KR900002873B1 - Process for preparing acyl ureido penicillin derivatives - Google Patents

Abstract

Acylureido penicillin derivatives of formula (I) and their salts are prepared. In (I), R1 is phenyl or hydroxy phenyl; R2 is hydrogen, protecting gp., Na, K, Ca or triethylamine; R3 is tocyl, methanesulphonyl or acetyl; n is 2, 3 or 4. (I) are useful as antibiotic agents and has a potent antibacterial property against gram-negative and gram-positive germ.

Description

Method for preparing acyl ureido penicillin derivative

The present invention relates to a novel method for preparing acylureido penicillin, which is effective as an antibiotic, and in particular, to a novel method for preparing the following general formula (I) compound and salt thereof, which has less side effects and strong antibacterial activity against gram-negative and gram-positive bacteria .

In the general formula, R ¹ is a phenyl or hydroxy phenyl group, R ² is hydrogen or a protecting group, sodium, potassium, calcium or triethylamine group, R ³ is a tosyl, methanesulfonyl or acetyl group, n is 2, 3 or 4.

Penicillin derivatives having an acyl ureido group in the a-position of the 6-acylamide side chain have already been reported, for example, in the patents of the Kingdom of Belgium, 767, 648, German Patent No. 2,318, 955 and 2,152,967, 2,152,968, US Pat. No. 2,985,648, Chem. Ab. 82,31313b (1975), and the like.

The production process according to the literature known to date produces the intermediate 1-chlorocarbonyl-3-methanesulfonyl-amidazolidin-2-one using phosgene gas, a generally toxic and difficult to handle material, as a starting material. This is then reacted with a penicillin derivative to produce the desired compound.

The phosgene gas used above is not only toxic and difficult to handle, but also has a low yield of N-methanesulfonyl imidazolinone and 1-chlorocarbonyl-3-methanesulfonyl-imidazolidin-2-one. There is a problem that is difficult to handle during manufacture.

The present invention not only does not use a toxic phosgene gas, but also can be prepared in a stable and high yield without producing toxicity by N-methanesulfonylation after the preparation of a dazolinone derivative by the use of 2-mercapto benzothiazole. In addition, the present invention provides a more economical and easy way to prepare the acylureido penicillin derivatives of general formula (I), which have less side effects and have high antibacterial effects against Gram-positive and Gram-negative bacteria by using a new starting material such as alkylene diisocyanate. In addition, it has the advantage of producing a material that is easy to preserve the intermediate.

According to the present invention, the compound of general formula (I) is prepared as follows.

An alkylene diisocyanate of the following general formula (II) and a thiol of the same equivalent or less than the thiol of the following formula (III) in the presence or absence of a catalyst such as triethylenediamine, N-methylmorpholine, dioxane, tetrahydrofuran, acetone, In a polar or non-polar organic solvent such as acetonitrile, methylene chloride, methyl ethyl ketone, benzene at -10 ° C to reflux temperature for 30 minutes to 4 hours to obtain a thioester of the general formula (IV) N'-substituted-N-substituted carbonyl-imidazolyl of the following general formula (VI) which is reacted with halides (preferably chloride) such as tosyl, methanesulfonyl and acetyl of formula (V) A compound of din-2-one is obtained and reacted with 6-substituted-aminophenicylic acid of formula (VII) to obtain the desired acylureido penicillin derivative of formula (I).

In the general formula, R ¹ , R ² , R ³ and n are as described above.

Alkylene diisocyanates of formula (II) are generally prepared by known methods (US Pat. No. 3,017,420, US Pat. No. 3,118,925, etc.).

Therefore, the present invention provides a breakthrough method for producing the desired acylureido penicillin derivative of the general formula (I) as a starting material with no alkylene diisocyanate, which has never been used in the prior art, in a more economical and high yield.

The present invention will be described in more detail with reference to the following examples, which are not intended to limit the present invention.

Example 1

A) Add 2.8 g (25 mmol) of ethylene diisocyanate to 50 ml of acetone and add 0.01 g of triethylenediamine.

The temperature was raised to reflux, and a solution of 3.4 g (20 mmol) of 2-mercapto benzodiazole suspended in 50 ml of acetone was slowly added dropwise over 2 hours, and the reaction solution was further stirred at reflux for 30 minutes. To complete the reaction.

Excess acetone was removed by distillation under reduced pressure, and then recrystallized with acetone, filtered and washed with a small amount of tetrahydrofuran and dried under reduced pressure at 40 ° C. to give 5.01 g of colorless crystals N- (2-benzothiazolyl mercaptocarbonyl ) -Imidazolidin-2-one is obtained. Melting Point: 216 ~ 219 ° C IR (KBr): 3275, 1740, 1665cm ^-1

B) To 100 ml of dried dioxane, add 1.4 g (5 mmol) of material obtained from a) and 0.63 g (5.5 mmol) of methanesulfonyl chloride, and raise the temperature to reflux 0.55 g of triethylamine in 50 ml of dioxane over 10 minutes. (5.5 mmol) was added dropwise and further refluxed for 5 minutes, the solvent was evaporated and concentrated, and the obtained solid was filtered, and then stirred in a mixed solvent of 20 ml of water and 20 ml of methylene chloride, followed by stirring. After washing, dehydration with forget-me-not and evaporation of the solvent under reduced pressure yielded 1.16 g of N-methanesulfonylated acylureido derivative. Melting Point: 157-159 ° C. IR (KBr): 1755, 1683, 1370, 1180cm ^-1

C) 0.4 g (1 mmol) of 6- [D (-)-a-aminophenylacetamido] phenicylic acid trihydrate was added to 20 ml of water, cooled with stirring to maintain 5 ° C, and 0.1N sodium hydroxide solution was added. It was slowly added dropwise to dissolve to pH7.5 to 8.2, and then raised to room temperature.

Here, 0.42 g (1.2 mmol) of the compound prepared in b) was dissolved in 10 ml of acetone and 10 ml of acetonitrile, and then slowly added dropwise thereto.

At this time, pH adjustment is performed at 7.5 to 8.7 with 0.1 N sodium hydroxide solution. After the temperature of the liquid is raised to 60 ° C. to terminate the reaction, the mixture is kept at the same temperature for 20 minutes and then cooled.

Remove acetone and acetonitrile under reduced pressure under 60 ℃, add 20ml of water, cool below 5 ℃, filter out unreacted a) step, and adjust the pH to 1.5 with 0.1N hydrochloric acid. Stirring while giving white crystals, which were filtered, washed with a small amount of ether, and dried under reduced pressure at 40 ° C. or lower to give 0.34 g of D-(-)-a- (imidazolidin) -2-one-3- Methanesulfonyl-1-yl-carbonylamino) -benzyl penicillin is obtained. Melting Point: 168 to 170 ° C IR (KBr): 1780, 1735, 1685, 1320, 1175cm ^-1

Claims (7)

The alkylene diisocyanate of formula (II) and the tool of formula (III) are reacted in an inert solvent with or without a catalyst to give a thioester of formula (IV), and the thioester thus obtained is The compound of N'-substituted-N'-substituted carbonyl-imidazolidin-2-one (VI) was obtained by reacting with a halide of the general formula (V) in a strong solvent in the presence of an acid acceptor in a polar solvent. A method for producing an acyl ureido penicillin derivative of the following general formula (I) by reacting a compound with 6-substituted-aminopenicillin acid of the following general formula (VII).

In the general formula, R ¹ represents a phenyl or hydroxyphenyl group, R ² represents a hydrogen or a protecting group, sodium, potassium, calcium or triethylamine, R ³ represents a tosyl, methanesulfonyl or acetyl group, n is 2 , 3, or 4. A process according to claim 1, wherein triethyldiamine or N-methylmorpholine is used as catalyst in the preparation of compound (IV). The process according to claim 1, wherein the reaction solvent used in the preparation of compound (IV) is an inert polar or nonpolar solvent. The method according to claim 3, wherein dioxane, tetrahydrofuran, acetone, acetonitrile, methylene chloride, methylethylketone or benzene is used alone or as a mixed solvent as an inert polar or nonpolar solvent. The process according to claim 1, wherein in the preparation of compound (IV), the reaction temperature is from -10 ° C to reflux temperature. A process according to claim 1, wherein in the preparation of compound (I), the reaction solvent is carried out in an inert polar or nonpolar solvent. The reaction temperature according to claim 1, wherein in the preparation of compound (I), the reaction temperature is -10 ° C to reflux temperature.