KR20000051463A - 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same - Google Patents

Abstract

PURPOSE: 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoates as an intermediate useful for synthesizing cisapride and methods for preparing thereof are provided which can produces cisapride effectively without any side effect. CONSTITUTION: 4-Amino-5-chloro-2-methoxybenzoic acid is reacted with dithiobisbenzothiazole to give a new intermediate compound (III) of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoates using one or more solvents selected from the group consisting of ester, ether, halogenated alkane and an aromatic solvent at -10 to 50°C, which is reacted with cis-1-£3-(4-fluorophenoxy)propyl|-4-piperidineamine) of formula (IV) to give cisapride of formula (I). The process generates almost no side-products and prepares the title compound at a high yield.

Description

2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate Same}

The present invention relates to a novel process for preparing cisapride represented by the following structural formula (I).

More specifically, the present invention relates to a compound (III) (2-benzothiazolyl 4-amino-5, which is a novel intermediate from compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) in the following scheme. -Chloro-2-methoxythiobenzoate) and reacted with compound (IV) (cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidinamine) The present invention relates to a novel process for producing cisapride.

Cisapride is a drug that is widely used to normalize its function by regulating the motility of the gastrointestinal tract. This compound and its preparation are known from European Patent No. 76530, Korean Patent Publication Nos. 86-1584 and 86-1603.

Korean Patent Publication No. 86-1584 discloses a method for synthesizing cisapride by reacting compound (II) with compound (IV) to form an amide bond, as shown in the following scheme.

At this time, since compound (II) and compound (IV) do not have a large activity between them to directly react with each other, the compound (II) is activated to be converted to compound (II-1) and then reacted with compound (IV). Compound (II-1) is obtained by converting Compound (II) into an acid halide or a mixed acid anhydride.

When preparing an acid halide activated by this method and synthesizing cisapride, for example, compound (II) is reacted with thionyl chloride or oxalate and the like first to give 4-amino-5-chloro-2-methoxy. A benzoyl chloride compound (II-1a) should be prepared. At this time, any reaction solvent may be used as long as it is inert to the reaction conditions, and an excess of thionyl chloride or oxalate may be used as a solvent by itself without using a separate solvent. However, when it is desired to synthesize cisapride by this method, since the reactivity of compound (II-1a) obtained as an intermediate is too strong, compound (II-1a) produces side reactions with amine groups already present in itself. In many cases, this may be a factor for providing impurities to the reaction, and thus not only lowers the yield of the reaction, but also causes a lot of problems in purifying the desired product. In addition to these problems, both the reagents used and the by-products after the reaction are highly toxic and corrosive, and have a fatal disadvantage in that their use and post-treatment must be carefully considered.

Another method of activating the compound (II) described in Korean Patent Publication No. 86-1584 is to convert the compound (II) into a highly active hybrid acid anhydride and use it in the reaction. Reagents such as substituted sulfonyl halides, alkyl haloformates are often used to make hybrid acid anhydrides. The hybrid acid anhydride thus obtained can be reacted with amine (IV) to obtain the desired amide compound. However, hybrid acid anhydrides are very reactive and not only produce unwanted side reactions, but are also unstable by themselves and easily decomposed by moisture.

Thus, when synthesizing cisapride by activating compound (II) with an acid halide or a mixed acid anhydride, not only these actives should be prepared immediately before the synthesis of cisapride, but also corrosiveness, toxicity, The costs associated with environmental pollution treatment and manufacturing and storage problems associated with chemical instability remain.

Korean Patent Publication No. 86-1603, on the other hand, suggests by first synthesizing an amide compound (V) and then combining 3- (4-fluorophenoxy) propyl chloride represented by compound (VI), as shown in the following scheme. Another method of synthesizing the pride is disclosed.

When preparing cisapride by this method, compound (V) can be synthesized only when the activation of compound (II) is premised. Therefore, all of the problems of this method are the same as those already presented above, but it is not possible to expect any unique advantages other than the disadvantages of longer reaction stages.

Accordingly, the present inventors have diligently researched to develop a method for improving these various problems in the synthesis of cisapride, easily removing the by-products generated, and having a high yield of reaction because there are few side reaction products. 2-benzothiazolyl 4-, an intermediate compound (III) that can be very useful for the synthesis of cisapride by reaction with-(4-fluorophenoxy) propyl] -4-piperidinamine (IV) As a result of the new synthesis and use of amino-5-chloro-2-methoxythiobenzoate, the side reaction was caused by the fact that the compound (III) is suitable for reacting with the compound (IV) and is not affected by the amino group in itself. It was confirmed that the cisapride can be efficiently produced with little product, and the present invention was completed.

After all, the main object of the present invention is to provide a novel method for preparing cisapride.

Another object of the present invention is to provide 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate which is an intermediate used in the preparation method of electric cisapride and a preparation method thereof.

The present inventors have found that compound (III) (2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzo, which is a useful intermediate from compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) Ate) was synthesized and reacted with compound (IV) (cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidinamine) to prepare cisapride.

Hereinafter, the preparation method of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate and cisapride using the same according to the present invention will be described in more detail.

First Step: Preparation of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate

Compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) was reacted with dithiobisbenzothiazole to yield 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate ( Compound (III)) is synthesized. To synthesize compound (III), compound (II) and dithiobisbenzothiazole must be reacted with a suitable base such as triphenylphosphine, triethylamine, and the like as an active medium in a solvent inert to the reaction. The solvent inert to the reaction can be appropriately selected from esters such as ethyl acetate, ethers such as tetrahydrofuran, halogenated alkanes such as methylene chloride and chloroform, and aromatic solvents such as benzene and toluene. It can also be used as the above mixed solvent. The reaction can usually be carried out in the range of about −10 ° C. to 50 ° C., and may also be conveniently performed at room temperature. When the reaction is carried out by appropriately selecting a solvent, the compound (III) produced by the reaction can be easily separated by filtration without contamination of other by-products. The synthesized compound (III) is a stable compound, which is not easily decomposed by water, and has a stability such that its physical properties are not easily changed even when stored in air at room temperature. This new compound is not as active as conventional acid halides or hybrid acid anhydrides, and thus is not affected by amino groups in itself, and if necessary, for example, when a substitution reaction is made with another amine to form an amide compound, Can cause the desired reaction.

Second Step: Preparation of Cisapride

The previously synthesized compound (III) (2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate) is added to compound (IV) (cis-1- [3- (4) in a suitable inert solvent. Direct reaction with fluorophenoxy) propyl] -4-piperidinamine) results in the formation of the desired amide bond to produce cisapride. In this case, the reaction solvent may be appropriately selected from esters such as ethyl acetate and methyl acetate, hydrocarbon chlorides such as methylene chloride and chloroform, amides such as dimethylacetamide and dimethylformamide, ethers such as tetrahydrofuran and diisopropyl ether, and the like. These solvents may be used alone or as mixed solvents of two or more thereof. The reaction proceeds easily at room temperature to produce the desired compound, which may be heated or cooled as necessary. Preferable reaction temperature can be made to react conveniently by adjusting between 0 degreeC and 50 degreeC, More preferably, between 15 degreeC and 30 degreeC.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1: Preparation of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate

0.42 g of triphenylphosphine and 1.72 g of dithiobisbenzothiazole were added to 50 ml of methylene chloride, and the mixture was stirred at room temperature for one hour. After the temperature was lowered to 10 ° C., 0.992 g of 4-amino-2-methoxy-5-chlorobenzoic acid was added thereto, followed by stirring for 30 minutes. After the temperature was lowered to 5 ° C., 0.69 ml of triethylamine was slowly added dropwise over 20 minutes. Then warmed to room temperature over one hour and then stirred at room temperature for one hour. The material produced in the reaction solution was filtered under reduced pressure, and the filtered solid was washed in order of 5 ml of methylene chloride, 5 ml of isopropanol, and 5 ml of ether. The resultant solid compound was dried in a hot air at 40 ° C. for one day to obtain 1.58 g (92%) of the title compound as a pale yellow to colorless solid.

¹ H-NMR (DMSO-d _6, ppm): 8.12 (d, 1H), 7.97 (d, 1H), 7.70 (s, 1H), 7.49 (m, 2H),

6.75 (b, 2H, NH ₂ ), 6.51 (s, 1H), 3.93 (s, 3H)

Melting Point (℃): 225 (Decomposition)

Example 2: cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3

-Methoxy-4-piperidinyl] -2-methoxybenzamide (cisapride)

10 g of cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidineamine and 2-benzothiazolyl 4-amino-2-methoxy-5-chlorothiobenzoate in 80 ml of methylene chloride 12.4g was added and stirred at room temperature for 1 hour. After the reaction, 7.76 g of 20% hydrochloric acid solution dissolved in ethanol was added dropwise to the reaction solution for 20 minutes and stirred for one hour. The solid of the resulting cisapride hydrochloride was filtered under reduced pressure and washed with 10 ml of methylene chloride. The obtained solid was put into 100 ml of water in which 9.6 g of sodium hydroxide was dissolved, and 100 ml of methylene chloride was added thereto, followed by stirring for three hours. The organic phase was separated, washed with 100 ml of water, dried over 10 g of anhydrous magnesium sulfate, filtered under reduced pressure, and the solvent was evaporated. The resulting evaporated residue was dissolved in reflux stirring in 90 ml of methyl isobutyl ketone, and then, 20 ml of methanol and 3.0 ml of water were added to lower the temperature to 10 DEG C over two hours, followed by further stirring at the same temperature for four hours to crystallize. . The product was filtered under reduced pressure and dried for one day with hot air at 40 ° C. to obtain 15.9 g (93%) of the title compound as a monohydrate of white fine crystals.

Moisture content: 3.8%

¹ H-NMR (CDCl ₃ , ppm): 8.21 (d, 1H), 8.10 (s, 1H), 6.95 (m, 2H), 6.83 (m, 2H),

6.29 (s, 1H), 4.38 (s, 2H), 4.21 (m, 1H), 3.97 (m, 2H),

3.89 (s, 3H), 3.45 (m, 1H), 3.43 (s, 1H), 3.05 (m, 1H),

2.80 (m, 1H), 2.54 (m, 2H), 2.19 (m, 2H), 1.98 (m, 2H),

1.86 (m, 1 H)

Melting Point (℃): 133 Degrees

As described and demonstrated in detail above, the present invention provides a novel 2-benzothiazolyl 4-amino-2-methoxy-5-chlorothiobenzoate and a method for preparing cisapride using the same. Using the method of the present invention it is possible to synthesize cisapride in very mild reaction conditions. In addition, the reaction according to the present invention can not only easily remove the by-products generated, but also there is little side reaction product because the reaction occurs quantitatively, and thus the yield of the reaction is very high.

Claims (8)

2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate represented by the following structural formula (III): 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate comprising the step of reacting 4-amino-5-chloro-2-methoxybenzoic acid (II) with dithiobisbenzothiazole ( III) Manufacturing Method: The method of claim 2, Solvents include esters, ethers, halogenated alkanes and aromatic solvents. Characterized by using at least one solvent selected from the group consisting of Method for preparing 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate. The method of claim 2, Using triphenylphosphine and triethylamine as active mediators Characterized by Method for preparing 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate. The method of claim 2, The temperature of the reaction is characterized in that -10 ℃ to 50 ℃ Method for preparing cisapride. The 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate (III) of claim 1 is converted to cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidine Process for preparing cisapride (I) comprising the step of reacting with amine (IV): The method of claim 6, The solvent is characterized by using at least one solvent selected from the group consisting of esters, hydrocarbon chlorides, amides and ethers. Method for preparing cisapride. The method of claim 6, The temperature of the reaction is characterized in that 0 ℃ to 50 ℃ Method for preparing cisapride.