DE2161420A1 - Penicillin derivatives and processes for their preparation - Google Patents

Description

1 A - 302

TOYAMA CHEMICAL CO. LTD.,
Tokyo, Japan

Penicillin derivatives and processes for their preparation

The invention relates to penicillin derivatives and processes for their preparation.

Ss is already known (J ^ -aminobenzylpenicillin as valuable antibacterial substance to use, especially as medicine for diseases caused by Gram-positive and G-ramt -negative bacteria hovorgerufea "Since these penicillins are acid-proof, it is possible to administer them orally. Their absorption however, by the living body when administered orally is compared with by. Given injection Resources still insufficient.

Ss are also pivaloyloxymethyl esters of ^ -aminobenzylpenicillin known (journal of Medicinal Chemistry, Vol. 1, pages 607-612 (197O), Chemical Abstracts, Vol. 72, 132761 (1970)).

It is therefore an object of the present invention to create penicillin derivatives which are administered orally are easily absorbed, as well as processes for their preparation.

209831/1136

According to the invention, this object is achieved by a penicillin derivative the general formula

HR ³

, N-Cv N-c H-CONH

COOCH ₂ OCOR

1 2 where R is a lower alkyl group, R and H are water.

Substance atom, a lower alkyl group or an aryl group or together with the adjacent nitrogen atom one

3 mean he terozyklischeη ring and where R is a lower one

Means alkyl group.

The penicillin derivatives according to the invention, which at the Amino groups are protected by ß-Ite to acid amides, show strong antibacterial properties in vivo, as well as high blood levels when administered orally.

R is a lower alkyl group, preferably having fewer than 6 carbon atoms, such as. B. a methyl, Ethyl, propyl, butyl, amyl, isopropyl or t-butyl

1 2
Group, R and R, can be the same or different and denote hydrogen or a lower alkyl group, preferably with fewer than 6 carbon atoms, such as. B, methyl, ethyl, propyl or butyl groups or the like or an aryl group, preferably with 1 to 12 carbon atoms, which can optionally be substituted, preferably with halogen atoms, with nitro, amino or hydroxyl groups or with alkyl -, alkoxy, alkylamino or acylamino groups with in particular

1 2

especially 1 to 5 carbon atoms. R and R can also together with the neighboring nitrogen

209831/1138

atom is a heterocyclic ring, preferably with 1 to 12 carbon atoms and 1 to 3 O, S or N atoms form, such as B. a Morpliolin, piperidine or

3
Pyrrolidine ring. R is a lower alkyl group, preferably having fewer than 6 carbon atoms, such as. B. a methyl, ethyl, propyl or Butj ^r l group or the like.

Some examples of the penicillin derivatives according to the invention are given below: Pivaloyloxymethyl ester of 6- J N- (l \ f, N-dimethylaminocarbonylpropen-2-yl) - vL -aminophenylace tatnido J penicillanic acid, pivaloyloxymethyl ester of 6- J N- (1- Morpholinocarbonylpropen-2-yl) -Λ-aminophenylacetamido 1 penicillanic acid, pivaloyloxymethyl ester of 6- Γ * Ν- (1-aminocarbonylpropen-2-yl) - O ^ -aminophenylacetamido J penicillanic acid, pivaloyloxymethyl ester of 6-anilynocyl-anilynocyl -2-yl) - ^ C -aminophenylacetamidojpenicillanic acid, pivaloyloxymethyl ester of G- Γν- (1-piperidinocarbonylpropen-2-yl) -oC-aminophenylacetamido jpenicillanic acid, pivaloyloxymethyl ester of 6- I N- (1-pyrrolidinocarbonyl) yl) - W-aminophenylacetamido J penicillanic acid etc.

The acyloxyalkyl esters of 6- (N-substituted- ^ (- aminophenylacetamido) penicillanic acid can be made as follows:

Procedure 1

209831/1138

Procedure 1

COOCH ₂ OCOR

(II)

H l

N-CH-COOH

l Ph

(III)

12th

In this formula shetna the radicals R, R, R and R have the meaning given above.

According to this process, the compound of the formula I is obtained by reacting the acyloxyalkyl ester (II) of 6-aminopenicillanic acid with an N-substituted-of-aminophenyl acetic acid (III) or its derivatives.

The compound of formula (III), which as a starting material used in this procedure is new. It can be obtained by reacting Ä-aminophenylacetic acid (iv) with ß-keto acid amides (v) according to the following Reaction scheme can be prepared, with the groups have the meaning given above.

209831/1131

H ₂ N-CH-COOH

^Ph (IV)

* (III)

R ¹

J) N-CO-CH ₂ -CO-R ³
R ²

CV)

The following are some examples of the β-keto acid amides given according to formula (v):

Ν, Ν-dimethylacetoacetamide, Ν, Ν-diethylacetoacetamide, 1-morpholinocarbonylacetone, 1-piperidinocarbonylacetone, 1-pyrrolidinocarbonylacetone and 1-anilinocarbonylacetone.

The reactive derivatives of the compound according to formula (ill) include mixed acid anhydrides, e.g. B, by reaction with dimethylacetyl _{halide f} trimethylacetyl halide, diphenylacetyl halide, diethylacetyl halide, ethyl chloroformate _f isopropyl chloroformate, isobutyl chloroformate, benzyl chlorofomiate, the like, and also intermediate compounds such as e.g. . N ₁ N ¹ -dicyclohexylcarbodiimide, N, N ¹ -carbonylditriazol, N, N ^f -Carbodiimidazol, or the like, or esters such. B. p-methoxyphenyl ester, p-nitrophenyl ester, propargyl ester, carboxymethylthio ester, ester of N-hydroxy succinic acid imide and cyanomethyl ester or the like.

209831/1131

When carrying out the method according to the invention the reactive derivatives of the compound of the formula (ill) are prepared in an inert solvent, like 25, B. in methylene chloride, acetone, ethyl ethyl ketone, Acetonitrile, chloroform, ethylene chloride, dimethylformamide, Dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, Dimethyl sulfoxide, ethyl acetate, butyl acetate or the like and if the aqueous, partially aqueous or non-aqueous solution of the compound of Formula (il) is added dropwise at a temperature of -50 C to room temperature, so the compounds of the formulas (IX) and (ill) react rapidly at the same temperature and give the compound of formula (i).

Procedure 2

H ₂ N-CH-CONH-

Ph

(VI)

(V)

Ti-C. X-CH-CONH

% ■■■ / i

Ph

(VII)

+ ROCOCH ₂ X

(I)

200831/1138

In these formulas, X denotes an halogen atom and the other sulfate substituents have the meanings given above. In this process, the compound of formula (i) is obtained by reacting J ^ -aminobenzylpenicillin (Vl) with ß-keto acid amides (V) with the formation of N-substituted-j (-aminobenzylpenicillin of the formula (VIl), whereupon with the acyloxymethyl halide (VIII) is implemented.

The acyloxymethyl halide (Viii) includes e.g. B. the following connections:

Acetoxymethyl halide, propionyloxymethyl halide, n-Dutyroxymethyl halide, isobutyryloxymethyl halide, Pivaloyloxymethyl halide, dimethylacetoxymethyl halide, Diethyl acetoxymethyl halide or the like. Suitable halides are chloride, bromide or iodide and in particular Iodides due to their superior reactivity. The iodides are obtained simply by taking the appropriate Chloride treated with alkali iodide in acetone or alcohol. However, the same effect is achieved if you alkali iodide the reaction system in which the Implementation takes place, adds. When carrying out the process according to the invention, β-keto acid amides are used (V) reacted with the compound of the formula (VI) or salts thereof. The salts are alkali metal salts, alkaline earth metal salts, Trialkylamine salts, N-Hethyl-piperidine salts, N-methylmorpholine salts, lutidine salts, collidine salts or the like in question, natriura salts, potassium salts or triethylamine salts are preferred.

The reaction of the compound of the formula (VI) with the Compound of formula (v) is made by dissolving the compound of formula (VI) in one or more inert Solvents such as B methylene chloride, ether,

209831/1136

Chloroform, ethylene chloride, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, Dimethylformamide, dimethylacetamide, ethyl acetate, Butyl acetate, dimethyl sulfoxide or the like. and adding the Compound of formula (v) carried out so that the reaction at a temperature of -20 C to +30 C takes place.

In this reaction can magnesium sulfate, calcium sulfate or molecular sieve can be added as a dehydrating agent.

The reaction of the compound of formula (VIl) with Acyloxymethyl halide (VIII) is carried out by one or more of the above solvents or acetone, methyl ethyl ketone, methyl isobutyl ketone or the like is used and the temperature is set to -20 C to 4o C. When the acyloxymethyl halide one Is chloride or bromide, a small amount of alkali iodide, such as. B. sodium iodide or potassium iodide can be added to the reaction system to accelerate the reaction.

The compound of the formula (VIl) can alternatively be prepared by reacting 6-aminopenicillanic acid (IX) with N-substituted- tk -aminophenylacetic acid (III) or derivatives thereof.

209831/1136

H ₂ N-

(IX)

CH ₃
^V COOH

+ (III)

In these formulas, the substituents have the meanings given above. The reaction of the compound of the Formula (ix) with the compound of formula (ill) carried out in a manner similar to the reaction of the compound of the formula (II) with the compound of the formula (IIX) in procedure 1.

Procedure 3

H ₂ N-CH-CONH

Ph (X)

COOCH ₂ OCOR

(V)

(I)

In these formulas, the substituents have the meanings given above. The compound of formula (i) will prepared by the axyloxyalkyl ester (x) des (K-aminobenzylpenicillins with ß-keto acid amides (ν) implements. The reaction of the compound of the formula (x) with the compound of the formula (v) is carried out in a similar manner how the reaction of the compound of formula (v) with the compound of formula (VI) in process 2 is carried out.

209831/1136

216U20

The compound of formula (i) thus obtained is excellent antibacterial properties. ¥ enn this connection treated with an acidic aqueous solution containing hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid or p-toluenesulfonic acid was adjusted to a pH of 2.0 to 3.5, so the protective group on the amino group is removed and the penicillin ester known per se is obtained.

The following describes the pharmacological properties of the acyloxyalkyl esters of 6- (N-substituted-bC ~ ^am i ^no ~ phenylacetamido) penicillanic acid (I).

£ a]) _ blood level

The antibiotics were administered orally to dogs in amounts equivalent to 30 mg / kg of o ( -aminobenzylpenicillin (AB-PC). The blood of the dogs was periodically drawn and the antibiotic level in the serum was measured by the disc method, where An agar-planar medium containing Bacillus subtilis spores was used, and the results are shown in Table 1.

Table 1

X ^ time
Anti - \ ^
biotics \ 0.5 1 2 3 k
! 5 6 h AB-PC 0.62. .0.92 1.03 0.97 0.92
J - PC-1 1.38 3.55 5.09 2.80 - --I
0.89 0.24 0.03 PC-2 0.30 0.64 0.91 o, i4 0.08 - - PC-3 0.75 2.94 6 _f 4o 4.40 0.97 0.80 0.51

209831/1138

Note 1. The numbers in Table 1 have the

Unit jug / inl.
Note 2. PC-1: Pivaloyloxymethyl ester des ^ -amino-

benzylpenicillins

PC-2j pivaloyloxymethyl ester der

6-JjN "- (1 -NjN-Dimethylaminocarbonylpropen-2-yl) -K-aminophenylacetamidoj penicillanic acid

PC-3: Pivaloyloxymethyl ester of 6- | N- (i-morpholino-carbonylpropen-2-yl) - (A- aminophenylacetamidο / penicillanic acid.

£ b ^ Efficacy in staph infection

0.5 ml of the antibiotic were suspended in 5 ^c p gum arabic salt water and administered to mice orally. Thirty minutes after the administration, 10 cells of Staphylococcus aureus Smith were injected intraperitoneally, and the survival ratio of the mice was observed. The results are shown in Table 2.

Table 2

> v dose
^ ■ Qng / kg)
Anti-> v
biotics N. 60 -]
30th 15th
'j 7.5 ED ₅₀ (mg / kg) AB-PC S / 15 7/15 7/15 5/15 3O-6O PC-1 V5 3/5 2/5 2/5 15-30 PC-2 5/5 3/5 3/5 2/5 7.5-15 PC-3 7/10 6/10 6/10 5/10 7.5

209831/1136

Note: The numbers follow the expression survive de mice / total number of mice tested.

Antibacterial activity

The bacteria cultivated for 24 hours at 37 ° C. in trypticose soya broth were inoculated into a StricbJcultur on heart infusion agar with several times diluted concentration of the antibiotics. After incubation at 37 ° C. for 1k hours, the minimum ilemm concentration was measured. The results are shown in Table 3.

Table_3

Minimum inhibitory concentration (pg / ml)

Tribes ^ "~ ^Ν * ·> - ^^ AB-PC PC-1 !
PC-2 PC-3 pc-4 Staphylococcus aureus
209-P 0.15 0.25 0.25 0.15 0.25 Streptococcus Pyogenes
Group A (Τ-4) 0.015 0.0078 0.015 0.15 0.25 Esherichia CoIi (o-6) 5 2.5 2.5 2.5 5.0 Salmonella Typhi (N-901j
J 2.5 10 2.5 1.25 5.0 Shigella Sonnei 20th 20th 20th 20th 20th

Note: PC-4: pivaloyloxymethyl ester of 6-JN- (I-

lino-earbonylpropen-2-yl) -ft-aminophenylacetamidoijpenicillanic acid .

209831/1 136

£ c [2_Acute_Toxicity

The antibiotics were suspended in 0.5 ^ü ß> carboxymethyl cellulose and administered orally DDY-S mice (weighing 20 to Zk g). The results are shown in Table 4.

Table k

link

AB-PC ^ 5

PC-1> 5

PC-2> 5

PC-3> 5

In the following, the invention is explained in more detail with the aid of exemplary embodiments.

example 1

3 »13 g of sodium N- (Ι-Ν, Ν-dimethylaminocarbonylpropen-2-yl) -D (-) - fcC-aminophenyl acetate were in 15 ml of acetone suspended and with two drops of N-methylmorpholine -4o ° C offset. To the solution, 1.33 g of ethyl chlorocarbonate in 2 ml of acetone was added dropwise over a period of 5 minutes, and the reaction was carried out at carried out at the same temperature for 90 minutes,

On the other hand, there was 3 to 7 g of pivaloyloxymethyl ester hydrochloride of 6-aminopenicillanic acid in 14 ml of acetone and suspended 1 ml of water and 1.1 g of triethylamine

209831/1136

were added with transparent dissolution. The solution was added dropwise to the mixed anhydride obtained beforehand at -ko C over 15 minutes. After the mixture was reacted at the same temperature for 3 hours, it was filtered to remove the insoluble matter. Acetone was distilled off under reduced pressure. The residue was dissolved in 30 ml of ethyl acetate and 30 ml of ice water were added while cooling with Sis, and the pH was adjusted to 7 to 7> 5. The water layer was separated off and extracted with 15 ml of ethyl acetate, an organic layer being obtained which was washed twice with 15 ml of saturated saline solution. It was then dried over anhydrous magnesium sulfate. After the drying agent had been filtered off, the ethyl acetate was distilled off under reduced pressure and petroleum ether was added to the residue obtained. The petroleum ether layer was separated by decanting. The residue was then dissolved in a small amount of ether and petroleum ether was added for crystallization.

7 g (83.5 ° β>) of the pivaloyloxymethyl ester of 6 [N- (1-N, N-dimethylamino-carbonylpropen-2-yl) -D (-) - OC-aminophenylacetamidoj-penicillanic acid were obtained . The product consisted of white amorphous crystals with a melting point of 70 ° C to 73 ° G (dec.).

The process according to Example 1 was repeated under the same reaction conditions, except that 3.7 g of Natriura-N- (i-morpholinocarbonylpropen-2-yl) -D (-) - |> C-aminophenyl acetate instead of the sodium N- (Ι-Ν, Ν-dimethylaminocarbonylpropen-2-yl-D (-) - · {-ami nophe ny lace tat s were used .

209831/1136

-15- 216H20

There were 5. k g (86 5 °) pivaloyloxymethyl ester of 6-ΓΚΓ- (1 -Ilorph.olinocarbonylpropen-2-yl) -Di -) - φζ-aminophenylacetamidojpenicillanäure obtained. The product

stood out from white amorphous crystals with a melting point of 78 ⁰ C to 80 ° C.

Example 3

(i) 3 ^ »5 β anhydrous ^ -aminobenzylpenicillin and hü g anhydrous magnesium sulfate were suspended in 100 ml of methylene chloride and 13 g of triethylamine and 15» 5 g of NjN-dimethylacetoacetamide were added dropwise at 0 C with stirring, after which the reaction at the same temperature took place for 10 hours. The reaction solution was filtered off and the piltrate was evaporated under reduced pressure, and ether was added to the residue. There were 52 g (87 tf _a ) triethylamine salt of 6- (n- (Ι-Ν, Ν -ditnethylaminocarbonylpropen-2-yl) -D (-) - iC-aminoplienylacetamidojpenicillanäure in the form of white crystals with a melting point of 191 C received.

(ii) The triethylamine salt of the 6-Πί- (ΐ-Ν, Ν-dimethylaminocarbonylpropen-2-yl) —d (-) - iC-aminopheaylacetamidojpenicillanic acid thus obtained was dissolved in 100 ral dimethyl sulfoxide and 18 g pivaloyloxytethyl chloride were added dropwise at 12 added to 15 C and the reaction was carried out for 18 hours at the same temperature. After the reaction had ended, 200 ml of ethyl acetate were added to the reaction mixture and the precipitate of triethylamine hydrochloride was filtered off. The filtrate was diluted with 100 ml of ice water, and the organic layer was washed twice with 50 ml of water and then dried over anhydrous magnesium sulfate. Then the organic layer was concentrated and after reaching the syrupy state with petroleum

2 0 9 831/1136

ether added and brought to crystallization. There were 42 g (80 %) of pivaloyloxymethyl ester of 6-IN- (TN, N-Dimetb.ylamino-carbonylpropen-2-yl) -D ^ -) -J ^ -aminophenylacetamidojpenicillanäure in the form of white crystals with a melting point of 70 up to 73 C (decomp.). The overall yield from reactions (i) and (ii) was 69.5%.

IR (KBr) cm " ¹ j yc = o 1790, 1760 UV7 \ .max (Et0H) m | i: 2O6, 294

Example 4

(i) The procedure of Example 3 (i) was carried out under the same reaction conditions repeated, but with morpholinoacetoacetamide instead of Ν, Ν-dimethylacetoacetamide was used in reaction (i) in Example 3. It became the triethylainin salt of 6-Γν- (1-Μογ-pholinocarbonylpropen-2-yl) -D (-) - iC-aminophenylace tamidol penicillanic acid with a melting point of 152 C (dec.) obtain,

(ii) The procedure of Example 3 (ii) was followed under the same reaction conditions repeated, with 4.8 g of triethylamine salt of 6-JN- (1-morpholinocarbonylpropen-2-yl) -D (-) -% (- aminophenylacetamidojpenicillanic acid N- (1-N, N-Di-

methylamino-carbonylpropen-2-yl) -d (-) - flC-aminophenylacetamidoj penicillanic acid in reaction (ii) of Example 3 were used. 5 »4 g (86 ^) of the pivaloyloxymethyl ester of 6-Γν- ( 1-morpholinocarbonylpropen-2-yl) -D (~) -H-aminophenylacetamidojpenicillanic acid were obtained in the form of white crystals with a melting point of 78 to 80 ° C .

209831/1136

IR (KBr) cm " ¹ s yC = o 1790, '1760 UV χ max (EtOIl) mu: 206, 294

Example 5

(i) The procedure according to Example 3 (i) was repeated under the same reaction conditions, but with Piperidino-acetoacetamide instead of Ν, Ν-dimethylacetoacetamide was used in reaction (i) of Example 3. The triethylamine salt of 6-fisT- (ipiperidinocarbonylpropen-2-yl) -d (-) - 0 (-aminophenylace tamidoj penicillanic acid with a melting point of 94 ° C (decomp.).

(ii) The procedure according to Example 3 (u) was repeated under the same reaction conditions, except that the triethylamine salt of 6- / N- (I-piperidinocarbonylpropen-2-yl) -D (-) - oC-a-minophe Nylace tamidojpenicillanic acid instead of the triethylamine salt of 6- [n- (1-Ν, Ν-dimethylaminocarbonylpropen-2-yl) -D (-) - & C -aminophenylace tamidoj penicillanic acid in reaction (ii) of Example 3 was used.

The pivaloyloxymethyl ester of 6-yi- (1-piperidinocarbonylpropen-2-yl) -D (-) - | (-aminophenylacetamidoj penicillanic acid with a melting point of k6 to 48 ° C. was obtained.

IR (KBr) cm " ¹ : yc = o 1790, 176O UV- ^. Max (Et OH) mp: 206, 294

Example 6

The procedure of Example 3 (i) was followed by the same Reaction conditions repeated, but with pyrrolidinoacetoacetamide instead of Ν, Ν-dimethylaceto-

209831/1136

acetamide was used in reaction (i) of Example 3. The triethylamine salt obtained 6-ΓΝ- (1 -PyrBDlidino-carbonylpropen-2-yl) -D (-) - J (-arainophenylacetamido-penicillanic acid with a melting point of 65 to 15 C was obtained.

IR (KBr) cm " ¹ 1 ^ c = O 1790," 76 "UV ^ V. Max (EtOH) mu: 206, 294

Example 7

The procedure according to Example 3 (i) was repeated under the same reaction conditions, but with Anilinoacetoacetamide instead of Ν, Ν-dimethylacetoacetamide was used in reaction (i) of Example 3. The triethylamine salt of 6-IN- (1-anilinocarbonylpropen-2-yl) -d (-) - fl ^ -aminophenylacetamido-penicillanic acid obtain. Then this product was under the same reaction conditions as in reaction (ii) of Example 3 treated. In this way the pivaloyloxymethyl ester became the 6-Γν- (1-anilino-carbonylpropen-2-yl) -D (-) ~ gll-aminophenylacetamido J penicillanic acid obtained with a melting point of 48 to 50 C.

Example 8,

1.0 g of the potassium salt of N- (1-N, N-dimethylaminocarbonylpropen-2-yl) -D (-) - e ^ -aminophenyl acetate were suspended in 15 ml of dry methylene chloride and with one drop N-methylmorpholine is added at -10 ° C. It was then on -45 ° C cooled. A solution of 0.4 g of ethyl chlorocarbonate in 3 ml of acetone was then added for 5 minutes added drop by drop. After mixing, the reaction was carried out at the same temperature for 90 minutes and the solution with 1.06 g of the triethylamine salt

209831/1136

6-aminopenicillanic acid in 10 ml of methylene chloride was added dropwise at -45 ° C. over a period of 15 minutes. After the mixture had reacted at -45.degree. C. for 1 hour, the temperature was gradually increased to 0.degree. The reaction solution was filtered off and freed from inorganic salts. The filtrate was then concentrated under reduced pressure and the residue was treated with dry ether. 1.5 g (86.6 fo) of the triethylamine salt of 6- | N- (1-Ν, Ν-dimethylaminocarbonylpropen-2-yl) ~ D (-) - • ^ -aminophenylacetamidoJ penicillanic acid were obtained. When this product is recrystallized from a mixture of chloroform and ether, white crystals with a melting point of 1 ° 1 C (decomp.) Appear.

The product thus obtained was treated under the same reaction conditions as in reaction (ii) of Example 3, the pivaloyloxymethyl ester of 6- [N- ( 1 -NfN-dimethylaminocarbonylpropene ^ -yl) -D (-) - · (- aminophenylacetamidojpenicillanic acid was obtained.

Example_9

3 g pivaloyloxymethyl ester of 6-Id (-) - 1 ^ -aminoph.enylacetamidojpenicillanic acid were in 25 tnl methylene chloride dissolved and mixed with 2.05 g of morpholinoacetoacetamide and together with 2 g of anhydrous magnesium sulfate during Stirred for 15 hours at room temperature. The desiccant was then filtered off and the filtrate became concentrated under reduced pressure, whereupon the residue was taken up in 30 ml of ethyl acetate. To the solution, 20 ml of ice water were added while cooling with ice and the The solution was immediately adjusted to a pH of 7 | 0. The aqueous layer was separated and extracted with 20 ml of ethyl acetate. The organic layers

209831/1 136

were combined and washed with saturated salt water. The solution was then dried with anhydrous ilagnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and petroleum ether was added to wash. This gave 5.7 C (90.7 p) of the pivaloyloxyuiethyl ester of 6-jN- (1-I-Iorpliolinocarbonylpropeii-2-yl) -D (-) - ^ -ajninoplienylace tamidojpenicillanäure in the form of white crystals with a melting point of 73 to uO C obtained.

Example 10

The procedure of Example 9 was repeated under the same reaction conditions, with 1.55 g of Ν, Ν-dimethylacetoacetamide instead of ilorpholinoacetoacetanide in Example 9 being used. 5.0 g (39 <f) of the pivaloyloxymethyl ester of 6-Γν- (1-Ν, ^ Γ-Diuie thylaminocarbonylpropen-2-yl) -D (-) - ^ -atniaophenylacetamidoj-penicillanic acid in the form of white crystals obtained with a melting point of 70 ° C to 73 ° C.

Example 11

Fe 2.0 g of the pivaloyloxymethyl ester hydrochloride of oD (-) - oL -aminophenylacetatnidopenicillanic acid were dissolved in 20 ml of methylene chloride, Wach addition of 0.5-S

at ο,
Triethylamine was added / 0 C 0.7 ^ S pyrrolidinoacetoacetamide and 2.0 g of anhydrous magnesium sulfate and the reaction was carried out with stirring for 20 hours at the same temperature. The reaction solution was alifiltrated and the filtrate was evaporated under reduced pressure. The residue obtained was dissolved in 13 ml of ethyl acetate. After the "./as before η with water, the ethyl acetate layer was dried over anhydrous magnesium sulfate. The ethyl acetate solution was under

BATHROOM 2 0 9 8 3 1/113 6

216U20

reduced pressure concentrated and the residue was washed with petroleum ether to give 2.2 g of the pivaloyloxymethyl ester of the 6-IN- (1 -Pyrrolidiiiocarbonylpropen-2-yl) -D (-) IZ-aminoplienylacetamidoJ-penicillanic acid with a melting point of 65 C to 66 C.

IR (EiJr) cn " ¹ : yc = o 1790, 176O UV ¹ JV max (D tüil) au: 205, 2 94

Example Ί_2

2.0 g of the pivaloyloxymethyl ester hydrochloride of f - D (-) - l ^ -aminophenylacetaniidopenicillanic acid were dissolved in 20 nil of ethylene chloride. To the solution 52 g were Triätliylamin j β at 0 C and then the llischung with 0, Ά g Piperidinoace toacetamid and 2.0 g of anhydrous magnesium sulfate was added and the reaction was carried out hours at the same temperature during the twentieth

The reaction solution was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in 15 ml of ethyl acetate and washed with water. After drying the methyl acetate layer over pure sodium sulfate, the same was concentrated under reduced pressure and petroleum ether was added to the residue to carry out crystallization. 2.25; "Pivaloyloxynethyl-ester of 6-Γν- (1-N-piperid i.10-carbonylpropen-2-yl) -D (-) - p (-aniiriophenylacet ^ midoj -ponicillansäuro r.rit a Schuielapuiikt from h '> C bin - ¹ I .- C. ¹ obtained.

_ -1

IR (i: .5r) cm: yc = o 17 ^r - ^-) j 17 ^ 0 ia; -: (^ tüil) mti: 206, 29 ^z l ·.

BATH

209831/1136

Claims (1)

1 where R is a lower alkyl group, where R and R is hydrogen, a lower alkyl group or a Mean aryl group or with the adjacent nitrogen atom together form an Ixeterocyclic ring and wherein R represents a lower alkyl group. 2. Process for the preparation of the penicillin derivative according to Claim 1,. characterized in that one ^ -Amiaobenzylpenicillin or its salt with a ß-keto acid amide of the form I .1 R R * N-Cu-CII ₀ -CO-R "1 O ^ l - where R, R and R have the meaning given above, whereupon the N-substituted φζ-aminobenzylpenicillin formed with an acyloxymethyl halide of the formula ROCOCH ₀ X 209831/1 136 is implemented, where X is an Ilalogenatom and R has the meaning given above, 3. \ ^r learn after. Claim 2, characterized in that a sodium salt, a potassium salt or a triethylamine salt of J (-arninobenzylpeuicillin is used. H. Process according to one of Claims 2 or 3 »characterized in that the reaction between the (^ -aminobenzylpenicillin or its salt with the β-keto acid amide is carried out at a temperature of -20 C to 30 C. 5 «Method according to one of claims 2 to 4, characterized in that that the reaction between the J ^ -atninobenzylpenicillin or its salt with the IJ-keto acid atnide carried out in the presence of a dehydrating agent. 6. The method according to claim 5 »characterized in that the dehydrating agent used is magnesium sulfate, calcium sulfate or molecular sieve. 7. Method according to one of claims 2 to 6, characterized in that that the reaction between the N-substituted βζ-aminobenzylpenicillin and the acyloxymethyl halide is carried out at a temperature of -20 ° C to 40 ° C. B. "process for producing the penicillin derivative according to claim 1 characterized in _t that is an acyloxy esters of 6-aminopenicillanic acid of the formula 2 0 9 8 3 1/113 8 -Zk- • V ^s Λ —ν CH, COOCH ₂ OCOR with the N-substituted j (-atninophenylacetic acid of formula HR ³ 1 · f MR N-CH-COOH Ph 12 3 reacted, where R ₁ R, R and R have the meaning given above. 9. The method for preparing the penicillin derivative according to claim 1, characterized in that one Acyloxyalkyl ester of% i-aminobenzylpenicillin der formula H ₉ N-CH-CONH-2 ι Ph with a ß-keto acid amide of the formula , CH. CH. 'COOCH ₂ OCOR 12 3 converts, where R, R, R and R are those given above Have meaning. 209831/1136