KR810000389B1 - Process for preparing -lactam antibiotic derivatives - Google Patents

Abstract

β-Lactam antibiotic deriv., e.g. I, cephalosporin (R = H, OH ; R1= H, alkali metal, etc. ; Het= triazol, etc.), was prepd. by reaction of cephalosporin deriv. II (A = (CH2)n, arylen ; B = H, OCOCH3, halogen ; R, R' given) with thio compounds III( M = H, alkali metal ; Het given) and then hydrolysis of IV (R, R1, Het, A given).

Description

Method for preparing β-lactam antibiotic derivative

The present invention relates to a method for preparing β-lactam antibiotics of the following structural formula (I).

Wherein R is hydrogen or a hydroxy group, R ₁ is hydrogen, a lower alkyl, an alkali metal, or a phthalidyl group, and Het is a substituted or unsubstituted chienyl, isoxazolyl, chizolyl, tetrazolyl or triazole group to be.

The compound of formula (I) of the present invention has an effective antimicrobial activity as a known compound.

Methods for preparing the compound of formula (I) are known in various ways, and described in British Patent No. 1,328,340, US Patent No. 4067976, Australian Patent No. 37950, and Korean Patent No. 5380.

The production methods are acephalic phosphine after acylation of the amino acid derivatives or their reactive derivatives protecting the amino group in various forms such as acid addition salts, enamines, and Schiff bases, by acting on the amino group at the 7-position of cephalosporin. Compounds of formula (I) were prepared by introducing a thiol group at position 3 or by acylating the thiol group. These methods are not only difficult to protect the amino group and complicated to process, but also have a high manufacturing cost using expensive reagents. The present invention solves the above-mentioned shortcomings by using a novel compound of formula (II), and is an economical method in which the operation is easy and the target object can be produced with high yield.

New compounds of formula (II) are described in detail in patent application 3757 filed October 29, 1979.

The present invention is described in detail as follows.

The compound of formula (II) is reacted with a compound of formula (III), and then hydrolyzed under acidic conditions to prepare the compound of formula (I).

Wherein R, R ₁ and Het are as described above, A is-(CH ₂ ) n- or allylene group (where n is an integer of 0 or 1-4), B is chlorine, cancelled, etc. Halogen, or —OCOCH ₃ — group, M is hydrogen or an alkali metal.

The thiol compound of the formula (III) is Het is chienyl, isoxazolyl, chiazolyl, tetrazolyl or triazole group which may be substituted by lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Thiol compounds, and sodium, potassium salts and the like as these alkali metal substituents. The present invention is carried out in a common inert solvent, and as the solvent, acetone, ether, chloroform, nitrobenzene, dimethylformamide, methanol, ethanol, dimethyl sulfoxide or other organic solvents which are not involved in the reaction can be used.

When using a hydrophilic solvent among these solvents, it can also mix and use with water. In addition, the present reaction may be carried out in neutral, weakly alkaline or weakly acidic acid. When cephaphosphoranic acid of formula (II) is used in the form of a free acid, the reaction may be carried out in the presence of alkali (tricarbonate), triethylamine and pyridine bases. In the case where the reaction is performed under weak acidity, the reaction is preferably performed in a buffer solution having a pH of 4-5.6.

In this case, as the buffer, all weak acid buffers may be used, but it is preferable to react in the phosphate buffer.

There is no restriction | limiting in particular in reaction temperature, In many cases, it reacts at 0 degreeC-80 degreeC.

The reaction for preparing the compound of formula (I) by hydrolysis of the compound of formula (IV) is carried out by a known method.

In other words, two molecules of the compound of formula (I) can be easily obtained by hydrolysis under acidic conditions of pH 1-3.

In the present reaction, when water is used as a solvent or a hydrophilic solvent or a buffer solution is used, the protecting group can be removed by hydrolysis in the same reaction system by adjusting the pH by adding an acid without separating the reaction product.

The invention can be explained in more detail by the following examples, which do not limit the invention.

Example 1

N, N '-(1,2-ethanediylidene) bis-7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3-acetyloxymethyl-3- Preparation of Triethylamine Salt of Cefem-4-carboxylic Acid.

8.42 g (0.02 M) of 7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3-acetyloxymethyl-3-cepem-4-carboxylic acid Suspended in 40 ml of '-dimethylformamide and 30 ml of acetonitrile, 2.8 ml (0.02 M) of triethylamine was added at room temperature, stirred at the same temperature for 30 minutes, and the reaction solution was cooled again to 5 ° C. 7 g of magnesium and 1.12 ml (0.01 M) of 40% aqueous solution of glyoxal were added thereto, followed by 3 hours at the same temperature.

The reaction solution was filtered, 55 ml of ethyl ether was added to the pale yellow gum-like substance obtained by vacuum concentration at room temperature, and it stirred vigorously for 3 hours, maintaining 0 degreeC, and 9.8 g (91.8%) of yellow-white crystals were obtained.

Example 2

N, N '-(1,2-ethanediylidene-bis-7- [D-(-)-α-amino- (P-hydroxyphenal) acetamido] -3- [S- (1, 2,3-triazol-5yl) thiomethyl] -3-cepem-4-carboxylic acid.

5.33 g (0.005 M) of the bismuth prepared in Example 1 was suspended in 40 ml of phosphate buffer solution at pH 6.4, and 0.7 g (0.005 M) of 5-mecapto-1,2,3-triazole potassium salt was added thereto. .

After adding 0.05 g (0.0125 M) of sodium bicarbonate to the reaction solution, the reaction temperature was gradually warmed and maintained at 65 ° C.-70 ° C., and stirred for 3 hours and 15 minutes. Then, the reaction solution was cooled to 5 ° C., pH was adjusted to 4.5 with dilute hydrochloric acid, and stirred for 1 hour. The crystals were filtered, washed several times with water, dissolved in 40 ml of ethyl acetate, washed again with water, separated and dehydrated, and the solution was concentrated in vacuo to give 2.42 g (51.2%) of the desired pale yellow substance.

Example 3

7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (1,2,3-triazol-5-yl) thiomethyl] -3- Preparation of Cefem-4-carboxylic Acid.

1 g (1.06 mM) of the bismuth prepared in Example 2 was dissolved in an acetone and acetonitrile (5: 3) mixed solution, a small amount of water was added thereto, followed by stirring and mixed with trifluoroacetic acid and hydrochloric acid at room temperature. After adjusting the pH to 1.5-2.5, the mixture was stirred for 45 minutes, and the hydrolyzed solution was concentrated in vacuo at room temperature to obtain a pale yellow oily substance. 30 ml of ethyl acetate was added thereto, and the pH was adjusted to a small amount of triethylamine with vigorous stirring. Adjust to 4.0 and wash with 10 ml of water.

The organic layer was separated, concentrated under reduced pressure, and 20 ml of water was added thereto. Then, anion exchange resin IR-4B was added thereto, adjusted to pH 5.0, filtered, cooled, left to stand overnight, filtered again, and freeze-dried to give 0.77 g of white crystalline powder. (78.5%) was obtained.

Example 4

N, N '-(1,2-ethanediylidene) -bis-7- [D-(-)-α-amino-α-phenylacetamido] -3-acetoxymethyl-3-cepem-4 Preparation of Triethylamine Salt of Carboxylic Acids.

8.1 g (0.02 M) of 7- [D-(-)-α-amino-α-phenylacetamido] -3-acetoxymethyl-3-cepem-4-carboxylic acid is suspended in 40 ml of acetonitrile, Triethylamine 2.8 ml (0.02 M) was added dropwise and stirred at room temperature for 30 minutes.

After adding 7 g of anhydrous magnesium sulfate and dropping 1.12 ml (0.01 M) of 40% glyoxal aqueous solution, and reacting at 5 ° C. for 3 hours, the reaction solution was filtered and 55 ml of ether was added to the pale yellow gum material obtained by vacuum concentration at room temperature. The mixture was stirred vigorously for 3 hours.

The crystals thus formed were filtered, washed several times with ether, and dried to obtain 9.86 g (95.2%) of pale yellow crystals.

Example 5

7- [D-(-)-α-amino-α-phenylacetamido] -3- [S (1,2,3, -triazol-5-ylomethyl] -3-cepem-4-carboxyl Preparation of the acid.

5.2 g (0.005 M) of the bismuth obtained in Example 4 was suspended in 40 ml of pH6.4 40 ml phosphate buffer, 0.75 g (5.4 mM) of 5-mecapto-1,2,3-triazole potassium salt and sodium bicarbonate. 1.1 g (13 mM) was added thereto, followed by stirring at 70 ° C. for 2 hours 30 minutes.

After cooling to room temperature, the unreacted material was filtered off, and the aqueous layer was adjusted to pH 4.0 using 2-ethylhexanoic acid and left at 0 ° C. for 4 hours to collect the resulting crystals, and then washed several times with cold water. And 35 ml of acetonitrile.

The mixture was adjusted to pH 1.5-2.5 using concentrated hydrochloric acid at room temperature, stirred at 0-5 ° C. for 1.5 hours, and concentrated in vacuo at room temperature to obtain a slightly yellow oil. Then, 60 ml of water is added to the oily substance to dissolve. The insolubles are filtered, and the aqueous layer is saturated with sodium chloride and extracted twice with 25 ml of methyl ethyl ketone. After separation, the pH was adjusted to 4.0 using triethylamine salt in the organic layer and washed with 10 ml of water. The organic solvent layer was collected, dehydrated with anhydrous forget-me-not, concentrated under reduced pressure, and distilled for about 3/5. The mixture was added dropwise to 45 ml of ethyl ether and crystallized.

The crystals were filtered, washed several times with ether, and then vacuum dried at room temperature for 6 hours to obtain 0.68 g (33.6%) of pale yellow crystalline powder.

Example 6

N, N '-(1,2-ethanediylidene) -bis-7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3-acetyloxymethyl-3 Preparation of Cefem-4-carboxylic Acid Triethylamine Salt.

9.15 g (0.02 M) of 7- [D-(-)-α-amino- (P-hydroxyphenyl) -acetamido] -3-acetoxy methyl-3-cepem-4-carboxylic acid dihydrate Suspended in 45 ml of acetonitrile, 10 g of anhydrous magnesium sulfate and 2.8 ml (0.02 M) of triethylamine were added, followed by addition of 1.12 ml (0.01 M) of 40% aqueous glyoxal solution, and the reaction temperature was maintained at 10 ° C. for 2 hours 30 After stirring for 5 minutes, the reaction solution was filtered and the filtrate was concentrated under reduced pressure at room temperature to obtain a gum-like substance.

80 ml of ether was added to the concentrate, which was stirred vigorously at 0 ° C. to obtain 9.53 g (89.3%) of white crystals. The bis bodies obtained by this method were the same substance as compared with the compound obtained in (Example 1).

Example 7

7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (1,2,3-triazol-5-yl) thiomethyl] -3- Preparation of Cefem-4-carboxylic Acid.

8.82 g (0.02 M) of 7- [D-(-)-α-amino- (P-hydroxyphenyl] acetamido-3-acetoxymethyl-3-cepem-4-carboxylic acid dihydrate is diluted with acetonitrile and di It was suspended in 35 ml of a mixture of methylformamide (10: 1), and then 1.12 ml (0.01 M) of triethylamine 2.8 g (0.02 M) 40% glyoxal aqueous solution was added and stirred at 5 ° C. for 3 hours.

Subsequently, 100 ml of 0.1 M phosphate buffer solution at pH 6.4 was added, followed by addition of 2.16 g (0.03 M) of sodium bicarbonate and 2.8 g (0.02 M) of 5-mecapto-1,2,3-triazole potassium. It kept at +/- 5 degree | times, and stirred for 3 hours and 15 minutes.

The reaction solution was cooled, the resulting crystals were removed and concentrated in vacuo at 30 ° C. to remove the organic solvent. The mixture was adjusted to pH 4.0 with 2-ethyl hexanoic acid and stirred at room temperature for 30 minutes.

The crystals were filtered and washed several times with water and dissolved in 65 ml of acetonitrile and 20 ml of water. Then, 0.3 g of 10% pd / c was added, and hydrogen gas was supplied in a pressurized hydrogen reactor for 4-5 hours. When the reaction was completed, a cake was formed. After stirring for 2 hours, the reaction solution was cooled to 0-5 ° C., stirred for 1 hour, filtered, the cake was washed several times with ethyl acetate, dispersed in 100 ml of water, and stirred with basic ion exchange resin IR-4B. The mixture was stirred until the pH was 5.5 and filtered quickly.

The cake was lyophilized to yield 4.99 g (53.8%) of product. IR NMR analysis showed the same material as the compound obtained in Example 3.

Example 8

7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (1-methyl-tetrazol-5-yl) thiomethyl] -3-cepem- Preparation of 4-carboxylic acids.

5.33 g (0.005 M) of the bismuth prepared in Example 1 was dispersed in 50 ml of water, and then the pH was adjusted to 5.0-5.5 by adding 5% sodium bicarbonate solution to the 1-methyl-5-mecapto tetrazole- 0.78 g (00505 M) of potassium salt was added thereto, and the mixture was warmed to 60 ° C. and stirred for 4-6 hours while maintaining pH 7-8. After the reaction, 100 ml of acetone is added, vigorously stirred, and distilled under reduced pressure to form an oily cake. 50 ml of methyl isobutyl ketone and 20 ml of water are added thereto, and then the pH is adjusted to 1.0-2.0 with concentrated hydrochloric acid while maintaining the temperature at 5-10 ° C. After stirring for 30 minutes. After saturating with sodium chloride, the layers were separated, the organic layer was washed with 10 ml of water, and then the separated organic layer was adjusted to pH 5.0 with triethylamine, washed once with a small amount of water and the organic layer was distilled under reduced pressure. 30 ml of acetone was added to the yellow cake on the top, and the mixture was stirred vigorously and left overnight.

After filtration the cake was dried to 7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (1-methyl-tetrazol-5-yl) thio 2.88 g (60.2%) of methyl] -3-cepem-4-carboxylic acid were obtained.

Example 9

7- [D (-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (2-methyl-1,3,4-thiadiazol-5-yl) -thio Methyl] -3-cepem-4-carboxylic acid.

5.33 g (0.005 M) of the bismuth prepared in Example 1 was suspended in 50 ml of phosphate buffer at pH 6.0, and 5% potassium bicarbonate solution was added thereto, followed by vigorous stirring, and 5-mecapto-2-methyl-1 in 30 ml of water in advance. A solution of 0.86 g (0.0058 M) of 3,4-thiadiazole-potassium salt was added thereto, followed by warming up to 60-70 ° C., followed by stirring for 5 hours to complete the reaction. After the reaction, the mixture was cooled, and 30 ml of ethyl acetate was vigorously stirred for 1 hour, and then concentrated under reduced pressure. The resulting oily cake was dissolved in 50 ml of acetone, 20 ml of water was added thereto, and the pH was adjusted to 1.5-2.0 with concentrated hydrochloric acid. Was stirred.

After distillation under reduced pressure, 30 ml of methyl isobutyl ketone and 20 ml of water were added thereto, and then saturated with sodium chloride and stirred for 1 hour. Two layers were separated, 50 ml of 5% sodium bicarbonate solution was added to the organic layer, and extracted at room temperature.

This operation was repeated twice.

Next, the aqueous layer was collected, 60 ml of ethyl acetate was added, the pH was gradually adjusted to 5.0 with 2-ethyl-hexanoic acid, and the mixture was stirred vigorously for 1 hour. The two layers were separated and the organic layer was distilled under reduced pressure and dispersed in ether almost in gel state. Yellow 7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- 2.88 g (58.3%) of [S- (2-Methyl-1,3,4-thiadiazol-5-yl) -thiomethyl] -3-cef-4-carboxylic acid were obtained.

Example 10

N, N '(1,2-ethanediylidene) bis-7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3-chloromethyl-3-cepem- Preparation of 4-carboxylic acid triethyl amine salt.

40 g (0.01 M) of 7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3-chloromethyl-3-cepem-4-carboxylic acid dimethylsulfoxide 20 ml After suspension in 10 ml of acetonitrile, 1.4 ml (0.01 M) of triethamine was added thereto while maintaining the temperature at 20 ° C. and reacted at the same temperature for 2 hours. Next, 0.56 ml (0.005 M) of 40% glyoxal was added to the reaction solution, and the reaction solution which was stirred at the same temperature for 4 hours was concentrated in vacuo and dispersed in water when the gel became almost gel.

The dispersion was stirred for about 30 minutes, filtered and the cake dried under reduced pressure to obtain 4.75 g (93.2%) of the title compound as an off-white crystal.

Example 11

7- [D-(-)-α-amino- (P-hydroxyphenyl) acetamido] -3- [S- (4,5-dimethyl-isoxazolyl-3-yl) thiomethyl]- Preparation of 3-Cefem-4-carboxylic Acid.

4.5 g (0.0044 M) of the biscuit cake obtained in Example 10 was suspended in 50 ml of water, followed by complete dissolution by addition of a 5% sodium bicarbonate solution and 0.77 g of 3-mecapto-4.5-dimethyl-isoxazole potassium salt in 20 ml of water in advance. (0.0046M) was added, and the dissolved solution was slowly added and then warmed to 70 ° C. After stirring at the temperature for 4-6 hours, the mixture was cooled to room temperature, 50 ml of acetone was added thereto, and the solvent was removed by distillation under reduced pressure.

Immediately before drying, the solution was dissolved in 50 ml of methyl isobutyl ketone and 20 ml of H ₂ O, and then the pH was adjusted to 1.5-2.5 with concentrated hydrochloric acid, followed by stirring at the temperature for 40 minutes with concentrated hydrochloric acid.

Next, after saturating with sodium chloride, the two layers were separated, and dibutyl amine was added to the organic layer to adjust the pH to 4.5, and then washed once with 10 ml of water to remove insoluble matters, and the organic layer was concentrated under reduced pressure.

At this time, a yellowish brown oily cake was formed, which was left overnight by adding ethyl acetate. The cake was then filtered, dispersed in 30 ml of water and adjusted to pH 5.0 using LA-2 anion exchange resin, filtered again, washed with acetone and dried to give an off-white 7- [D-(-) -α-amino- (P-hydroxy phenyl) acetamido] -3- [S- (4,5-dimethyl-isoxazolyl-3-yl) thiomethyl] -3-cepem-4-carboxylic acid 2.8 g (57.4%) was obtained.

Claims (1)

The cephalosporin compound of the following formula (II) is prepared by reacting the cephalosporin derivative of the following formula (II) with the thiol compound of the following formula (III) to hydrolyze the compound of the following formula (VI) under acidic conditions. Way.

Wherein R is hydrogen or a hydroxy group, R ₁ is hydrogen, a lower alkyl, an alkali metal or a phthalidyl group, and Het is a substituted or unsubstituted chienyl, isoxazolyl, chizolyl, tetrazolyl or triazole group A is a-(CH ₂ ) n- group or an arylene group, where n is an integer of 0 or 1-4, B is hydrogen, halogen, or -OCOCH _3- , and M is hydrogen or an alkali metal to be.