WO2000035553A1

WO2000035553A1 - Method of separating compound of group iii or iv metal

Info

Publication number: WO2000035553A1
Application number: PCT/JP1999/007044
Authority: WO
Inventors: Hideo Hashimoto; Tadashi Fukui; Tadashi Hanaoka
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1998-12-16
Filing date: 1999-12-15
Publication date: 2000-06-22
Also published as: AU1686200A

Abstract

A method which comprises mixing (1) a solution containing an organic compound which is oleophilic in the range of pH's higher than 2 and an alkoxide of a Group III or IV metal of the short-form Periodic Table with (2) water and (3) a polybasic carboxylic acid to thereby transfer the metal compound to the aqueous layer. Thus, the metal compound can be easily separated from the organic compound. This method is industrially advantageous.

Description

Description Method for separation of Group II, Group IV metal compounds

The present invention relates to a method for separating an organic compound exhibiting lipophilicity at a pH region higher than PH2 and a metal compound belonging to Group III or IV, and is particularly applied to the separation and purification of a target compound in the field of synthesis of organic compounds. Things. Background art

Alkoxides of Group II or Group IV metals in the short-periodic periodic table are often used in organic synthesis reactions. However, at the end of the reaction, an operation of decomposing with addition of water is performed in order to invalidate the effect. The metal compound formed by this decomposition is soluble in water under strongly acidic conditions of less than pH 2, but is generally insoluble in both water and organic solvents under conditions of pH 2 or more. On the other hand, some of the target compounds in the chemical reaction show lipophilicity in the pH range higher than any pH of 2 or more, but show hydrophilicity or non-hydrophilicity under strongly acidic conditions below any pH. Some are stable. When an alkoxide of the above-mentioned metal is used in the synthesis of such a compound, in order to separate the target compound from the decomposition product of the above-mentioned metal alkoxide after completion of the reaction, the solvent is used as an extraction solvent under conditions of pH 2 or more. Addition of an oily organic solvent is performed. However, the compound of the metal formed by the decomposition of the metal alkoxide cannot be separated by liquid separation because it is present as fine particles in both the aqueous layer and the lipophilic organic solvent layer, and the separation by filtration requires a long time. It was very disadvantageous industrially. Disclosure of the invention

The present invention provides an industrially advantageous method for separating a target compound from a Group II, Group IV metal compound under a condition of pH 2 or more.

The present inventors have conducted intensive studies and have found that any organic compound having a pH of 2 or more can be obtained by an organic synthesis reaction using an alkoxide of a Group III or Group IV metal in the short periodic table. When an organic compound exhibiting lipophilicity in the pH range higher than the above value is synthesized, at the end of the reaction, the pH of the aqueous layer together with the lipophilic organic solvent for extraction and water is adjusted to the pH within the range where the target compound exhibits lipophilicity. Surprisingly, when a polybasic carboxylic acid (a carboxylic acid having a plurality of carboxylic acid groups) is added, it is insoluble in both water and lipophilic organic solvents, even when the liquidity is pH 2 or higher. It was found that the target compound was distributed to the organic layer, and the Group III and Group IV metal compounds were distributed to the aqueous layer, thereby completing the present invention.

That is, the present invention

(1) 1) A solution containing an organic compound exhibiting lipophilicity in a pH range higher than pH 2 and an alkoxide of a Group III or Group IV metal in the short-periodic periodic table (hereinafter referred to as “solution II”).

') And 2) water (hereinafter referred to as water ②) and 3) polybasic carboxylic acid (hereinafter referred to as polybasic carboxylic acid ③) to transfer the metal compound to the aqueous layer. Separating the organic compound and the metal compound,

(2) The method according to (1) above, wherein a lipophilic organic solvent (hereinafter referred to as lipophilic organic solvent ④) is further added during mixing.

(3) The method according to (1) above, wherein the solution (2) is mixed with an aqueous solution of the polybasic ruponic acid (3),

(4) The lipophilic organic solvent ④ is a halogenated hydrocarbon having 1 to 2 carbon atoms, an ether having 2 to 6 carbon atoms, a lower alkyl ester of a lower aliphatic carboxylic acid, or an aromatic carbonization having 6 to 8 carbon atoms. Hydrogens, aliphatic hydrocarbons having 5 to 7 carbon atoms, alicyclic hydrocarbons having 5 to 7 carbon atoms, a mixed solvent of two or more of these, or a mixture of these solvents and other solvents The method according to (2) above, which is a solvent,

(5) The method according to the above (1), wherein the alkoxide of a Group III or Group IV metal in the short-periodic table is an alkoxide of titanium, zirconium or aluminum.

(6) Polybasic carboxylic acid ③ is oxalic acid, malonic acid, konoic acid, oxalic acid, daltaric acid, adipic acid, maleic acid, fumaric acid, fumaric acid, isophthalic acid, terephthalic acid, citric acid Or the method according to the above (1), which is a mixture of two or more of these,

(7) The amount of polybasic carboxylic acid ③ used in Group III or The method according to the above (1), wherein the amount is 0.5 to 10 mol per 1 mol of the alkoxide of the Group IV metal,

(8) The method according to the above (1), wherein the amount of water used is 0.1 to 100 liters per 1 mol of an alkoxide of a Group III or Group IV metal in the short-periodic periodic table.

(9) The method according to the above (1), wherein the alkoxide of a Group II or Group IV metal in the short-periodic periodic table is a titanium alkoxide.

(10) As described in (1) above, when the metal compound is transferred to the aqueous layer, the pH of the mixed solution is adjusted to a pH range in which an organic compound exhibiting lipophilicity in a pH range higher than pH 2 exhibits lipophilicity. the method of,

(1 1) An organic compound exhibiting lipophilicity in a pH range higher than PH2 is represented by the formula:

[In the formula, Ar represents a phenyl group optionally substituted with halogen, X represents a lower alkylene group, and (R) represents a steric configuration. Wherein the alkoxide of a Group II or Group IV metal in the short-periodic table is an alkoxide of titanium, and the polybasic carboxylic acid ③ is a di- or tricarboxylic acid having 2 to 8 carbon atoms. Wherein the lipophilic organic solvent で is a lower alkyl ester of a lower aliphatic carboxylic acid,

(12) A solution containing an organic compound exhibiting lipophilicity and an alkoxide of a Group III or Group IV metal in the short-periodic periodic table (hereinafter referred to as solution I) is mixed with water II and polybasic rubonic acid ③. A method for separating the organic compound and the metal compound, wherein the method comprises transferring the metal compound to an aqueous layer;

Equation (13):

(Wherein, Ar represents a phenyl group optionally substituted by halogen, and (R) and (S) represent a steric configuration.) A compound represented by the following formula: H ₂ N— X— OH (111)

(Wherein, X represents a lower alkylene.) A compound represented by the following formula:

[Wherein each symbol has the same meaning as described above. ] A reaction mixture containing the compound represented by the formula, water②, a di- or tricarboxylic acid having 28 carbon atoms and a lipophilic organic solvent④ are mixed, and the titanium compound is transferred to an aqueous layer. A method for producing the compound represented by (I),

(14) The method according to (13), wherein the titanium alkoxide is titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide or titanium (IV) butoxide.

(15) The lipophilic organic solvent according to the above (13), wherein the lipophilic organic solvent is benzene, chloroform, carbon tetrachloride, dichloroethane, dichloromethane, diethyl ether, diisopropyl ether, ethyl acetate, hexane, pentane, toluene or xylene. Manufacturing method, and

(16) The method according to (13), wherein the pH of the mixed solution is adjusted to 7.0 to 10.0 when the titanium compound is transferred to the aqueous layer.

About.

The lipophilic organic compound is an organic compound that is more soluble in a lipophilic organic solvent than in water. Whether the organic compound is more soluble in water or the lipophilic organic solvent is determined by adding the organic compound to an equal volume of water and the lipophilic organic solvent, mixing the mixture, and then allowing the mixture to stand. Can be determined by measuring the amount of the organic compound contained in each of the above. In this case, the conditions such as the temperature may be adjusted to the conditions for actually implementing the present invention. The above-mentioned organic compound exhibiting lipophilicity in a pH region higher than pH 2 is a compound which is more soluble in a lipophilic organic solvent than water in a pH region higher than an arbitrary pH value higher than 2 in water. Lipophilic organic solvent in the pH range below any pH value Ricoh refers to an organic compound that is soluble in water in large quantities or decomposed partly or entirely. Examples of such a compound include organic compounds having a basic substituent, for example, an amino group which may be substituted (eg, an alkylamino group such as methylamino, ethylamino, propylamino, and butylamino, and an acylamino group such as acetylamino, propioamino, and propylamino). ), And a heterocyclic group having an optionally substituted nitrogen atom (eg, optionally substituted pyridyl, pyrimidinyl, triazinyl, pyrrolyl, diazolyl, triazolyl, oxazolyl, oxaziazolyl, imidazolyl, imidazolidinyl, etc.) And an organic compound having the following group. The compound represented by the formula (I) is also an example. For example, (2R, 3R) -2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino]- 1- (1H-1,2,4-triazol-1-yl) -2-butanol is lipophilic above pH 3 and hydrophilic below pH 3.

Alkoxides of Group III or Group IV metals in the short-periodic table include, for example, Group III metals such as aluminum, scandium and gallium or Group IV metals such as titanium, germanium, zirconium, tin and namari. Alkoxides of metals (for example, alkoxides having 1 to 5 carbon atoms such as methoxide, ethoxide, propoxide, isopropoxide, butoxide, isobutoxide, t-butoxide, sec-butoxide). Among them, alkoxides of titanium, zirconium or aluminum are preferred. Particularly preferred are titanium alkoxides, such as, for example, titanium (IV) methoxide, titanium (IV) butoxide, titanium diisopropoxide bis (2,4-pentanedionate), and titanium (IV). ) Ethoxide, titanium (IV) 2-ethylhexoxide, titanium (IV) isopropoxide, titanium (IV) propoxide and the like.

The solution ① may contain other substances in addition to the organic compound and the metal alkoxide. This solution is usually a reaction mixture in organic synthesis, which contains the organic compound and the alkoxide of the metal, as well as unreacted raw materials, catalyst, 畐 (J products, decomposition products, organic solvents, etc.) .

The amount of water used is not particularly limited. The amount is usually 0.1 to 100 L (liter), preferably 0.5 to 50 L (liter), per 1 mol of the alkoxide of the Group IV metal.

Polybasic liponic acid ③ refers to liponic acid having a plurality of lipoxyl groups in one molecule. Specific examples thereof include oxalic acid, malonic acid, succinic acid, glutaric acid, and adipic acid. Dicarboxylic acid having 2 to 8 carbon atoms such as maleic acid, fumaric acid, fumaric acid, isofluoric acid, terephthalic acid, and tricarboxylic acid having 6 to 10 carbon atoms such as citric acid. Among them, di- or tricarboxylic acids having 2 to 8 carbon atoms such as oxalic acid and citric acid are preferred. Also, a mixture of two or more of these may be used. The amount of the polybasic carboxylic acid ③ used is usually 0.2 to 20 mol, preferably 0.5 to 0.5 mol, per mol of the alkoxide of the Group III or Group IV metal in the short-periodic periodic table. Is a mole.

In the separation method of the present invention, the lipophilic organic solvent must be contained in the mixture when the metal compound is transferred to the aqueous layer. When mixing, if solution (1) already contains lipophilic organic solvent (2), only water (2) and polybasic carboxylic acid (3) need to be added, but solution (2) contains lipophilic organic solvent (2). If not, you need to add it.

The lipophilic organic solvent ④ may be any solvent which can be separated from water, for example, halogenated hydrocarbons having 1 to 2 carbon atoms such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc. C2-C6 ethers such as getyl ether, diisopropyl ether, dimethylene glycol dimethyl ether, and diethylene glycol getyl ether; C1-C3 lower aliphatic carboxylic acids such as methyl acetate, ethyl acetate, propyl acetate, and butyl acetate C1-C4 lower alkyl esters of acids, C6-C8 aromatic hydrocarbons such as benzene, toluene and xylene; C5-C7 alicyclic hydrocarbons such as cyclohexane, pentane Solvents such as aliphatic hydrocarbons having 5 to 7 carbon atoms, such as hexane, hexane and heptane. Lower alkyl esters of lower aliphatic carboxylic acids are preferred. Preferred specific examples of the lipophilic organic solvent include benzene, chloroform, carbon tetrachloride, dichloroethane, dichloromethane, dimethyl ether, diisopropyl ether, ethyl acetate, hexane, pentane, toluene and xylene. Ma Further, a mixed solvent of two or more of these, or a mixed solvent of these solvents and other solvents may be used. The amount of the lipophilic organic solvent to be used is not particularly limited, but is from 0.01 to: L 0 0 L (liter) per mole of the alkoxide of the Group II or Group IV metal in the short-periodic periodic table. Preferably, it is 0.1 to 50 L (liter). When the lipophilic organic solvent 既に is already contained in the reaction mixture, the lipophilic organic solvent しない can be omitted or the amount added can be reduced.

In the present invention, an alkoxide of a Group II or Group IV metal in the short-periodic table is decomposed by contact with water. Due to this decomposition, the alkoxide of the Group II or Group IV metal in the Short Periodic Table is probably an oxide of the Group II or Group IV metal in the Short Periodic Table. In the present invention, this refers to a compound of a Group II or Group IV metal in the short-periodic periodic table. In the separation method of the present invention, the order of mixing these may be any order. For example, a method of mixing solution (1) and water (2), and then mixing this with polybasic sulfonic acid (3), solution (2) And polybasic acid ruponic acid ③, then mix it with water 、, mix water ② with polybasic carboxylic acid ③, then mix this with solution 、, solution ① and water ② (4) A method of mixing a part of the polybasic carboxylic acid (3) and then mixing the remainder of the water (3) and the polybasic carboxylic acid (3). In addition, when a lipophilic organic solvent is newly mixed, for example, a solution is mixed with water and water, and then a polybasic carboxylic acid and lipophilic organic solvent are sequentially mixed. A method of mixing this with lipophilic organic solvent ④ and then with polybasic carboxylic acid ③, mixing solution ① and water 、, then adding polybasic carboxylic acid ③ and lipophilic organic solvent ④ A mixture of solution ②, lipoic acid ③ and lipophilic organic solvent ② with water 、, a mixture of solution ① and lipophilic organic solvent ② with water ② and polybasic A method of mixing a part of the carboxylic acid ③ and then sequentially mixing the water ② and the rest of the polybasic carboxylic acid ③ can be mentioned.

In the present invention, an organic compound which exhibits hydrophilicity at an arbitrary pH lower than an arbitrary pH higher than pH 2 is used, but is intended to separate an unstable organic compound at an arbitrary pH lower than the arbitrary pH. In such a case, it is necessary to prevent the pH of the aqueous layer from being lower than the arbitrary pH during mixing in the present invention. Therefore, the amount of polybasic ruponic acid ③ is p The range is such that H does not fall below the arbitrary pH. However, a basic compound may be used together with the polybasic force ruponic acid ③ to maintain the pH of the aqueous layer at a pH at which the target compound shows lipophilicity. In order to avoid a decrease in pH, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or the like, or an organic base such as triethylamine or pyridine may be added. Originally, the pH of the solution containing the target compound was high, and even if the required amount of polybasic liponic acid ③ was added, it was not necessary to add these if the target compound had a lipophilic pH. Further, in the present invention, when the purpose is to separate an organic compound that is stable but hydrophilic under a condition of an arbitrary pH value higher than pH 2 but lower than pH 2, the pH temporarily decreases during mixing. After mixing, the pH may be set to a pH region higher than the arbitrary pH value.

In the present invention, any of the above solutions (1), (2) and polybasic carboxylic acids (3) or solutions (1), (7), polybasic sulfonic acid (3) and a lipophilic organic solvent (4) having a liquid property higher than pH 2 When the organic compound is stirred for a while in the ρΗ region where the organic compound exhibits lipophilicity in the ρΗ region higher than the ρΗ value of the above, the compound of the metal, which is a decomposition product of the alkoxide of the metal, migrates to the aqueous layer if left standing. Then, it is separated into two layers: a lipophilic organic solvent layer containing an organic compound showing lipophilicity in a pH region higher than any pH value higher than ρΗ2, and an aqueous layer containing a decomposition product of the above-mentioned metal alkoxide. . If τ and the amount of the lipophilic organic solvent are small, they may not separate into two layers. In this case, add both water and / or the lipophilic organic solvent, stir and allow to stand. It can be separated into layers. If the alkoxide decomposition product remains as an insoluble material, polybasic carboxylic acid ③ may be added. When fine particles of the metal compound remain in the lipophilic organic solvent layer, the same operation may be repeated by further adding water (2) and polybasic carboxylic acid (3).

Then, by separating the lipophilic organic solvent layer by a conventional method, the target compound containing no or almost no fine particles of the metal compound (the lipophilicity in a pH region higher than ΗΡ2) is obtained. (An organic compound shown). The target compound can be obtained from the lipophilic organic solvent layer containing the target compound by a usual method, for example, separation, concentration, distillation, crystallization, or a combination thereof. Can be.

The present invention is generally applied to separation and purification of a target compound at the end of an organic synthesis reaction. For example, a compound represented by the formula (I) as a target compound is prepared from a reaction solution obtained by reacting a compound represented by the formula (II) with a compound represented by the formula (III) in the presence of a titanium alkoxide. It can be used for separation and purification. This reaction is usually performed in a solvent-free or organic solvent. In the formulas (I) and (II), the phenyl group which may be substituted by the octogen represented by Ar may be substituted by, for example, one or two of fluorine, chlorine, bromine, iodine and the like. Specific examples thereof include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, and 2-fluorophenyl. Preferable phenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl and the like are preferable, and among them, 2-fluorophenyl and 2,4-difluorophenyl are particularly preferable. In the formula (I), examples of the lower alkylene represented by X include a methylene chain having 1 to 4 carbon atoms such as methylene, ethylene and propylene. Examples of the organic solvent include methanol, ethanol (including various denatured ethanols), 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, Alcohols such as -methyl-2-propanol, ethylene glycol, methylene glycol monomethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, halogens such as dichloromethane, chloroform, carbon tetrachloride, dichloroethylene, etc. Hydrocarbons, ethers such as tetrahydrofuran, dioxane, geethylether, diisopropyl ether, dimethyleneglycoldimethylether, and dimethyleneglycolether, aromatic hydrocarbons such as benzene, toluene, and xylene Hydrogens, ketones such as acetone and ethyl methyl ketone, nitriles such as acetonitrile and benzonitrile, hydrocarbons such as cyclohexane, hexane, heptane and pentane, dimethylformamide, dimethylsulfoxide, dimethyla Aprotic polar solvents such as cetamide and hexamethylphosphoric triamide; and nitrogen-containing aromatics such as pyridine. Also, a mixed solvent of two or more of these, or a mixture of these solvents and other solvents May be used as a mixed solvent. Further, a solvent-free solution may be used. There is no particular limitation on the amount of solvent used,

It is preferable to use 0.01 to 100 L per 1 mol of the alkoxide of the Group III or Group IV metal in the short period type periodic table. The reaction temperature is suitably about 40 to 200 ° C, preferably about 70 to 180 ° C. Reaction times of about 1 to 80 hours are suitable, and about 5 to 50 hours are preferred.

In this reaction, the compound represented by the formula (III) is used in a larger amount than the compound represented by the formula (I) to increase the reaction rate. Therefore, the reaction mixture contains the unreacted compound represented by the formula (III) and is basic, and in this case, it may not be necessary to add a base. To this is added a di- or tricarboxylic acid having 2 to 8 carbon atoms and a lipophilic organic solvent ④. By this operation, the titanium compound, which is a decomposition product of the titanium alkoxide, moves to the aqueous layer, and the target compound moves to the lipophilic organic solvent layer. Therefore, the titanium compound and the target compound represented by the formula (I) are converted. Can be separated.

As described above, according to the separation method of the present invention, the target compound and the metal compound can be separated only by a simple liquid separation operation, which is advantageous for industrially producing the target compound. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1

(2 R, 3R)-2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino]-1- (1 H-1,2,4-triazol-1-y ) Synthesis of 2-butanol (2R, 3R)-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2,3 -Epoxybutane 7.0 kg, titanium tetraisoproxide 12.3 kg, ethanolamine 10.3 kg, 1-butanol 23 L were mixed and reacted under reflux for about 8 hours with stirring. . To the reaction solution, 35 L of ethyl acetate and 23 L of a 20% aqueous solution of citric acid were added, and further 12 L of water was added. The organic layer was concentrated under reduced pressure. Oy (2R, 3R) -2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino] -1- (1H-1,2,4_triazole (1-yl) -2-butanol (8.44 kg, yield: 97%) was obtained.

Example 2

(2R, 3R) -2- (2,4-difluorophenyl) -3 -_ [N- (2-hydroxyethyl) amino]-1- (1H-1,2,4-triazole-1- Synthesis of 2-butanol) (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl)- 7.0 kg of 2,3-epoxybutane, 12.3 kg of titanium tetraisoproxide, 10.3 kg of ethanolamine, and 23 L of 1-butanol were mixed and stirred under reflux for about 8 hours to react. I let it. 35 L of ethyl acetate and 23 L of a 20% aqueous solution of citric acid were added to the reaction solution, and 12 L of water was further added. A 20% aqueous solution of citric acid was added dropwise to the mixture, adjusted to pH 9.0, and separated. 23 L of water was added to the organic layer, and the mixture was adjusted to pH 11.0 with 30% Na〇H water and separated. To the organic layer was added 23 L of 1N-HC1, then adjusted to pH 1.0 with 6N-HC1, and separated. 123 L of IN-HC1 was added to the organic layer, and the mixture was extracted and separated. The aqueous layers were combined, 23 L of ethyl acetate was added, the mixture was adjusted to 30% Na〇I ^ i? PH 9.0, and the layers were separated. 23 L of ethyl acetate was added to the aqueous layer to separate the layers. The organic layers were combined and concentrated under reduced pressure. (2R, 3R) -2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino] -1- (1H-1,2,4-triazole in oil form 8.61 kg (-1-yl) -2-butanol was obtained (yield: 99%). Comparative Example 1

(2 R, 3 R) -2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino]-1- (1H- 1,2,4-triazol-1 Synthesis of (2-yl) -2-butanol (2R, 3R) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazole-1-yl ) 7.0 g of -2,3-epoxybutane, 12.3 g of titanium tetraisoproxide, 10.3 g of ethanolamine and 2 Oml of 2-propanol were mixed and reacted under reflux for about 20 hours with stirring. 35 ml of ethyl acetate and 25 ml of water were added to the reaction solution. The precipitated particulate compound was removed by filtration (using a filter paper on which a filter aid was placed), and washed with 10 ml of ethyl acetate. The filtrate and the washing were separated. 25 ml of water was added to the organic layer. The precipitated particulate compound is removed by filtration. The filter paper was used) and washed with 10 ml of ethyl acetate. The filtrate and the washing were separated. 25 ml of saturated aqueous sodium hydrogen carbonate was added to the organic layer. The precipitated particulate compound was removed by filtration (using a filter paper on which a filter aid was placed), and washed with 1 Oml of ethyl acetate. The filtrate and the washing were separated. 25 ml of saturated aqueous sodium hydrogen carbonate was added to the organic layer. The precipitated fine particles of the compound were removed by filtration (using a filter paper on which a filter aid was placed), and washed with 10 ml of ethyl acetate. The filtrate and the washing were separated. 25 ml of a 0.001 N aqueous sodium hydroxide solution was added to the organic layer. The precipitated particulate compound was filtered off (using a filter paper on which a filter aid was placed), and washed with ethyl acetate 1 Om1. The filtrate and the washing were separated. 25 ml of a 0.001N aqueous sodium hydroxide solution was added to the organic layer. The precipitated particulate compound was filtered off (using a filter paper on which a filter aid was placed) and washed with 10 ml of ethyl acetate. The filtrate and the washing were separated. 25 ml of a 0.001N aqueous sodium hydroxide solution was added to the organic layer, and the mixture was separated. The organic layer was washed with 25 ml of water. Again, the organic layer was washed with 25 ml of water. The organic layer was concentrated under reduced pressure. (2R, 3R) -2- (2,4-difluorophenyl) -3- [N- (2-hydroxyethyl) amino] -1-(1H-1,2,4-triazole in oily form -1-yl)-3.9 g (yield: 45%) of 2-butanol were obtained.

Reference example 1

Synthesis of 1-p-aminophenyl-1H-tetrazole

In a nitrogen stream, 44 kg of 1-P-nitrophenyl-1H-tetrazole and 88 kg of water were mixed, heated to about 75 ° C, and 85 kg of 34% sodium hydrosulfide was added dropwise at 83 ° C or less. The reaction was carried out by stirring at about 80 ° C. After cooling, the crystals were collected by filtration and washed with 98 kg of water. 41 kg of l_p-aminophenyl-1H-tetrazole wet crystals were obtained. Industrial applicability

The decomposition of the alkoxide of a Group III or Group IV metal with water in the short-periodic periodic table can be separated from the organic compound by a simple liquid separation operation, which is advantageous for industrially producing the target compound. is there.

Claims

The scope of the claims

(1) 1) Organic compounds exhibiting lipophilicity in the pH range higher than pH 2 and short-periodic type solutions containing alkoxides of Group III or IV metals in the periodic table; 2) Water and 3) Polybasic carboxylic acids And transferring the compound of the metal to an aqueous layer by mixing the organic compound and the compound of the metal.

(2) The method according to claim 1, wherein a lipophilic organic solvent is further added during the mixing.

(3) A method comprising mixing a solution containing an organic compound exhibiting lipophilicity in the pH region higher than pH 2 and an alkoxide of a Group III or Group IV metal in the short-periodic periodic table with an aqueous solution of polybasic carboxylic acid. The method of paragraph 1.

(4) The lipophilic organic solvent is a halogenated hydrocarbon having 1 to 2 carbon atoms, an ether having 2 to 6 carbon atoms, a lower alkyl ester of a lower aliphatic carboxylic acid, or an aromatic hydrocarbon having 6 to 8 carbon atoms. , Aliphatic hydrocarbons having 5 to 7 carbon atoms, alicyclic hydrocarbons having 5 to 7 carbon atoms, mixed solvents of two or more of these, or mixed solvents of these solvents with other solvents 3. The method of claim 2, wherein

(5) The method according to claim 1, wherein the alkoxide of the Group III or Group IV metal in the short-periodic table is an alkoxide of titanium, zirconium or aluminum.

(6) The polybasic carboxylic acid is oxalic acid, malonic acid, succinic acid, daltaric acid, adipic acid, maleic acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, citric acid or any of these 2. The method according to claim 1, which is a mixture of two or more.

(7) The method according to claim 1, wherein the amount of the polybasic carboxylic acid used is 0.5 to 10 mol per 1 mol of the alkoxide of the Group III or Group IV metal in the short period periodic table.

(8) The method according to claim 1, wherein the amount of water used is 0.1 to 100 liters per mole of the alkoxide of a Group III or Group IV metal in the short-periodic periodic table.

(9) The method according to claim 1, wherein the alkoxide of a Group III or Group IV metal in the short period periodic table is a dimethyl alkoxide.

(10) When transferring the metal compound to the aqueous layer, adjust the pH of the mixed solution from pH2. 3. The method according to claim 1, wherein the organic compound exhibiting lipophilicity in a high pH region is adjusted to a pH region exhibiting lipophilicity.

(1 1) An organic compound having lipophilicity in a pH range higher than pH 2 is represented by the formula:

[In the formula, Ar represents a phenyl group optionally substituted with halogen, X represents a lower alkylene group, and (R) represents a steric configuration. Wherein the alkoxide of the Group II or Group IV metal in the short-periodic table is an alkoxide of titanium and the polybasic carboxylic acid is a di- or tricarboxylic acid having 28 carbon atoms. 2. The method according to claim 1, wherein the lipophilic organic solvent is a lower alkyl ester of a lower aliphatic carboxylic acid.

(12) 1) A solution containing an organic compound exhibiting lipophilicity and an alkoxide of a Group III or Group IV metal in the short-periodic periodic table is mixed with 2) water and 3) a polybasic carboxylic acid, A method for separating the organic compound and the metal compound, wherein the metal compound is transferred to an aqueous layer.

Equation (13):

[In the formula, Ar represents a phenyl group which may be substituted with halogen, and (R) and (S) represent a steric configuration. And a compound represented by the formula:

H ₂ N— X— 0H (Ml)

[Wherein each symbol has the same meaning as described above. A mixture of water, a di- or tricarboxylic acid having 2 to 8 carbon atoms and a lipophilic organic solvent, and transferring the titanium compound to an aqueous layer. A method for producing a compound represented by the formula (I):

(14) The method according to claim 13, wherein the titanium alkoxide is titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, or titanium (IV) butoxide.

(15) The process according to claim 13, wherein the lipophilic organic solvent is benzene, chloroform, carbon tetrachloride, dichloroethane, dichloromethane, dimethyl ether, diisopropyl ether, ethyl acetate, hexane, pentane, toluene or xylene. .

(16) The method according to claim 13, wherein the pH of the mixture is adjusted to 7.0 to 10.0 when the titanium compound is transferred to the aqueous layer.