DE1795702C3 - 6-aminopenicillanic acid ester - Google Patents

Description

The invention relates to 6-aminoptnicillanic acid esters of the general formula

S CH ₃

/ \ / X '-NH-CH-CH C

O = C N '

in which A is an alkyl group with 1 to 4 carbon atoms or denotes the phenyl or pyridyl group and X 'represents a hydrogen atom, a triphenymethyl group or a trialkylsilyl group of up to 5 Carbon atoms in the alkyl chain, as well as their salts with pharmaceutically acceptable acids and Process for their manufacture.

The alkyl groups or saturated aliphatic hydrocarbon groups with 1 to 4 carbon atoms and straight or branched carbon chains are the methyl, ethyl, propyl, isopropyl, butyl, sec. Butyl and tert. Butyl group.

The compounds of general formula I are interesting intermediates in the synthesis of important pharmaceutically usable penicillin esters and are substituted with derivatives of the -amino for this purpose Phenylacetic acid implemented.

The compounds of general formula I are in a manner known per se by treating the 6-aminopenicillanic acid in the form of its salt, e.g. B. their alkali salt or triethylammonium salt with a substituted methyl ester of the general formula

R CH ₁ OCO Λ

(ID

in which R is a halogen atom, preferably a chlorine atom -CH-COOCH ₂ OCO-A

or bromine or an alkyl or aryl sulfonyloxy group, z. B. is a methylsulfonyloxy or toluenesulfonyloxy group and A is that given above Meaning has established. The 6-aminopenicillanic acid can be used as such or it can be used during the Esterification of the 6-amino group by a triphenylmethyl or trialkylsilyl group with up to 5 carbon atoms Substance atoms in the alkyl chain are protected. These protective groups can easily split off again without destroying the lactam ring or the ester group. The implementation is in an inert organic solvent such as acetone, dimethylformamide or methylene chloride and at Room temperature or below or made at slightly elevated temperatures. Such implementations are known per se, e.g. from FR-PS 14 91 583. If the amino group was protected beforehand, it can ho this protective group can be split off in various ways, e.g. B. by hydrogenolysis or Hydrolysis under neutral or acidic conditions that does not affect the O-lactam ring and the ester group attack. The reaction products are expediently> 5 Usually in the form of their acid addition number with ζ. Β p-Toluenesulfonic acid or other inorganic or organic salts such as sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, maleic acid or

Tartaric acid isolated.

According to a modification of the Herstellungsverfahns any industrially available penicillin is preferably its salt with a compound of general formula 11 under similar conditions, _w ie already described, esterified and represents;>^"r the side chain of Penicillinesters obtained abge ami; this is the 6- Amino-penicillanic acid ester according to general formula 1 or its corresponding. ·. Sal /.

^e Cleavage of the amide bond can be carried out according to a modification of the method 98 6 5% described in the Belgian patent specification, by the 6-Acylaminopenicillansäureester of an acid acceptor such as quinoline or pyridine is reacted with an acid halide in the presence of. Phosphorus penile chloride is preferably used for this reaction, because in this case the reaction can be carried out at low temperatures which increase the stability of the intermediate product formed, which is presumably an iminohalide. The reaction can take place in various solvents; chloroform and methylene chloride are preferred.

The intermediate product is not isolated, but with a primary alcohol in excess to form one Iminoether implemented. The reaction temperature and reaction time depend on the alcohol used away; in most cases temperatures from - 20 ° C to + 20 ° C are appropriate.

The lminoether is not isolated, but rather subjected to an acidic alcoholysis or hydrolysis, as a result of which split the carbon-nitrogen double bond and the corresponding 6-aminopenicillanic acid ester of the general formula 1 is formed. With the help of the usual working methods s the level of the b-aminopenicillanic acid from the reaction mixture as such or in the form of their salt with an inorganic or organic acid, e.g. B. des Hydrochloride or tosylate, isolated.

The esters available from the inventive compounds according to processes known per se o ■ the iX-Amino'oenzylpenicillins of the general formula

CH-CO-NH-CH-CH C

NH ₁

CH,

O = - C - N CH - CO - OCH ₂ OCO-A

are more absorbable than ampicillin and give higher blood levels, as from the following Test report can be seen.

Α-Aminobenzylpenicillin esters prepared with the aid of the compounds according to the invention were used purebred beagle dogs administered and the achieved mean penicillin level in the blood plasma of the dogs with the corresponding values for known penicillins - ampicillin, penicillin G and penicillin G-acetoxymethyl ester - compared.

The experiments were carried out with anesthetized dogs (35 mg / kg pentobarbital iv) in the following way: A midline incision was made on the ventral side of the anesthetized animals, the jejunum was identified and an approx. 15 cm long section of the jejunum without interrupting the blood supply Intestinal clamps clamped off. Solutions or suspensions of the test compounds (25 mg of substance - ampicillin or penicillin equivalent in 5 ml of saline solution) were injected into the isolated section of the small intestine, the section of the small intestine was carefully placed back into the abdominal cavity, and the incision site was covered with sponges soaked in saline. The temperature of the dogs was kept ^{at 37 to 38 ° C. with the aid of heating pads.} At time 0 and after 15 minutes, 30 minutes, 1, 2 and 4 hours, blood samples were taken from the femoral vein, centrifuged quickly, and the blood plasma was placed in sterile plastic tubes for microbiological analysis. The analysis was carried out according to the usual (standard) method.

Each compound was tested on two dogs. The results are summarized in the following table - Test Compound
--A

Milllerer Ampidllin level in blood plasma (ng / ml) after

0.25 h 0.5 h 1

4 h

40 C-ICH,), 1.40 1.94 1.32 0.72 0.17 Λ 1.19 1.91 1.63 0.80 0.36

so -CH ₂ CH ₂ CH,
-CH ₃

Ampicillin irihydrate ampicillin
hydrochloride

Penicillin G.

Penicillin G-

acetoxymethyl

ester 0.96
0.85
0.77
0.34

1.37 1.31 1.32 0.54

1.25 1.31

1.27 0.77

0.28 1.15 1.73

0.21
0.25

0.57 0.26

0.78 0.24

0.78 0.79 0.76 0.82

0.48 0.13

<0.2>

example 1 acetoxymethyl p-toluenesulfonate

6-aminopenicillanate

A. Cine acetoxymethyl-6-tritylaminopenicillanat solution of! 1,5g 6-Tritylaminopenicillansaure in 65 cm ³ of acetone was cooled to 0 ⁰ C, with 4.2 cm ⁵ of triethylamine and then 2.45 cm ³ Acetoxymethylbro-

mid shifted; the reaction mixture was kept with stirring at 0 ° C. for 2 hours and finally at room temperature for 1 hour. The precipitated triethylammonium bromide (3.5 g) was filtered off, the Filtr H evaporated, the residue taken up in 175 cm ^{3 of} ethyl acetate, the solution washed twice with cold aqueous 2% NaHCOi solution and with ice water and finally the ethyl acetate layer over MgSO ₄ dried. After evaporation, the desired pure acetoxymethyl ester remained as an amorphous powder.

Calculation for C _3U H ₃ | N ₂ O ₅ S:

C 67.77, H 5.87, N 5.27, S 6.04%; found:

C 67.73, H 5.91, N 5.22, S 6.00%.

[<χ.] ΐ: +109.8 (c = 2; CHCl ₃ ).

Thin layer chromatography on silica gel showed the product to be pure.

Rf = 0.71 (butanol-ethanol-H ₂ O 8 + 2 + 2). Rf = 0.78 (butanol-acetic acid-H ₂ O 8 + 2 + 2)

B. p-toluenesulfonate of acetoxymethyl-6-aminopenicillanate

1. 3.71 g of acetoxymethyl 6-tritylaminopenicillanate in 120 cm ^{3 of} acetone (0.2% H ₂ O) were treated with 1.21 g of anhydrous p-toluenesulfonic acid. After _{standing for 1/2} hour at room temperature, 0.14 cm ^{3 of} water was added and the p-toluenesulfonate was ^{precipitated by adding 300 cm 3 of} petroleum ether. The crude salt was filtered off and washed successively with acetone / petroleum ether, ethyl acetate and ether.

After recrystallization twice from acetone-ether, a colorless crystalline product became with Melting point 132.5 to 134 ° C (decomp.).

Ber. for C ₁₈ H ₂₄ N ₂ O ₈ S ₂ :

C 46.95, H 5.25, N 6.08, S 13.92%; found:

C 46.84, H 5.17, N 5.86, S 13.79%.

[ot] ^! _D ⁴ : + 127.5 ° (c = 1; ethanol).

Thin layer chromatography on silica gel: Rf = 0.51 (butanol-ethanol-H2O, 8 + 2 + 2) Rf = 0.53 (butanol-CH ₃ COOH-H ₂ O, 8 + 2 + 2)

The iodometric determination showed a purity of 99% using 6-aminopenicillanic acid as standard.

2. A dispersion of 4.32 g of 6-aminopenicillanic acid in 140 cm ^{3 of} acetone was admixed with 6.3 cm ^{3 of} triethylamine at 0 ° C. while stirring. 3.92 cm ^{3 of} acetoxymethyl bromide were added dropwise and the mixture was kept at room temperature for 4 hours with constant stirring. The precipitated triethylammonium bromide (3.5 g) was filtered off, the filtrate was evaporated to dryness in vacuo and the residue was ^{treated with 140 cm 3 of} ethyl acetate and 110 cm ^{3 of} cold 2% sodium bicarbonate solution. After shaking and separating, the ethyl acetate solution was shaken with ice water and dried over magnesium sulfate.

When the solution evaporated, 5.2 g of substance remained. The crude ester, dissolved in 200 cm ^{3 of} acetone, was mixed with 3.5 g of anhydrous p-toluenesulfonic acid and the p-toluenesulfonic acid salt was ^{precipitated by adding 750 cm 3 of} ether. The salt was filtered off and washed with ethyl acetate and ether. Complete identity with the product obtained according to 1. was verified by comparing the melting points, IR spectra and RF values.

The IR spectrum (KBr) showed strong bands at:

1785 cm
1370 cm ~
1225 cm
1123 cm-1006 cm-811 cm- ^!

1758 cm '

1325 cm- ¹

1170 cm '

1030 cm ¹

972 cm- '

681 cm- ¹

Implementation with Λ-amino-phenylacetyl chloride hydrochloride led to acetoxymethyl a-aminobenzyl penicillinate, identified by its IR spectrum (CHCIj): bands at 3300 cm- '(NH); 1875 cm- '(ß-lactam), 1760 cm-' (ester carbonyl) and 1680 cm- '(amide).

Example 2

p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate

First 1.08 cm ^{3 of} triethylamine and then 1.6 cm ^{3 of} chloromethyl pivalate and 2.3 g of triethylammonium iodide were added to a solution of 5.6 g of triethylammonium 6-tritylaminopenicillanate in 25 cm ^{3 of} acetone at ^{0 ° C. with stirring.} The mixture was stirred for a further half an hour at 0 ° C. and then for 20 h at room temperature. The precipitated triethylammonium chloride was filtered off, the filtrate was evaporated and the residue was ^{treated with 75 cm 3 of} ethyl acetate. The solution was shaken with cold aqueous 1% NaHCO ₃ solution and with ice water, the ethyl acetate layer was separated off, _{dried over MgSO 4} and evaporated in vacuo. The pivaloyloxymethyl ester of 6-tritylaminopenicillanic acid remained as an amorphous powder. The crude ester was dissolved in 40 cm ^{3 of} ethyl acetate and a solution of 1.90 g of p-toluenesulfonic acid ^{hydrate in 20 cm 3 of} ethyl acetate was added to the solution at 0 ° C. After stirring for two hours at room temperature, the desired tosylate was collected on a filter and washed with ethyl acetate and ether.

Recrystallization from acetone-ether gave the pure crystalline compound with a melting point of 138 up to 139 ° C (decomp.).

Ber. for C ₂ IH ₃₀ N ₂ O ₈ S ₂ :

C 50.18, H 6.01, N 5.57, S 12.76%;

found:

C 50.46, H 6.15, N 5.36, S 12.57%.

[ot] i ': + 131 ° (c = 1; ethanol).

IR spectrum (KBr): strong bands at 1795, 1768, 1750, 1545, 1485, 1465, 1375, 1365, 1315, 1210, 1160, 1115, 1030,1010,980,815 and 680 cm- '.

Iodometrically determined purity, with 6-aminopenicillanic acid as reference 99%.

Thin layer chromatography on silica gel:
Rf = 0.66 (n-butanol-ethanol-H ₂ 0.4 + 1 +1).
Rf = O. ^ cyclohexane-ethyl acetate, 1 + 1).

Example 3

p-Toluenesulfonat des Pivaloyloxymethylö-aminopenicillanat

4.32 g of 6-aminopenicillanic acid, dispersed in 140 cm ^{3 of} acetone, was mixed ^{with 6.4 cm 3 of} triethylamine at 0 ° C

treated. With constant stirring at 0 ° C., 5.9 cm ^{3 of} chloromethyl pivalate and 4.6 g of triethylammonium iodide were added and the mixture was allowed to stand at room temperature for 20 hours. The precipitated triethylammonium chloride (2.9 g) was filtered off, the filtrate was evaporated and the residue was worked up according to Example 2 to give the crude pivaloyloxymethyl ester. The crude compound was taken up in 45 cm ^{3 of} ethyl acetate, and 3.4 g of anhydrous p- ^{toluenesulfonic acid in 50 cm 3 of} ethyl acetate were added. The crystalline tosylate which precipitated out immediately was filtered off and washed with ethyl acetate and ether. The pure colorless substance was found to be identical to the analytically pure compound from Example 2.

Example 4

p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate

A dispersion of 2.16 g of 6-aminopenicillanic acid in 70 cm ³ of acetone was added at 0 ° C and then added with 3.22 cm ³ of triethylamine with 3.92 g Brommethylpivalat (bp. 50-51 ⁰ C / 10 mm Hg), that from pivaloyl bromide and paraformaldehyde according to the in J. Amer. formerly Soc, 89, 5442 (1967) described preparation of chloromethyl pivalate had been obtained.

After stirring for 20 hours at room temperature, the precipitate of triethylammonium bromide (1.63 g) was collected on a filter, the filtrate was evaporated and the residue was worked up as in Example 2. The crude pivaloyloxymethyl ^{ester was dissolved in 45 cm 3 of} ethyl acetate and precipitated in the form of its pure tosylate by adding 1.72 g of anhydrous p-toluenesulfonic acid in 25 cm ^{3 of} ethyl acetate. The salt was filtered off, washed with ethyl acetate and ether; it was identical to the compound from Example 2.

Example 5

ρ toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate

2.16 g of 6-aminopenicillanic acid, ³ dispersed in acetone 60 cm, was added at 0 ⁰ C successively with 1.8 cm ³ of triethylamine and 10 cm ³ of a Acfctonlösung added of 3.2 g of pivaloyloxymethyl p-toluenesulfonate. The mixture was stirred for 1/2 h at 0 ^° C. and for 20 h at room temperature. The clear solution obtained was evaporated in vacuo and the residue was worked up as in Example 2. The crude ester was taken up in 75 cm ^{3 of} ethyl acetate and 1.7 g of anhydrous p-toluene sulfonic acid in 25 cm ^{3 of} ethyl acetate were added. The crystalline precipitate was filtered off and washed with ethyl acetate and was found to be identical to the compound prepared according to Example 2.

The starting material pivaloyloxymethyl-p-toluenesulfonate was prepared by the silver salt of p-toluenesulfonic acid with chloromethyl pivalate in dry Acetonitrile was reacted for 4 days at room temperature. Mp 44 to 44.5 ° C.

Example 6

p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillant

To a dispersion of 2.16 g of β-aminopicnicillant and 1.0 g of sodium bicarbonate in 70 cm ^{1 of} acetone were added 1.76 cm of chloromethyl pivalite and 280 mg of culium iodide. The mixture was stirred and refluxed for 5 hours. The solids were filtered off and the acetone solution was evaporated in vacuo. The residue was ^{stirred with 80 cm 3 of} ethyl acetate and filtered, and 1.72 g of anhydrous p-toluenesulfonic acid in 40 cm ^{3 of} ethyl acetate were added to the cooled ethyl acetate solution. The precipitated tosylate was collected on a filter and washed with ethyl acetate and ether. Melting point 1R spectrum and thin layer chromatography of the colorless crystalline substance proved the identity with the compound obtained according to the preceding examples.

Example 7
Pivaloyloxymethyl-6-aminopenicillanate hydrochloride

A solution of 2.1 g of PCI5 in 20 cm ^{3 of} dry, alcohol-free chloroform was mixed with 2.26 cm ^{3 of} dry quinoline while stirring. The suspension obtained was adjusted to - 30 ⁰ C cooled and treated with 4.0 g Pivaloyloxymethylbenzylpenicillanat. After 30 minutes stirring at -5 ° C to - 1O ⁰ C, the solution was cooled to -3O ⁰ C and once with 6.7 cm ³ of dry n-propanol was added. The temperature rose to -15 to - 10 to ⁰ C. ^{The reaction temperature was then increased to 0} ° C. in the course of 15 min and kept at this temperature for 30 min; the solution was then added, with stirring, to an ice-cold mixture of 25 cm ^{3 of} water and 40 cm ^{3 of} hexane. The aqueous phase was separated off and the organic phase was ^{extracted three times with 25 cm 3 of} ice-cold In HCl. The aqueous phases were combined and stirred at 0 ⁰ C and 90 cm ³ of ethyl acetate, the pH-value with NaHCCb was adjusted to 7.5. The organic phase was separated off, dried and concentrated in vacuo

steams. An oil remained which was dissolved ^{in 50 cm 3 of isopropanol at 0 ° C.} The desired hydrochloride was precipitated by adding 1.75 cm ^{3 of} an 8 η anhydrous solution of hydrochloric acid in isopropanol with stirring. It was filtered off and washed successively with isopropanol and ether. The pure compound melted at 156 to 16O ⁰ C with decomposition.

Be ^ forC ₁₄ H ₂₃ CIN ₂ O ₅ S:
C 45.84, H 6.32, Cl 9.66, N 7.63, S 8.74%;
found:

C 45.60, H 6.39, Cl 9.76, N 7.54, S 8.83%.

[«.]? + 183 ° (c = 1; 0.1 n-HCl).

so the IR spectrum had characteristic strong Carbonyl bands at 1790, 1767 and 1756 cm- '.

When reacted with D (-) - a-Phenylglycylchloride hydrochloride became pivaloyloxymethyl-D (-) - "- aminobenzyl-penicillinate hydrochloride obtained, m.p. (from Isoss propanol): 155 to 156 ° C (decomp.).

The starting material can be produced in the following ways:

Pivaloyloxymcylbenzylpcnicillinate

^{8.3 cm 3 of} chloromethyl pivalate and a solution of 1.25 g of sodium iodide in 5 cm ^{1 of} water were added successively to a suspension of 19.0 g of potassium benzylpenicillinut in 200 cm ^{3 of} acetone. The mixture was refluxed for 5 hours. After cooling it was

(, s the potassium chloride filtered off. The filtrate was with Water is added and the desired compound is added as a colorless crystalline substance with a melting point of 114 to 115 "CaUSgCfUlIt.

The pivaloyloxymethyl-6-aminopenicillanate was made in an analogous manner obtained when phenoxymethylpenicillin was used instead of benzylpenicillin.

Example 8
Pivaloyloxymethyl-δ-aminopenicillanate

A suspension of 24.0 g of p-toluenesulfonate of pivaloyloxymethyl-δ-aminopenicillanate in 1.1 l of ethyl acetate was admixed with 760 cm ^{3 of} aqueous 2% sodium bicarbonate solution with vigorous stirring. The layers were separated and the ethyl acetate solution was shaken thoroughly with 600 cm ^{3 of} ice water, mixed with 25 cm ^{3 of} 2% sodium bicarbonate solution.

The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. 200 cm ^{3 of} petroleum ether (boiling point <50 ° C.) were added to the residue; After stirring for 2½ hours, the analytically pure ester, melting point 60 to 65 ° C., crystallized out.

BeHfUrCi ₄ H ₂₂ N ₂ O ₅ S:
C 50.90, H 6.71, N 8.48, S 9.71%;
found:
_{| o} C 51.15, H 6.77, N 8.36, S 9.63%.

/ "" / '? + 194 ° (c = 1; C ₂ H ₅ OH).
[αϊ] '" + 184 ° (c = 1; CHCl ₃ ).

The IR spectrum showed characteristic bands at 3400, 1780 and 1750 cm- ¹ .

Claims (2)

Claims: 1. 6-Aminopeniciüansäureester of the general formula: S CH X'-NH-CH-CH O - = - · CN CH --COOCH ₂ OCO- Λ in which A is an alkyl group with 1 to 4 carbon atoms or the phenyl or pyridyl group and X 'represents a hydrogen atom, a triphenylmethyl group or a trialkylsilyl group with up to 5 carbon atoms in the alkyl chain, as well as their salts with pharmaceutical compatible acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that one a salt of 6-aminopenicillanic acid or 6-aminopenicillanic acid, the amino group of which is replaced by a Triphenylmethyl or trialkylsilyl group with up to 5 carbon atoms in the alkyl chain is protected with a substituted methyl ester of the general formula: _R _CH ₂ -OCO-A in which R is a halogen atom or an alkylsulfonyloxy or arylsulfonyloxy group and A has the meaning given in claim 1, in itself brings to implementation in a known manner and optionally splits off the protective group.