Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-30
2001-06-12
Fan, Jane (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06245913
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to synthetic procedures for the manufacture of 1H-benzimidazole intermediates and their conversion to Omeprazole by an efficient and economical oxidation.
2. Background of the Art
Omeprazole (5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole) is a known inhibitor of gastric acid secretion and is prescribed for the treatment and prevention of gastrointestinal inflammatory diseases such as gastritis, gastric ulcer and duodenal ulcers. Omeprazole has the following structural formula of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methysulfinyl]-1H-benzimidazole hydrochloride.
Synthetic preparations of Omeprazole typically involve several steps and utilize either 2,3,5-collidine or 3,5-Lutidine as starting material. U.S. Pat. No. 4,255,431 and U.S. Pat. No. 4,620,008 disclose processes for the synthesis of Omeprazole from 3,5-Lutidine. There 3,5-Lutidine is converted to 2-Chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride which is then coupled with 5,4-methoxy-2-mercaptobenzimidazole followed by oxidation with metachloroperoxy benzoic acid.
European Patent Application No. 484265 A1 describes a synthesis of Omeprazole from 2,3,5-Collidine and involves the oxidation of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-IH-benzimidazole (II) with meta chloroperoxybenzoic acid or with hydrogen peroxide in the presence of ammonium molybdate,
Substituted benzimidazoles containing a pyridine radical of the formula II are disclosed, for example, in European patent No. 0005 129. A problem with these compounds is their stability characteristics. Upon storage without any special precautions being taken, they are degraded at a rate which is higher than desired. When Omeprazole (which is a substituted benzimidazole disclosed in this European Patent cited above) is stored at accelerated conditions, that is at 37° C. and at a relative humidity of 80% for a period of 6 months, about 6% of the substance is converted to degradation products.
U.S. Pat. No. 4,620,008 also describes a process for 2-Chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride from 2,3,5-Collidine. U.S. Pat. No. 4,620,008 particularly provides novel compounds which are useful as intermediates in the preparation of therapeutically active compounds such as benzimidazole derivatives which contain a pyridylmethyl radical of the formula II, and methods for the preparation of such compounds of a defined formula I wherein R is H or CH3, are novel and useful intermediates in the preparation of pharmaceutically useful compounds, e.g., substituted benzimidazoles of the general formula I. The compounds of the defined formula are the products obtained from a preceding nitration reaction, for which the N-oxide form may be considered necessary, and the following substitution reaction in which the pyridine N-oxide form is very advantageous considering the yields. In addition, the N-oxide state of the compounds of the defined formula is very advantageous for the subsequent conversion to the 2-hydroxymethylpyridine (procedures A and B). Direct hydroxymethylation of the corresponding non-oxidized pyridines only gives low yields (<20%).
The non-oxidized pyridines may advantageously be prepared by processing both the nitration step and the substitution step without isolation of the intermediate nitro-pyridine. Furthermore they are stable and can be stored in bulk form. For example, the non-oxidized pyridines are useful as intermediates in the preparation of the corresponding 2-hydroxymethylpyridine and reactive derivatives thereof or a salt thereof, in which an ortho methanol or reactive esterified methanol group is present for the preparation of the ultimate compound, e.g. Omeprazole. The reactive 2-hydroxymethylpyridine intermediate is then reacted in known manner with a benzimidazole derivative, e.g., 5-methoxy-benzimidazole, where after oxidation the reaction process is performed according to standard Omeprazole synthetic techniques. A preferred method described in U.S. Pat. No. 4,620,008 of preparing Omeprazole is to use a non-oxidized pyridine as an intermediate wherein the variable group ortho to the oxygen group is H or CH
3
.
Several other reagents for the oxidation of this thioether intermediate (11) have been reported and some of them are perbenzoic acid and peracetic acid (EO 240158), hypohalite salts (EP 268956), iodosobenzene, 3-methyl iodosobenzene (ES 540147) and hydrogen peroxide in combination with a vanadium catalyst (EP 302720). EP 533264 describes an oxidation method which uses magnesium monoperoxy phthalate.
There are several problems in oxidation of 5-methoxy-2-[(4methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-IH-benzimidazole (11) with the oxidizing agents mentioned above. The reaction will not proceed to completion in many cases and the yields are low because of degradation or production of a large number of by-products. The reagents are expensive or the process involves the presence of toxic substances like vanadium salts.
SUMMARY OF THE INVENTION
The present invention provides a simple and efficient oxidation process for the preparation of Omeprazole. The oxidation agent employed here is economical and free from toxic components which are associated with other oxidizing agents described in certain other prior art processes.
The process of the present invention may be-described as a process for the preparation of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole comprising the following steps:
a) oxidizing 3,5-Lutidine to 3,5-Lutidine-N-Oxide by hydrogen peroxide in acetic acid;
b) reducing excess hydrogen peroxide with analdehyde;
c) nitrating 3,5-Lutidine-N-Oxide to give a nitro compound product;
d) isolating the nitro compound product by filtration after neutralization of the nitration reaction mixture with caustic lye in the presence of water sufficient to dissolve the salts of neutralization;
e) reacting the nitro compound with dimethyl sulfate in a first solvent to give a dimethyl sulfate adduct;
f) reacting the dimethyl sulfate adduct with aqueous ammonium persulfate in alcohol to provide an hydroxymethyl compound;
g) reacting the hydroxymethyl compound with SOCl
2
to give a chloromethyl compound;
h) coupling the chloromethyl compound with 5-methoxy-2-mercaptobenzimidazole in a dichloromethane with sodium hydroxide or potassium hydroxide in the presence of a phase transfer catalyst to form a coupled product;
i) nucleophilic substitution of NO
2
on the 4-position of the coupled product with a methoxy group to form a thioether;
j) conversion of the thioether compound to its hydrochloride salt; and
k) oxidizing the thioether hydrochloride salt to Omeprazole; or
a process for the preparation of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole comprising the following steps:
a) oxidizing 3,5-Lutidine to 3,5-Lutidine-N-Oxide by hydrogen peroxide in acetic acid;
b) reducing excess hydrogen peroxide with formaldehyde;
c) nitrating 3,5-Lutidine-N-Oxide to give a nitro compound product;
d) isolating the nitro compound product by filtration after neutralization of the nitration reaction mixture in the presence of water sufficient to dissolve the salts of neutralization;
e) reacting the nitro compound with dimethyl sulfate in a first solvent to give a dimethyl sulfate adduct;
f) reacting the dimethyl sulfate adduct with aqueous ammonium persulfate in alcohol to provide an hydroxymethyl compound;
g) reacting the hydroxymethyl compound with SOCl
2
to give a chloromethyl compound;
h) coupling the chloromethyl compound with 5-methoxy-2-mercaptobenzimidazole in a haloalkane with an alkali metal hydroxide or alkaline metal hydroxide in the presence of a phase transfer catalyst to form a coupled product;
i) nucleophilic substitution of NO
2
on the 4-position of the coupled product to form a thioether compound;
j) conversion of the thioether compound to its hydrochlo
Kulkami Dilip Ganesh
Mukarram Siddiqui Mohammed Jaweed
Purohit Manish
Singh Shiva P.
Fan Jane
Schwegman Lundberg Woessner & Kluth P.A.
Wockhardt Europe Limited
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