KR20140015878A - New process for the preparation of optical active piperidine compounds - Google Patents

Abstract

The present invention relates to a new method for producing (S)-4-[4-[(4-chlorophenyl)-(2-piridyl)methoxy] piperidine-1-yl]butanoic acid represented by the chemical formula (I) and more specifically, to a method for facilitating the production of an optically pure target compound, the chemical formula (I), with high yeilds and high purity by halogenating (S)-(+)-∂-(4-chlorophenyl)-2-pyridinemethanol (II) compound under the presence of thionylchloride and organic bases for inversion and obtaining (R)-(-)-α-(4-chlorophenyl)-2-pyridylmethylhalide (II'), then inversely reacting it with 4-(4-hydroxypiperidyl)-butane derivatives (III) and producing the chemical formula (IV) using a method different from the previous known methods, then hydrolyzing the chemical formula (IV) using a general method. In the chemical formulas, A is protected carboxyl group or nitryl group, and M is hydrogen, alkaline metals, or alkaline earth metals, and X is a halogen atom.

Description

New process for the preparation of optical active piperidine compounds}

The present invention provides a benzene sulfonic acid salt of (S) -4- [4-[(4-chlorophenyl) -2-pyridyl] methoxy] piperidino butanoic acid (I) having excellent antihistamine activity and antiallergic activity. A novel process for the preparation of (S) -4- [4-[(4-chlorophenyl) -2-pyridyl] methoxy] piperidino butanoic acid, which is a key intermediate of benzoic acid salts.

The present invention is characterized in that the compound of formula (I) can be produced more easily with optically higher purity than a known production method.

Bepotastine represented by the above formula (I) has a chemical name of (S) -4- [4-[(4-chlorophenyl) -2-pyridyl] methoxy] piperidino butanoic acid Acid addition salts bepotastine besylate or bepotastinebenzoate compounds obtained by reacting with benzene sulfonic acid or benzoic acid exhibit potent antihistamine and antiallergic activity.

Conventional manufacturing methods include US Pat. No. 4,953,638, European Patent No. 335586, 949260, and the like. In particular, Japanese Patent Application Laid-Open No. 2-25465 discloses bepotastine as a racemic compound for the first time. -198784 discloses a racemic compound (V) with an optically active propionic acid compound (VI) or an optically active N-acyl-amino acid, and the two diastereomeric salts produced by using a solubility difference using poorly soluble diastereomers. The salts are separated and collected, and then the salts are liberated in (S) -4-[(4-chlorophenyl) -2-pyridyl] methoxy] piperidine (VIII). The acid ester is reacted to give free bepotastine ester (Ⅸ), which is hydrolyzed to obtain compound (I), and then subjected to salt formation reaction with benzenesulfonic acid or benzoic acid to give an optically active piperidine compound (I). Benzenesulfonic Acid Salt Or a method for producing a benzoic acid salt.

In said formula, R represents lower alkyl groups, such as a methyl group and an ethyl group,

X is a halogen atom, Y is a hydrogen atom or a halogen atom, and Z represents a lower alkoxy group.

However, the conventional method as described above is difficult to react, complicated and purity is also undesirable.

The present invention is to further simplify the reaction process and to obtain the target compound (I) in high purity and high yield.

The present invention is to invert the (S)-(+)-a- (4-chlorophenyl) -2-pyridinmethanol (II) compound optically partitioned by a known method in the presence of thionyl halide and an organic base. To give (R)-(-)-∂- (4-chlorophenyl) -2-pyridylmethylhalide (II ') to give this compound 4- (4- (activated) hydroxypiperiline of formula (III). (D) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] moiety which is an optically active compound by inversion reaction with a dill) -butanoic acid derivative compound A carbonic acid derivative compound is prepared, and a carboxylic acid protecting group or a nitrile group is hydrolyzed under acidic or alkaline conditions by a general method to formula (I) Compound (S)-(+)-4- [4-[(4-chlorophenyl An object thereof is to provide a method for easily preparing a)-(2-pyridyl) methoxy] piperidino] butanoic acid compound.

The present invention described above has the advantage that the reaction process is very simple and the target compound (I) can be obtained optically with high purity and high yield.

The present invention, as shown in the following reaction step 1, known method, Tetrahedron Letters vol 37, No 32, pp 5675-5678 (1996): (S)-"Subsynthesis of Carbinoxamine" After preparing (S)-(+)-α- (4-chlorophenyl) -2-pyridylmethanol compound of), the compound is reacted with thionyl chloride in the presence of pyridine to give (R)-(-)- α- (4-chlorophenyl) -2-pyridylmethylchloride compound (II ') is prepared or (S)-(+)-α- (4-chlorophenyl) -2- of formula (II) in the presence of pyridine. The pyridylmethanol compound is reacted with para-toluenesulfonyl chloride to protect the hydroxyl group and then halogenated with thionyl halide to give (R)-(-)-α- (4-chlorophenyl) -2-pyridyl Methyl halide compound (II ') is obtained.

It is condensed with 4- (4- (activated) hydroxypiperidyl) -butanoic acid derivative compound of formula (III) to give (S) -4- [4-[(4-chlorophenyl)-of formula (IV). A (2-pyridyl) methoxy] piperidino] butanoic acid derivative compound is prepared and hydrolyzed by carboxylic acid protecting group or nitrile group by a general method to give the desired bepotastine intermediate (S). 4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid and its salt compounds are prepared. This is represented by the following formula.

Wherein A is a protected carboxyl or nitrile group, M is hydrogen, an alkali metal or an alkaline earth metal, and X is a halogen atom.

In more detail, the formula (II ′) (R)-(-)-α- (4-chlorophenyl) -2-pyridylmethylhalide compound is represented by the formula (II) compound (S)-(+)- α- (4-chlorophenyl) -2-pyridylmethanol is dissolved directly in an organic base such as quinoline, pyridine, dimethylaniline, triethylamine, diisofurophylethylamine, diisofurophylamine, or benzene, toluene, The mixture is dissolved with a solvent such as xylene, tetrahydrofuran, dioxane, chloroform, dichloromethane, diethyl ether, acetonitrile, ethyl acetate, and the like, and the reaction temperature is -75 to 25 ° C, preferably -50 to 10 ° C. More preferably, the halogenation reaction is carried out using a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus tribromide or the like as a halogenating agent between -20 and 0 ° C.

At this time, the equivalent of the organic base used is 1 to 5 times equivalent, preferably 2 to 4 times equivalent to the starting material (S)-(+)-a- (4-chlorophenyl) -2-pyridyl methanol Preferably 2.5 to 3.5 times the equivalent amount of the halogenating agent is also used 1 to 10 times equivalents, preferably 2 to 8 times equivalents, more preferably 3 to 6 times the equivalent of the starting material (S) It is possible to purely convert 99% or more of the three-dimensional compound of the-(+)-form to the (R)-(-)-form compound.

In addition, the hydroxyl group of the compound of formula (II) (S)-(+)-∂- (4chlorophenyl) -2-pyridylmethanol may be selected from quinoline, pyridine, dimethylaniline, triethylamine, diisopurofylethylamine, Excellent leaving groups such as methanesulfonylchloride, para-toluenesulfonyl chloride, 4-nitrobenzylchloride, 4-nitrobenzenesulfonylchloride and the like are introduced as protecting groups in the presence of an organic base such as diisofurophylamine and the like. The solvent used at this time is dimethyl sulfoxide, dimethylformamide, dioxane, benzene, toluene, xylene, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, chloroform, dichloromethane, dietel ether Reaction is carried out using a single solvent such as tetrahydrofuran or two or more mixed solvents. The reaction temperature is maintained at -75 to 25 ° C, preferably at -50 to 10 ° C, more preferably at -20 to 0 ° C, and then as the halogenating agent, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, Phosphorus bromide or the like is used to cause the chloro bromination reaction.

At this time, the equivalent of the organic base used is 1 to 5 times equivalent, preferably 2 to 4 times equivalent to the starting material (S)-(+)-α- (4-chlorophenyl) -2-pyridylmethanol. Preferably 2.5 to 3.5 times the equivalent and the protecting group 1 to 2 times the equivalent of the starting material, preferably 1 to 1.6 times, more preferably 1 to 1.3 times the equivalent.

The amount of the halogenating agent used is also 1 to 10 times equivalent to the starting material, preferably 2 to 8 times equivalent, more preferably 3 to 6 times the equivalent of the (S)-(+)-former It is possible to convert more than 99% purely to (R)-(-)-form compound. Thus prepared (R)-(-)-α- (4-chlorophenyl) -2-pyridylmethylhalide compound and the 4- (4-hydroxypiperidyl) -butanoic acid derivative compound of formula (III) In the reaction, using an organic solvent such as toluene, dioxane, xylene, methylisobutyl ketone or dimethylformamide, etc., at a temperature of 80-140 ° C, preferably 100-140 ° C, more preferably 120-140 ° C, for example For example, the conversion reaction in the presence of an acid acceptor of an alkali metal carbonate or bicarbonate, such as sodium carbonate, sodium amide, sodium hydride, metal sodium, potassium amide, potassium thibutoxide, potassium carbonate, sodium bicarbonate, sodium bicarbonate, etc. Compound (IV) (S)-(+)-4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid derivative compound was prepared as follows. Ester protecting group or nitrile group Hydrolysis of compound (Ⅰ), (S) - (+) - 4- [4 - [(4- chloro-phenyl) - (2-pyridyl) methoxy] piperidino] Part tansanreul obtained.

Carboxylic protecting groups and nitrile groups are refluxed for 2-20 hours under reflux using an aqueous 6-10 N concentration of an inorganic acid solution such as hydrochloric acid or sulfuric acid, preferably 6-14 hours, to remove the protecting group or a general inorganic alkali, caustic soda or potassium. The reaction is carried out under alkaline conditions such as hydroxide for 2-20 hours at room temperature or under reflux, preferably for 6-14 hours.

The reaction solution is washed with an organic solvent such as ether, ethyl acetate, benzene, toluene, xylene, and the like, and then alkalinized with a strong alkali solution such as concentrated ammonia water, sodium or potassium hydroxide, or acidified with an aqueous solution of concentrated inorganic acid to form an organic solvent. Extract it.

At this time, the organic solvent is extracted with a solvent such as chloroform, methylene chloride, benzene, xylene, toluene, ethyl acetate to obtain the compound (1).

When M in the compound of formula (III) is hydrogen, hydrogen can be further activated by substitution with an alkali metal or an alkaline earth metal by a conventional method, and such a method is a technique generally performed in the field of organic chemistry. In this case, the reaction may be performed directly with an alkali metal or an alkaline earth metal, and may be substituted by other conventional methods.

What has been described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1.

Synthesis of (R)-(-)-a- (4-chlorophenyl) -2-pyridylmethylchloride

5 g (22.8 mM) of (S)-(+)-(4-chlorophenyl) -2-pyridylmethanol was added to 30 ml of xylene, 7.5 ml (11 mM) of pyridine was added thereto, followed by 2 ml (25 mM) of thionyl chloride. Is added dropwise at 0 ° C. After stirring for 2 hours, the temperature is gradually raised to 20 ℃, further stirred at 30 ℃ for 2 hours and then cooled to 0 ~ 5 ℃ again. 30 ml of distilled water is carefully added to the mixture, followed by slowly adding 35 ml of concentrated ammonia water. After confirming that the mixed solution became strong alkali, the layers were separated, and the organic layer was washed with distilled water saturated brine distilled water in 10 ml steps. The solution is dried for 10 minutes with anhydrous magnesium sulfate and filtered. The filtrate is distilled off under reduced pressure to remove xylene to obtain 0.5 g (92.3%) of the target compound. 1 H NMR (CDCl ₃ ): δ 5.6 (1H) 7.0-.2 (2H), 7.2-.6 (4H) 7.6-.81H), 8.5 (1H)

This material is used for the next reaction without the aftertreatment process.

Example 2.

Synthesis of (R)-(-)-a- (4-chlorophenyl) -2-pyridylmethylchloride

5 g (22.8 mM) of (S)-(+)-(4-chlorophenyl) -2-pyridylmethanol was added to 50 ml of methylene chloride, and 7.5 ml (11 mM) of pyridine was added thereto, followed by 4.4 g of paratoluenesulfonyl chloride. (23 mM) is added at 0 ° C. While maintaining this temperature, the mixture was stirred for 3 hours, and then cooled to the reaction temperature of -30 ° C. 2 ml (25 mM) of thionyl chloride is added dropwise to the reaction mixture. Stir for 2 hours and then slowly raise the temperature to 30 ° C. and stir at this temperature for 3 hours. After confirming that the reaction is completed and cooled to 0 ~ 5 ℃. 60 ml of distilled water is slowly added dropwise to this mixture, followed by 70 ml of concentrated ammonia water. After confirming that the solution became alkaline, the layers were separated, and the organic layer was washed with distilled water, saturated brine, and distilled water in order of 20 ml. The solution is dried for 10 minutes with anhydrous magnesium sulfate and filtered. The filtrate was distilled off under reduced pressure to remove methylene chloride to obtain 0.51 g (93.9%) of the target compound.

1 H NMR (CDCl ₃ ): δ 5.6 (1H), 7.0-7.2 (2H) 7.2-7.6 (4H), 7.6-7.8 (1) 8.5 (1H)

Example 3.

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl ester

23.8 g (0.1 mol) of (R)-(-)-4-chlorophenyl-2-pyridyl-methylchloride and 21.2 g (0.1 mol) of ethyl 4- (4-hydroxypiperidinyl) -butanoate It is added in 200 ml of methyl ethyl ketone and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure and purified to obtain 36.2 g of (S)-(+)-4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid ethyl as an oil. Got it. (Yield 90%, Optical Purity 99.9%, ee).

¹ H NMR (CDCl ₃ ): δ 1.0-1.3 (3H), 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 4.0 (2H), 5.45 (1H ), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 4.

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl ester

23.8 g (0.1 mol) of (R)-(-)-[4-chlorophenyl-2-pyridyl] methylchloride and 21.2 g (0.1 mol) of ethyl 4- (4-hydroxypiperidinyl) -butanoate Is added in 200 ml of methyl isobutyl ketone and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure and purified to obtain 36.2 g of ethyl (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl butanoate as an oil. (Yield 90%, Optical Purity 99.9%, ee).

¹ H NMR (CDCl ₃ ): δ 1.0-1.3 (3H), 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 4.0 (2H), 5.45 (1H ), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 5

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl ester

28.3 g (0.1 mol) of (R)-(-)-4-chlorophenyl-2-pyridyl-methylbromide and 21.2 g (0.1 mol) of ethyl 4- (4-hydroxypiperidinyl) -butanoate It is added in 200 ml of acetone and reacted for 4 hours under reflux. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure and purified to obtain 36.2 g of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid ethyl ester as an oil. (Yield 90%, Optical Purity 99.9%, ee).

¹ H NMR (CDCl ₃ ): δ 1.0-1.3 (3H), 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 4.0 (2H), 5.45 (1H ), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 6

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] -butyronitrile

23.8 g (0.1 mol) of S-(+)-4-chlorophenyl-2-pyridylmethylchloride is dissolved in 200 ml of anhydrous acetonitrile, to which 2.53 g (0.11 mol) of sodium are added. 16.7 g (0.1 mol) of ethyl 4- (4-hydroxypiperidinyl) -butyronitrile are added to dissolve and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure to obtain 35.9 g of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butyronitrile as an oil. (Yield 97%, Optical Purity 99.9%, ee).

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 7

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] -butyronitrile

28.3 g (0.1 mol) of S-(+)-4-chlorophenyl-2-pyridyl-methylbromide is dissolved in 200 ml of anhydrous tetrahydrofuran, to which 2.53 g (0.11 mol) of sodium are added. Water was blocked and 16.7 g (0.1 mol) of ethyl 4- (4-hydroxypiperidinyl) -butyronitrile was added to dissolve and reacted under reflux for 4 hours. The solution is cooled and the precipitated crystals are filtered off. The solution was concentrated under reduced pressure to obtain 35.9 g of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butyronitrile as an oil. (Yield 97%, Optical Purity 99.9%, ee).

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2. (4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (2), 7.2- 7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 8

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid

36.2 g (0.1 mol) of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] ethyl carbonate obtained in Example 2 in 220 ml of ethanol After dissolution, 34.7 ml of 5 N sodium hydroxide solution was left overnight, and then neutralized by addition of 5 N hydrochloric acid equivalent. The precipitated sodium chloride was filtered off and the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 170 ml of dichloromethane, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated to give amber syrup (33.6 g).

[α] _D25 + 3.4 ° (c = 5, MeOH).

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 9

Synthesis of (S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butanoic acid

37 g (0.1 mol) of S) -4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino] butyronitrile obtained in Example 6 was dissolved in 5 N sodium hydroxide solution 40 It was added to ml and refluxed overnight, then neutralized by addition of 5 N hydrochloric acid equivalent. The precipitated reaction mixture was filtered to give amber syrup (38.7 g).

[α] _D25 + 3.4 ° (c = 5, MeOH).

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (2H), 7.2-7.6 (4H), 7.6-7.8 (1H), 8.5 (1H).

Example 10

Ethyl 4- [4-hydroxypiperidinyl] butyrate synthesis

18 g of 4-hydroxypiperidine, 450 ml of methyl isobutyl ketone, 30 ml of ethyl 4-bromo butyrate, 49 g of potassium carbonate and a catalytic amount of potassium iodine are added and heated. After refluxing for 24 hours, it is cooled to room temperature and 100 ml of cold water are added. 100 ml of ethyl acetate was extracted, the layers were separated, dried over a forget-me-not, and the solvent was removed under reduced pressure to obtain 28.5 g (74.5%) of the target compound as an oil.

¹ H NMR (CDCl ₃ ): δ 1.2 (3H), 1.8-2.2 (4H), 2.3-2.6 (6H), 2.4-2.8 (4H), 3.4 (1H), 4.0 (2H).

Example 11

Synthesis of 4- [4-hydroxypiperidinyl] butyronitrile

18 g of 4-hydroxypiperidine, 450 ml of methyl isobutyl ketone, 20 ml of 4-bromo butyronitrile, 49 g of potassium carbonate and a catalytic amount of potassium iodine are added and heated. After refluxing for 24 hours, it is cooled to room temperature and 100 ml of cold water are added. 100 ml of ethyl acetate was extracted, the layers were separated, dried over a forget-me-not, and the solvent was removed under reduced pressure to obtain 24 g (80%) of the target compound as an oil.

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (4H), 2.3-2.6 (6H), 2.4-2.8 (4H), 3.4 (1H).

 Example 12

Preparation of (S) -Bepotastine Benzene Sulfonate

5.0 g of (S) -bepotastine is added to 260 ml of ethyl acetate to dissolve, and then 2 g of benzenesulfonic acid monohydrate is added to make a homogeneous solution. The solvent was removed under reduced pressure, and 260 ml of ethyl acetate was further added to the residue, followed by stirring overnight. The solvent was again removed by darkening, 100 ml of acetonitrile were added to the residue, and stirred for 3 days at room temperature to obtain 3 g of the target compound.

Melting Point: 159-163

¹ H NMR (CDCl ₃ ): δ 1.8-2.2 (6H), 2.3-2.6 (4H), 2.4-2.8 (4H), 3.5 (1H), 5.45 (1H), 7.0-7.2 (2H), 7.2-7.6 (9H), 7.6-7.8 (1H), 8.5 (1H).

Claims (2)

(R)-(-)-a- (4-chlorophenyl) -2-pyridylmethylhalide of formula (II ') is then added to 4- (4-hydroxypiperidyl) -part of formula (III). (S)-(+)-4- [4-[(4-chlorophenyl)-(2-pyridyl) methoxy] piperidino of the formula (IV) ] Butane derivatives are prepared, and the carboxyl protecting group or nitrile group of the compound is hydrolyzed to give the following formula (I)-(+)-4- [4-[(4-chlorophenyl)-(2-pyri) Dill) methoxy] piperidino] butanoic acid.

Wherein A is a protected carboxyl or nitrile group,
M is hydrogen, an alkali metal or an alkaline earth metal, and X is a halogen atom.
4- (4-substituted piperidyl) -butane derivative of formula (III)

Wherein A and M are the same as in claim 1.