JPH05194509A - Method for purifying quinuclidine-4-carboxamide - Google Patents

Abstract

PURPOSE:To obtain high-purity quinuclidine-4-carboxamide useful as an intermediate for medicines. CONSTITUTION:Quinuclidine-4-carboxamide having low purity is successively mixed with two or more organic solvents to give high-purity quinuclidine-4- carboxamide.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for purifying quinuclidine-4-carboxamide which can be used as an intermediate for medicines, a chemical reagent and the like.

[0002]

2. Description of the Related Art Modifiers for cephalosporin antibiotics,
Quinuclidine, which is expected to be used as a chemical reagent
4-Carboxamide is synthesized by synthesizing 4-cyanoquinuclidine using 4-carbamoylpiperidine as a starting material and subjecting this 4-cyanoquinuclidine to a hydrolysis reaction.

As a method for producing quinuclidine-4-carboxamide, for example, ice is added to a sulfuric acid solution of 4-cyanoquinuclidine to hydrolyze the nitrile, and an aqueous solution of potassium hydroxide is added to neutralize it. A method is known in which quinuclidine-4-carboxamide is isolated from the residue obtained by distilling off water with acetone. [Fische
r, H. P. , Grob, C .; A. , Helv. Chi
m. Acta, 51 (1), 153-163 (196)
8)].

[0004]

However, the quinuclidine-4-carboxamide obtained by this method is 4
With many by-products including carboxyquinuclidine,
Purity was not satisfactory. For example, when quinuclidine-4-carboxamide obtained in the previous formulation was subjected to high performance liquid chromatography, the purity was about 85 to 95%, and the melting point was 222 to 224 ° C at normal pressure.

Therefore, an object of the present invention is to obtain a high-purity quinuclidine-4-carboxamide in a high yield by subjecting low-purity quinuclidine-4-carboxamide to a simple operation and industrial treatment. It is to provide a method for purifying quinuclidine-4-carboxamide that can be obtained.

[0006]

DISCLOSURE OF THE INVENTION As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that by simply adding two or more kinds of organic solvents in order to remove the crystallized impurities, The present invention was completed by discovering that pure quinuclidine-4-carboxamide can be obtained in good yield.

The method of the present invention will be described step by step.
Crude quinuclidine-4-carboxamide is dissolved or dispersed in alcohol, then an organic solvent other than alcohol is added,
Completely dissolve the undissolved quinuclidine-4-carboxamide.

However, if it has sufficient solubility in alcohol, it may be omitted. Subsequently, an organic solvent other than the above is added to crystallize impurities. By filtering it off and concentrating the filtrate, a highly pure quinuclidine-4-carboxamide can be obtained in good yield. The purity of the crude quinuclidine-4-carboxamide is not particularly limited, but it is preferably 70% or more. The alcohol can be selected with 1 to 8 carbon atoms, but preferably has 2 carbon atoms.
~ 4. The amount of alcohol added varies depending on the temperature and cannot be generally determined, but it is preferably 2 to 50 g per 1 g of crude quinuclidine-4-carboxamide. More preferably, it is 5 to 10 g.

As an organic solvent other than alcohol for completely dissolving quinuclidine-4-carboxamide, an organic solvent which is miscible with alcohol and which increases the solubility of quinuclidine-4-carboxamide in the coexistence with alcohol is also used. Is.

For example, aromatic hydrocarbons such as benzene, toluene, xylene, carbon tetrachloride, chloromethane,
Halogenated hydrocarbons such as 1,2-dichloromethane,
Examples include ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, and mixed solvents thereof. The amount added may be at least the amount required to increase the solubility of quinuclidine-4-carboxamide. Usually, the amount is equal to or less than that of alcohol. Organic solvents for crystallizing impurities include hexane, octane and other aliphatic hydrocarbons, methyl acetate, ethyl acetate and other esters, cyclohexane and other alicyclic hydrocarbons, dioxane, diethyl ether, tetrahydrofuran and other ethers. And aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and mixed solvents thereof.

The amount of the organic solvent added can be arbitrarily changed depending on the amount of impurities. The addition temperature of the organic solvent may be not higher than the reflux temperature and can be selected according to the type of the organic solvent,
It may be performed at room temperature to improve workability.

The crystallized product can be easily removed by subjecting it to a conventional separation means such as centrifugation or filtration. The quinuclidine-4-carboxamide in the obtained filtrate can be easily isolated by a conventional separation method, for example, dry distillation, concentrated filtration, solvent extraction method, or a simple method combining these methods. The quinuclidine-4-carboxamide may be isolated by a method such as column chromatography.

[0013]

Example 1 To 5.0 g of crude quinuclidine-4-carboxamide (purity 91.9%), 30.0 g of ethanol was added and dissolved by stirring at room temperature, and then 40.0 g of hexane was added to form a precipitate. ..

The precipitate was filtered and the filtered liquid was distilled to dryness to obtain 4.6 g of crystals. When the crystals were subjected to high performance liquid chromatography and a melting point measuring instrument, they each had a purity of 98.8% and a melting point of 234 to 234.5 ° C. (Yield 98.9%)

[0015]

Example 2 6.0 g of crude quinuclidine-4-carboxamide (purity 91.9%) and 30.0 g of isopropanol.
15.0 g of toluene was added to the slurry-like mixed solution consisting of, and dissolved by stirring at 40 ° C., then cooled to room temperature, and then 53.0 g of hexane was added. At that time, a precipitate came out, which was filtered off, and the filtrate was distilled to dryness to obtain 5.4 g of crystals. When these crystals were subjected to high performance liquid chromatography and a melting point measuring instrument, the respective purity was 99.3%,
The melting point was 234.5-235 ° C. (Yield 97.2
%)

[0016]

Example 3 3.0 g of crude quinuclidine-4-carboxamide (purity 81.5%) and 18.0% of isopropanol.
1,2-dichloroethane (18.0 g) was added to the slurry mixture consisting of g, and dissolved with stirring at room temperature, and then hexane (5) was added.
A precipitate was formed by adding 0.0 g.

The precipitate was filtered and the filtered solution was distilled to dryness to obtain 2.0 g of crystals. When these crystals were subjected to high performance liquid chromatography and a melting point measuring instrument, they each had a purity of 99.0% and a melting point of 234.3 to 234.7 ° C.
Met. (Yield 81.0%)

[0018]

INDUSTRIAL APPLICABILITY According to the method of the present invention, low-purity quinuclidine-4-carboxamide can be produced in a simple operation with a high yield, and the purity can be industrially improved.

Claims (1)

[Claims] 1. A quinuclidine-4-carboxamide having a high purity is obtained by sequentially adding two or more kinds of organic solvents to low-purity quinuclidine-4-carboxamide to crystallize impurities. Purification method of carboxamide.