Specification
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10; Rule 13)
TITLE
A PROCESS FOR PREPARING FORM A OF (S)-5-METHOXY-2-[[(4-METHOXY-3,5-DIMETHYL-2-PYRIDINYL)-METHYL]SULFINYL]-1H-BENDIMIDAZOLE MAGNESIUM DIHYDRATE
APPLICANT
CIPLA LIMITED
NATIONALITY: INDIA
OF 289 BELLASIS ROAD, MUMBAI CENTRAL,
MUMBAI 400008, MAHARASHTRA
INDIA
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
This application is divided out of Indian application no. 1579/MUMNP/2009
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of polymorphic Form A of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-
benzimidazole magnesium dihydrate i.e. esomeprazole magnesium dihydrate, a novel polymorph of the intermediate 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyI] thio]-1H-benzimidazoIe and its synthesis.
BACKGROUND OF THE INVENTION
Omeprazole is chemically termed as 5-methoxy-2-[[(4-methoxy-3]5-dimethyl-2--pyridinyl)
methyI]suIfinyl]-1H-benzimidazoie. The S-enantiomer is chemically known as (S)-5-
methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H- benzimidazole and
hence named "esomeprazoie". The magnesium salt of esomeprazoie is represented by formula I.
Esomeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-EIIison syndrome. Esomeprazole is the S-enantiomer of omeprazole (marketed as Losec/Prilosec).
A process for asymmetric oxidation of sulphides to sulfoxides has been developed by Kagan and co-workers (J. Am. Chem. Soc. 1984; 106, 8188-8193), the oxidation is performed by using tert-butyl hydroperoxide (TBHP) as oxidizing agent in the presence of one equivalent of a chiral complex.
Various metal catalysed enantioselective oxidations or stoichiometric transrtion-metai-promoted reactions are described in the literature to prepare chiral sulfoxides by oxidation of the corresponding sulphides (Kagan H.B. In Catalytic Asymmetric Synthesis; Madesclaire M. Tetrahedron 1986; 42, 5459-5495; Procter D.J Chem. Soc Perkin Trans 1999; 835-872; Fernandez et. AL, Chem Review 2002; 2002). Metal catalysed enantioselective oxidations involve a metal catalyst complexed with a chiral ligand such as diethyl tartrate, trialkanolamine titanium (IV) complex, zirconium (IV) complexes etc. in the presence of various oxidants.
Omeprazole and therapeutically acceptable salts thereof, are first disclosed in EP 5129 and US 4255431. The specific alkaline salts of omeprazole are also disclosed in US 4738974, US 5714504 and US 5877192.
The resolution processes of racemates of omeprazole are for example disclosed in DE 4035455 and WO 94/27988.
An enantioselective synthesis of omeprazole by asymmetric oxidation is reported in WO 96/02535 (equivalent patents US 5948789 and EP 0773940), which claims a process for enantioselective synthesis of the sulphoxide either as a single enantiomer or in an enantiometrically enriched form characterized in that a pro-chira! sulphide is oxidized in an organic solvent with an oxidizing agent in the presence of a chiral titanium complex
optionally in the presence of a base, wherein the titanium complex has been prepared in the presence of the pro-chiral sulphide. From the description and the examples of the patent it is clearly understood that the absence of base yields a product having low enantiomeric purity as shown in examples 7 and 8. An excess enantioselectivity is obtained due to the presence of base in the reaction and preparation of the chiral complex in the presence of the pro-chira] sulphide. Examples 6, 7, 8, A, B and C in WO 96/02535 disclose processes for preparing the suiphoxide in the absence of a base. The amount of desired suiphoxide produced in the exemplified processes ranges from 22 to 31%.
Preparations of optically pure sulfoxides are claimed in WO 04/02982. The patent discloses a method of forming transition metal complexes at acid sulfoxide group which is reacted with a chiral acid to form an addition product, followed by separation.
US patent 6369085 discloses various forms of esomeprazole magnesium trihydrate and dihydrate prepared from the corresponding potassium salt
EP 0897386 claims a process for the preparation of the magnesium salt of esomeprazole comprising direct conversion of the suiphoxide to the magnesium salt in the presence of an organic base with a pKa from 7-12 and a magnesium source.
WO 04/046134 discloses crystalline Form II of esomeprazole magnesium trihydrate.
Amorphous esomeprazole magnesium and a process for its preparation are disclosed in patents WO 01/ 87831, WO 04/235903, US 3212274 and WO 06/96709.
WO 05/23797 discloses novel salts of R and S omeprazole.
US 2006-0089386 discloses a process in which sulfoxide derivatives are treated with a chiral acid such as camphor sulfonyl chloride followed by fractional crystallization, deprotection and conversion to a salt.
A similar method is also disclosed in WO 05/116011 and US 6166986 in which benzimidazole sulfide derivatives are reacted with a chiral acid reagent, oxidized, followed by separation of diastereomers, finally deprotection.
US 6369085 discloses esomeprazole magnesium dihydrate Form A and B. The process for preparation of esomeprazole magnesium dihydrate Form A is not industrially efficient as it often results in.the dihydrate being converted to the trihydrate or amorphous esomeprazole magnesium. This process is disadvantageous as the polymorph A of the dihydrate cannot be obtained, consistently as the wet dihydrate gets converted during drying to the trihydrate or amorphous form. Use of acetone to slurry the product and dry, results in an inconsistent polymorph.
Hence there is a need for a robust process for the synthesis of esomeprazole magnesium dihydrate in good yield consistently on a large scale and in a reproducible manner. The present invention provides an industrially suitable process for preparation of esomeprazole magnesium dihydrate. More particularly Form A of esomeprazole magnesium dihydrate.
OBJECTIVES OF THE INVENTION
The object of the present invention is to provide an improved process for the preparation of esomeprazole magnesium dihydrate Form A from oxidizing the intermediate, 5-methoxy-2-[[(4-methoxy-3,5-dimethyi-2-pyridinyl)methyi]thio}-1H-benzimtdazole.
Another object of the present invention is to provide an improved process for the preparation of esomeprazole magnesium dihydrate Form A by oxidizing a novel polymorph of intermediate, 5-methoxy-2H(4-methoxy-3)5-dimethyl-2-pyridinyl)methyr|thio]-1H-benzimidazole.
Another object of the present invention is to provide a consistent process for the preparation of esomeprazole magnesium dihydrate Form A on a large scale.
Another object of the present invention is to provide a process for the preparation of a novel polymorph of 5-methoxy-2[[(4-rnethoxy-3,5-dimethyl-2-pyridiny!)methyrl]thio]-1H-benzimidazole.
Yet another object of the present invention is to provide pharmaceutical compositions comprising a polymorphic form of esomeprazole magnesium dihydrate prepared using the novel processes.
Yet another object of the present invention is to provide therapeutic uses and therapeutic methods of treatment employing compositions comprising a polymorphic form of esomeprazole magnesium dihydrate.
STATEMENTS OF INVENTION
According to a first aspect of the present invention, there is provided Form )i of 5-methoxy-
2-[[(4-methoxy-3,5-dimethyl-2-pyridiny!)-methyI]thio]-1H-benzimidazo]e. In an
embodiment, there is provided Form ll of 5-methoxy-2-[[(4~methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole, having an XRPD pattern with °2θ values, at 20.7, 20.9 and 25.6 ± 0.2 °2θ . The XRPD pattern may nave further peaks at 8.1, 23.0, 25.7 and 29.0 °2θ ± 0.2 °2θ . In an embodiment, there is provided Form U of 5-methoxy-2-[[(4-methoxy-3,5-dimethyi-2-pyridinyl)-methyI]thio]-1H-benzimidazole, having the, XRPD pattern as shown in Figure 2.
According to another aspect of the present invention, there is provided a process for preparing Form ll of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-
benzimidazole comprising crystallising or recrystallising crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazoIe from ethyl acetate, cooling and
isolating the Form ll of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H
benzimidazole. in an embodiment, the crystallisation or recrystallisation from ethyl acetate is carried out at a temperature ranging from 40°C to 70°c, preferably 50°C to 60°C. In an embodiment, the cooling is to a temperature ranging from -10DC to -5°C. Suitably, the
Isolation comprises filtration followed by washing with ethyl acetate. Optionally, the washed Form II of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is dried at a temperature ranging from 3rj°c to 35°C. In an embodiment, the crude 5-memoxy-2-[[(4-methoxy-3l5-dimethyl-2-pyridiny|).methyl]thio]-1 H-benzimidazole is extracted with a suitable organic solvent, such as methylene dichloride, before
recrystallisation
Suitably, the crude 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole is prepared by condensing 2-ch]oromethyi-3,5-dimethyl-4-me£hoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole The condensation may be carried out in the presence of a catalyst such as tetrabutyl ammonium bromide. The condensation may be carried out under basic conditions..
In an embodiment, the 2-chloromethyI-3,5-dimethyi-4-methoxy pyridine hydrochloride is prepared by converting 2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride to 2-chioromethyl-3,5-dimetnyl-4-methoxy pyridine. The 2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride may be converted to 2-chIoromethyl-3,5-dimethyl-4-methoxy pyridine by reaction with a chlorinating agent such as thionyl chloride. The chlorination may be carried out in a suitable organic solvent such as methylene chloride, chloroform or ethylene chloride, preferably methylene chloride. In an embodiment, the chlorination is carried out at a temperature ranging from 10°C to 25°C.
According to another aspect of the present invention, there is provided a process for preparing (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]sulfinyl]-1H-
benzimidazole comprising oxidising 5-methoxy-2-[[(4-methoxy-3,5-dimethy!-2-pyridinyi)-methyl]thio]-1 H-benzimidazole in the absence of a base, the oxidising comprising the
steps of preparing a chiral titanium complex, reacting the chirai tiianium complex with 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidizole and
adding an oxidising agent. Preferably, the oxidising agent is added to the reaction mixture at a temperature ranging from 5°C to 2CTC, preferably 10°C to 15°C. In an embodiment,
> the chiral titanium complex is prepared from D-(-)-diefhyf tartrate and titanium (IV)
isopropoxide. Preferably, the temperature of the reaction mixture during the preparation of
the chiral titanium complex ranges from 20°C to 35°C, preferably 25°C to 30°C.
Preferably, the temperature of the reaction mixture during the step of reacting the chiral
titanium complex with 5-methoxy-2-[[{4-methoxy-3,5-dimethyl-2-pyridinyl)-memyl]thio]-1H-
benzimidazole ranges from 60°C to 80°C, preferably 70 °C to 75aC. In an embodiment, the
oxidising agent is an organic peroxide, preferably cumene hydroperoxide. The oxidising
steps may be carried out in the presence of an organic solvent. Suitably, the solvent is
toluene or dichloromethane. Preferably, the solvent is toluene. Preferably, the reaction
mixture is not stirred after addition of the oxidising agent.
In an embodiment, the 5-methoxy-2-[[(4-methoxy-3)5-dimethyl-2-pyridinyl)-methyI]thio]-1H-benzimidazole is polymorphic Form I or polymorphic Form II. Preferably, the 5-methoxy-2-[[(4-methoxy-3,5-dimethyi~2-pyridinyl)-methyl]thio]-1H-benzimidazole is polymorphic polymorphic Form ll. The Form ll of 5-methoxy-2-n{4-methoxy-3,5-dimethyl-2-pyridinyI}-methyl]thio]-1H-benzimidazoie may be prepared by the process described above.
In an embodiment, the (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyI)-methyl]suifinyI]-1H-benzimidazole as prepared by the process described above is comverted to a salt thereof. Suitably, the salt is an alkali metal salt. Preferably, the alkali metal salt is the potassium salt. The (S)-5-methoxy-2-[[(4-methoxy-3,5Kiimethyl-2-pyridiny])—methyl]sulfinyl]-1 H-benzimidazole may be comverted to the potassium salt in the presence of a potassium source, such as methanolic potassium hydroxide (i.e. a solution of potassium hydroxide in methanol), methanolic potassium methoxide (i.e. a solution of potassium methoxide in methanol) or ethanolic potassium hydroxide (i.e. a solution of potassium hydroxide in ethanol). Preferably, the potassium source is methanolic
potassium hydroxide. The conversion to the potassium salt may be carried out at a temperature below 40°C. Suitably, the conversion is carried out for a period of time less than 5 hours, more preferably less than 3 hours. Optionally, the salt of (S)-5-methoxy-2-[[(4-methoxy-3l5-dimethyi-2-pyridinyI}-methyi]sulfinyl]-1H-benamidazole may be purified, for example by recrystallisation. The recrsytaliisafion may be from acetone and methanol.
In an embodiment, the salt of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H-benzimidazole is converted to (S)-5-methoxy-2-t[(4-methoxy-3s5-dimethyl-2-pyridinyl)-methyl]sulfinyI]-1H-ben2imidazole magnesium dihydrate in the presence of a magnesium source, such as magnesium chloride hexahydrate or magnesium sulphate. Preferably, the magnesium source is magnesium chloride hexahydrate. In an embodiment, the conversion to the magnesium salt is carried out in the absence of an organic base. Suitably, the conversion to the magnesium salt is carried out in an organic solvent, such as methanol, ethanol, denatured spirit, isopropyl alcohol or dimethyl formamide. Optionally, the salt of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyi-2-pyridinyl)-methyl]sulfinyl]-1 H-benzimidazole may be purified before being converted to the magnesium dihydrate, for example by recrystallisation. The recrsytallisation may be from acetone and methanol.
According to another aspect of the present invention, there is provided a process for
preparing Form A of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
methyf]sulfinyl]-1 H-benzimidazole magnesium dihydrate comprising crystallising or
recrystallising crude (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
methyi]sulfinyTj-1 H-benzimidazole magnesium dihydrate in the presence of ethyl acetate.
Surprisingly, it has been found that the use of ethyl acetate during recrystallisation of crude form A of magnesium dihydrate, and optionally stirring the product after recrystallisation, consistently results in form A of magnesium dihydrate in very high yield. The process can be easily carried out on a the laboratory scale as well as industrial scale.
In an embodiment, the crystallisation or recrystallisation is initiated by the addition of a solvent comprising ethyl acetate to the crude (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-
pyridinyl)-methyl]sulfinyl]]-1H-benzimidazole magnesium dihydrate. In an embodiment, the solvent is an ethyl acetate-water mixture. . Preferably, the crystallisation or ■
recrsytaliisation reaction mixture is stirred for a period of time ranging from 10 minutes to 3 -hours, preferably the crystallisation or recrsytaliisation reaction mixture is stirred for a period of time ranging from 15 minutes to 1 hour, more preferably the crystallisation or recrsytaliisation reaction mixture is stirred for a period of time ranging from 15 minutes to 30 minutes. The product of the crystallisation or recrystallisation may be filtered and
washed with ethyl acetate. The crystallised or recrystallised Form A of (S)-5-methoxy-2-
[[(4-methoxy-3,5
Documents
Application Documents
| # |
Name |
Date |
| 1 |
393-MUMNP-2014-HearingNoticeLetter22-08-2019.pdf |
2019-08-22 |
| 1 |
393-MUMNP-2014-MARKED COPY(FORM 1)-(30-11-2015).pdf |
2015-11-30 |
| 2 |
393-MUMNP-2014-CLAIMS [07-12-2018(online)].pdf |
2018-12-07 |
| 2 |
393-MUMNP-2014-GENERAL POWER OF AUTHORITY-(30-11-2015).pdf |
2015-11-30 |
| 3 |
393-MUMNP-2014-FORM NO.INC-22-(30-11-2015).pdf |
2015-11-30 |
| 3 |
393-MUMNP-2014-CORRESPONDENCE [07-12-2018(online)].pdf |
2018-12-07 |
| 4 |
393-MUMNP-2014-FORM 13-(30-11-2015).pdf |
2015-11-30 |
| 4 |
393-MUMNP-2014-FER_SER_REPLY [07-12-2018(online)].pdf |
2018-12-07 |
| 5 |
393-MUMNP-2014-OTHERS [07-12-2018(online)].pdf |
2018-12-07 |
| 5 |
393-MUMNP-2014-CORRESPONDENCE-(30-11-2015).pdf |
2015-11-30 |
| 6 |
ABSTRACT1.jpg |
2018-08-11 |
| 6 |
393-MUMNP-2014-ABSTRACT.pdf |
2018-08-11 |
| 7 |
393-MUMNP-2014-GENERAL POWER OF ATTORNEY(6-8-2014).pdf |
2018-08-11 |
| 7 |
393-MUMNP-2014-ANNEXURE TO FORM 3(6-8-2014).pdf |
2018-08-11 |
| 8 |
393-MUMNP-2014-FORM 5.pdf |
2018-08-11 |
| 8 |
393-MUMNP-2014-CLAIMS.pdf |
2018-08-11 |
| 9 |
393-MUMNP-2014-CORRESPONDENCE(18-8-2014).pdf |
2018-08-11 |
| 9 |
393-MUMNP-2014-FORM 3.pdf |
2018-08-11 |
| 10 |
393-MUMNP-2014-CORRESPONDENCE(5-5-2014).pdf |
2018-08-11 |
| 10 |
393-MUMNP-2014-FORM 2.pdf |
2018-08-11 |
| 11 |
393-MUMNP-2014-CORRESPONDENCE(6-8-2014).pdf |
2018-08-11 |
| 11 |
393-MUMNP-2014-FORM 2(TITLE PAGE).pdf |
2018-08-11 |
| 12 |
393-MUMNP-2014-CORRESPONDENCE.pdf |
2018-08-11 |
| 12 |
393-MUMNP-2014-FORM 18(5-5-2014).pdf |
2018-08-11 |
| 13 |
393-MUMNP-2014-DESCRIPTION(COMPLETE).pdf |
2018-08-11 |
| 13 |
393-MUMNP-2014-FORM 1.pdf |
2018-08-11 |
| 14 |
393-MUMNP-2014-DRAWING.pdf |
2018-08-11 |
| 14 |
393-MUMNP-2014-FER.pdf |
2018-08-11 |
| 15 |
393-MUMNP-2014-DRAWING.pdf |
2018-08-11 |
| 15 |
393-MUMNP-2014-FER.pdf |
2018-08-11 |
| 16 |
393-MUMNP-2014-DESCRIPTION(COMPLETE).pdf |
2018-08-11 |
| 16 |
393-MUMNP-2014-FORM 1.pdf |
2018-08-11 |
| 17 |
393-MUMNP-2014-FORM 18(5-5-2014).pdf |
2018-08-11 |
| 17 |
393-MUMNP-2014-CORRESPONDENCE.pdf |
2018-08-11 |
| 18 |
393-MUMNP-2014-CORRESPONDENCE(6-8-2014).pdf |
2018-08-11 |
| 18 |
393-MUMNP-2014-FORM 2(TITLE PAGE).pdf |
2018-08-11 |
| 19 |
393-MUMNP-2014-CORRESPONDENCE(5-5-2014).pdf |
2018-08-11 |
| 19 |
393-MUMNP-2014-FORM 2.pdf |
2018-08-11 |
| 20 |
393-MUMNP-2014-CORRESPONDENCE(18-8-2014).pdf |
2018-08-11 |
| 20 |
393-MUMNP-2014-FORM 3.pdf |
2018-08-11 |
| 21 |
393-MUMNP-2014-CLAIMS.pdf |
2018-08-11 |
| 21 |
393-MUMNP-2014-FORM 5.pdf |
2018-08-11 |
| 22 |
393-MUMNP-2014-ANNEXURE TO FORM 3(6-8-2014).pdf |
2018-08-11 |
| 22 |
393-MUMNP-2014-GENERAL POWER OF ATTORNEY(6-8-2014).pdf |
2018-08-11 |
| 23 |
393-MUMNP-2014-ABSTRACT.pdf |
2018-08-11 |
| 23 |
ABSTRACT1.jpg |
2018-08-11 |
| 24 |
393-MUMNP-2014-CORRESPONDENCE-(30-11-2015).pdf |
2015-11-30 |
| 24 |
393-MUMNP-2014-OTHERS [07-12-2018(online)].pdf |
2018-12-07 |
| 25 |
393-MUMNP-2014-FORM 13-(30-11-2015).pdf |
2015-11-30 |
| 25 |
393-MUMNP-2014-FER_SER_REPLY [07-12-2018(online)].pdf |
2018-12-07 |
| 26 |
393-MUMNP-2014-FORM NO.INC-22-(30-11-2015).pdf |
2015-11-30 |
| 26 |
393-MUMNP-2014-CORRESPONDENCE [07-12-2018(online)].pdf |
2018-12-07 |
| 27 |
393-MUMNP-2014-GENERAL POWER OF AUTHORITY-(30-11-2015).pdf |
2015-11-30 |
| 27 |
393-MUMNP-2014-CLAIMS [07-12-2018(online)].pdf |
2018-12-07 |
| 28 |
393-MUMNP-2014-MARKED COPY(FORM 1)-(30-11-2015).pdf |
2015-11-30 |
| 28 |
393-MUMNP-2014-HearingNoticeLetter22-08-2019.pdf |
2019-08-22 |
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