Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-15
2001-02-20
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S273700
Reexamination Certificate
active
06191148
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a novel improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole. Omeprazole and compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent and diminished levels of alcoholic solvent are also disclosed.
BACKGROUND OF THE INVENTION
Omeprazole, the generic name for 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1
H
-benzimidazole (denoted as Formula I below) is a well-described gastric proton-pump inhibitor and is on the market as LOSEC® or PRILOSEC® for the treatment of gastric and duodenal ulcers, gastritis, duodenitis, and reflux esophagitis (see Merck Index, 12th Ed., entry 6977, and references cited therein). Omeprazole is commercially prepared via a multi-step sequence, the last step of which is oxidation of the sulfide intermediate, 5-methoxy-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thiol]-1
H
-benzimidazole (denoted as Formula II below), known generically as pyrmetazole, which is typically effected with a peroxy acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S. Pat. Nos. 4,255,431; 5,386,032; and EPO 484,265), magnesium monoperoxyphthalate (MMPP) (U.S. Pat. No. 5,391,752), or peroxyacetic acid (WO 98/09962), in a suitable non-alcoholic organic reaction solvent.
Oxidants other than peroxyacids have also been used for the oxidation of pyrmetazole to omeprazole. EPO 302,720 utilizes aqueous hydrogen peroxide in the presence of a vanadium catalyst, Spanish application No. ES 550,070 discloses periodate as the oxidant, and Spanish applications No. ES 539,793 and ES 540,147 describe iodosobenzene and 3-methyliodosobenzene, respectively. A photooxidative method is disclosed in GB 2,239,453.
Reduction of omeprazole-
N
-oxide to omeprazole is described in WO 98/40377 and WO 98/40378.
The preferred oxidizing agent is usually MCPBA, and suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents, such as benzene and toluene or a mixture thereof, and chlorinated aliphatic hydrocarbon solvents, such as chloroform, 1,2-dichloroethane, and methylene chloride or a mixture thereof, in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol. The preferred non-alcoholic organic reaction solvent is usually chloroform, methylene chloride, or toluene, and the preferred alcoholic solvent is ethanol.
Prior processes to omeprazole have numerous disadvantages that limit both the yield and the purity of the final product.
A significant drawback of such prior methods is incomplete oxidative conversion of pyrmetazole into omeprazole as well as over-oxidation. Two such by-products of over-oxidation are the sulfone of structural formula V and the sulfone-
N
-oxide of structural formula VI. Incomplete and over-oxidation, characteristic of the previous methods, arise from ineffective control over the amount of the oxidizing agent as well as the manner in which the oxidizing agent is charged into the reaction vessel. Prior methods do not use accurately determined amounts of the oxidizing agent and do not provide for careful control of its addition to the reaction mixture. Incomplete and over-oxidation both contribute to the presence of impurities and loss of yield of the final desired product.
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridiny)methyl]sulfonyl]1H-benzimidazole[sulfone]
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl- 1-oxo-2-pyridinyl)methyl]sulfonyl]-1H-benzimidazole[sulfone-
N
-oxide]
Another disadvantage of prior procedures is the considerable loss of product in the purification and isolation steps due to solubility of omeprazole in the mother liquors and solvent washes.
A further drawback concerns diminished product quality resulting from occlusion of residual solvents and reaction by-products during the crystallization steps. It is desirable to eliminate residual levels of organic reaction solvent and recrystillization solvent impurities in the final crystalline product for toxicity/safety reasons.
It is therefore an object of the present invention to provide an improved process for the preparation, purification, and isolation of omeprazole that overcomes the yield and product purity limitations of prior methods.
It is also an object of the invention to provide omeprazole and compositions of omeprazole having lower levels of residual non-alcoholic organic reaction solvent after the initial crude reactive crystallization step.
It is a further object of the present invention to provide omeprazole and compositions of omeprazole that contain no residual non-alcoholic organic reaction solvent within the limits of chromatographic detection and lower levels of residual alcoholic solvent.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation, purification, and isolation of omeprazole of the Formula 1. The last chemical transformation in the preparation of omeprazole is the oxidative conversion of the sulfide intermediate pyrmetazole of the Formula II into its sulfoxide derivative omeprazole of the Formula 1.
In one embodiment of the improved process, the oxidizing agent is meta-chloroperoxybenzoic acid (MCPBA), and the non-alcoholic organic reaction solvent is a chlorinated aliphatic hydrocarbon solvent or an aromatic hydrocarbon solvent in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol, in particular, ethanol. In a class of this embodiment, the chlorinated aliphatic hydrocarbon solvent is chloroform, 1,2-dichloroethane, or methylene chloride or a mixture thereof, and the aromatic hydrocarbon solvent is benzene or toluene or a mixture thereof. In a subclass of this class, the chlorinated aliphatic hydrocarbon solvent is methylene chloride, and the aromatic hydrocarbon solvent is toluene. In this embodiment, oxidative conversion of pyrmetazole to omeprazole has been optimized by careful control of the amount of MCPBA charged to the reaction vessel. The use of one molar equivalent of MCPBA relative to the number of moles of pyrmetazole minimizes over-oxidation to the sulfone V and sulfone-
N
-oxide VI, and incomplete reaction to give back pyrmetazole II, resulting in fewer impurities and higher yields. In another embodiment of the present invention, the concentration of MCPBA in the charging solution is calculated using a novel analytical method based upon MCPBA oxidation of 3-methylisoquinoline to its
N
-oxide derivative and subsequent HPLC quantitation. Without this assay there exists no practical way to avoid either over-oxidation or incomplete conversion of pyrmetazole into omeprazole.
In a further embodiment of the present invention, control over localized over-oxidation is achieved by subsurface addition of MCPBA, providing for entry of the oxidizing solution into the reaction vessel slightly above the agitator blades and directed perpendicular to the flow from the impeller, with simultaneous control of the reaction temperature. Incorporation of these novel features into the process ensures complete conversion of pyrmetazole into omeprazole with minimal formation of over-oxidized by-products V and VI.
In another embodiment of the present invention, the isolation of the crude product has been improved by vacuum distillation of the crude aqueous phase after extraction of the reaction mixture prior to crystallization to remove most of the entrained chlorinated aliphatic hydrocarbon solvent or aromatic hydrocarbon solvent from the oxidation step. The concentration of the alcoholic solvent, in particular ethanol, is then re-adjusted in order to promote good crystal growth during the crude crystallization step. The crystallization step involves a two-stage neutralization with a C
1-3
alkyl formate, preferably methyl formate, or a solution of formic acid in aqueous methanol or ethanol, which is added subsurfacely through a diptube slig
Anousis Nick
Banks Benjamin Newton
Liu Hui
McManus James W.
Zhou Lingwen
Durette Philippe L.
Merck & Co. , Inc.
Morris Patricia L.
Winokur Melvin
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