KR100407720B1 - Preparing Method for N-[3-{3-(1-Piperidinylmethyl)phenoxy}propyl]acetoxyacetamide - Google Patents

Abstract

The present invention is named as loxatidine acetate and is useful for N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] acetoxyacetamide, which is useful as a powerful anti-ulcer agent acting as an H ₂ -receptor antagonist. A manufacturing method, which comprises a reaction of 3- [3- (1-piperidinylmethyl) phenoxy] propylamine with acetoxy acetic anhydride, which can reduce costs by using inexpensive raw materials. It is an efficient and economical manufacturing method which can prepare the loxathidine acetate which is a target compound from a starting raw material in situ in simple yet high yield under mild reaction conditions.

Description

Preparation method for N- [3- ｛3- (1-piperidinylmethyl) phenoxy｝ propyl] acetoxyacetamide {Preparing Method for N- [3- ｛3- (1-Piperidinylmethyl) phenoxy｝ propyl] acetoxyacetamide }

The present invention is made of N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] acetoxyacetamide of the following formula (1) which is named Roxatidine Acetate and acts as an H ₂ -receptor antagonist It is about a method.

[Formula 1]

As a conventional method for producing the loxatidine acetate, Japanese Patent Application Laid-Open No. 56-115750, Korean Patent Publication No. 87-271, Korean Patent Publication No. 90-5255, Korean Patent Publication No. 91-6126 and Korean Patent Publication 91-6981.

According to Japanese Patent Application Laid-Open No. 56-115750, 3- [3- (1-piperidinylmethyl) phenoxy] propylamine of the following Chemical Formula 2, as shown in Scheme 1 below, is represented by hydroxy acetic acid of the following Chemical Formula 3. N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] hydroxyacetamide of the following Chemical Formula 4 was synthesized, and then the compound of Chemical Formula 4 was reacted with acetic anhydride. To prepare the loxatidine acetate of the formula (1) to the desired compound.

Scheme 1

However, the conventional manufacturing method described above requires high temperature conditions of about 200 ° C. for the reaction with hydroxy acetic acid, which is inefficient in energy and difficult to work with, and the total yield to the final compound is about 69.8%, which is not satisfactory enough. There is a problem of being uneconomical.

In addition, Korean Patent Publication No. 87-271 describes a method for synthesizing loxatidine acetate by a method substantially the same as that of Scheme 1 described in Japanese Patent Application Laid-Open No. 56-115750. A characteristic feature of the method is that the yield is increased by treating the loxatidine acetate hydrochloride without isolating with hydrogen chloride and isolating it in the form of loxatidine acetate hydrochloride. However, this method is similar to the above-mentioned Scheme 1 in Japanese Patent Application Laid-Open No. 56-115750, in which the hydroxy acetic acid of Formula 3 and the compound of Formula 2 described above for the synthesis of the compound of Formula 4 In the reaction, high temperature conditions of 200 ° C. must be applied, resulting in inefficient economic efficiency due to inferior energy efficiency.

Korean Patent Publication No. 90-5255 discloses acetoxyacetyl of Formula 5 below with 3- [3- (1-piperidinylmethyl) phenoxy] propylamine of Formula 2, as shown in Scheme 2 below. By reacting with chloride to prepare the loxatidine acetate of the formula (1).

Scheme 2

However, the conventional method described above does not satisfy satisfactorily in terms of economy because it uses expensive raw material acetoxyacetyl chloride. Moreover, since acetoxyacetyl chloride is easily decomposed by water, there is a problem of poor storage and usability.

Another method for synthesizing loxatidine acetate is shown in Korean Patent Publication No. 91-6126, which indicates that 3- (1-piperidinylmethyl) phenol of Formula 6 is represented as shown in Scheme 3 below. It is reacted with a propylacetoxyacetamide derivative of the formula (7) to synthesize a loxathidine acetate as a target compound.

Scheme 3

However, there is a disadvantage in that expensive and unstable acetoxyacetyl chloride must be used for the synthesis of the 3-propylacetoxyacetamide derivative of Formula 7 as a starting material. In addition, the compound of Formula 7 is a substance containing an acetate group weak to the base, there is a fear that the acetate group is separated and converted to a hydroxyl group in the synthesis step of the final compound. Therefore, the yield of the final stage is also relatively low, such as 81%, there is no significant industrial and economic advantages.

Finally, according to Korean Patent Publication No. 91-6981, as shown in Scheme 4 below, N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] hydride of Formula 4 A method for synthesizing loxatidine acetate by reacting roxyacetamide with acetylchloride has been proposed.

Scheme 4

The conventional method described above does not directly describe a method for synthesizing N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] hydroxyacetamide of the general formula (4). It is believed to be synthesized by substantially the same method as that described in No. 56-115750 or Korean Patent Publication No. 87-271, and from this point of view, the compound of Formula 4 is a reaction temperature condition of 200 ℃ or more as described above It is not industrially desirable as it must be synthesized under the following conditions and is a dangerous and inefficient method.

The present inventors have intensively researched to solve the problems of the above-described conventional techniques. As a result, the present inventors prepared a loxatidine acetate, which is a target compound as an anti-ulcer agent, in a high yield from a simple synthetic material with a high process efficiency. Discovering a new manufacturing method that can be done, and a lot of efforts based on this resulted in the completion of the present invention.

Accordingly, it is an object of the present invention to provide a method for producing loxatidine acetate, which can reduce cost by using an inexpensive synthetic raw material.

Another object of the present invention is to provide a process for preparing a loxathidine acetate, which is a target compound, from a starting material in situ under relatively mild reaction conditions with simple and high process efficiency.

Still another object of the present invention is to provide a preparation method capable of producing a desired compound, loxatidine acetate, in high yield.

Hereinafter, the present invention will be described in detail.

As shown in Scheme 5, the present invention synthesizes anhydrous acetoxy acetic acid of Formula 8 below and organically synthesizes the compound with 3- [3- (1-piperidinylmethyl) phenoxy] propylamine of Formula 2 By reacting in a solvent, the loxatidine acetate of the following formula (1) as a target compound is synthesized in a simple and high yield.

Scheme 5

The anhydrous acetoxyacetic acid of the formula (8) in Scheme 5 is a very useful compound for the synthesis of the loxatidine acetate of the formula (1) because it has a left-right symmetric structure and there is no concern of impurities generated by side reactions.

In addition, anhydrous acetoxy acetic acid of Formula 8 can be easily obtained from hydroxy acetic acid by using inexpensive and easily available raw materials such as acetyl chloride, thionyl chloride, organic base, and the like as shown in Scheme 6 below. There is a number.

To hydroxy acetic acid of Formula 3, acetyl chloride was added without solvent, concentrated under reduced pressure without isolation of the reaction mixture, and then 1/2 equivalent of thionyl chloride was added to produce 1/2 equivalent of acetoxyacetyl chloride, Adding an appropriate organic base such as pyridine to it can synthesize very pure acetoxyacetic acid of the following formula (8).

Scheme 6

This reaction is a reaction that proceeds without isolation in one reactor, the byproducts of the reaction all have a low boiling point has the advantage that can be removed by simple vacuum concentration.

In addition, the present inventors apply the reactions of Scheme 6 and Scheme 5 to prepare and separate anhydrous acetoxyacetic acid of Formula 8, which is an intermediate compound, in one reactor from the hydroxy acetic acid of Formula 3, without a separate solvent. By reacting with 3- [3- (1-piperidinylmethyl) phenoxy] propylamine of the above Chemical Formula 2, the loxatidine acetate of the above Chemical Formula 1 can be obtained in high yield of 90% or more. have. This reaction has the advantage of being simple and high in process efficiency as an in situ reaction.

(Example)

It is to be understood that the following examples are merely to illustrate the invention and are not intended to limit the invention.

Example 1 Synthesis of Anhydrous Acetoxyacetic Acid

5.00 g of hydroxy acetic acid was added to the 100 ml reaction part, 10.4 ml of acetyl chloride was added thereto, and the mixture was left at room temperature for 16 hours. The reaction was complete when all of the hydroxy acetic acid had dissolved. The reaction mixture was concentrated under reduced pressure to remove any excess acetyl chloride, and then 50 ml of benzene was added. The temperature of the reaction portion was lowered to 5 ° C., 2.4 ml of thionyl chloride was added, and the mixture was further stirred at reflux for 24 hours. The temperature of the reaction portion was further cooled to 0 ° C., and 5.3 ml of pyridine was dissolved in 10 ml of benzene and added dropwise thereto. After confirming that the reaction was completed, the resulting pyridine hydrochloride was removed by filtration. The residue was concentrated under reduced pressure to give 6.65 g (92.7%) of acetoxy acetic anhydride (Formula 8). Used for the next step reaction without further purification.

¹ H NMR (CDCl ₃ , 300 MHz) (ppm): 2.11 (s, 6H), 4.65 (s, 4H)

Example 2 N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] acetoxyacetamide and its

Synthesis of Hydrochloride

Dissolve 6.31 g of 3- [3- (1-piperidinylmethyl) phenoxy] propylamine in 50 mL of chloroform, add 4.3 mL of triethylamine, and then cool the reaction solution to 0 ° C. I was. To this was slowly added dropwise a solution of 6.65 g of acetoxy acetic anhydride dissolved in 10 ml of chloroform. After confirming that the reaction was completed, the organic layer was washed sequentially with water and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 10 ml of isopropyl alcohol was added thereto to dissolve, and isopropyl alcohol saturated with hydrochloric acid was added to 9.00 g (92%) of N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] Acetoxyacetamide hydrochloride (hydrochloride of the final target compound of Formula 1) was obtained.

¹ H NMR (CDCl ₃ , 300 MHz) (ppm): 1.44-1.16 (d, 2H), 1.59-1.64 (m, 4H), 2.01-2.06 (m, 2H), 2.15 (s, 3H), 2.43 (s , 4H), 3.48 (s, 2H), 3.48-3.56 (q, 2H), 4.05-4.09 (t, 2H), 4.56 (s, 2H), 6.79-6.94 (m, 4H), 7.19-7.25 (t , 1H)

Example 3: N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] acetoxyacetamide and its

Synthesis of Hydrochloride

5 g of hydroxy acetic acid was added to the 100 ml reaction part, 10.4 ml of acetyl chloride was added thereto, and the mixture was left at room temperature for 16 hours. The reaction was complete when all of the hydroxy acetic acid had dissolved. The reaction mixture was concentrated under reduced pressure to remove any excess acetyl chloride, and then 50 ml of benzene was added. The temperature of the reaction portion was lowered to 5 ° C., 2.4 ml of thionyl chloride was added, followed by stirring under reflux for another 24 hours. Again, the temperature of the reaction portion was cooled to 0 ° C., and 5.3 ml of pyridine was dissolved in 10 ml of benzene. Was added dropwise. After confirming that the reaction was completed, a solution of 6.53 g of 3- [3- (1-piperidinylmethyl) phenoxy] propylamine dissolved in 15 ml of benzene was slowly added dropwise. After confirming that the reaction was completed, the organic layer was washed sequentially with water and saturated aqueous sodium bicarbonate solution, and the organic layers were collected. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 9.15 g (90%) of N- [3- {3- (1-piperidinylmethyl) phenoxy} propyl] acetoxyacetamide hydrochloride (final purpose of Formula 1) was added thereto by adding isopropyl alcohol saturated with hydrochloric acid. Hydrochloride of the compound).

¹ H NMR (CDCl ₃ , 300 MHz) (ppm): 1.44-1.16 (d, 2H), 1.59-1.64 (m, 4H), 2.01-2.06 (m, 2H), 2.15 (s, 3H), 2.43 (s , 4H), 3.48 (s, 2H), 3.48-3.56 (q, 2H), 4.05-4.09 (t, 2H), 4.56 (s, 2H), 6.79-6.94 (m, 4H), 7.19-7.25 (t , 1H)

As described above, the method for preparing the loxatidine acetate according to the present invention can reduce the cost by using an inexpensive synthetic raw material, and a gentle reaction in situ of the loxatidine acetate as a target compound from the starting raw material. It is an efficient and economical manufacturing method that can be manufactured in a simple and high yield under the conditions.

Claims (3)

Preparation of Roxatidine Acetate of Formula 1, consisting of reacting 3- [3- (1-piperidinylmethyl) phenoxy] propylamine of Formula 2 with anhydrous acetoxyacetic acid of Formula 8 Way. (Formula 2) (Formula 8) (Formula 1) From the hydroxy acetic acid of formula (3) below acetoxy acetic anhydride of formula (8) was synthesized and in situ 3- [3- (1-piperidinylmethyl) phenoxy] propyl of formula (2) A process for preparing the loxatidine acetate of formula (I), consisting of a single step of adding an amine. (Formula 3) (Formula 8) (Formula 2) (Formula 1) The loxathidine acetate according to claim 1 or 2, wherein acetoxy acetic anhydride of formula (8) is prepared by sequentially adding acetyl chloride, a halogenating agent, and an organic base to the compound of formula (3). Manufacturing method. (Formula 8) (Formula 3)