Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-16
2002-02-26
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S254000, C548S250000
Reexamination Certificate
active
06350880
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel crystalline or crystallized acid addition salt of Losartan, which has a superior antagonistic activity against angiotensin II, and to a purification method of Losartan, which comprises producing the crystalline or crystallized acid addition salt.
BACKGROUND OF THE INVENTION
2-n-Butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol of the following formula (Ia)
(hereinafter to be also referred to as Losartan) is a useful antihypertensive agent having a superior antagonistic activity against angiotensin II. Losartan is generally used in the form of a potassium salt. Inasmuch as purification of a potassium salt is not feasible, it is a typical practice to purify free Losartan to a high degree first and then convert it to a potassium salt.
However, purification of Losartan itself is also difficult and there are some purification methods proposed to achieve a higher purity of Losartan (WO93/10106, WO95/17396 etc.). These methods, nevertheless, are not entirely satisfactory and a feasible purification method to increase the purity of Losartan has been demanded.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a crystalline or crystallized acid addition salt of Losartan, which is useful for producing highly pure Losartan. Another object of the present invention is to provide an easy purification method for obtaining highly pure Losartan.
According to the present invention, there is provided a crystalline or crystallized acid addition salt of 2-n-butyl-4-chloro-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol (Losartan) of the formula (I)
wherein A is an acid.
Preferably, A in the above-mentioned formula (I) is selected from the group consisting of hydrochloric acid, hydrobromic acid and p-toluenesulfonic acid, with more preference given to p-toluenesulfonic acid.
Preferably, when A in the above-mentioned formula (I) is p-toluenesulfonic acid, the above-mentioned crystalline or crystallized acid addition salt is in the form of a solvate, wherein the solvent that forms the solvate is preferably tetrahydrofuran.
The present invention also provides a purification method of Losartan, which comprises a step for obtaining a crystalline or crystallized acid addition salt of Losartan of the formula (I)
wherein A is an acid, formed from Losartan and the acid.
Preferably, the acid (A) is selected from the group consisting of hydrochloric acid, hydrobromic acid and p-toluenesulfonic acid, with preference given to p-toluenesulfonic acid.
Preferably, when the acid (A) is p-toluenesulfonic acid, the above-mentioned crystalline or crystallized acid addition salt is in the form of a solvate, wherein the solvent that forms the solvate is preferably tetrahydrofuran.
Preferably, the above-mentioned crystalline or crystallized acid addition salt is formed in an organic solvent.
Preferably, the above-mentioned crystalline or crystallized acid addition salt in the form of a solvate is formed in a solvent containing a solvent that can form the solvate.
Preferably, the above-mentioned tetrahydrofuran solvate is formed in a solvent containing tetrahydrofuran.
DETAILED DESCRIPTION OF THE INVENTION
The crystalline or crystallized acid addition salt of Losartan of the above-mentioned formula (I) of the present invention is an acid addition salt formed from Losartan of the above-mentioned formula (Ia), which is a known compound, and an acid at an imidazole moiety of Losartan. The salt has crystallinity (i.e., property to become crystals) or is in the form of crystals. The solvates (e.g., monosolvate, disolvate, 1/2 solvate, 1/3 solvate, 1/4 solvate, 2/3 solvate, 3/2 solvate and the like) of the crystalline or crystallized acid addition salt are also encompassed in the present invention. Examples of the solvent to form the solvate include water, organic solvents such as ethers [e.g., tetrahydrofuran (THF) and the like] and lower alcohols having 1 to 4 carbon atoms (e.g., methanol, ethanol, propanol, butanol and the like), and the like.
The acid represented by A in the above-mentioned crystalline or crystallized acid addition salt is free of any particular limitation as long as the acid can form a crystalline or crystallized acid addition salt at the imidazole moiety of Losartan. Examples of the acid include hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid and the like. Of these, p-toluenesulfonic acid is preferable because the resulting crystalline or crystallized acid addition salt shows a high purity.
Since the above-mentioned crystalline or crystallized acid addition salt can be highly pure in the state of a solvate depending on the kind of acid, when the solvate is highly pure, it may be preferably in the form of a solvate in some cases.
Examples of preferable crystalline or crystallized acid addition salt mentioned above include hydrochloride, hydrobromide and p-toluenesulfonate, more preferably p-toluenesulfonate, particularly preferably p-toluenesulfonate THF solvate.
The Losartan in the above-mentioned crystalline or crystallized acid addition salt is a known compound, which can be produced according to a known method.
The above-mentioned-crystalline or crystallized acid addition salt can be produced from Losartan and the above-mentioned acid according to a method known as a general production method of acid addition salts. Preferably, Losartan is dissolved in an organic solvent capable of dissolving Losartan, such as monochlorobenzene (MCB), THF and the like, and an acid is added to the resulting solution.
Since the above-mentioned crystalline or crystallized acid addition salt can be purified to a high purity level, it is useful for obtaining highly pure Losartan. In other words, highly pure Losartan or a potassium salt etc. thereof can be obtained easily from the crystalline or crystallized acid addition salt.
The purification method of Losartan of the present invention is based on the finding that the crystalline or crystallized acid addition salt of Losartan, which is formed from Losartan and the above-mentioned acid, can be purified to a high level. The method comprises a step for obtaining a crystalline or crystallized acid addition salt of Losartan, which is formed from Losartan and the above-mentioned acid: a step for obtaining a crystalline or crystallized acid addition salt of Losartan by precipitation.
As used herein, by “obtaining a crystalline or crystallized acid addition salt of Losartan” is meant obtaining a crystalline or crystallized acid addition salt of Losartan as a real substance. Therefore, obtaining a crystalline or crystallized acid addition salt of Losartan dissolved in a solution state is not included in the context of “obtaining a crystalline or crystallized acid addition salt of Losartan”.
Losartan used as a starting compound in the purification method of the present invention can be any that is produced according to an optional production method, with no limitation imposed on purity and the like. It may be a known salt at the tetrazole moiety of Losartan, such as a potassium salt and the like. Examples of the salt of Losartan include salt with alkali metal, such as sodium, potassium, lithium and the like; salt with alkaline earth metal, such as calcium, magnesium and the like; salt with organic base, such as triethylamine, diisopropylethylamine and the like; and the like. These salts may be used in combination of two or more kinds thereof. When these salts are used as starting materials in the purification method of the present invention, a step for producing free Losartan by a conventionally-known method may be added as necessary before a step for producing a crystalline or crystallized acid addition salt.
The above-mentioned Losartan is preferably purified by an optional purification step to increase purity of the obtained crystalline or crystallized acid addition salt of Losartan. Examples
Itaya Nobushige
Katsura Tadashi
Shiratani Hiroshi
D'Souza Small Andrea
Higel Floyd D.
Leydig , Voit & Mayer, Ltd.
Sumika Fine Chemicals Co., Ltd.
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