KR100483317B1 - METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE - Google Patents

Abstract

According to the present invention, it is economical to easily mass-produce α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of the formula A manufacturing method is provided.

[Formula 1]

Scheme 5

Description

Method for preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride {METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE}

The present invention relates to a new process for the preparation of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula (1), which is excellent for the treatment of urinary incontinence.

Compounds of formula (1) have been found to be particularly effective in the treatment of urinary system pain and are known as effective compounds for the treatment of urinary incontinence associated with urinary tract.

The compound of Chemical Formula 1 is a compound developed by Schering, Germany in 1974. Patents related to chemicals or manufacturing methods include [German Patent No. 106,643] and [Chinese Patent No. 1,285,348].

Scheme of the preparation of the compound of formula (1) described in the preceding patents is as follows.

German Patent No. 106,643

The first reaction of the unit described in Scheme 1 is a reaction in which the reaction is carried out under mixed solvents of benzene and toluene, and the resulting water is continuously removed. In order to complete the reaction, a large amount of time is required and the yield is low, so that Compound 6 must be separated purely, and the reaction is troublesome, such as the preparation of Compound 7 by proceeding with the next reaction, chlorination.

Looking at the production method of the reaction scheme 1 in more detail as follows.

Compound 5 in Scheme 2 was mixed with sodium methoxide in a mixed solvent of benzene and toluene, and then the reaction temperature was controlled by reflux conditions of the solvent, and the reaction was completed by continuing to remove the generated water. The yield of the reaction is 60-70%, and a separate purification process (recrystallization in 1-butanol solvent conditions) is required to obtain pure compound 6. As such, it is economically disadvantageous in mass production due to the reaction conditions and the troublesome reaction conditions such as requiring a purification process for separating pure Compound 6.

Chinese Patent No. 1,285,348

The first reaction of the unit described in Scheme 3 was to proceed with the esterification reaction using a suitable base under toluene solvent conditions. In order to complete the reaction, it is economically disadvantageous in mass production because the reaction must proceed after activating the intermediate.

Looking at the production method of Scheme 3 in more detail as follows.

In order to proceed with the esterification of compound 8 using 5% sodium hydroxide in toluene solvent in Scheme 4, a piperidine derivative was subjected to a chlorination reaction as a previous step to synthesize 4-chloropiperidine derivative. After the esterification reaction was carried out. In addition, since the compound 9 needs to be purified to a high quality in order to proceed with the chlorination reaction, which is the synthesis step of the compound 10, it is economically disadvantageous in consideration of the cost and reaction complexity of the raw materials used in mass production.

Therefore, there is a need for a new manufacturing method that can maximize the industrial applicability by supplementing the problems of the prior art, in particular the above-described German patent and Chinese patent, and at the same time concise the reaction conditions.

The present inventors studied to develop a novel method for easily and economically synthesizing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of Formula 1, which is excellent in treating urinary incontinence, As a result, the present invention was completed by finding a new reaction route different from the existing method and appropriate reaction conditions to prepare a compound of formula 1 having high purity.

An object of the present invention is to provide a method for preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula (1) having excellent urinary incontinence treatment action.

[Formula 1]

Specifically, the method of the present invention comprises the following steps:

(1) reacting a compound of Formula 2 with thionyl chloride to prepare an acid chloride derivative of Formula 3;

(2) introducing an 4-hydroxypiperidine derivative into the acid chloride derivative of Formula 3 to prepare an ester derivative of Formula 4;

(3) preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula 1 using 1-propanol as a reagent and raw material in an ester derivative of formula 4;

(4) Purify it as needed:

The preparation method according to the present invention, i.e., the preparation method of the compound of Formula 1, may be represented as in Scheme 5.

The production process for synthesizing the α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of the present invention is different from the preparation method of the prior art, the reaction process is different, and the reaction is relatively The concise implementation of this has the advantage of increasing industrial availability.

That is, the synthesis method of the prior art has a lot of trouble, such as reaction conditions, intermediate purification process and the price of the raw material, but the present invention uses a more mild reaction conditions that can be generally carried out by relatively simple reaction To provide a method for preparing the target compound.

The present invention is explained in detail by the following examples. However, the present invention is not limited by the following examples.

Example 1 Chlorodiphenylacetyl Chloride Synthesis (Compound 3)

Compound 2 (50.0 g, 219.0 mmol) was suspended in toluene (250 mL), and thionyl chloride (87.0 g, 731.3 mmol) and N, N-dimethylformamide (10.0 ml) were reacted at room temperature (˜25 ° C.). It was added to and then stirred under reflux for 4.0 hours. The reaction solution was distilled under reduced pressure to remove the organic solvent and the used reagent to obtain the pale yellow title compound as an oily substance (55.8 g, yield 96.1%).

Compound 3 prepared in Example 1 was used in Example 2 without further purification.

¹ H NMR (400MHz, CDCl ₃ ) 7.43 ~ 7.37 (10H, m)

¹³ C NMR (400 MHz, CDCl ₃ ) 172.36, 137.94, 129.16, 128.67, 128.35, 82.85.

Example 2: Chlorodiphenylacetic acid 1-methyl-4-piperidinyl ester Synthesis (Compound 4)

Compound 3 (58.0 g, 218.7 mmol) obtained in Example 1 was dissolved in toluene (580 mL), followed by triethylamine (44.3 g, 437.8 mmol) and 4-hydroxy-1-methylpiperidine (37.8 g , 328.2 mmol) were added sequentially at room temperature (˜25 ° C.) and stirred for 2.5 hours. The reaction mixture was washed successively with 10% aqueous hydrochloric acid solution (580 mL) and 10% aqueous sodium carbonate solution (580 mL). The separated organic solution layer was washed successively with saturated brine solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to give compound 4 as pale yellow oil (64.8 g, yield 86.1%).

¹ H NMR (400 MHz, CDCl ₃ ) 1.77 (2H, m), 2.03 (2H, m), 2.26 (2H, m), 2.50 (2H, m), 5.03 (1H, m), 7.38 (10H, m) .

Example 3: Synthesis of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride (Compound 1)

Compound 4 (55.1 g, 160.2 mmol) obtained in Example 2 was dissolved in 1-propanol (220 mL) solution, and the reaction solution was refluxed for 8 hours. The reaction solution was distilled under reduced pressure to remove the solvent, ethyl acetate (551 mL) was added thereto to dissolve, and the mixture was stirred slowly at room temperature (˜25 ° C.). After the crystals were precipitated, the mixture was stirred for a further 2.0 hours, filtered, washed with ethyl acetate (110 mL), and the filtrate was dried at 40-45 ° C. to give a white high purity Compound 1 (61.2 g, 151.5 mmol, 99.2% purity), Yield 94.5%).

¹ H NMR (400 MHz, CDCl ₃ ) 0.92 (3H, t), 1.62 (2H, m), 1.91 (2H, d), 2.09 (2H, m), 2.46 (5H, m), 3.03 (2H, d) , 3.23 (2H, t), 5.30 (1H, m), 7.40 (10H, m).

Melting Point 213.3 ~ 214.2 ℃

Example 4: Purification of α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride (Compound 1)

Compound 1 (50.0 g, purity 99.2%) obtained in Example 3 was dissolved in dichloromethane (100 mL) at room temperature (˜25 ° C.) and ethyl acetate (250 mL) was slowly added dropwise for 30 minutes. The reaction solution was left at room temperature (˜25 ° C.) for 2 hours, cooled to 0-5 ° C., stirred for 1 hour, filtered, and dried at 40 ° C. to 45 ° C. to obtain white high purity Compound 1 (47.3 g, purity 99.8%). It was.

Melting Point 213.5 ~ 214.2 ℃

In addition to α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride, the method of the present invention can be applied to the preparation of derivatives thereof, and such a method is also included in the scope of the present invention. do.

According to the present invention, the α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula 1, which is excellent in treating urinary incontinence, can be prepared easily and economically, with high purity and high yield.

Claims (3)

A process for preparing α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of Formula 1 comprising the following steps: (1) reacting a compound of Formula 2 with thionyl chloride to produce a compound of Formula 3; (2) introducing a 4-hydroxypiperidine derivative to the compound of formula 3 to prepare a compound of formula 4; (3) reacting the compound of Formula 4 with 1-propanol to prepare α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of Formula 1: [Formula 1] [Formula 2] [Formula 3] [Formula 4] The method of claim 1, further comprising purifying the α-phenyl-α-propoxybenzeneacetic acid 1-methyl-4-piperidinyl ester hydrochloride of formula (I). The chlorodiphenylacetic acid 1-methyl-4-piperidi of the formula (4) according to claim 1 or 2, wherein the compound of formula (3) is reacted with 1-methylpiperidin-4-ol in step (2). Process for preparing the nile esters.