WO2002085858A1

WO2002085858A1 - Process for producing purified piperidine derivative

Info

Publication number: WO2002085858A1
Application number: PCT/JP2002/003955
Authority: WO
Inventors: Tomoko Taniguchi; Kazuhiko Hayashi; Kazuya Oharu
Original assignee: Asahi Glass Company, Limited
Priority date: 2001-04-20
Filing date: 2002-04-19
Publication date: 2002-10-31
Also published as: JPWO2002085858A1

Abstract

A process for producing a purified piperidine derivative, pyridine derivative, or quinoline derivative useful as an intermediate or starting material for medicines and agricultural chemicals through short steps and easy operations without necessitating a special reagent or apparatus. Any of those derivatives, which is insoluble or sparingly soluble in water, is dissolved in a medium under acidic conditions to form a salt, and the resultant solution is made basic to thereby precipitate the target compound.

Description

Specification

Method for producing purified piperidine derivative

The present invention relates to a method for producing a purified piperidine derivative useful as a pharmaceutical or agricultural chemical intermediate or a drug substance. Background technology>

As a general isolation and purification method for piperidine derivatives, there is a recrystallization method. Other methods include distillation and silica gel column chromatography.

The method of recrystallizing a water-insoluble piperidine derivative from water is inefficient because the amount of recrystallizable crystals is small. In addition, in the method of recrystallization from a solution of an organic solvent, the time until crystallization is generally long, and there is a problem when the method is industrially performed. There is also a problem that the organic solvent remains in the crystal.

In order to further improve the solubility in an organic solvent or water, there may be a method of forming a high-concentration piperidine derivative solution under acidic conditions and recrystallization from the solution. There is a problem of taking in soluble impurities contained in the piperidine derivative solution and crystallization. Further, when the impurities are soluble components that cause coloring of the crystals in a very small amount, there is a problem that the coloring of the crystals is recognized even if the purity of the obtained crystals is high. Since the piperidine derivative is also used as a variety of higher-order intermediates or drug substances, it is a problem that the coloring components based on impurities remain in the final preparation to be administered to the human body.

Methods for solving this problem include a distillation method and a silica gel column chromatography method. However, when the piperidine derivative has a high boiling point, the distillation method cannot be used. Also, even if the distillation method can be adopted, the desired piperidine There is a problem that the body is decomposed and the recovery rate decreases. In addition, the distillation method has a problem that coloring components cannot always be effectively removed.

Also, when performing large-scale purification by silica gel column chromatography, an enormous amount of silica gel and an organic solvent for development are required. The silica gel used is difficult to regenerate, causing problems such as the generation of large amounts of industrial waste and the increase in cost. In addition, the purification amount per unit time by the silica gel chromatography method is smaller than that of recrystallization / distillation, and its use on an industrial scale is not efficient. Disclosure of the Invention>

The present invention has been made for the purpose of solving the drawbacks of the conventional technology, and is a purified piperidine derivative that can be industrially easily and efficiently implemented, and that can be implemented at low cost without environmental problems. And a method for producing the same.

That is, the present invention provides a piperidine derivative by dissolving a piperidine derivative that is insoluble or hardly soluble in water in a medium under an acidic condition to form a solution, and then subjecting the solution to a basic condition. Provided is a method for producing a purified piberidine derivative, which is characterized in that the derivative is precipitated. BEST MODE FOR CARRYING OUT THE INVENTION>

The piperidine derivative in the present invention refers to a compound having a ring structure based on a piperidine ring as a basic skeleton. Examples of the ring structure based on a piperidine ring include a piberidine ring and a ring structure in which at least one carbon-carbon bond of the piperidine ring is an unsaturated bond (for example, a pyridine ring and the like). The ring structure having a piperidine ring as a basic skeleton may be one of the rings forming a condensed ring. Examples of the condensed ring include a quinoline ring and a naphthyridine ring. Further form these rings It is preferable that a hydrogen atom or a substituent is bonded to the carbon atom.

Substituents are selected from those that are inert to acids and bases, and include halogen atoms, hydroxyl groups, amino groups, alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, thioalkyl groups, nitro groups, and cyano groups. And at least one substituent selected from the group consisting of: Further, the carbon atom forming the ring may be an oxo group (c = o). Here, the halogen atom is one or more selected from a fluorine atom, a chlorine atom, a bromine atom, and a iodine atom.

Examples of the piperidine derivative in the present invention include a piperidine compound, a pyridine compound, a pyridone compound, and a naphthyridine compound. Preferable examples include 3- (phenylethynyl) pyridine-1-N-oxide, 1-methyl-3,4-difluoro-2-quinolone, and 5-methyl-111 Preferably it is phenyl-1 2 (1H) pyridone. The route of obtaining such a piperidine derivative is not particularly limited, and may be a commercially available product or a crude product after production. Further, the purity of the piperidine derivative before purification is preferably 90% by mass or more. Further, the piperidine derivative may contain a coloring component. The degree of coloring by the coloring component is preferably more than 20 and 60 or less as measured by the method for measuring yellowness described in the examples. For example, when the method of the present invention is applied to a piperidine derivative containing a coloring component, an uncolored piperidine derivative containing substantially no coloring component can be obtained.

The piperidine derivative in the present invention is insoluble or hardly soluble in water. In the present invention, the term "insoluble or poorly soluble in water" means that the amount of water required to dissolve 1 g of a target piperidine derivative is 3 OmL or more when measured at 20 ° C. The amount of the water is preferably at least 7 O mL, particularly preferably at least 10 O mL. In the present invention, a piperidine derivative insoluble in water or hardly soluble in water is dissolved in a medium under acidic conditions to form a solution. The acidic condition means that the pH is 6 or less, and in the present invention, the pH is preferably 4 or less.

In the present invention, it is preferable that one or more acids selected from organic acids and inorganic acids are contained in the medium to make the medium acidic. As the acid, one or more acids selected from acetic acid, formic acid, trifluoroacetic acid, trichloroacetic acid, benzoic acid, tartaric acid, malic acid, oxalic acid, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid are preferable, and acetic acid, hydrochloric acid, Or sulfuric acid is particularly preferred. In addition, when the piperidine derivative is used for medicine, the acid selected from acetic acid, benzoic acid, oxalic acid, malic acid, hydrochloric acid, sulfuric acid, and phosphoric acid among the acids specified as food additives is used. It is preferred to use. The acid may be used as it is or may be used as a solution. When a solution is prepared, it is preferably a solution of a medium other than an acid, particularly preferably a solution of ethanol, toluene, ethyl acetate, or water, and particularly preferably an aqueous solution. When the acid solution is used, the concentration of the acid is preferably 1 to 50% by mass, particularly preferably 3 to 30% by mass. As the medium in the present invention, when the acid itself is in a liquid state, The acid may be used as a medium, but a medium other than the acid is usually and preferably used. As a medium other than the acid, water and Z or an organic solvent are preferable.

Examples of the organic solvent include alcohol solvents such as methanol, ethanol, and isopropyl alcohol; ester solvents such as ethyl acetate and n-butyl acetate; hydrocarbon solvents such as toluene, xylene, cyclohexane, and n-hexane; Examples include halogenated hydrocarbon solvents such as dichloromethane, chloroform, benzene, etc., ether solvents such as getyl ether, diisopropyl ether, methyl-tert-butyl ether, tetrahydrofuran, and dioxane, and nitrile solvents such as acetonitrile. Can be As a medium, water is preferable because there is little problem when remaining. In the present invention, the piperidine derivative is dissolved in a medium under acidic conditions to form a solution. You. Preferably, substantially all of the piperidine derivative is dissolved in the medium, but some piperidine derivatives may be phase-separated from the medium. In order to dissolve substantially all of the piperidine derivative in the medium, when the medium is an acid alone, it is preferable to use 0.5 to 50 times the mass of the acid relative to the piperidine derivative, It is particularly preferable to use 1 to 10 times the mass. When the medium is an acid solution, the solution is preferably used in an amount of 2 to 20 times, more preferably 2 to 12 times, the mass of the piperidine derivative.

When the piperidine derivative is dissolved in a medium under acidic conditions, the temperature is preferably from 120 ° C to 150 ° C, particularly preferably from room temperature to + 120 ° C. The pressure is not particularly limited, and is usually preferably atmospheric pressure. Heating and stirring may be performed as necessary. When solid impurities are present, it is preferable to filter the acidic solution of the piperidine derivative.

Next, in the present invention, the acidic solution of the piperidine derivative is made basic. The basic condition means that pH is 8 or more, and in the present invention, pH is preferably 11 or more.

As a method for setting the basic conditions, it is preferable to include one or more bases selected from organic bases and inorganic bases or a solution of the selected bases in an acidic solution. Potassium, sodium carbonate, potassium carbonate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, pyridine, triethylamine, diisopropylethylamine, 1,8-diazabidicro [5,4,0] Or 1,5-diazabidiclo [4,3,0] non-5-ene is preferred, and sodium hydroxide and sodium carbonate are particularly preferred. When the piperidine derivative is used for medicine, sodium hydroxide, hydroxide hydroxide, sodium carbonate, or potassium carbonate is particularly preferable.

In the present invention, the base may be contained as it is in the acidic solution. Is preferably included as a solution. When the base is used as a solution, the solution is preferably formed using water or a medium other than the aforementioned acids, and particularly preferably an aqueous solution. The concentration of the base solution is preferably from 1 to 50% by mass, more preferably from 3 to 30% by mass.

When making the acidic solution of the piperidine derivative basic, the temperature is preferably from −20 ° C. to 120 ° C., particularly from room temperature to + 100 ° C. in terms of operability. Is preferred. In addition, the pressure is not particularly limited, and it is usually preferable to be atmospheric pressure. The amount of the base is such that the basicity falls within the above range, and can be appropriately changed.

In the present invention, the piperidine derivative is precipitated by making the acidic solution of the piperidine derivative basic. The piperidine derivative itself is basic, and its solubility is reduced under basic conditions to precipitate.However, if precipitation is difficult, increase the pH or lower the temperature of the solution. May be performed. In the case where crystals are precipitated as crystals, seed crystals may be added. Furthermore, the method of precipitating under basic conditions in the present invention not only significantly reduces the time required for crystallization, but also incorporates the coloring component even if the crystal before purification contains the coloring component. And a non-colored piperidine derivative crystal. The coloring component usually remains in the mother liquor from which the crystals have been separated.

The precipitated piperidine derivative is preferably subjected to ordinary post-treatments such as filtration, washing and drying. If necessary, the precipitated piperidine derivative may be pulverized. The purified piperidine derivative obtained by the method of the present invention generally has a high purity of about 99.0 to 100%, and a yellowness of 20 or less, preferably 1% or less. It becomes 0 or less. The difference in yellowness between the piperidine derivative containing a coloring component and the purified piperidine derivative is preferably 5 or more. The purified pyrididine derivative is usefully used as various higher intermediates of drugs and drug substances. In the present invention, a base is added to a vessel containing a piperidine derivative solution under acidic conditions. Is preferably obtained. According to this method, only one container needs to be used, and it is efficient from the viewpoint of operation. Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The yellowness in the examples is a value measured by the following method, and the closer to 0, the more uncolored. Normally, crystals are observed as white as they approach zero due to light scattering.

The yellowness of the present invention was measured according to the yellowness test method specified in JIS K7103. The sample was laid all over the surface of a 55 mm diameter quartz container to a height of 10 mm, and color measurement was performed using a color difference meter (CR310, manufactured by Minolta Co., Ltd.) with the standard light C using the Yxy color system. After converting the measurement results into tristimulus values XYZ, the yellowness was calculated by the equation [yellowness = 100 (1.28X-1.06Z) ZY] defined in JIS K7103, 6.1 Yellowness.

[Example 1]

Into a 1 L flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, light brown (yellowness 21.35) 5-methyl_1-phenyl-2- (1H) pyridone (52.62 g) Then, 5% acetic acid (487.92 g) was added, and the mixture was heated and dissolved at 90 ° C. A 25% aqueous solution of sodium hydroxide was added dropwise to the acidic solution until the pH of the solution became 13, the solution was cooled to 5 ° C, kept for 4 hours, and filtered. After sufficiently washing with water, drying was performed to obtain a white powder (yellowness: 8.27) of 5-methyl-11-phenyl-12 (1H) pyridone with a recovery of 84%.

[Example 2] 10-liter separable flask with stirrer, internal thermometer, gym funnel, and dropping funnel, pale brown (yellow 23) 5-methyl-1-phenyl-2- (1H) pyridone

(583.1 g), 5% acetic acid (546 lg) was added, and the mixture was heated and dissolved at 90 ° C. A 25% aqueous sodium hydroxide solution was added dropwise to the acidic solution until the pH of the solution became 13, then cooled to 5 ° C, kept for 4.5 hours, and filtered. After sufficiently washing with water, the product was dried to obtain 5-methyl-1,1-phenyl-2- (1H) pyridone as a pale yellowish white powder (yellowness 15.68) with a recovery of 83%.

[Example 3]

In a 50 OmL flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, put brown (yellowness 59.73) 3-((phenylenetin)) pyridine-N-oxide (30.85 g) into a 50-mL flask. Next, 10% acetic acid (157.64 g) was added and dissolved by heating at 100 ° C. A 25% aqueous solution of sodium hydroxide was added dropwise to the acidic solution until the pH of the solution became 13, then cooled to 0 ° C and maintained for 6 hours. A white powder (yellowness 9.21) of 3- (phenylenetin) pyridine-1-N-oxide was obtained with a recovery of 89%.

[Example 4]

In a 1-L flask equipped with a stirrer, internal thermometer, Dimroth, and dropping funnel, add yellow (yellowness 41.08) 1-methyl-3,4-difluoro-2-quinolone (48.91 g), and add 5% Acetic acid (454.83 g) was added and dissolved by heating at 90 ° C. A 25% aqueous solution of sodium hydroxide was added dropwise to the acidic solution until the pH of the solution became 13, cooled to 5 ° C, kept for 6 hours, and filtered. After sufficiently washing with water, drying was carried out to obtain 1-methyl-3,4-difluoro-12-quinolone as a white powder (yellowness 8.41) with a recovery of 79%. <Industrial applicability>

According to the method of the present invention, a purified piberidine derivative can be obtained from a piperidine derivative in a short step. The production method of the present invention can be carried out without using any special reaction conditions or reaction equipment, and has a high recovery rate in the purification step, and is therefore a useful method as an industrial large-capacity production method. Further, according to the method of the present invention, a colored component can be effectively removed in a short step, and a purified piperidine derivative useful as a high-quality pharmaceutical or agricultural chemical intermediate or a drug substance can be provided.

Claims

The scope of the claims

1. Dissolve the piperidine derivative, which is insoluble or poorly soluble in water, in a medium under acidic conditions to form a solution, and then precipitate the piperidine derivative by subjecting the solution to basic conditions. A method for producing a purified piperidine derivative, characterized in that:

2. The production method according to claim 1, wherein acidic conditions are used using acetic acid.

3. The production method according to claim 1, wherein the conditions are adjusted to basic conditions using sodium hydroxide.

4. The piperidine derivative which is insoluble or hardly soluble in water is a piperidine derivative containing a coloring component, and the purified piperidine derivative is a piperidine derivative substantially containing no coloring component. , 2, or 3.

5. The piperidine derivative containing a coloring component has a yellowness of more than 20 and 60 or less according to a test method according to JISK 7107, and the purified piperidine derivative has a yellowness of 20 or less. Item 4. The production method according to Item 4.

6. The method according to any one of claims 1 to 5, wherein the piperidine derivative has a boiling point of 250 ° C or more.

7. The method according to any one of claims 1 to 6, wherein the piperidine derivative is precipitated as crystals.

8. The production method according to any one of claims 1 to 7, wherein the piperidine derivative is 5-methyl-11-phenyl-2 (1H) pyridone.

9. The production method according to claim 1, wherein the piperidine derivative is 3- (phenylethynyl) pyridine-1-N-oxide.

10. The method according to claim 1, wherein the piperidine derivative is 1-methyl-3,4-difluoro-2-quinolone.