DE2046349A1 - New cephalosporanic acid derivatives - Google Patents

Description

DR. WALTER NIELSCH Patent attorney

! Hamburg 70 · P.O. Box 109U

Telephone: 4529707

Yamanouchi Pharmaceutical Co., Ltd. Tokyo / Japan New Cephalosporanic Acid Derivatives.

The present invention relates to new compounds having excellent antibiotic activity, More specifically, the invention relates to cephalosporanic acid derivatives having the formula II

H ₂ NCHCONH

wherein X is a hydrogen atom or an acetoxy group and Y represents a 3,5-di-tert-butyl-4-hydroxybenzyl group or a bis (p-methoxyphenyl methyl group.

The cephalosporanic acid derivatives according to the above formula II are effective against "Gram-positive" bacteria and "Gram-negative" bacteria and they have a broad antibacterial spectrum. When administered, for example, orally to warm-blooded animals, they are easily absorbed into the body tissues and the ester bond of the compound is gradually opened by enzymes and the like in the blood and body tissues, with 7- (a-aminophenyl-

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acetamido) cephalosporanic acid (cephaloglycine) or 7- (α-aminophenylacetamide) -desacetoxycephalosporanic acid (Cephalexin), which are present in high concentrations in the blood and in the body tissues. the Concentration is maintained in these for a long period of time. It is for this reason that the cephalosporanic acid derivatives are used this invention new useful antibiotics which can be administered orally.

If the cephalosporanic acid derivatives according to the formula II are treated with a basic material, their will Ester bond is opened very easily and then the connection can be made to 7- (a-aminophenylacetamido) -cephalosporanic acid (Cephaloglycine) or 7- (α-aminophenyl-acetamido) desacetoxycephalosporanic acid (Cephalexin), which is an applicable antibiotic with a broad antibacterial spectrum.

The compounds of this invention according to the formula II already mentioned are prepared by reacting 7-aminocephalosporanic acid derivatives according to the following formula I.

NH ₂ -

COOY

in which X and Y have the meaning already mentioned, and phenylglycine or its reactive derivatives are prepared.

The 7-Aminoeephaloeporansäureeater one of the 7-Amino-

cephaloeporanafture derivatives of the formula I, in which X an actoxy group, which is the starting material

of this invention can be obtained by treating dea i

3,5-di-tert-butyl- ¹ -hydroxybene 3rleaters or dea Bie (p- '

109814/2279

methoxyphenyl) methyl ester of Cephalosprin C according to a known method (see Dutch Patent Specification 6 513 095) by, for example, iminohalogenation and itaino etherification of the aminoadipyl group in the 7-position of the ester and subsequent chemical deacylation of the ester by hydrolysis.

Likewise, the 7-aminodeacetoxycephalosporanic acid ester can be another of the 7-aminocephalosporanic acid derivatives according to formula I, in which X represents a hydrogen atom, by treating 3 »5-di-tert-butyl- ^I J-hydroxybenzyl ester or bis (pHnethoxyphenyl) methyl ester according to a natural penicillin a known process, for example described in Belgian patent 717 7 ¹ Ii, for example sulfoxidation of the ester, ring enlargement, iminohalogenation and iminoetherification of the aoyl group in the 7-position of the ester and then by chemical deacylation by hydrolysis of the product.

The compounds of this invention represented by the formula II may be prepared by reacting 7-Aminoeephalosporansäurederivaten according to the formula I and an equimolar or a little excess amount of phenylglycine or one of its reactive derivatives, with cooling, preferably at ⁰ ° C to -25 ° C in an inert organic solvent such as chloroform, toluene, dichloroethane, trichloroethylene, dichloromethane, tetrahydrofuran and the like.

As a reactive derivative of phenylglycine, an acid halide such as acid chloride and acid bromide, an acid anhydride and Jl-phenyl-2,5-oxazolidinedione may be mentioned for clarification. When % -phenyl-2,5-oxaxolidinediön is used as a reactive derivative of phenylglyein im

1098U / 2279

Pall the chemical deacylation of the acyl group in the 7-position of the cephalosporin C or the acyl group in the 7-position of the cephalosporin produced by ring enlargement of natural penicillin according to a known methods, the compounds of this invention according to formula II by iminohalogenation and Imino etherification of the acyl group in the 7-position of the cephalosporin mentioned or the cephalosporin mentioned can be obtained according to a known method without forming the compound of the formula I by hydrolysis * and then by reaction with 4-phenyl-2,5-oxazolidinedione.

When the compound of formula I is reacted with phenylglycine in which the amino group is protected by a protective group such as an o-nitrophenylthio group or 2-ethoxycarbonyl-1-methylvinyl group, tert-amyloxycarbonyl group or the like has been protected, it becomes preferably the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide, pivalic acid chloride or the like and removal of the protecting group is accomplished by treating the product with an acid such as hydrochloric acid, acetic acid or fc the same is carried out according to a conventional method.

The separation and purification of the compounds of this invention prepared in this way according to the formula II can conventional chemical processes such as extraction, concentration, recrystallization, reprecipitation and the like be performed.

The invention is further illustrated by the following examples.

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Example 1:

a) In 18 ml of ethyl acetate was added to 1.2 g of 7-aminodesacetoxycephalosporanic acid * 3 ', 5'-di-tert-buty1-4'-hydroxybenzyl ester dissolved while stirring the solution at -1O ⁰ C. 0.87 g of DN-co-nitrophenylthio) phenylglycine was dissolved therein. Then 0.63 g of N, N ¹ -dicyclohexylcarbodiimide was added to the solution and, after stirring the mixture for 6 hours at ⁰ ° C. to -10 ° C., the mixture was left to stand ^{at 0 ° C. for 16 hours.}

The precipitated Ν, Ν'-dicyclohexylurea was filtered off. The filtrate was washed twice with 10 ml of 2 / S aqueous sodium bicarbonate solution each time and then washed with water and dried over anhydrous sodium sulfate.

The ethyl acetate solution was concentrated to 6 ml under reduced pressure at low temperature. When the concentrate was dispersed in 50 ml of η-hexane, yellow precipitates were deposited. The precipitates were separated by filtration, washed with a small amount of η-hexane and dried. 1.92 g of D-7- [aN- (o-nitrophenylthio) aminophenylacetamido 1-deacetoxycephalosporanic acid 3 ', 5' -ditered. -buty 1-4 '-hydroxybenzyl ester with a melting point of 123-125 ° C obtained in a yield of 96% .

Elemental analysis as 0 - HiJ ₂ O ₇ NJiSp:

C (*) H <*) N (*) S (Ji)

Calculated: 61.82 5.89 7.79 8.92

Found: 62.19 6.30 7.63 8.74

1 0 ^ ι hl 2 2 7 9

b) In 60 ml of IN hydrochloric acid-acetone mixture solution (volume ratio I: ¹ !) 1.2 g of D-7- j α-Ν- (ο-nitrophenylthio) aminophenylacetamidoJ desacetoxycephalosporanic acid «3 ¹ , 5'-di-tert. ~ butyl-4 ^l -hydroxybenzyl ester dissolved. The solution was allowed to stand at room temperature for 1.5 hours. The acetone was distilled off under reduced pressure at room temperature, and after adding 60 ml of ethyl acetate to the liquid residue containing oily matter and stirring sufficiently, the formed ethyl acetate layer was separated.

The ethyl acetate layer was washed twice with 30 ml of cold 3% aqueous sodium bicarbonate solution and then washed twice with 40 ml of cold water and then dried over anhydrous sodium sulfate.

The ethyl acetate solution thus obtained was concentrated to 5 ml under reduced pressure and low temperature. When the concentrate obtained was dispersed in 80 ml of petroleum ether, white precipitates were deposited. The crystals were separated off by pinning and reprecipitated from ethyl acetate / petroleum ether. When the precipitates thus formed were separated by filtration and dried, 0.89 g of white powdery crystals of D-7- (α-arenophenylacetamido) desacetoxycephalosporanic acid · 3 ', 5 ^f di-tert-butyl-4'-hydroxybenzyl ether with a Melting point of 106-108 ° C obtained in a yield of 94.45t.

Element ar analysis as Ο, ^ Η-ηΝ, Οι-δ:

C (Ji) H (*) N (ί) S (Jf)

Calculated: 65.82 6.95 7.43 5.67

Found: 66.18 7.04 6.96 5.35

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Example 2:

a) 1.51 g of Da ~ phenyl-N ~ (2-ethoxycarbonyl-1-methy Iviny DgIy cinkaliuinsalz were suspended in 20 ml of tetrahydrofuran and, after the dropwise addition of 5 ml of tetrahydrofuran, which contained 0.6 g of pivalic acid chloride, was suspended in the course of ten Minutes while stirring the suspension at -7 ⁰ C to -10 ° C, the mixture was stirred for a further 80 minutes at the same temperature.

The reaction mixture thus obtained was added dropwise to 20 ml of 1,2-dichloroethane, which 1.73 g of 7-amino |

desacetoxycephalosporanic acid _"S 3 ¹ 5 '-di-tert-butyl-V-hydroxybenzyl ester containing added at -10 ⁰ C and after stirring for a further 5 hours at -10 ⁰ C, the mixture was then further 16 hours at -5 C was allowed to stand =

The reaction mixture was poured into 15 ml of water and after 20 ml of 1,2-dichloroethane had been added and the mixture was then sufficiently stirred, the l ^ -dichloroethane layer thus formed was separated off. <; no. v- ^ rcle the 1 ^ 2-dichloroethane solution twice with 30 ml of 3% - ßfiT aqueous sodium bicarbonate solution and then washed with water. The solution was then dried over anhydrous sodium sulfate. The solvent was "

distilled off under reduced pressure at low temperature. The white crystalline residue thus obtained was dissolved in 5 ml of ethyl acetate, and then the solution was dispersed in 100 ml of η-hexane, whereby white powdery crystals were deposited. The crystals were separated by filtration, washed with a small amount of η-hexane and dried. 2.28 g of D-7- r ° * - <2-ethoxycarbonyl-1-methylvinyaminophenylacetamido J desacetoxycephalosporanic acid · 3 ' »5 ¹ -di-tert-butyi-V-hydroxybenzyl ester with a melting point of 111-115 ° C were obtained in one

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SAO ORIGINAL

- 8 prey out of 84.2? obtain.

Elemental analysis as < -l H H ₄₇ N ₃ O 7 ^S: N (S) S {% C (S) 6th (?) 6th , 20 4.73 Calculated: 65.56 6th , 99 6th , 46 4.74 Found: 65.33 , 93

b) In 40 ml of 1N hydrochloric acid / acetone mixture solution (volume ratio 1: 4) 1.0 g of D-7- | _a- (2-ethoxycarbonyl-1-methylvinyl) aminophenylacetamidoJ desacetoxycephalosporanic acid 3 ', 5' -di-tert-butyl-4 ^f -hydroxybenzyl ester and the solution was left to stand at room temperature for 30 minutes.

Acetone was distilled off under reduced pressure at room temperature. The concentrate contained oily materials and was mixed with 40 ml of ethyl acetate and then sufficiently stirred. The ethyl acetate layer thus formed was separated. The ethyl acetate solution was washed twice with 20 ml of cold 3 / K aqueous sodium bicarbonate solution each time and then twice with 30 ml of cold water each time. The extract thus washed was dried over anhydrous sodium sulfate. The ethyl acetate extract was concentrated to about 3 ml under reduced pressure and at low temperature. The concentrate obtained was dispersed in 50 ml of petroleum ether, whereby white precipitates were deposited. The precipitates were separated by filtration and reprecipitated from ethyl acetate-petroleum ether. The precipitates formed were separated by filtration and dried. It was 0.76 g of D-7- (o-aminophenylacetamido) desacetoxycephalosporanic acid '3', 5 ¹ -di-tert-butyl-4 * -hydroxybenzyl ester with a melting point of 106-108 ° C in an ex

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- 9 loot obtained from 91% .

Example 3 '

a) In 16 ml of ethyl acetate was I O ₉ g 7-Airdnodesacetoxycephalosporansäure x 3 '' 5 '-di-tert-butyl-4'-hydroxybenzyl ester dissolved. The solution was ^{cooled to -10 0} C and after adding O ₅ 64 g of DN- (tert-AmyI-oxycarbonyD-phenylglycine with stirring to the solution, 0.52 g of Ν, Ν'-dicyclohexylcarbodiimide was added to the solution and that The mixture was ^{stirred at 0} ° C. to -10 ° C. for 5 hours.

After the reaction mixture had been left to stand for 16 hours at -5 ° C., the nitr-dicyclohexylurea which had separated out was filtered off. The Piltrat was twice with 10 ml of a 3 # i _t .5N aqueous sodium bicarbonate solution; and then washed with water and then dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated to about 3 ml under reduced pressure at low temperatures. When 40 ml of η-hexane was added to the concentrate, white precipitates were deposited. The precipitates were separated by filtration, and after washing with a small amount of η-hexane, the crystals (|

dried. 1.56 g of white powdery D-7-jjx-N- (tert-amyloxycarbonyDaminophenylacetamido J desacetoxycephalosporanic acid · 3 ', 5' -di-tert-butyl-4 ¹ -hydroxybenzyl ester with a melting point of 108.5 ~ 109 ⁰ C obtained in a yield of 99%.

Elemental analysis as C. C (%) 1 O:.; 57 (JS) 3 ^S: N (5C) S. (*) 65.37 H , 26 6, 18th 4, 72 Calculated: 65.62 7th , 54 6, 24 4, 70 Found: 7th '!' /? 9 27

ίο -

b) In 40 ml of a 5N hydrochloric acid-acetone ™ mixture solution (volume ratio 1: 4) 1.0 g of D-7- j_a-N- (tert-amyloxy carbonyl) aminophenylacetamido] desacetoxycephalosporanic acid · 3 ' , 5 ¹ -di-tert-butyl-4 ^f -hydroxybenzyl ester and the solution was left to stand for 16 hours at room temperature. After the acetona had been distilled off under reduced pressure and at room temperature, the residue, which contained oily materials, was mixed with 40 ml of ethyl acetate and stirred for a sufficiently long time. Then the ethyl acetate layer thus formed was separated. The ethyl acetate extract obtained in this way was washed twice with 20 ml of 35 ml of cold aqueous sodium bicarbonate solution each time and then with 30 ml of cold water and finally dried over anhydrous sodium sulfate.

When the ethyl acetate extract is concentrated to about 3 ml under reduced pressure at low temperature and the concentrate was dispersed in 50 ml of petroleum ether white precipitates were deposited. When the precipitates are separated by filtration were, they were reprecipitated from ethyl acetate-petroleum ether and the precipitates were separated and dried. It became 0.65 g of D-7- (α-aminophenylacetamido) -desacetoxycephalosporanic acid «3 '> 5' -di-tert-butyl-4'-hydroxybenzyl ester obtained with a melting point of 106 108 ° C in a yield of 78.255.

Example 4:

a) 25.7 g of the sodium salt of cephalosporin C was suspended in 220 ml of dimethylformamide and, after the addition of 15-rcl triethylamine was slowly over the course of about 20 minutes 41.2 g of bis (p-methoxyphenyl) methyl chloride were added while the suspension was stirred and then the mixture was further for 5 hours at room temperature

109 i! 14/2279

- li -

rature stirred. After allowing the mixture to stand overnight at room temperature, it became liquid The reaction product is dispersed in about 1 kg of ice water and then extracted twice with 500 ml of ether each time.

After the ether solution thus obtained had been washed with 5% aqueous hydrochloric acid solution and then with sufficient amounts of water, the solution was dried over anhydrous sodium sulfate. When the ether was distilled off under reduced pressure to 52 g of a light brown, sticky N-bis (p-methoxyphenyl) methyl · cephalosporin C-bis- | _Up (p-methoxy ~ j phenyDmethyl ester in a yield of 95 ₃ 32 obtained .

b) 11 g of N-bis (p-methoxyphenyl) methylcephalosporin Obis-Tbis {p-methoxy- * methyl ester were dissolved in 100 ml of 1,2-dichloroethane and after adding 4 ml of pyridine the mixture was brought to 0 ° - -5 ⁰ C cooled. Then 2.5 g of phosphorus pentachloride was added to the mixture and the resulting mixture was stirred at ⁰ ° C. to -5 ° C. for 2 hours. Mach addition of 2.4 g Magnesiurncarbonat to the reaction product mixture was stirred the mixture for 6 hours with addition of 40 ml of methanol, the mixture was cooled to -20 ⁰ C to -30 ° C. The mixture was left to stand at 0 ° C. overnight. The suspension thus obtained was cooled to -30 ⁰ C to -40 ° C and after addition of 1 ml of pyridine while stirring the mixture, a solution of 50 ml of 1,2-Dichioroäthan which 4.4 g of D-4-PIienyl- 2,5-oxazolidinedione was added dropwise to the suspension over 2 hours. The mixture was stirred at -30 ° C to -40 ° C for 5 hours and then left to stand at -15 ° C to -20 ° C overnight.

1 Ci Ö ο U / 2 2 7 9

20A6349

The reaction mixture was made with perlite, a filter aid mixed on a mineral basis (compare Römpp, Chemie-Lexikon, 6th edition, p. 3, column 4764) and the mixture was filtered. The filtered off perlite was washed with 20 ml of 1,2-dichloroethane and the wash liquid was combined with the piltrate.

The mixture was cooled to 0 ⁰ C to -5 ⁰ C, and 100 ml of water was added with stirring. Then P adjusted the pH of the solution to 4 to 5 with 10% aqueous

Ammonia solution adjusted and after stirring for 30 minutes at the same temperature, the organic Separated solvent.

After washing the organic solvent layer with 0.1N hydrochloric acid, water, aqueous solution Sodium bicarbonate solution and then water with cooling, the washed solution became over dried anhydrous magnesium sulfate. The solvent was distilled off and the oily thus obtained Material was dissolved in 100 ml of cyclohexane. The * solution was cooled in a refrigerator and that

oily material was separated by decantation and dissolved in 10 ml of ethyl acetate. The ethyl acetate solution was dispersed in 100 ml of η-hexane to form precipitates, which were separated by filtration. These were washed with a small amount of η-hexane, reprecipitated from ether-petroleum ether and dried. There were 3.5 g of colorless powdery crystals of D-7- \ jx- aminophenylacetamideqJ cephalosporanic acid di (p-methoxyphenyl) methyl ester with a melting point of 68-71 ° C in a yield of 55.4? obtain.

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2Ü46349

Elemental analysis as C ~, H ,, N, OgS:

Calculated: N 6 ₃ β5%
Found: N $ 6.34

Example 5 '

_{a) 10 9} 9 g of N-phthaloylcephalosporin were dissolved in 110 ml of dimethyl sulfoxide and then 6 g of potassium bicarbonate were added while stirring the solution. To the suspension was slowly added 12.4 g of 3 ₃ 5-di-tert-butyl-4-hydroxybenzyl bromide in a nitrogen atom at room temperature in the dark with stirring. The mixture was stirred for 2 hours.

The reaction mixture was poured into about 600 g of ice water dispersed and after adding 600 ml of ether with stirring, the ether layer formed was separated off. The ether layer was washed with 100 ml of aqueous sodium bicarbonate solution and then with each 200 ml of 5 # aqueous sodium chloride solution three times washed. The solution was then dried over anhydrous magnesium sulfate.

The ether was distilled off and the oily material thus formed was washed five times with 600 ml of petroleum ether washed and after removal of the bis (3 »5-di ~ tert-butyl-4-hydroxyphenyl) ethane the residue was dried. It became 14.6 g of yellowish viscous N-phthaloyl., Cephalosporin C-bis (3,5-di-tert-butyl-4-hydroxybenzyl) ester in a yield of 74.3? obtain.

b) In 100 ml of 1,2-dichloroethane was 9.8 g of N-phthaloylcephalosporin C-bis (3,5-di-tert-butyl-4-hydroxybenzyl) ester dissolved. After adding 4 ml of pyridine

10 Π Ίu / 2 2 7 9

2QA6349

the mixture was cooled at O ⁰ C to -5 ⁰ C. Then 2.5 g of phosphorus penta chloride was added to the mixture and the resulting equipment was stirred at 0 ° C to -5 ° C for 2 hours.

The reaction mixture was mixed with 2.4 g of magnesium carbonate, and ml after stirring the mixture for 6 hours with addition of 40! "! Ethanol while cooling the mixture to -20 ⁰ C to ~ 30 ° C the mixture was left for 16 hours at 0 ° C calmly.

The suspension thus formed was cooled to -30 ⁰ C to -40 ° C by adding 1 ml of pyridine with stirring and 50 ml of 1,2-dichloroethane solution containing 4.4 g of D-4-phenyl-2,5- oxazolidinedione was added dropwise to the mixture over 2 hours. The mixture was then stirred for 5 hours at -30 ⁰ C to -40 ° C and the reaction was for 16 hours at -15 ° C to -20 ° C allowed to stand.

After adding perlite as a filter aid to the reaction mixture, the perlite was filtered off and washed with 200 ml of 1,2-dichloroethane. The Piltrat "was combined with the washing solution and the mixture

was cooled to 0 ⁰ C to -5 ° C. After adding 100 ml of water, the pH of the solution was adjusted to 4 to 5, with 10K aqueous ammonia solution. The solution was stirred after 30 minutes, after which the organic solvent layer was separated.

The organic solution thus obtained was washed successively with 100 ml of 0.1 N hydrochloric acid, water and 1% aqueous sodium bicarbonate solution each while cooling. The final washing was carried out by water treatment twice with 50 ml of water each time.

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The solution was then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure and the slightly brownish powdery material thus obtained was washed with 100 ml of cyclohexane. The undissolved residue was dissolved in 80 ml of ether and a small insoluble portion was filtered off. The piltrate was dispersed in 400 ml of petroleum ether and, after standing in the refrigerator for several hours, the precipitates thus formed were separated off by filtration, washed with a small amount of petroleum ether and then dried. It has 3 * 9 g of D-7 ~ | having a melting point of 125 a-j Airinophenylacetamido CEPHALOSPORANIC ACID · 3 ''5'-di-tert-butyl-V-hydroxybenzyl ester - 129 ⁰ C obtained as a brown powdery material. The yield was 62.5%.

Element ar analysis as CH ₁ J ₁ O ₇ NLS:

Calculated: N 6,? 455
Found N 6.15! I

1 0 S '/./2279

Claims (1)

204634 - 16 patent claims: New 7- (α-aminophenylacetamido) cephalosporanic acid ester derivatives with the formula H ₀ NCHCONH ₀ NCHCONH; 0 '' COOY wherein X represents a hydrogen atom or an acetoxy group and Y represents a 3,5-di-tert-buty1-4-hydroxybenzyl group or a bis (p-methoxyphenyl) methyl group. . 7- (et-aminophenylacetamido) desacetoxycephalosporanic acid -3'j5'-di-tert-butyl-4'-hydroxybenzyl ester. 3. 7- (ct-aminophenylacetamido) cephalosporanic acid · 3 ' _S 5' ~ di-tert. -butyl- *! ' hydroxybenzyl ester. 4. 7- (ot-aminophenylacetamido) cephalosporanic acid bis (pmethoxyphenyDmethyl ester. 5. Use of those mentioned in claims 1 to 4 Compounds used as an antibacterial agent for the manufacture of pharmaceutical preparations for the treatment of humans and animals. COPY 109 8 U / 2279