred for 25-35 minutes at 25-35°C. The layers were separated and the organic layer was combined with the previous organic layer, followed by the addition of a solution of sodium chloride (30 g) in purified water (600 ml) and then stirring the resulting mass for 20-30 minutes at 25-35°C. The layers were separated and the resulting organic layer was distilled under vacuum for complete removal of the solvent at below 50°C. To the resulting mass, ethyl acetate (315 ml) and dimethyl acetamide (720 ml) were added at below 50°C, followed by the addition of fumaric acid (28.6 g) at 47-53°C and then stirring the mass for 3 hours at the same temperature. The resulting mass was cooled to 25-30°C and then stirred for 3 hours at the same temperature. The separated solid was filtered and washed the bed with a mixture of ethyl acetate (50 ml) and dimethyl acetamide (100 ml). The bed was further washed with ethyl acetate (100 ml) and then suck dried thoroughly till mother liquors expelled out completely. The resulting material was dried in vacuum oven at 25-35°C for 2 to 3 hours and then further dried at 47-53°C for 5 to 6 hours to produce 90.2g of crude Vonoprazan fumarate as a white to off white or light brown color powder [Purity by HPLC: 99.73%].
Content of Nitrosamine Impurity (Impurity-A) by HPLC-MS: 0.211 ppm (i.e., 211 ppb).
Content of known impurities by HPLC: Impurity-B: 0.01%; Impurity-C: 0.03%; Impurity-E: Below Limit Detection (BLD); Impurity-F: 0.08%; Impurity-G: 0.01%.

Example 3
Preparation of pure Vonoprazan fumarate (crystalline Form A)
Methanol (1250 ml) and purified water (1250 ml) were added to crude Vonoprazan fumarate (100 g, obtained in Example 2) at room temperature. The resulting mass was heated to 50-56°C and then stirred for 10-15 minutes at the same temperature to form a clear solution. To the resulting solution, activated carbon (5 g) was added at50-56°C and then stirred for 10-20 minutes at the same temperature. The resulting mass was filtered through hyflo bed and washed the bed with hot mixture of methanol (100 ml) and purified water (100 ml). The filtrate was cooled to 25-35°C and then stirred for 1 hour at the same temperature. The resulting mass was further cooled to 0-6°C and the stirred for 2 hours at the same temperature. The resulting mass was filtered, washed the bed with a pre-cooled solution of aqueous methanol (75 ml of methanol in 75 ml of purified water). The bed was suck dried thoroughly till mother liquors expelled out completely. The resulting solid was dried in a vacuum tray drier at 25-35°C for 2 hours and then further dried at 47-53°C for 6 hours to produce 80 g of highly pure Vonoprazan fumarate as a white color powder [Purity by HPLC: 99.9%; and Water content by KF: 0.20%w/w; XRPD, IR and DSC data are depicted in Figures 1, 2 and 3 respectively; The exemplary Particle size distribution (PSD) Histogram is depicted in Figure 4].
1H-NMR [400 MHZ, DMSO-d6 in d (ppm)]:10.56 (br, 2-OH), 10.56 (br, NH), 8.88-8.87 (dd, 1H), 8.56-8.55 (d, 1H), 7.88-7.86 (m, 1H),7.77 (d, 1H), 7.62-7.59 (m, 1H), 7.53-7.51 (m, 1H), 7.24-7.22 (m, 1H), 7.21-7.19 (m, 1H), 7.11-7.09 (dt, 1H), 6.50 (d, 1H), 6.48 (s, 2H), 3.91 (s, 2H), 2.45 (s, 3H); 13C-NMR [400 MHZ, DMSO-d6 in d (ppm)]: 168.57, 161.43-158.97, 155.06, 146.88, 135.27, 134.73, 134.16, 132.70, 131.80-131.72, 128.39, 124.56, 123.91, 120.19, 118.44-118.31, 118.31, 115.40-115.19, 43.47, 31.70.
Content of Nitrosamine Impurity (Impurity-A) by HPLC-MS: 0.034 ppm (i.e., 34 ppb)
Content of known impurities by HPLC: Impurity-B: BLD; Impurity-C: BLD; Impurity-F: 0.07%; Impurity-G: BLD.
PSD of the Vonoprazan Fumarate obtained in Experiment No.1: D(90) = 294.68 µm, D(50) = 144.79 µm and D(10) = 40.96 µm, Specific Surface Area: 80.45 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Experiment No.2: D(90) = 265.94 µm, D(50) = 135.86 µm and D(10) = 39.11 µm, Specific Surface Area: 75.37 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Experiment No.3: D(90) = 322.54 µm, D(50) = 157.76 µm and D(10) = 44.00 µm, Specific Surface Area: 75.43 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Experiment No.4: D(90) = 275.31 µm, D(50) = 136.16 µm and D(10) = 38.83 µm, Specific Surface Area: 88.67 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Experiment No.5: D(90) = 271.88 µm, D(50) = 137.76 µm and D(10) = 39.66 µm, Specific Surface Area: 86.41 m2/kg.

Example 4
The Particle size of the Vonoprazan Fumarate material (obtained as per the process exemplified in example 3) was further reduced by being passed through a Pulverizer (Make: Sri Magaa Enterprises; Material of Construction: SS316; Capacity: 8”/4”) having Mesh size: 0.5 mm and collected the material into double lined bags [The exemplary PSD Histogram is depicted in Figure 5].
PSD of the Vonoprazan Fumarate obtained in Pulverization Trial-1: D(90) = 42.6 µm, D(50) = 16.0 µm and D(10) = 6.21 µm, Specific Surface Area: 473.6 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Pulverization Trial-2: D(90) = 42.6 µm, D(50) = 14.8 µm and D(10) = 5.56 µm, Specific Surface Area: 511.2 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Pulverization Trial-3: D(90) = 42.8 µm, D(50) = 15.9 µm and D(10) = 6.18 µm, Specific Surface Area: 475.3 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Pulverization Trial-4: D(90) = 43.5 µm, D(50) = 15.7 µm and D(10) = 6.11 µm, Specific Surface Area: 477.2 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Pulverization Trial-5: D(90) = 41.9 µm, D(50) = 13.7 µm and D(10) = 5.10 µm, Specific Surface Area: 547.7 m2/kg.

Example 5
Micronization of Vonoprazan Fumarate
Micronization of Vonoprazan Fumarate (obtained as per the process exemplified in example4) was performed with Micronizer (Model: M-200; Make: Microtech Engineering Company; Material of Construction: SS316). The following working parameters were used for the micronization: Micronization Limit: 4 - 6.5kg/cm2; Micronization pressure range: 2.0 - 4.5kg/cm2; RPM: 10-30. Each micronization trial was performed on at least 2 kgs of Vonoprazan Fumarate using this equipment and working parameters and the micronized material was collected into double lined bags. The micro particles of Vonoprazan fumarate comply with the following particle size specification: the D90 is less than 15 µm (for example 7 to 14 µm), the D50 is less than 10 µm (for example 4 to 10 µm), and the D10 is less than 7 µm (for example 2 to 7 µm). The Specific Surface Area of the obtained Vonoprazan fumarate material is greater than about 800 m2/kg (for example between 600 and 1400 m2/kg) [The exemplary PSD Histogram is depicted in Figure 6].
PSD of the Vonoprazan Fumarate obtained in Micronization Trial-1: D(90) = 11.0 µm, D(50) = 6.29 µm and D(10) = 3.37 µm, Specific Surface Area: 1019 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Micronization Trial-2: D(90) = 10.7 µm, D(50) = 6.24 µm and D(10) = 3.41 µm, Specific Surface Area: 1022 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Micronization Trial-3: D(90) = 9.85 µm, D(50) = 5.42 µm and D(10) = 2.92 µm, Specific Surface Area: 1174 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Micronization Trial-4: D(90) = 9.88 µm, D(50) = 5.44 µm and D(10) = 2.93 µm, Specific Surface Area: 1170 m2/kg.
PSD of the Vonoprazan Fumarate obtained in Micronization Trial-5: D(90) = 10.5 µm, D(50) = 5.86 µm and D(10) = 3.13 µm, Specific Surface Area: 1096 m2/kg.

Example 6
Vonoprazan Fumarate (obtained as per the process exemplified in example 3) was fine-milled by being passed through a grinder (Make: Preethi, Model: Galaxy 750W-MG 225) having stainless steel liquidizing blade for about 2 to 6 minutes to obtain 90 volume-% (D90) of the particles of Vonoprazan Fumarate having a diameter of less than or equal to about 100 µm.
PSD of the Vonoprazan Fumarate obtained in Milling Trial-1: D(90) = 28.4 µm, D(50) = 9.6 µm and D(10) = 3.3 µm.
PSD of the Vonoprazan Fumarate obtained in Milling Trial-2: D(90) = 80.6 µm, D(50) = 23.6 µm and D(10) = 4.7 µm.
PSD of the Vonoprazan Fumarate obtained in Milling Trial-3: D(90) = 56.4 µm, D(50) = 17.1 µm and D(10) = 4.4 µm.

Example 7
Preparation of N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine (Vonoprazan nitrosamine compound or Nitrosamine impurity or Impurity-A)
Purified water (100 ml), concentrated hydrochloric acid (100 ml) and methylene dichloride (1000 ml) were taken into a reaction flask at 25-30°C. The resulting mixture was cooled to 0-6°C, followed by the addition of a solution of crude Vonoprazan (100 g) in dichloromethane (100 ml) and then stirring for 5-15 minutes at the same temperature. To the resulting mass, a solution of sodium nitrite (25.2 g) in purified water (100 ml) was slowly added at 0-6°C. The temperature of the resulting mass was raised to 25-30°C and then stirred for 18 hours. After completion of reaction, purified water (1000 ml) and dichloromethane (1000 ml) were added to the resulting mass at 25-30°C and stirred for 25-35 minutes at the same temperature. The layers were separated and the organic layer was kept aside. Dichloromethane (600 ml) was added to the aqueous layer and stirred for about 20-30 minutes at 25-35°C. The layers were separated. The combined organic layers were taken into a reaction flask and purified water (1000 ml) was added. The resulting mass was stirred at 25-35°C for about 20-30 minutes. The layers were separated and the solvent was distilled off from the organic layer at below 40°C. The resulting mass was cooled to 25-30°C, followed by the addition of hexane (400 ml) and then stirring for 30 minutes at the same temperature. The solid obtained was filtered, washed the bed with hexane (200 ml), dried the material at 25-35°C for about 2 hours and then further dried at 45-50°C for about 6 hours. Hexane (500 ml) and ethyl acetate (500 ml) were added to the resulting dried compound at 25-30°C and then stirred for about 30 minutes at the same temperature. The solid obtained was filtered, washed the bed with hexane (200 ml), dried the material at 25-35°C for about 2 hours and then further dried the material at 45-50°C for about 6 hours to obtain 80 g of Vonoprazan nitrosamine compound.
The Vonoprazan nitrosamine compound is characterized by the following data: 1H NMR (300 MHz, DMSO-d6) d(ppm): 8.88-8.87 (dd, 1H), 8.62-8.61 (d, 1H), 7.92-7.89 (m, 1H), 7.64-7.60 (m, 1H), 7.76 (s, 1H), 7.54-7.49 (m, 1H), 7.24-7.23 (m, 1H), 7.21-7.20 (m, 1H), 7.16-7.12 (dt, 1H), 6.38 (d, 1H), 5.21 (s, 2H), 2.92 (s, 3H); 13C NMR: 161.30-158.85, 154.99, 146.83, 134.68, 134.05, 132.62, 131.67-131.59, 129.08, 124.50, 123.84, 123.32, 122.82, 118.47-118.32, 117.39, 115.29-115.08, 49.02, 30.98; MS: EI+ m/z (M+H)+: 375.1; and IR spectra on KBr pellet having absorption bands at about 3137, 3095, 3040, 2930, 1689, 1621, 1575, 1564, 1469, 1423, 1381, 1335, 1227, 1263, 1180, 1126, 1109, 850, 819 and 743 cm-1.

Example 8
Preparation of Bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine (Dimer Compound or Dimer impurity or Impurity-B)
Toluene (500 ml) and sodium borohydride (25 g) were taken into a reaction flask at 25-35°C. The resulting mixture was cooled to 5-15°C, followed by the slow addition of acetic acid (127 g) at the same temperature. Adjust the temperature of the reaction mass to 25-30°C and then stirred for 18 hours at the same temperature. To the resulting mass, 5-(2-fluoro-phenyl)-1H-pyrrole-3-carbaldehyde (100 g) and [5-(2-fluoro-phenyl)-1H-pyrrol-3-ylmethyl]-methyl amine (129.4 g) were added at 25-30°C and stirred for 3 hours at the same temperature. After completion of the reaction, a solution of hydrochloric acid (60 g) in purified water (600 ml) was added and maintained the pH of the reaction mass at about 1 to 2. The temperature of the resulting mass was adjusted to 15-20°C and stirred for 30 minutes at the same temperature. To the resulting mass, a solution of ammonia (200 ml) in purified water (200 ml) was added and adjusted the pH of the reaction mass at above 9. To the resulting mixture, purified water (500 ml) and ethyl acetate (1000 ml) were added at below 30°C and stirred for 25-35 minutes at the same temperature. The layers were separated and the organic layer was kept aside. Ethyl acetate (600 ml) was added to the aqueous layer and stirred the mixture for 20-30 minutes at 25-35°C. The layers were separated. The combined organic layers were taken into a separate reaction flask and a solution of sodium bisulphate (25 g) in purified water (250 ml) was added at 25-35°C and stirred for 20-30 minutes at the same temperature. The layers were separated. A solution of sodium chloride (30 g) in purified water (600 ml) was added to the organic layer and stirred for 20-30 minutes at 25-35°C. The layers were separated and the organic layer was distilled under vacuum below 50°C for the complete removal of the solvent. The resulting mass was cooled to 25-30°C followed by the addition of hexane (200 ml) and stirred for 15-45 minutes at the same temperature. The solid obtained was filtered, the bed was washed with hexane (100 ml) and the material was dried at 25-35°C for 2 hours and further dried at 45-50°C for about 6 hours to produce 70 g of bis-[5-(2-fluoro-phenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine as an off white to brown colour solid.
The dimer compound is characterized by the following data: 1H NMR (300 MHz, DMSO-d6) d(ppm): 9.24 (br, NH), 7.64-7.59 (m, 2H), 7.13-7.04 (m, 6H), 6.93 (br, 2H), 6.65 (br, 2H), 3.69 (s, 4H), 2.35 (s, 3H); 13C NMR: 159.73-157.31, 127.09-127.01, 127.01, 124.63, 119.94, 118.04, 116.25-116.02, 109.4, 52.23, 40.06; MS: EI+ m/z (M+H)+: 378.1; and IR spectra on KBr pellet having absorption bands at about 3247, 2962, 1615, 1575, 1517, 1489, 1459, 1261, 1216, 1105, 813 and 754 cm-1.

Example 9
Preparation of N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine as a fumarate salt
Methanol (500 ml) and 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde (100 g) were taken into a reaction flask at 25-30°C, followed by the addition of dimethylamine (34% in methanol) (52.18 g) and then stirring the mass for 25-35 minutes at the same temperature. The resulting mass was cooled to 0-5°C, followed by the slow addition of sodium borohydride (4.58 g) and then stirring the mass for 1 hour at the same temperature. After completion of reaction, a solution of hydrochloric acid (60 g) in purified water (600 ml) was added and adjusted the pH of the reaction mass at about 1 to 2. The temperature of the resulting mass was adjusted to 15-20°C and stirred for 25-35 minutes at the same temperature. To the resulting mass, a solution of ammonia (200 ml) in purified water (200 ml) was added and maintained the pH of the reaction mass at above 9. To the resulting mixture, water (500 ml) and ethyl acetate (1000 ml) were added at below 30°C and then stirred for 25-35 minutes at the same temperature. The layers were separated and the organic layer was kept aside. Purified water (700 ml) and ethyl acetate (600 ml) were added to the aqueous layer and stirred the mixture for 20-30 minutes at 25-35°C. The layers were separated. The combined organic layers were taken into a separate reaction flask and a solution of sodium chloride (30 g) in purified water (600 ml) was added at 25-35°C. The layers were separated and the combined organic layers were distilled under vacuum at below 50°C for the complete removal of the solvent, followed by the addition of ethyl acetate (500 ml) at the same temperature. The reaction mass temperature was adjusted to 47-53°C, followed by the addition of fumaric acid (35.13 g) and then stirring the mass for 2 hours at the same temperature. The temperature of the resulting mass was cooled to 25-30°C and stirred for 3 hours at the same temperature. The solid obtained was filtered, washed the bed with ethyl acetate (100 ml), dried the material at 25-35°C for about 2 hours and further dried at 47-53°C for 6 hours at 47-53°C to produce 72.5 g of [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethylamine fumarate as an off-white colour solid.

Example 10
Preparation of [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol
Methanol (500 ml) and 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde (100 g) were taken into a reaction flask at 25-30°C. The resulting mass cooled to 0-5°C, followed by the slow addition of sodium borohydride (6.0 g) and then stirring the mass for 1 hour at the same temperature. After completion of reaction, a solution of hydrochloric acid (60 g) in purified water (600 ml) was added and maintained the pH of the reaction mass at about 1 to 2. The temperature of the resulting mass was adjusted to 15-20°C, and stirred for 25-35 minutes at the same temperature. To the resulting mass, a solution of ammonia (200 ml) in purified water (200 ml) was added and maintained the pH of the reaction mass at above 9. To the resulting mixture, water (500 ml) and ethyl acetate (1000 ml) were added at below 30°C and stirred for 25-35 minutes at the same temperature. The layers were separated and the organic layer was kept aside. Water (700 ml) and ethyl acetate (600 ml) were added to the aqueous layer and stirred the mixture for 20-30 minutes at 25-35°C. The layers were separated. The combined organic layers were taken into a separate reaction flask and a solution of sodium chloride (30 g) in water (600 ml) was added at 25-35°C. The layers were separated and the combined organic layers were distilled under vacuum at below 50°C for the complete removal of the solvent, followed by the addition of hexane (200 ml) at the same temperature. The resulting mass was distilled at below 50°C for the complete removal of the solvent and the mass obtained was cooled to 25-35°C to obtain 80 g of [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol as a brown colour semi-solid.
, Claims:We Claim:
1. A highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G, wherein the impurities are characterized having the following chemical names:
Impurity A: N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine;
Impurity B: Bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine;
Impurity C: N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methylamine;
Impurity D: Pyridine-3-sulfonic acid;
Impurity E: 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde;
Impurity F: N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine;
Impurity G: [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol; and wherein the highly pure Vonoprazan fumarate is having the chemical purity of about 99.8% to about 99.99% as measured by HPLC; and comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.3 ppm (300 ppb) as measured by HPLC-MS/MS, and the impurities B, C, D, E, F and/or G, each one, in an amount of less than 0.1% as measured by HPLC.
2. The compound as claimed in claim 1, wherein the Vonoprazan fumarate comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.1 ppm (100 ppb) as measured by HPLC-MS/MS, and the impurities B, C, D, E, F and/or G, each one, in an amount of less than 0.05% as measured by HPLC.
3. The compound as claimed in claim 1, wherein the Vonoprazan fumarate comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.04 ppm (40 ppb) as measured by HPLC-MS/MS, and the impurities B, C, D, E, F and/or G, each one, in an amount of less than 0.01% as measured by HPLC.
4. A process for the preparation of highly pure Vonoprazan of formula (I):

or its fumarate salt substantially free of the impurities A, B, C, D, E, F and/or G; which comprises:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II:

or a salt thereof with pyridine-3-sulfonyl chloride of formula III:

or a salt thereof, in the presence of an organic base and a catalyst in a ketone solvent to produce 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV:

(b) reacting the compound of formula IV with monomethylamine in an alcohol solvent to produce a reaction mass containing the intermediate compound, N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethylene]-methylamine, of formula V:

(c) combining the reaction mass containing the compound of formula V obtained in step-(b) with a suitable reducing agent to produce Vonoprazan free base of formula I;
(d) dissolving the Vonoprazan free base obtained in step-(c) in a suitable solvent and then adding aqueous hydrobromic acid solution to produce a reaction mass containing the Vonoprazan hydrobromide;
(e) isolating the crystalline form of Vonoprazan hydrobromide salt by cooling the reaction mass obtained in step-(d) to a temperature of below 15ºC;
(f) neutralizing the Vonoprazan hydrobromide salt obtained in step-(e) with a base in a suitable solvent while adjusting the pH of the resulting mass to above 9 to produce pure Vonoprazan free base;
(g) converting the Vonoprazan free base obtained in step-(f) into Vonoprazan fumarate salt by treating with fumaric acid in a suitable solvent or a mixture of suitable solvents; and
(h) purifying the Vonoprazan fumarate salt obtained in step-(g) with a suitable solvent or a mixture of suitable solvents to produce highly pure Vonoprazan fumarate substantially free of the impurities.
5. The process as claimed in claim 4, wherein the ketone solvent used in step-(a) is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof; wherein the organic base used in step-(a) is selected from the group consisting of diethylamine, diisopropyl amine, diisopropylethylamine, triethylamine, and mixtures thereof; wherein the catalyst used in step-(a) is selected from the group consisting of N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine, hydroxybenzotriazole, and mixtures thereof; wherein the reaction in step-(a) is carried out at a temperature of above about 25°C; wherein the pH of the reaction mass obtained in step-(a) is adjusted to 4 to 5 with an acid and further adjusting the pH of the resulting mass to above 8 with an inorganic base to produce compound of formula IV; wherein the monomethylamine used in step-(b) is in form of an aqueous monomethylamine or a solution of monomethylamine in an alcohol; wherein the alcohol solvent used in step-(b) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, and mixtures thereof; wherein the reducing agents used in step-(c) is selected from the group consisting of sodium borohydride, potassium borohydride sodium cyanoborohydride, sodium triacetoxy borohydride, nickel borohydride, zinc borohydride and lithium aluminium hydride; wherein the reaction in step-(c) is carried out at a temperature of below about 10°C; wherein the solvent used for dissolving the Vonoprazan free base in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, 2-butanone, methyl isobutyl ketone, and mixtures thereof; wherein the dissolution in step-(d) is carried out at a temperature of about 30ºC to about 50ºC; wherein the addition of aqueous hydrobromic acid solution to the solution of Vonoprazan free base in step-(d) is carried out slowly at a temperature of about 20°C to about 30°C; wherein the reaction mass in step-(e) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; wherein the isolation of the pure crystalline form of Vonoprazan hydrobromide salt in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, drying, or a combination thereof; wherein the neutralization in step-(f) is carried out at a temperature of about 25ºC to about 35ºC and pH of the reaction mass is adjusted to above 9.5; wherein the solvent used in step-(f) is selected from the group consisting of water, ethyl acetate, propyl acetate, butyl acetate, and a mixture thereof; wherein the inorganic base used for adjusting the pH of the reaction mass in step-(f) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof; wherein the solvent used in step-(g) is selected from the group consisting of an ester solvent, a polar aprotic solvent or a mixture thereof; wherein the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of above 35ºC; wherein the purification of Vonoprazan fumarate in step-(h) is carried out by the methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof; wherein the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and an alcohol solvent; and wherein the Vonoprazan fumarate obtained in step-(h) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C.
6. The process as claimed in claim 5, wherein the ketone solvent used in step-(a) is acetone; wherein the organic base used in step-(a) is diisopropylethylamine; wherein the catalyst used in step-(a) is 4-dimethylaminopyridine; wherein the reaction in step-(a) is carried out at a temperature of about 25°C to about 55°C; wherein the acid used for adjusting the pH of the reaction mass obtained in step-(a) is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, tartaric acid, acetic acid and mixtures thereof; wherein the inorganic base used for adjusting the pH of the resulting mass in step-(a) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof; wherein the monomethylamine used in step-(b) is a solution of monomethylamine in methanol; wherein the alcohol solvent used in step-(b) is methanol; wherein the reducing agent used in step-(c) is sodium borohydride; wherein the reaction in step-(c) is carried out at a temperature of about -10°C to about 10°C; wherein the solvent used for dissolving the Vonoprazan free base in step-(d) is ethanol; wherein the dissolution in step-(d) is carried out at a temperature of about 35ºC to about 40ºC; wherein the addition of aqueous hydrobromic acid solution is carried out drop wise or in one portion or in more than one portion; wherein the reaction mass in step-(e) is cooled to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; wherein the solvent used in step-(f) is a mixture of water and ethyl acetate; wherein the inorganic base used for adjusting the pH of the reaction mass in step-(f) is aqueous ammonia solution; wherein the solvent used in step-(g) is selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate, dimethylformamide, dimethylacetamide and mixtures thereof; wherein the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of about 45ºC to about 55ºC; wherein the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and methanol; and wherein the Vonoprazan fumarate obtained in step-(h) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 35°C to about 65°C.
7. The process as claimed in claim 6, wherein the acid used for adjusting the pH of the reaction mass obtained in step-(a) is aqueous hydrochloric acid; wherein the inorganic base used for adjusting the pH of the resulting mass in step-(a) is aqueous sodium bicarbonate solution; wherein the reaction in step-(c) is carried out at a temperature of about -5°C to about 5°C; wherein the reaction mass in step-(e) is cooled to a temperature of about 0°C to about 6°C while stirring for about 2 hours to 3 hours; and wherein the solvent used in step-(g) is a mixture of ethyl acetate and dimethylacetamide.
8. A process for the preparation of highly pure Vonoprazan fumarate substantially free of the impurities A, B, C, D, E, F and/or G; which comprises:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II or a salt thereof, with pyridine-3-sulfonyl chloride of formula III or a salt thereof in the presence of an organic base and a catalyst in acetone solvent to produce a reaction mass, followed by adjusting the pH of the reaction mass to 4 to 5 with aqueous hydrochloric acid solution and further adjusting the pH of the resulting mass to above 8 with aqueous sodium bicarbonate solution to produce 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV;
(b) reacting the compound of formula IV obtained in step-(a) with monomethylamine in an alcohol solvent to produce a reaction mass containing the compound, N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethylene]-methylamine, of formula V;
(c) combining the reaction mass obtained in step-(b) with sodium borohydride to produce a reaction mass, followed by adjusting the pH of the reaction mass to 1 to 2 with an acid and further adjusting the pH of the resulting mass to above 9 with an inorganic base to produce Vonoprazan free base;
(d) dissolving the Vonoprazan free base obtained in step-(c) in a suitable solvent and then adding aqueous hydrobromic acid solution to produce a reaction mass containing the Vonoprazan hydrobromide;
(e) isolating the crystalline form of Vonoprazan hydrobromide salt by cooling the reaction mass obtained in step-(d) to a temperature of below 15ºC, wherein the crystalline form of Vonoprazan hydrobromide is characterized by an X-ray powder diffraction pattern having two or more 2-theta peaks at about 11.48, 13.94, 15.18, 15.58, 16.67, 18.45, 18.70, 19.67, 22.04, 23.14, 24.43 and 25.39 ± 0.2 degrees substantially in accordance with Figure 7;
(f) neutralizing the Vonoprazan hydrobromide salt obtained in step-(e) with a base in a suitable solvent while adjusting the pH of the resulting mass to above 9 to produce pure Vonoprazan free base;
(g) converting the Vonoprazan free base obtained in step-(f) into Vonoprazan fumarate salt by treating with fumaric acid in a suitable solvent or a mixture of suitable solvents; and
(h) purifying the Vonoprazan fumarate salt obtained in step-(g) with a suitable solvent or a mixture of suitable solvents to produce highly pure Vonoprazan fumarate substantially free of the impurities.
9. The process as claimed in claim 8, wherein organic base used in step-(a) is selected from the group consisting of diethylamine, diisopropyl amine, diisopropylethylamine, triethylamine, and mixtures thereof; wherein the catalyst used in step-(a) is selected from the group consisting of N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine, hydroxybenzotriazole, and mixtures thereof; wherein the monomethylamine used in step-(b) is in the form of an aqueous monomethylamine or a solution of monomethylamine in an alcohol solvent; wherein the alcohol solvent used in step-(b) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, and mixtures thereof; wherein the reaction in step-(c) is carried out at a temperature of below about 10°C; wherein the acid used for adjusting the pH of the reaction mass obtained in step-(c) is selected from the group consisting of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, tartaric acid, acetic acid and mixtures thereof; wherein the inorganic base used for adjusting the pH of the resulting mass in step-(c) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof; wherein the solvent used for dissolving the Vonoprazan free base in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, tert-butanol, acetone, 2-butanone, methyl isobutyl ketone, and mixtures thereof; wherein the dissolution in step-(d) is carried out at a temperature of about 30ºC to about 50ºC; wherein the addition of aqueous hydrobromic acid solution to the solution of Vonoprazan free in step-(d) is carried out slowly at a temperature of about 20°C to about 30°C; wherein the reaction mass in step-(e) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; wherein the isolation of the highly pure crystalline form of Vonoprazan hydrobromide salt in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation, drying, or a combination thereof; wherein the neutralization in step-(f) is carried out at a temperature of about 25ºC to about 35ºC while adjusting the pH of the resulting mass to above 9.5; wherein the solvent used in step-(f) is selected from the group consisting of water, ethyl acetate, propyl acetate, butyl acetate, and a mixture thereof; wherein the base used for adjusting the pH in step-(f) is an inorganic base selected from the group of consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof; wherein the solvent used in step-(g) is selected from the group consisting of ethyl acetate, propyl acetate, butyl acetate, dimethylformamide, dimethylacetamide and mixtures thereof; wherein the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of above 35ºC; wherein the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and an alcohol solvent; and wherein the Vonoprazan fumarate obtained in step-(h) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C.
10. The process as claimed in claim 9, wherein organic base used in step-(a) is diisopropylethylamine; wherein the catalyst used in step-(a) is 4-dimethylaminopyridine; wherein the monomethylamine used in step-(b) is a solution of monomethylamine in methanol; wherein the alcohol solvent used in step-(b) is methanol; wherein the reaction in step-(c) is carried out at a temperature of about -5°C to about 5°C; wherein the acid used for adjusting the pH of the reaction mass obtained in step-(c) is dilute hydrochloric acid; wherein the inorganic base used for adjusting the pH of the resulting mass in step-(c) is aqueous ammonia solution; wherein the solvent used for dissolving the Vonoprazan free base in step-(d) is ethanol; wherein the dissolution in step-(d) is carried out at a temperature of about 35ºC to about 40ºC; wherein the addition of aqueous hydrobromic acid solution is carried out drop wise or in one portion or in more than one portion; wherein the reaction mass in step-(e) is cooled to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; wherein the solvent used in step-(f) is a mixture of water and ethyl acetate; wherein the inorganic base used in step-(f) is aqueous ammonia solution; wherein the solvent used in step-(g) is a mixture of ethyl acetate and dimethylacetamide; wherein the conversion of Vonoprazan free base into Vonoprazan fumarate in step-(g) is carried out at a temperature of about 45ºC to about 55ºC; wherein the solvent used for purification of Vonoprazan fumarate in step-(h) is a mixture of water and methanol; and wherein the Vonoprazan fumarate obtained in step-(h) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 35°C to about 65°C.
11. A process for the preparation of 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV, comprising:
(a) reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehydeof formula II or a salt thereof, with pyridine-3-sulfonyl chloride of formula III or a salt thereof in the presence of diisopropylethylamine or triethylamine and a catalyst in acetone solvent to produce a reaction mass containing 5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-carbaldehyde of formula IV;
(b) adjusting the temperature of the reaction mass obtained in step-(a) to 25-30°C followed by the addition of water;
(c) adjusting the pH of the reaction mass obtained in step-(b) to about 4 to 5 with a dilute hydrochloric acid solution followed by the addition of water and then stirring the mass at 25-30°C;
(d) cooling the mass obtained in the step-(c) further to below 10°C and then isolating the crude compound of formula IV;
(e) combining the crude compound obtained in step-(d) with an inorganic base while adjusting the pH of the resulting mass to above 8; and
(f) collecting the pure compound of formula IV obtained in step-(e).
12. The process as claimed in claim 11, wherein the catalyst used in step-(a) is selected from the group consisting of N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine, hydroxybenzotriazole, and mixtures thereof; wherein the inorganic base used for adjusting the pH of the resulting mass in step-(f) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, aqueous ammonia, and mixtures thereof; and wherein the collection of the compound of formula IV in step-(f) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
13. The process as claimed in claim 12, wherein the catalyst used in step-(a) is 4-dimethylaminopyridine; and wherein the inorganic base used for adjusting the pH of the resulting mass in step-(f) is aqueous sodium bicarbonate solution.
14. A purification process for the preparation of highly pure crystalline Form A of Vonoprazan fumarate characterized by an X-ray powder diffraction pattern having 2-theta peaks at about 5.1, 10.2, 11.4, 11.7, 12.2, 13.5, 15.1, 15.3, 16.9, 20.4 and 22.4 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infrared absorption spectrum (IR) having two or more characteristic IR bands at about 3433±5, 3135±3, 3010±3, 2806±3, 2757±3, 2593±3, 2520±3, 1698±2, 1637±2, 1575±2, 1563±2, 1526±2, 1471±2, 1418±2, 1373±2, 1282±2, 1229±2, 1175±2, 1033±2, 1018±2, 996±2, 935±2, 903±2, 819±2, 758±2, 749±2 and 700±2 (cm-1) substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having an endotherm peak at about 209.86°C (± 3°C) with an onset temperature at about 206.53°C (±3°C) substantially in accordance with Figure 3, which comprises:
(a) providing a solution of Vonoprazan fumarate in a solvent medium comprising methanol and purified water at a temperature of about 45°C to about 65°C, wherein the quantity of solvent medium employed is about 15 volumes to about 35 volumes with respect to the quantity of Vonoprazan fumarate used;
(b) optionally, subjecting the solution obtained in step-(a) to carbon treatment at reflux temperature to obtain a filtrate;
(c) cooling the solution obtained in step-(a) or step-(b) at a temperature of below about 35°C to cause crystallization; and
(d) collecting the highly pure crystalline Form A of Vonoprazan fumarate formed in step-(c).
15. The process as claimed in claim 14, wherein the amount of solvent medium employed in step-(a) is about 16 volumes to about 32 volumes with respect to the quantity of Vonoprazan fumarate used; wherein the quantity of methanol used in step-(a) is about 0.8 to 1.6 volumes with respect to the volume of purified water used; wherein the solution of Vonoprazan fumarate in step-(a) is prepared by dissolving Vonoprazan fumarate in the solvent medium at a temperature of about 45°C to about 65°C; wherein the crystallization in step-(c) is accomplished by cooling the solution initially to a temperature of about 20°C to about 35°C and the resulting mass is further cooled to a temperature of about -5°C to about 15°C while stirring for at least 10 minutes; wherein the collection of the pure Vonoprazan fumarate in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the Vonoprazan fumarate obtained in step-(d) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C.
16. The process as claimed in claim 15, wherein the amount of solvent medium employed in step-(a) is about 24 volumes to about 26 volumes with respect to the quantity of Vonoprazan fumarate used; wherein the quantity of methanol used in step-(a) is about 1 to 1.2 volumes with respect to the volume of purified water used; wherein the solution of Vonoprazan fumarate in step-(a) is prepared by dissolving Vonoprazan fumarate in the solvent medium at a temperature of about 50°C to about 60°C; wherein the crystallization in step-(c) is accomplished by cooling the solution initially to a temperature of about 25°C to about 30°C and the resulting mass is further cooled to a temperature of about -0°C to about 6°C while stirring for about 20 minutes to about 5 hours; and wherein the Vonoprazan fumarate obtained in step-(d) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 35°C to about 65°C.
17. A highly pure crystalline form of Vonoprazan hydrobromide which is characterized by an X-ray powder diffraction pattern having two or more 2-theta peaks at about 11.48, 13.94, 15.18, 15.58, 16.67, 18.45, 18.70, 19.67, 22.04, 23.14, 24.43 and 25.39 ± 0.2 degrees substantially in accordance with Figure 7; and/or an infrared absorption spectrum (IR) having two or more characteristic IR bands at about 3433±5, 3142±3, 2980±3, 2919±3, 2870±3, 2738±3, 2700±3, 2560±3, 2447±3, 1584±2, 1525±2, 1470±2, 1429±2, 1385±2, 1309±2, 1205±2, 1105±2, 1064±2, 1025±2, 994±2, 821±2, 762±2, 743±2 and 699±2 (cm-1) substantially in accordance with Figure 8; and/or a Differential Scanning Calorimetric (DSC) thermogram having an endotherm peak at about 197.10°C (± 3°C) with an onset temperature at about 193.76°C (± 3°C) substantially in accordance with Figure 9.
18. A process for the preparation of highly pure crystalline form of Vonoprazan hydrobromide, comprising:
a) providing a solution of Vonoprazan free base in ethanol solvent at a temperature of about 30°C to about 50°C;
b) cooling the solution obtained in step-(a) to a temperature of below 30°C;
c) combining the solution obtained in step-(b) with aqueous hydrobromic acid solution at a temperature of about 20°C to about 30°C to produce a reaction mass;
d) cooling the reaction mass obtained in step-(c) further to a temperature of below about 15ºC to cause crystallization; and
e) collecting the highly pure crystalline form of Vonoprazan hydrobromide obtained in step-(c); and optionally converting the Vonoprazan hydrobromide obtained into a highly pure Vonoprazan fumarate salt.
19. The process as claimed in claim 18, wherein the solution in step-(a) is prepared by dissolving Vonoprazan free base in ethanol at a temperature of about 30°C to about 40°C; wherein the solution in step-(b) is cooled to a temperature of about 20°C to about 30°C; wherein the combining of the solution with aqueous hydrobromic acid solution in step-(c) is carried out by adding the aqueous hydrobromic acid solution (48%) slowly to the solution of Vonoprazan free base solution at a temperature of about 20°C to about 30°C; wherein the reaction mass obtained after addition of aqueous hydrobromic acid solution in step-(c) is stirred at a temperature of about 20°C to about 30°C for at least 10 minutes; wherein the reaction mass in step-(d) is cooled to a temperature of about -5°C to about 15°C while stirring for at least 30 minutes; wherein the collection of the highly pure crystalline form of Vonoprazan hydrobromide in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof; and wherein the Vonoprazan fumarate obtained in step-(e) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 30°C to about 100°C.
20. The process as claimed in claim 19, wherein the solution in step-(b) is cooled to a temperature of about 25°C to about 30°C; wherein the addition of aqueous hydrobromic acid solution in step-(c) is carried out drop wise or in one portion or in more than one portion a temperature of about 25°C to about 30°C; wherein the reaction mass obtained after addition of aqueous hydrobromic acid solution in step-(c) is stirred at a temperature of about 25°C to about 30°C for about 20 minutes to about 3 hours; wherein the reaction mass in step-(d) is cooled to a temperature of about 0°C to about 10°C while stirring for about 1 hour to about 6 hours; and wherein the Vonoprazan fumarate obtained in step-(e) is further dried, under reduced pressure, and/or at atmospheric pressure, at a temperature of about 35°C to about 65°C.
21. A highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of less than or equal to about 350 microns, D50 particle size of less than or equal to about 200 microns, and/or the Specific Surface Area of greater than or equal to about 60 m2/kg.
22. A highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of about 5 microns to about 100 microns, D50 particle size of about 3 microns to about 40 microns, and/or the Specific Surface Area of about 350 m2/kg to about 1400 m2/kg.
23. A highly pure Vonoprazan fumarate substantially free of impurities for use in the manufacture of pharmaceutical compositions, wherein the Vonoprazan fumarate has a D90 particle size of about 8 microns to about 60 microns, D50 particle size of about 4 microns to about 25 microns, and/or the Specific Surface Area of about 400 m2/kg to about 1200 m2/kg.
24. A pharmaceutical composition comprising the highly pure Vonoprazan fumarate substantially free of impurities obtained by the processes as claimed in claims 4, 8 and/or 14, and one or more pharmaceutically acceptable excipients.
25. A pharmaceutical composition comprising the highly pure Vonoprazan fumarate substantially free of impurities as claimed in claims 1, 2 and/or 3, and one or more pharmaceutically acceptable excipients.
26. A pharmaceutical composition comprising the highly pure Vonoprazan fumarate substantially free of impurities and one or more pharmaceutically acceptable excipients, wherein the Vonoprazan fumarate has a D90 particle size of less than or equal to about 350 microns, D50 particle size of less than or equal to about 200 microns, and/or the Specific Surface Area of greater than or equal to about 60 m2/kg.
27. A pharmaceutical composition comprising the highly pure Vonoprazan fumarate substantially free of impurities and one or more pharmaceutically acceptable excipients, wherein the Vonoprazan fumarate has a D90 particle size of about 5 microns to about 100 microns, D50 particle size of about 3 microns to about 40 microns, and/or the Specific Surface Area of about 350 m2/kg to about 1400 m2/kg.
28. A pharmaceutical composition comprising the highly pure Vonoprazan fumarate substantially free of impurities and one or more pharmaceutically acceptable excipients, wherein the Vonoprazan fumarate has a D90 particle size of about 8 microns to about 60 microns, D50 particle size of about 4 microns to about 25 microns, and/or the Specific Surface Area of about 400 m2/kg to about 1200 m2/kg.
29. A highly pure Vonoprazan fumarate comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.3 ppm (300 ppb) or less than 0.2 ppm (200 ppb) as measured by HPLC-MS/MS.
30. A highly pure Vonoprazan fumarate comprising the nitrosamine impurity (Impurity-A) in an amount of less than 0.1 ppm (100 ppb) or less than 0.04 ppm (40 ppb) as measured by HPLC-MS/MS.
31. A process for the preparation of Vonoprazan nitrosamine compound, N-[5-(2-Fluorophenyl)-1-(3-pyridinylsulfonyl)-1H-pyrrole-3-ylmethyl]-N-methyl-nitrosamine, of formula A, which comprises reacting Vonoprazan free base with sodium nitrite in the presence of concentrated hydrochloric acid in a solvent medium comprising water and dichloromethane.
32. A dimer compound, bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine, of formula B:

or a salt thereof.
33. A process for the preparation of the dimer compound, bis-N-[5-(2-Fluorophenyl)-1H-pyrrol-3-ylmethyl]-methyl-amine, of formula B or a salt thereof comprising reacting 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde of formula II or a salt thereof with [5-(2-Fluoro phenyl)-1H-pyrrol-3-ylmethyl]-methylamine of formula C or a salt thereof in the presence of sodium borohydride and acetic acid in toluene solvent.
34. A process for the preparation of the dimethyl-vonoprazan compound (Impurity-F), N-[5-(2-Fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-ylmethyl]-dimethyl-amine, of formula F comprising reacting 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde of formula IV with sodium borohydride and dimethylamine in methanol solvent followed by the addition of fumaric acid.
35. A process for the preparation of Vonoprazan alcohol compound (Impurity-G), [5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-methanol, of formula G comprising reacting 5-(2-Fluoro-phenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-carbaldehyde of formula IV with sodium borohydride using methanol solvent.