KR20110093130A - Preparation method of 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine - Google Patents

Abstract

PURPOSE: A method for preparing 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine is provided to improve reaction speed and to obtained the compound of high yield. CONSTITUTION: A method for preparing 4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidine comprises: a step of reacting (4-chlorophenyl)(pyridine-2-yl)methanol of chemical formula 2 with trichloroacetonitrile in an organic solvent under the presence of a base catalyst to prepare (4-chlorophenyl)(pyridine-2-yl)methyl 2,2,2-trichloroaceteimidate of chemical formula 3; a step of reacting the compound of chemical formula 3 with tert-butyl-4-hydroxypiperidine-1-carboxylate of chemical formula 4 under the presence of an organic solvent and Lewis acid to prepare a tert-butyl-4-[(4-chlorophenyl)(pyridine-2-yl)methoxy]piperidine-1-carboxylate of chemical formula 5; and a step of deprotecting the compound of chemical formula 5 using acid.

Description

Preparation method of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine {Preparation method of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine}

The present invention relates to a process for the preparation of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine used as pharmaceutical intermediate.

4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine is one of the piperidine derivatives widely used as pharmaceutical intermediates as a compound represented by the following general formula (1).

<Formula 1>

The most important step in the process for preparing 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine is O-alkylation. Conventionally, in the preparation of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine, as an O-alkylation method, (4-chlorophenyl) (pyridin-2-yl is represented by Scheme 1 below. Methanol and a halogenated compound are reacted in the presence of a base to prepare a desired compound, or (4-chlorophenyl) (pyridin-2-yl) methanol is converted to a halogenated compound as shown in Scheme 2 below, and then alcohol and base The reaction was carried out in the presence of the present invention to prepare the target compound.

<Scheme 1>

<Scheme 2>

(X in Scheme 1 and Scheme 2 is Cl, Br, OTs or OMs.)

However, the production methods of Schemes 1 and 2 have a disadvantage in that a variety of impurities are generated by causing a reaction for a long time at a high temperature, causing problems in the purification process, yield is not high.

Therefore, the present inventors are shortening the production time in preparing the 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine, and while studying a method for producing in high yield, The present invention was completed by finding out that the reaction rate is high and the target compound can be prepared in high yield by performing a low temperature reaction in the presence of a Lewis acid instead of a high temperature reaction in the presence of a base.

An object of the present invention is to provide a method for shortening the reaction time and producing 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine in high yield.

Another object of the present invention is to provide an intermediate compound produced in the preparation of the 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.

In order to achieve the above object, the present invention

(4-chlorophenyl) (pyridin-2-yl) methanol is reacted with trichloroacetonitrile in the presence of a base catalyst in an organic solvent to give (4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2- Obtaining trichloroacetimidate (step 1);

(4-Chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidaate obtained in step 1 was prepared by tert-butyl-4-hydroxypiperi in the presence of an organic solvent and a Lewis acid. Reacting with dine-1-carboxylate to give tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate (step 2) ; And

The tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate obtained in step 2 was subjected to deprotection using acid to give 4- 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperi comprising the step of obtaining [(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (step 3) Provided is an improved method for preparing a dean.

The present invention also provides (4-chlorophenyl) (pyridin-2-yl) methyl2, which is an intermediate compound produced during the preparation of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine. , 2,2-trichloroacetimidadate is provided.

According to the present invention, in the preparation of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine, the O-alkylation reaction is carried out by low temperature reaction in the presence of Lewis acid instead of high temperature reaction in the presence of a base. The reaction rate can be improved, and the 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine can be obtained in high yield, which can be usefully used for the production of medicines using piperidine derivatives. Can be.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

As the present invention is shown in Scheme 3,

(4-chlorophenyl) (pyridin-2-yl) methanol of formula (2) was reacted with trichloroacetonitrile in the presence of a base catalyst in an organic solvent to (4-chlorophenyl) (pyridin-2-yl) methyl Obtaining 2,2,2-trichloroacetimidadate (step 1);

(4-Chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate obtained in step 1 was prepared by tert-butyl-4-hydride of formula 4 in the presence of an organic solvent and a Lewis acid. Reaction with oxypiperidine-1-carboxylate yields tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate of formula 5 (Step 2); And

The tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate obtained in step 2 was subjected to deprotection using acid to formula 1 4-[(4-chlorophenyl) (2-pyridyl) methoxy comprising the step (step 3) of obtaining 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine Provides an improved method for preparing piperidine:

<Scheme 3>

First, step 1 is a reaction of (4-chlorophenyl) (pyridin-2-yl) methanol of formula (2) with trichloroacetonitrile in the presence of a base catalyst in an organic solvent to (4-chlorophenyl) (pyridine- 2-yl) methyl 2,2,2-trichloroacetimidadate.

In the production method according to the present invention, the organic solvent used in step 1 may be methylene chloride, acetonitrile, tetrahydrofuran, toluene, N, N- dimethylformamide and the like, but is not limited thereto.

In the production method according to the present invention, the trichloroacetonitrile is preferably used 1 to 2 molar equivalents relative to 1 molar equivalent of (4-chlorophenyl) (pyridin-2-yl) methanol.

In the production method according to the present invention, the base catalyst may be cesium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate or the like, but is not limited thereto.

In the production method according to the present invention, the base catalyst is preferably used from 0.1 molar equivalents to 1 molar equivalents to 1 molar equivalent of (4-chlorophenyl) (pyridin-2-yl) methanol.

Next, the step 2 is the (4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate obtained in the step 1 in the presence of an organic solvent and Lewis acid -Butyl-4-hydroxypiperidine-1-carboxylate reacted with tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1 Obtaining a carboxylate.

In the preparation method according to the present invention, methylene chloride, acetonitrile, tetrahydrofuran, toluene, N, N-dimethylformamide, etc. may be used as the organic solvent used in step 2, but is not limited thereto.

In the preparation method according to the invention, the tert-butyl-4-hydroxypiperidine-1-carboxylate is [(4-chlorophenyl) (pyridin-2-yl)] methyl 2,2,2- It is preferable to use 1 to 1.5 molar equivalents relative to 1 molar equivalent of trichloroacetimidate.

In the preparation method according to the present invention, the Lewis acid may be TfOH, TMSOTf, Cu (OTf) ₂ , BF ₃ OEt ₂ , HBF ₄ , but is not limited thereto.

In the preparation method according to the present invention, the Lewis acid is 0.1 molar equivalent to 1 molar equivalent relative to 1 molar equivalent of [(4-chlorophenyl) (pyridin-2-yl)] methyl 2,2,2-trichloroacetimimate Preference is given to using.

Next, step 3 is stripped using tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate obtained in step 2 using an acid. Gelatinization step yields 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine of the formula (1).

In the production method according to the present invention, the acid used in step 3 may be phosphoric acid, hydrochloric acid, sulfuric acid, etc., but is not limited thereto.

In the preparation method according to the invention, the acid is 2 molar equivalents to 1 molar equivalent of tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate Preference is given to using from 5 molar equivalents.

In the production method according to the invention, the reaction of the steps 1 to 3 may be carried out at 0 ℃ to 30 ℃.

Such a preparation method is a low temperature in the presence of Lewis acid instead of high temperature reaction in the presence of a base O-alkylation reaction in the preparation of 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine By reacting, the reaction time can be shortened by 24 to 48 hours compared to the conventional production method, and the yield is improved to 20 to 30%, thereby yielding the above 4-[(4-chlorophenyl) (2-pyridyl) methoxy] in high yield. Piperidine can be obtained and can be usefully used for the production of pharmaceuticals using piperidine derivatives.

The present invention also provides (4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidade of formula (3) produced as an intermediate in the preparation method.

The (4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate can be prepared by the method described above.

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

< Example  1> 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Preparation of Piperidine

Step 1: (4- Chlorophenyl ) (Pyridin-2-yl) methyl  2,2,2- Trichloroacetimidate  Produce

(4-chlorophenyl) (pyridin-2-yl) methanol (20 g) was dissolved in methylene chloride (80 ml) and cooled to 0 ° C. Thereafter, trichloroacetonitrile (19.7 g) and Cs ₂ CO ₃ (7.4 g) were added thereto, and the reaction temperature was increased to 20-30 ° C. and stirred for 3 hours. After the reaction was completed, the insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Thereafter, vacuum-dried to completely remove trichloroacetonitrile in a concentrated oily compound in the form of a vacuum, (4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimim as an off-white solid. Dates were obtained (29.8 g, 90% yield).

¹ H-NMR (CDCl ₃ , ppm): δ 8.6 (d, 1H), 8.5 (s, 1H), 7.7 (t, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 7.3 (m , 2H), 7.2 (m, 1H), 6.9 (s, 1H)

Step 2: Tert -Butyl-4-[(4- Chlorophenyl ) (Pyridin-2-yl) Methoxy ] Piperidine-1- Carboxylate  Produce

(4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate (30 g) prepared in step 1 was dissolved in methylene chloride (150 ml) and cooled to 0 ° C. . Thereafter, tert-butyl-4-hydroxypiperidine-1-carboxylate (16.4 g) and Cu (OTf) ₂ (14.8 g) were added, and the reaction temperature was raised to 20 to 30 ° C. and stirred for at least 10 hours. . After the reaction was completed, water (200 ml) was added to the reaction, neutralized with 1N NaOH to remove the water layer, and the organic layer was washed twice with saturated NaHCO ₃ aqueous solution (100 ml). Next, the organic layer was washed with a saturated NaCl aqueous solution (100 ml), MgSO ₄ (20 g) was added to the organic layer, the mixture was stirred, and water was completely removed and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate containing impurities (29.7 g, yield 90). %).

¹ H-NMR (CDCl ₃ , ppm): δ 8.5 (d, 1H), 7.7 (t, 1H), 7.5 (d, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 7.1 (m , 1H), 5.6 (s, 1H), 3.7 (m, 2H), 3.6 (m, 1H), 3.1 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H)., 1.4 (s , 9H).

Step 3: 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Preparation of Piperidine

Tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate (29.7 g) prepared in step 2 was added to methylene chloride (75 ml). It was dissolved and 85% phosphoric acid (25.6 ml) was added dropwise and stirred for 5 hours at 20-30 ℃. Water (100 ml) was added to the reaction solution, followed by stirring to separate the layers. The organic layer was removed. The water layer was adjusted to pH 3 using a 25% NaOH aqueous solution, and washed with ethyl acetate (60 ml). Thereafter, the water layer was adjusted to pH 6-7 using a 25% NaOH aqueous solution, and then washed with ethyl acetate (60 ml). Next, the water layer was adjusted to pH 9-10 using a 25% aqueous NaOH solution, and then the product was extracted with methylene chloride (150 ml × 3 times). The combined organic layers were washed with saturated aqueous NaCl solution (60 ml), and stirred with MgSO ₄ (30 g) in the organic layer, followed by complete removal of water and filtration. The filtrate was concentrated under reduced pressure to give 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine (20.3 g, 91% yield).

¹ H-NMR (CDCl ₃ , ppm): δ 8.5 (d, 1H), 7.8 (t, 1H), 7.6 (d, 1H), 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (m , 1H), 5.6 (s, 1H), 2.8 (m, 5H), 2.1 (s, 1H), 1.7 (m, 2H), 1.5 (m, 2H)

< Example  2> 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Production of Piperidine 2

Step 1: (4- Chlorophenyl ) (Pyridin-2-yl) methyl  2,2,2- Trichloroacetimidate  Produce

It was carried out in the same manner as step 1 of Example 1.

Step 2: Tert -Butyl-4-[(4- Chlorophenyl ) (Pyridin-2-yl) Methoxy ] Piperidine-1- Carboxylate  Produce

(4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate (5 g) prepared in step 1 was dissolved in methylene chloride (25 ml) and cooled to 0 ° C. . Thereafter, tert-butyl-4-hydroxypiperidine-1-carboxylate (2.8 g) and TfOH (1.1 g) were added thereto, and the reaction temperature was raised to 20 to 30 ° C. and stirred for 24 hours. After the reaction was completed, the mixture was washed twice with 50 ml aqueous NaHCO ₃ solution. Thereafter, the organic layer was washed with a saturated NaCl aqueous solution (100 ml), MgSO ₄ (10 g) was added to the organic layer, the mixture was stirred, and then water was completely removed and filtered. The brown oil obtained by concentrating the filtrate under reduced pressure was separated by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane (volume ratio 1: 1) as a developing solvent. The target compound was concentrated under reduced pressure to obtain tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate as an oil (3.1 g, yield 53%). .

Step 3: 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Preparation of Piperidine

It was carried out in the same manner as step 3 of Example 1.

< Example  3> 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Preparation of Piperidine 3

Step 1: (4- Chlorophenyl ) (Pyridin-2-yl) methyl  2,2,2- Trichloroacetimidate  Produce

It was carried out in the same manner as step 1 of Example 1.

Step 2: Tert -Butyl-4-[(4- Chlorophenyl ) (Pyridin-2-yl) Methoxy ] Piperidine-1- Carboxylate  Produce

(4-chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate (5 g) prepared in step 1 was dissolved in methylene chloride (25 ml) and cooled to 0 ° C. . Thereafter, tert-butyl-4-hydroxypiperidine-1-carboxylate (2.8 g) and HBF ₄ (0.6 g) were added thereto, and the reaction temperature was raised to 20 to 30 ° C. and stirred for 24 hours. After the reaction was completed, the mixture was washed twice with 50 ml aqueous NaHCO ₃ solution. Thereafter, the organic layer was washed with a saturated NaCl aqueous solution (100 ml), MgSO ₄ (10 g) was added to the organic layer, the mixture was stirred, and then water was completely removed and filtered. The brown oil obtained by concentrating the filtrate under reduced pressure was separated by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane (volume ratio 1: 1) as a developing solvent. The target compound was concentrated under reduced pressure to obtain tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate as an oil (2.9 g, yield 52%). .

Step 3: 4-[(4- Chlorophenyl )(2- Pyridyl ) Methoxy ] Preparation of Piperidine

It was carried out in the same manner as step 3 of Example 1.

Claims (7)

As shown in Scheme 3 below,
(4-chlorophenyl) (pyridin-2-yl) methanol of formula (2) was reacted with trichloroacetonitrile in the presence of a base catalyst in an organic solvent to (4-chlorophenyl) (pyridin-2-yl) methyl Obtaining 2,2,2-trichloroacetimidadate (step 1);
(4-Chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidadate obtained in step 1 was prepared by tert-butyl-4-hydride of formula 4 in the presence of an organic solvent and a Lewis acid. Reaction with oxypiperidine-1-carboxylate yields tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate of formula 5 (Step 2); And
The tert-butyl-4-[(4-chlorophenyl) (pyridin-2-yl) methoxy] piperidine-1-carboxylate obtained in step 2 was subjected to deprotection using acid to formula 1 4-[(4-chlorophenyl) (2-pyridyl) methoxy comprising the step (step 3) of obtaining 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine ] Improved Method of Making Piperidine.
<Scheme 3>

<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

<Formula 5>

According to claim 1, wherein the organic solvent of step 1 and step 2 is selected from the group consisting of methylene chloride, acetone, acetonitrile, ethyl acetate, tetrahydrofuran, benzene, toluene and N, N- dimethylformamide Characterized in the manufacturing method.
The method according to claim 1, wherein the trichloroacetonitrile of step 1 is used in an amount of 1 to 2 molar equivalents relative to 1 molar equivalent of (4-chlorophenyl) (pyridin-2-yl) methanol.
The method of claim 1, wherein the base catalyst is selected from the group consisting of cesium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate.
The method of claim 1, wherein the Lewis acid of step 2 is selected from the group consisting of TfOH, TMSOTf, Cu (OTf) ₂ , BF ₃ OEt ₂ and HBF ₄ .
The method of claim 1, wherein the Lewis acid of step 2 is 0.1 molar equivalent to 1 molar equivalent relative to 1 molar equivalent of [(4-chlorophenyl) (pyridin-2-yl)] methyl 2,2,2-trichloroacetimidadate Manufacturing method characterized in that using.
(4-Chlorophenyl) (pyridin-2-yl) methyl 2,2,2-trichloroacetimidade compound represented by the following formula (3).
<Formula 3>