KR100337037B1 - Process for preparing intermediates of pyridone carboxylic acid derivatives - Google Patents

Abstract

PURPOSE: A process for preparing intermediates of pyridone carboxylic acid derivatives is provided, thereby cheaply preparing the intermediates of pyridone carboxylic acid derivatives in higher yield. CONSTITUTION: A process for preparing intermediates of pyridone carboxylic acid derivatives represented by the formula(I) comprises halogen reaction of a compound of the formula(II), followed by the reaction with base in an organic solvent, wherein R1 and R2 are independently hydrogen or C1 to C5 lower alkyl, provided that one of two is hydrogen; R3 and R4 are independently hydrogen or C1 to C5 lower alkyl, provided that one of two is hydrogen; R5 is hydrogen or C1 to C5 lower alkyl; P is an amine protecting group; the organic solvent is selected from the group consisting of chloroform, acetone, acetonitrile, diethylether, benzene, xylene, carbon tetrachloride, toluene and dichloromethane; the base is selected from the group consisting of triethylamine, pyridine, N,N'-dimethylaniline, N,N'-diethylaniline, trimethylamine and 1,8-diazabicyclo£5,4,0|-7-undecane; and the reaction is carried out at 30 to 200 deg. C for 1 to 10 hours.

Description

Method for preparing intermediates of pyridone carboxylic acid derivatives.

The present invention relates to a new method for synthesizing intermediates through the process of synthesizing new amines, which are the most important substituents of novel carboxylic acid derivatives that can be used in medicine, veterinary medicine, and medicinal diseases as antimicrobial substances with excellent antimicrobial sulfur. will be.

Synthesis methods known to date have not been effective because the process is complicated and the raw material costs are high, the yield is low. Heterocycles, vol 25, No 1, 1989 teach a method for preparing NP-toluenesulfonyl-8-oxo-3-azabicyclo [3,2,0] heptane, as illustrated by Scheme I below. do.

In Scheme I, a compound of formula (III) is reacted with tricyclicunhydride and collidine to undergo a [2 + 2] ring reaction through an keteninium-form intermediate of formula (IV) However, this process is very expensive because of the high cost of triplenhydride, and secondly, the process is expensive at -10 ° C to -15 ° C. It is a low temperature reaction in which the reaction proceeds, and it is very difficult to carry out the reaction after it is anhydrous. Third, a large amount of oily impurities, which are considered to be polymers, are generated in this process. Fourth, the yield is large, and the yield is 50-60% lower than the manufacturing cost consumed in this process.

Accordingly, an object of the present invention is to improve such an inefficient manufacturing process and to provide a novel manufacturing method having a simple process, low raw material costs, and high yield.

The present invention provides a process for preparing bicyclic ketones of the general formula (I) by halogenating a compound of the general formula (II) in an organic solvent and reacting the resulting compound with a base:

In the above formula,

R ₁ and R ₂ are each independently hydrogen or a lower alkyl group, provided that one of the two is hydrogen;

R ₃ and R ₄ are each independently hydrogen or a lower alkyl group, provided that one of them is hydrogen;

R ₅ is hydrogen or a lower alkyl group;

P is an amine protecting group.

In the present invention, lower alkyl groups include, for example, matyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and neopentyl.

The amine protecting group can be removed during the reaction of the process of the present invention without destroying the structure of the compound or proceeding with side reactions. For example, hydrolyzable groups such as acetyl, trifluoroacetyl, ethoxycarbonyl groups or benzyl or earth It is a practical skill.

As an example of Np-toluenesulfonyl-8-oxo-3-azabicyclo [3,2,0] heptane, which is an example of a compound of formula (I) according to the present invention, is represented by the following structural formula (IV) The halogenated product obtained by reacting a compound of) with thionyl chloride is prepared via a [2 + 2] ring reaction via a ketene intermediate of formula (V) by reacting a halogenated product with triethylamine base.

Suitable halogenating agents in the present invention include thionyl chloride, phosphorous pentachloride, phosphorus oxychloride, phosphorotrichloride, phosphorotribromide and the like.

Suitable bases for the process of the invention are triethylamine, pyridine, N, N'-dimethylaniline, N, N'-diethylaniline, trimethylamine, 1,8-diazabicyclo [5,4,, 0]- 7-undecene and the like.

In the process of the present invention, the first step, the halogenation reaction and the second step, the cyclization reaction are performed for 1 to 10 hours at a temperature of 30 to 200 ℃.

Suitable organic solvents in the process of the invention include chloroform, acetone, acetonitrile, diethyl ether, benzene, xylene, carbon tetrachloride, toluene, dichloromethane or dichloroethane.

Compounds of formula (II) used in the present invention may be prepared by starting with a compound of formula (III), known from Chem Lett., 980, 11, 1389:

Wherein R ₆ and R ₇ represent hydrogen or a lower alkyl group, and P is an amine protecting group that can be removed without disrupting the structure of the compound or advancing side reactions during the reaction.

As a representative example of the compound of formula (II), 3- [N-4-toluenesulfonyl-N'-2-methyl-2-propenyl] aminopropionic acid is Np-toluenesulfate as illustrated in Scheme III below. Phonyl beta alanine ethyl ester is prepared by reacting with 1-chloro-2-methylpropene in the presence of a base and then hydrolyzing it.

The following examples specifically illustrate the preparation of the compounds of the present invention. However, this embodiment is intended to illustrate the invention, not the invention.

Reference Example 1

Preparation of 3- [N-4-toluenesulfonyl-N'-2-methyl-2-propenyl] aminopropionic acid

60 g of known compound Np-toluenesulfonyl beta alanine ethyl ester, 60 g of 3-chloro-2-methylpropene, 61.3 g of calcium carbonate, 12 g of potassium iodine and 3 g of tetrabutylammonium iodine are suspended in 120 mL of water and 120 mL of acetonitrile. The mixed solution was heated to reflux for 5 hours. After cooling to 30 ° C., 7 mL of 0.5 M sodium thiosulfate solution was added to the solution, followed by washing. The organic layer was taken out, and 3-chloro-2-methylpropene was recovered by simple distillation. The remaining acetonitrile is removed by distillation under reduced pressure to give a yellow oily compound. This was dissolved in 60 mL of ethanol, and a solution of 10 g of sodium hydroxide in 100 mL of water was added dropwise to the ethanol solution over about 1 hour, followed by stirring at 30-35 ° C. for 1 hour. After distillation under reduced pressure, ethanol was removed, and 100 mL of water and 50 mL of toluene were added and stirred for 30 minutes. The organic layer was separated and separated, and concentrated hydrochloric acid was added dropwise while cooling to adjust the pH to 6.0-6.2, followed by stirring for 1 hour to precipitate a solid. To this was added dropwise concentrated hydrochloric acid to adjust pH to 0.5 and stir for 30 minutes. The solid was filtered, washed with water and dried to give 66 g of the title compound (yield 94%).

Example 1

Preparation of N-p-toluenesulfonyl-1-methyl-6-oxo-3-azabicyclo [3,2,0] heptane

For reference, 100 g of the compound of 1 was suspended in 100 mL of toluene, 27 mL of thionyl chloride was added, and the internal temperature was heated to 85 to 90 ° C. The mixture was stirred for 2 hours while maintaining the same temperature, followed by distillation under reduced pressure to remove toluene and sulfur dioxide gas. To this was added dropwise a solution diluted in 300 mL of toluene at the same temperature over 5 hours. When the addition is completed, the mixture is stirred for 2 to 3 hours at the same temperature. After cooling to room temperature, 80 mL of concentrated hydrochloric acid is washed with a solution of 200 mL of water. Take the organic layer, wash with water and remove toluene to obtain 75g of yellow solid as target compound. (Yield 80%)

Claims (5)

A process for preparing a compound of formula (I) by halogenating a compound of formula (II) in an organic solvent and then reacting the resulting product with a base: In the above formula, R ₁ and R ₂ are each independently hydrogen or a lower alkyl group having 1 to 5 carbon atoms, one of which must be hydrogen; R ₃ and R ₄ are each independently hydrogen or a lower alkyl group having 1 to 5 carbon atoms, one of which must be aquatic; R ₅ is hydrogen or a lower alkyl group of 1 to 5 carbon atoms; P is an amine protecting group. The organic solvent of claim 1, wherein the organic solvent is chloroform, acetone, acetonitrile, diethyl ether, benzene, xylene, carbon tetrachloride, toluene, dichloromethane, ryl, diethyl ether, benzene, xylene, carbon tetrachloride, toluene, dichloromethane, and dichloromethane. A process for the production, characterized in that it is selected from the group consisting of ethane. The method of claim 1, wherein the bases are triethylamine, pyridine, N, N'-dimethylaniline, N, N'-diethylaniline, trimethylamine and 1,8-diazabicyclo [5,4,0] -7 -A method of production, characterized in that it is selected from the group consisting of undekenes. The method of claim 1, wherein the whole reaction proceeds for 1-10 hours at a temperature of 30 ~ 200 ℃. The process according to claim 1, wherein the halogenating agent is selected from the group consisting of thionyl chloride, phosphorus pentachloride, phosphorus oschloride, phosphorotrichloride and phosphorotribromide.