Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-26
2001-10-16
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S304000, C546S312000
Reexamination Certificate
active
06303787
ABSTRACT:
FIELD OF INVENTION
The present invention, relates to process for the preparation of Omeprazole. This invention particularly relates to an alternate process for the preparation of Omeprazole of formula-I,
using novel intermediates, 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine of formula-II,
and novel intermediate, 2-chloromethyl-3,5-dimethyl-4-nitro pyridine of formula-III.
Omeprazole is one of the world's widely used drugs for the treatment of ulcer disease. This compound act by irreversible inhibition of the H
+
K
+
ATPase enzyme, which is part of the ‘proton pump’ located in the parietal cell of the stomach wall.
PRIOR ART
Omeprazole is first disclosed in Swedish patent 7804231 and the corresponding patents EP-0005129 A1 and U.S. Pat. No. 4,255,431.
2-(Lithium methyl sulphinyl)-5-methoxy-1H-benzimidazole of formula I-a where M is K, Na and Li is reacted with 2-chloro-3,5-dimethyl-4-methoxy pyridine of formula I-b, where z is a leaving group, to get Omeprazole of formula-I.
The following intermediates of formulae-c to m and IV, for the preparation of Omeprazole and the synthetic scheme for their improved processes have been disclosed in European patent-0103553 AI and are shown in schemes B and C.
is oxidized with acetic acid and hydrogen peroxide to get 2,3,5-collidine N-oxide of formula-d,
which on treatment with nitrating mixture yields 4-nitro-2,3,5-trimethylpyridine-N-oxide of formula IV.
The compound of formula-IV is treated with methanol and sodium hydroxide to get 4-methoxy-2,3,5-trimethylpyridine-N-oxide of formula-e,
which on treatment with acetic anhydride gives 2-acetyloxymethyl-3,5-dimethyl-4-methoxypyridine of formula-f,
which on hydrolysis gives 2-hydroxymethyl-3,5-dimethyl-4-methoxy pyridine of formula-g.
The compound of formula-g is reacted with thionyl chloride to get 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride of formula-h.
is reacted with acetic acid and hydrogen peroxide to get 3,5-dimethylpyridine-N-oxide of formula-j.
which on reaction with nitrating mixture gives 4-nitro-3,5-dimethylpyridine-N-oxide of formula-k.
The compound of formula-k is reacted with sodium hydroxide and methanol to get 4-methoxy-3,5-dimethylpyridine-N-oxide of formula-l
The compound of formula-l is reacted with dimethyl sulphate to get 3,5-dimethyl-1,4-dimethoxypyridinium methosulphate of formula-m,
which on treatment with methanol and ammonium persulphate yields the compound of formula-g.
The Spanish patent No 9002764/European Patent No.0484265 A
1
also discloses an alternate process for the preparation of Omeprazole (Schemes-D&E) and the intermediate 2-hydroxymethyl-3,5-dimethyl-4-nitro pyridine hydrochloride (Scheme-F).
is reacted with phosphorous trichloride to get 4-nitro-2,3,5-trimethylpyridine of formula-V,
which on reaction with trichloro isocyanuric acid gives 2-chloromethyl-3,5-dimethyl-4-nitro pyridine hydrochloride of formula-VI
The compound of formula-VI is reacted with sodium hydroxide and methanol with 5-methoxy-2-mercapto benzimidazole of formula-VII,
To get compound of formula VIII.
The compound of formula-VIII is reacted with sodium methoxide and benzyl triethyl ammonium chloride in methanol to get desoxyomeprazole of formula-IX.
The compound of formula-IX (as 2-ethylhexanoic acid salt) is reacted with hydrogen peroxide in the presence of ammonium molybdate to get omeprazole of formula-I.
which on reaction with phosphorous trichloride to get 2-chloromethyl-3,5-dimethyl-4-nitro-pyridine hydrochloride of formula-VI.
The compound of formula-VI is converted to Omeprazole of formula-I as mentioned in scheme-D.
which on acid hydrolysis gives 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine hydrochloride of formula-XII
On our repeating the process disclosed in ES 9002764/EP 0484265A
1
for obtaining Omeprazole, we found that the Omeprazole obtained is contaminated with chlorine containing impurities at about 2% level. The cause for this impurity was traced to the instability of HCl salts of compounds of the formulae-VI and XII resulting in formation of 4-chloro derivatives by displacement of 4-nitro group of the formula by chloride ion.
In other words, the impurity 2-chloromethyl-4-chloro-3,5-dimethylpyridine of formula-XIII,
originates from 2-chloromethyl-3,5-dimethyl-4-nitropyridine hydrochloride of formula-VI (as HCl), the impurity 2-hydroxymethyl-4-chloro-3,5-dimethyl pyridine of formula-XIV,
originates from 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine hydrochloride of formula-XII (as HCl salt)
In our sustained efforts to produce omeprazole minimizing the formation of impurities of the formula-XIII, formula-XIV and in the later stage the impurity 5-methoxy-2-(((4-chloro -3,5-dimethylpyridinyl)methyl)thio)-1H-benzimidazole of formula-XV,
with limit less than 0.1%, we could develop a process based on our findings that the compound of formula-XI is hydrolyzed by base hydrolysis avoiding acid hydrolysis, and in the subsequent stage the compound 2-chloromethyl-3,5-dimethyl-4-nitropyridine of formula-III is isolated in base form by neutralizing immediately after completion of the reaction with a base. Such a procedure avoids the formation of impurities 2-hydroxymethyl-3,5-dimethyl-4-chloropyridine of formula-XIV, 2-chloromethyl-3,5-dimethyl-4-chloropyridine of formula-XIII and the impurity of formula-XV,
in the later stage.
2,3,5-trimethyl-4-nitropyridine-N-oxide, of formula-IV, can then be rearranged to 2-acetyloxymethyl-3,5-dimethyl-4-nitropyridine of the formula-XI, which on base hydrolysis gives 2-hydroxymethyl-3,5-dimethyl-4-nitropyridine, of the formula-II. This intermediate of formula-II is purified by re-crystallization from different solvents.
The compound, of the formula-II is reacted at a temperature in the range of 0-15° C. with a chlorinating agent, such as thionyl chloride to get 2-chloromethyl-3,5-dimethyl-4-nitro-pyridine hydrochloride of the formula-VI which is neutralized immediately to obtain compound of formula-III in base form with the impurity 2-chloromethyl-4-chloro-3,5-dimethylpyridine of formula-XIII in less than 0.2% level.
The 2-chloromethyl-3,5-dimethyl-4-nitropyridine of formula-III is dissolved in a protic solvent and reacted with 2-mercapto-5-methoxy benzimidazole of the formula-VII with a base to get 5-methoxy-2-(((3,5-dimethyl-4-nitro-2-pyridinyl)methyl)thio)-1H-benzimidazole of formula-VIII. After recrystallization from suitable solvents, pure compound-VIII is obtained with an impurity, 5-methoxy-2-(((3,5-dimethyl-4-chloro-2-pyridinyl)methyl)thio-1H-benzimidazole, of formula-XV less than 0.1%.
The compound of the formula-VIII is refluxed with methanolic sodium methoxide solution to obtain 5methoxy-2-(((3,5-dimethyl-4-methoxy-2-pyridinyl)methyl)thio)-1H-benzimidazole, of the formula-IX.
The desoxy omeprazole of the formula-IX is reacted with oxidizing agent in the presence of a protic solvent at low temperature i.e. −5 to 0° C. to get pharmacopeial grade Omeprazole. The Omeprazole thus prepared contains impurities 5-methoxy-2-(3,5-dimethyl-4-chloro-2-pyridinyl)methyl sulphinyl)-1H-benzimidazole of formula-XVI,
and 5-methoxy-2-(3,5-dimethyl-4-chloro-2-pyridinyl)methylsulphonyl)-1H-benzimidazole of formula-XVII,
at less than 0.1% level.
The present invention provides an alternate process for the preparation of omeprazole using novel intermediates 2-hydroxymethyl-3,5-dimethyl-4-nitro pyridine of formula-II and 2-chloro methyl-3,5-dimethyl-4-nitro pyridine of formula-III. These two intermediates are very stable when compared to its hydrochloride salts. These two compounds are reacted with para toluene sulphonic acid and to get para toluene sulphonate salts of formulae XVIII and XIX.
The 2-Hydroxymethyl-3,5-dimethyl-4-nitropyridine of formula-II and 2-chloro methyl-3,5-dimethyl-4-nitro pyridine of formula-III both in their base form, are prepared according to the process disclosed above. These compounds are very stable when compared to their hitherto known hydrochloride salts which are produced according to the process disclosed in the above Spanish patent. The employment of thes
Merchant & Gould P.C.
Natco Pharma Limited
Rotman Alan L.
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