KR20110036191A - Method for preparing active piperidine compound by optical separation - Google Patents

Abstract

The present invention relates to a method for preparing (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidine of the following general formula (II), more specifically (±) -4- [(4-Chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl-R (III) compound was prepared by a method different from the conventionally known methods, and was prepared using an optically active separating agent. After the optical separation in the yield, the protective group (R) is removed by a general method to obtain a target compound (II) of high optical purity.

Where

R is amino protecting groups, such as an acetyl group, a benzoyl group, and a benzyl group.

Description

Process for the preparation of active piperidine compounds by optical isolation

The present invention provides a key intermediate of the benzene sulfonic acid salt or benzoic acid salt of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidino butanoic acid (I), which has excellent antihistamine activity and antiallergic activity. A novel process for the preparation of phosphorus (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidine (II).

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

Bepotastine represented by the formula (I) is a benzene sulfonic acid salt or benzoic acid having a chemical name of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidino butanoic acid. Salt, and exhibits strong antihistamine activity 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 (II) which reacts with an optically active propionic acid compound (IV) or an optically active N-acyl-amino acid and generates two types of diastereomeric salts using different solubility solubility diastereomers. The salt is separated and the halogen acid ester represented by the formula (V) is applied to (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidine obtained by decomposing the salt. To obtain free bepotastine (VI), and hydrolyze it to obtain compound (I), followed by further salt formation reaction with benzenesulfonic acid or benzoic acid to give an optically active piperidine compound represented by the above formula (I) Ⅰ) It relates to a process for preparing benzenesulfonic acid salts or benzoic acid salts.

In the above formula, R represents a lower alkyl group such as methyl group or ethyl group, W represents leaving group such as halogen atom or reactive ester group such as methanesulfonyl oxy group, p-toluene sulfonyloxy group, and Y represents hydrogen atom or 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 a high purity target compound (II).

The present inventors condensed the compound of formula (VII) optically divided by a known method with a compound of formula (VII) to obtain a compound of formula (III) which is an optically active compound or a racemic intermediate of formula (VII). After condensation with a compound to obtain a racemic compound of formula (III), the compound was subjected to dia using R-(-)-10-camphorsulfonic acid or (-)-dibenzoyl-D-tartaric acid as an optically active separating agent. (S) -4-[(4-chlorophenyl) -2-pyridylmethene of formula (II) having high optical purity and chemical purity by the method of optical separation using a suitable solvent after forming a stereomeric salt. It is an object of the present invention to provide a method for easily preparing oxy] piperidine.

The present invention described above has the advantage that the reaction process is very simple, and the target product can be obtained with high purity.

The present invention provides a well-known method, Tetrahedron Letters vol 37, No 32, pp 5675-5678 (1996): (S)-"Subsynthesis of Carbinoxamine" and Bull. Chem. Soc. Jpn ,. Vol 60, pp 2651-2655 (1987) After the preparation of the compound of formula (VIII) as shown in "Preparation of alpha-aryl-2-pyridylmethanol", the compound (v) is condensed with the compound of formula (VIII) To prepare the compound of formula (III) and to remove the protecting group by the general method to produce the desired intermediate (II) compound.

                                 [Reaction Process 1]

Wherein R is an acetyl, benzoyl, benzyl group,

X is halogen, fluorine, chlorine, cancelled, iodine or an alkyl or arylsulfonyloxy group.

In more detail, when the compound of formula (V) is reacted with the compound of formula (V), an organic solvent such as toluene, dioxane, xylene, methyl isobutyl ketone or dimethylformamide may be used at a temperature of 80-140 ° C., preferably Is condensed at 100-140 ° C., more preferably 120-140 ° C., in the presence of an acid acceptor of an alkali metal carbonate or bicarbonate such as, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium bicarbonate, etc. (III) is obtained and the protecting group (R) is removed by the following general method to obtain compound (II).

That is, when R of the compound (III) thus obtained is benzyl, the benzyl group is cleaved by the catalytic reduction method.

At this time, the catalyst used may be removed by using a metal catalyst such as palladium, palladium, or a common benzyl group removal method.

When R is acetyl or benzoyl, the protecting group is removed by refluxing for 2-20 hours, preferably 6-14 hours, under reflux using an aqueous 6-10 N concentration of an inorganic acid solution such as hydrochloric acid or sulfuric acid.

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 and extracted with an organic solvent.

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

In another process, as shown in Reaction Step 2, a racemic compound (VII ') of the compound of formula (VII) After chlorination with onyl chloride, the compound of formula (V) is condensed to the obtained compound of formula (VII), and then (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidine- is obtained. The 1-yl-R (III) racemic mixture was reacted with R-(-)-10-camphorsulfonic acid or (-)-dibenzoyl tartaric acid as an optically active separating agent in a racemic mixture in high yield, high purity ( After optical separation of only the S) body, the protecting group (R) is removed in a general manner to prepare the compound of formula (II).

[Reaction Process 2]

Wherein R is as defined above and X is a hydroxyl group.

In more detail, the reaction step 2 is obtained by halogenating a racemic compound of formula (VII) with a halogenating agent such as thionyl chloride, phosphorus tribromide, phosphorus obromide, phosphorus oxychloride, ) Is condensed with the compound (iii).

In the reaction, using an organic solvent such as toluene, dioxane, xylene, methyl isobutyl ketone or dimethylformamide, or without solvent, at 80-140 ℃, preferably 100-140 ℃, more preferably 120-140 ℃, For example, compound (II) is obtained by conducting a condensation reaction in the presence of an acid acceptor of an alkali metal carbonate or bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate and sodium bicarbonate.

Compound (II) thus obtained is chlorinated with a racemic compound with an acid having optical activity such as R-(-)-10-camphorsulfonic acid or (-)-dibenzoyl tartaric acid in acetone solvent, followed by constant optical rotation. By continuously recrystallizing the salts until the product indicated is obtained and releasing left-rotating isomers from the salts with a base, the compound of formula (II) having excellent purity as the target compound is obtained.

The thus obtained formula (II) salt compound is further recrystallized in a suitable organic solvent, preferably R-(-)-10-camphorsulfonic acid salt of compound (II) having a yield of 60-80% and high optical purity. Or (-)-dibenzoyl tartaric acid salt.

Optical purity is at least about 95-99.9%, preferably about 98-99.9%.

Preferred cosolvents are selected from the group consisting of dimethyl formamide, dimethyl sulfoxide, toluene, heptane, dimethylacetamide.

Preferred acid acceptors are bases.

The definition is as set forth above and the number of moles used is 1-4 times the number of moles.

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

[ Example ]

(Example 1) Preparation of 4-hydroxy-1-benzoyl-piperidine

5.5 g of sodium borohydride is added to 1,200 ml of dichloromethane, and 24 g of 1-benzoyl-4-piperidine is added to 80 ml of dichloromethane while stirring at room temperature, followed by dropwise addition while maintaining the above temperature.

After complete addition, the temperature is raised to room temperature and then stirred at the same temperature for 6 hours.

After confirming that the reaction was completed, slowly added to 1,200 ml of saturated aqueous sodium bicarbonate solution and stirred for 10 minutes at the same temperature.

The layers were separated and the organic layer was washed with 500 ml of distilled water, dried over 5 g of anhydrous magnesium sulfate, and filtered.

The filtrate was removed under reduced pressure to give 20 g (yield 82%) of the title compound as an oil.

1 H NMR (CDCl 3): δ 1.96 (4H, -CH 2-), 2.24 (4H, -CH 2-), 3.44 (1H), 7.44 (2H, aromatic core), 7.51 (1H, aromatic core), 7.95 (2H, Direction nucleus)

( Example 2) Preparation of 4-hydroxy-1-acetyl piperidine

Add 0.69 g of sodium borohydride to 50 ml of dichloromethane, add 0.9 ml of 1-acetyl-4-pyridone at room temperature and stir for about 10 hours.

After the reaction was completed, the reaction solution was added to 50 ml of saturated aqueous sodium bicarbonate solution and stirred for 10 minutes.

Extract twice with 100 ml of dichloromethane.

The organic layer was washed twice with 50 ml of purified water and dried over 5 g of dry forget-me-not.

Filtration and removal of the filtrate by reduced pressure yielded 0.8 g (86.8%) of the title compound.

1 H NMR (CDCl 3): δ 1.65 (4H, -CH 2-), 2.0 (1H, -OH), 2.02 (3H, -CH 3), 3.34 (4H, -CH 2-)

(Example 3) Preparation of 4-bromo-1-benzoyl-piperidine

20 g of 4-hydroxy-1-benzoyl piperidine are added to 80 ml of benzene and dissolved.

11 ml of phosphorus tribromide are slowly added and heated to reflux for 3 hours.

Confirm that the reaction is complete and cool to room temperature.

200 ml of purified water was added to the reaction solution, the mixture was stirred at room temperature for 10 minutes, followed by layer separation. The organic layer was taken out and washed twice with 50 ml of purified water.

The organic layer is dried over anhydrous forget-me-not and filtered.

The filtrate is removed in vacuo to give 11.6 g (45% yield) of the title compound as an oil.

1 H NMR (CDCl 3): δ 1.96 (4H, -CH 2-), 3.34 (4H, -CH 2-), 3.44 (1H), 7.44 (2H, aromatic nucleus), 7.51 (1H), 7.95 (2H)

(Example 4) Preparation of 4-bromo-1-benzyl piperidine

0.83 g of 4-hydroxy-1-benzylpiperidine is added to 4 ml of benzene and dissolved, followed by 1.43 g of tribromoin.

Warm to reflux for 5 hours and then cool to room temperature.

5 ml of cold water is added to the reaction mixture, which is stirred for 5 minutes, followed by strong alkaline with concentrated ammonia water.

The layers are separated and the organic layer is taken and washed twice with 2 ml of purified water.

The organic layer is dried over anhydrous forget-me-not, filtered and the filtrate is removed by reduced pressure to give 0.35 g (yield 32%) of the title compound.

1 H NMR (CDCl3): δ 1.96 (4H, -CH2-), 3.24 (4H, -CH2-), 3.44 (1H), 3.62 (2H, -CH2-), 7.06 (2H, aromatic nucleus), 7.07 (1H) , Direction nucleus), 7.14 (2H, direction nucleus)

(Example 5) Preparation of 4-Bromo-1-Acetyl-piperidine

0.83 g of 4-hydroxy-1-acetylpiperidine is added to 4 ml of benzene to dissolve, followed by 1.43 g of tribromoin.

Warm to reflux for 5 hours and then cool to room temperature.

5 ml of cold water is added to the reaction mixture, which is stirred for 5 minutes, followed by strong alkaline with concentrated ammonia water.

The layers are separated and the organic layer is taken and washed twice with 2 ml of purified water.

The organic layer was dried over anhydrous forget-me-not, filtered and the filtrate was removed by reduced pressure to give 0.42 g (yield 35%) of the title compound.

1 H NMR (CDCl 3): δ 1.96 (4H, -CH 2-), 2.03 (3H), 3.24 (4H, -CH 2-), 3.44 (1H)

( Example 6) Preparation of alpha-p-chlorophenyl-2-pyridine chloromethane

8 g of alpha-p-chlorophenyl-2-pyridine methanol are added to 54 ml of benzene, dissolved and cooled.

6 ml of thionyl chloride is added to the solution, and the mixture is stirred overnight at room temperature.

After the reaction was completed, 50 ml of 10% aqueous ammonia was added to the mixture, followed by layer separation.

The organic layer is dried over anhydrous forget-me-not and filtered to remove the filtrate by reduced pressure.

6 g (yield 70%) of the title compound are obtained.

1 H NMR (CDCl 3): δ 6.04 (1H), 7.18 (1H), 7.20 (2H), 7.27 (2H), 7.50 (1H), 7.67 (1H), 8.61 (1H)

Example 7 alpha - [(p- chlorophenyl-2-pyridinyl) methoxy] Preparation of 1-benzoyl-4-piperidine

0.55 g of 4-hydroxy-1-benzoyl piperidine is added to 3 ml of toluene and 62 mg of metal sodium are carefully added at room temperature.

After complete addition, the mixture is heated and stirred until all of the metal sodium is dissolved.

Then 0.74 g of alpha-p-chlorophenyl-2-pyridine chloromethane is dissolved in 3 ml of toluene and carefully added slowly over 60 minutes.

After the addition, the mixture was stirred under reflux for 36 hours and then cooled to room temperature.

5 ml of purified water is added and 3 ml of dilute hydrochloric acid is added for washing.

The organic layer was separated by layer separation, dried over 0.1 g of anhydrous manganese, filtered and the organic solvent was removed by reduced pressure.

0.9 g (yield 82.6%) of the title compound is obtained.

1H NMR (CDCl3): δ 1.63 (4H, -CH2-), 2.85 (1H), 3.34 (4H, -CH2-), 5.41 (1H), 7.13 (2H, direction nucleus), 7.18 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 8) (±) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of benzyl piperidin-

2.4 g of 4-hydroxy-1-benzylpiperidine, 2.7 g of sodium carbonate and 32 ml of methyl isobutyl ketone are added and refluxed for 1 hour.

6 g of alpha-p-chlorophenyl-2-pyridine chloromethane is added to 5 ml of methyl isobutyl ketone and dissolved and added dropwise to the mixed solution over 90 minutes.

It is refluxed for 36 hours after the addition.

After cooling to room temperature, the solvent was removed under reduced pressure, 50 ml of dichloromethane was added and washed with 30 ml of purified water.

Dry over anhydrous forget-me-not, filter and remove the filtrate by reduced pressure.

4 g (yield 80%) of the title compound are obtained.

1 H NMR (CDCl 3): δ 1.63 (4H, -CH2-), 2.85 (1H), 2.24 (4H, -CH2-), 5.41 (1H), 7.06 (2H, direction nucleus), 7.14 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 9) (±) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of acetyl piperidine

2.4 g of 4-hydroxy-1-acetylpiperidine, 2.7 g of sodium carbonate and 32 ml of methyl isobutyl ketone are added and refluxed for 1 hour.

6 g of alpha-p-chlorophenyl-2-pyridine chloromethane is added to 5 ml of methyl isobutyl ketone and dissolved and added dropwise to the mixed solution over 90 minutes.

It is refluxed for 36 hours after the addition.

After cooling to room temperature, the solvent was removed under reduced pressure, 50 ml of dichloromethane was added and washed with 30 ml of purified water.

Dry over anhydrous forget-me-not, filter and remove the filtrate by reduced pressure.

4.6 g (yield 80%) of the title compound are obtained.

1 H NMR (CDCl 3): δ 1.63 (4H, -CH2-), 2.3 (3H), 2.85 (1H), 3.24 (4H, -CH2-), 5.41 (1H), 7.06 (2H, aromatic nucleus), 7.50 ( 1H, Directional Core), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 10) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] Preparation of -N- benzoyl piperidine

(s) 5.6 g of 4-chlorophenyl-2-pyridyl methanol, 2.7 g of sodium carbonate and 16 ml of methyl isobutyl ketone were added and refluxed for 30 minutes, followed by 3.4 g of 4-bromo-1-benzoyl piperidine. It is added to 4 ml of methyl isobutyl ketone and dissolved, and then added dropwise to the solution over 90 minutes.

After complete addition, reflux for 12 hours.

After cooling to room temperature, 32 ml of dichloromethane is added, stirred for 10 minutes, and washed with 20 ml of purified water.

The layers are separated and the organic layer is taken, dried over 0.5 g of dry forget-me-not, filtered and the filtrate is removed by reduced pressure.

7.3 g (yield 70%) of the title compound are obtained.

1H NMR (CDCl3): δ 1.63 (4H, -CH2-), 2.85 (1H), 3.34 (4H, -CH2-), 5.41 (1H), 7.13 (2H, direction nucleus), 7.18 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 11) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of benzyl piperidin-

(s) 5.6 g of 4-chlorophenyl-2-pyridyl methanol, 2.7 g of sodium carbonate, and 16 ml of methyl isobutyl ketone were added and refluxed for 30 minutes, followed by 3.2 g of 4-bromo-1-benzyl piperidine. It is added to 4 ml of methyl isobutyl and dissolved, and then slowly added to the solution.

After complete addition, reflux for 12 hours.

After cooling to room temperature, 32 ml of dichloromethane was added, stirred for 10 minutes, and 20 ml of purified water was added thereto.

After stirring for 10 minutes at room temperature, the layers are separated and the organic layer is taken.

After drying with 0.5 g of dry forget-me-not, the filtrate is removed by reduced pressure.

8.0 g (yield 80%) of the title compound are obtained.

1H NMR (CDCl3): δ 1.63 (4H, -CH2-), 2.85 (1H), 2.24 (4H, -CH2-), 5.41 (1H), 7.06 (2H, direction nucleus), 7.14 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 12) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of acetyl piperidine

(s) 5.6 g of 4-chlorophenyl-2-pyridyl methanol, 2.7 g of sodium carbonate and 16 ml of methyl isobutyl ketone were added and refluxed for 30 minutes, followed by 5.2 g of 4-bromo-1-acetyl piperidine. It is added to 4 ml of methyl isobutyl and dissolved, and then slowly added to the solution.

After complete addition, reflux for 12 hours.

After cooling to room temperature, 32 ml of dichloromethane was added, stirred for 10 minutes, and 20 ml of purified water was added thereto.

After stirring for 10 minutes at room temperature, the layers are separated and the organic layer is taken.

After drying with 0.5 g of dry forget-me-not, the filtrate is removed by reduced pressure.

7.0 g (yield 80%) of the title compound are obtained.

1 H NMR (CDCl 3): δ 1.63 (4H, -CH2-), 2.3 (3H), 2.85 (1H), 3.24 (4H, -CH2-), 5.41 (1H), 7.44 (2H, aromatic nucleus), 7.50 ( 1H, Directional Core), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 13) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of benzyl piperidin-

44 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine are added to 184 ml of acetone and stirred at room temperature.

15.4 g of R-(-)-10-camphorsulfonic acid is added to 62 ml of acetone solution to dissolve and then added at 20-25 ° C.

After stirring for 1 hour at room temperature, the resulting (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine camphorsulfonic acid salt is cooled and crystallized.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 23 g (yield 33%) of the title compound is obtained.

56.3 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine camphorsulfonic acid salt was added to 100 ml of dichloromethane and the reaction mixture was stirred for 10 minutes. Stir.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

This gives 34 g (96% yield) of the title object as an oil.

1H NMR (CDCl3): δ 1.63 (4H, -CH2-), 2.85 (1H), 2.24 (4H, -CH2-), 5.41 (1H), 7.06 (2H, direction nucleus), 7.14 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 14) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] Preparation of -N- benzoyl piperidine

45.5 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine are added to 184 ml of acetone and stirred at room temperature.

15.4 g of R-(-)-10-camphorsulfonic acid is added to 62 ml of acetone solution to dissolve and then added at 20-25 ° C.

After stirring for 1 hour at room temperature, the resulting (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine camphorsulfonic acid salt is cooled and crystallized.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 23.6 g (yield 33%) of the title compound are obtained.

57.5 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine camphorsulfonic acid salt was added to 100 ml of dichloromethane and the reaction mixture was stirred for 10 minutes. Stir.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

This gives 35 g (96% yield) of the title object as an oil.

(Example 15) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of acetyl piperidine

38.6 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetyl piperidine are added to 184 ml of acetone and stirred at room temperature.

15.4 g of R-(-)-10-camphorsulfonic acid is added to 62 ml of acetone solution to dissolve and then added at 20-25 ° C.

After stirring for 1 hour at room temperature, the resulting (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetyl piperidine camphorsulfonic acid salt is cooled and crystallized.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 25.8 g (40% yield) of the title compound are obtained.

25.8 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetyl piperidine camphorsulfonic acid salt was added to 100 ml of dichloromethane and the reaction mixture was stirred for 10 minutes. Stir.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

Thus, 24 g (yield 93%) of the target substance is obtained as an oil phase.

1 H NMR (CDCl 3): δ 1.63 (4H, -CH2-), 2.3 (3H), 2.85 (1H), 3.34 (4H, -CH2-), 5.41 (1H), 7.44 (2H, aromatic nucleus), 7.50 ( 1H, Directional Core), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 16) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of benzyl piperidin-

45.5 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine are added to 184 ml of acetone and stirred at room temperature.

42 g of (-)-dibenzoyl-L-tartaric acid-hydrate are added to 62 ml of acetone solution and dissolved, and then added at 20-25 ° C.

After stirring for 1 hour at room temperature, the resulting (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine (-)-dibenzoyl-L-tartaric acid salt Cool and crystallize.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 30 g (yield 35%) of the title compound is obtained.

69.2 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine (-)-dibenzoyl-L-tartaric acid salt thus obtained was added to 100 ml of dichloromethane. And the reaction mixture is stirred for 10 minutes.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

This affords 34.7 g (98% yield) of the title object as oil.

(Example 17) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] Preparation of -N- benzoyl piperidine

45.5 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine are added to 184 ml of acetone and stirred at room temperature.

42 g of (-)-dibenzoyl-L-tartaric acid-hydrate are added to 62 ml of acetone solution and dissolved, and then added at 20-25 ° C.

After stirring for 1 hour at room temperature, the resulting (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine (-)-dibenzoyl-L-tartaric acid-salt Cool and crystallize.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 30.6 g (yield 35%) of the title compound are obtained.

70.5 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine (-)-dibenzoyl-L-tartaric acid salt thus obtained was added to 100 ml of dichloromethane. And the reaction mixture is stirred for 10 minutes.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

This affords 34.8 g (95% yield) of the title object as oil.

1H NMR (CDCl3): δ 1.63 (4H, -CH2-), 2.85 (1H), 3.34 (4H, -CH2-), 5.41 (1H), 7.13 (2H, direction nucleus), 7.18 (1H, direction nucleus) , 7.20 (2H, direction nucleus), 7.44 (2H, direction nucleus), 7.50 (1H, direction nucleus), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 18) (s) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] -N- Preparation of acetyl piperidine

38.6 g of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetyl piperidine are added to 184 ml of acetone and stirred at room temperature.

42 g of (-)-dibenzoyl-L-tartaric acid-hydrate are added to 62 ml of acetone solution and dissolved, and then added at 20-25 ° C.

(S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetyl piperidine (-)-dibenzoyl-L-tartaric acid-salt formed after stirring for 1 hour at room temperature Cool and crystallize.

Seeding is done if necessary.

If there is much crystallization, the mixture is heated to reflux and then cooled to 25 ° C.

The crystals are then filtered off, washed with acetone and then dried under reduced pressure. 31 g (40% yield) of the title compound is obtained.

31 g of (S) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-acetylpiperidine (-)-dibenzoyl-L-tartaric acid salt thus obtained was added to 100 ml of dichloromethane. And the reaction mixture is stirred for 10 minutes.

A solution of 9.1 g of potassium carbonate dissolved in 70 ml of purified water is then added.

The layers are separated and the organic layer is taken and the aqueous layer is extracted several times with dichloromethane.

The organic layers are combined and concentrated in vacuo.

This gives 30 g (yield 96.7%) of the title object as an oil.

1 H NMR (CDCl 3): δ 1.63 (4H, -CH2-), 2.3 (3H), 2.85 (1H), 3.34 (4H, -CH2-), 5.41 (1H), 7.44 (2H, aromatic nucleus), 7.50 ( 1H, Directional Core), 7.51 (1H), 7.67 (1H), 7.95 (2H), 8.61 (1H)

(Example 19) (S) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] piperidine Preparation of

39.3 g of (s) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzyl piperidine are added to 300 ml of methanol and 3 g of palladium charcoal.

5 ml of glacial acetic acid are mixed together, hydrogen gas is injected while stirring, and the mixture is stirred for 12 hours while maintaining the atmospheric pressure.

After confirming that the reaction is completed, the filtrate is removed and the filtrate is removed by reduced pressure.

36.6 g (93% yield) of the title compound is obtained.

Chiral Purity: 100%

1 H NMR (CDCL3): δ 1.63 (4H, -CH2-), 2.74 (4H, -CH2-), 2.85 (1H), 5.41 (1H), 7.13 (2H), 7.18 (1H), 7.20 (2H), 7.50 (1 H), 7.67 (1 H), 8.61 (H)

(Example 20) (S) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] piperidine Preparation of

40.7 g of (s) -4-[(4-chlorophenyl) -2-pyridylmethoxy] -N-benzoyl piperidine are added to 300 ml of 6 N-hydrochloric acid and stirred at reflux for 24 hours.

After the reaction was completed, the reaction solution was alkalined with concentrated ammonia water and extracted three times with 500 ml of chloroform.

The extract is dried over anhydrous forget-me-not, filtered and the filtrate is removed by reduced pressure.

36.6 g (yield 90%) of the title compound are obtained.

Chiral Purity: 100%

1 H NMR (CDCL3): δ 1.63 (4H, -CH2-), 2.74 (4H, -CH2-), 2.85 (1H), 5.41 (1H), 7.13 (2H), 7.18 (1H), 7.20 (2H), 7.50 (1 H), 7.67 (1 H), 8.61 (H)

(Example 21) (S) -4 - [ (4- chlorophenyl) -2-pyridyl methoxy] piperidine Preparation of

34.5 g of (s) -4-[(4-chlorophenyl)-(2-pyridylmethoxy] -N-acetyl piperidine are added to 300 ml of 6 N-hydrochloric acid and stirred at reflux for 48 hours.

After the reaction was completed, the reaction solution was alkalined with concentrated ammonia water and extracted three times with 500 ml of chloroform.

The extract is dried over anhydrous forget-me-not, filtered and the filtrate is removed by reduced pressure.

27.3 g (yield 90%) of the title compound are obtained.

Chiral Purity: 100%

1 H NMR (CDCL3): δ 1.63 (4H, -CH2-), 2.74 (4H, -CH2-), 2.85 (1H), 5.41 (1H), 7.13 (2H), 7.18 (1H), 7.20 (2H), 7.50 (1 H), 7.67 (1 H), 8.61 (H)

Claims (2)

The compound of formula (VII) is condensed at 80-140 ° C. in the presence of the compound of formula (VII), an organic solvent and an acid acceptor to obtain a compound of formula (III), and a protecting group of the compound of formula (III) R) is removed, the process for preparing the compound of formula (II).

Wherein R is an acetyl, benzoyl, benzyl group, X is halogen, fluorine, chlorine, cancelled, iodine or an alkyl or arylsulfonyloxy group. The racemic compound (VII ') of the compound of formula (VII) is reacted with a halogen compound to obtain compound (VII), and the obtained compound (VII) is present in the presence of the compound of formula (VII), an organic solvent and an acid acceptor. Condensation reaction at 140 ° C. to obtain a racemic compound of formula (III) The resulting mixture of (±) -4-[(4-chlorophenyl) -2-pyridylmethoxy] piperidin-1-yl-R (III) as R-(-)-10-camphorsulfur as an optically active separating agent Preparation of Structural Formula (II) Compounds Having Optical Separation of (S) Only in Racemic Mixtures with High Yield High Purity Using Phonic Acid or (-)-Dibenzoyl Tartaric Acid, and then Removing the Protecting Group (R) by a Common Method Way.

In the above formula, R is an amino protecting group such as acetyl, benzoyl, benzyl group, and X is a hydroxyl group.