DE1795702A1 - 6-AMINOPENICILLANIC ACID ESTER - Google Patents

Description

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

X '.HN .CH-Ch "C

I I I

O = C Ii CH. COO. CH ₂ ο OCO (CH ₂ ) _n ~ J

(D

in which η is an integer from 0 to 5, A is an optionally substituted aliphatic, alicyclic, aromatic or heterocyclic group and X ^{1 is} a hydrogen atom, a sialkylsilyl group with up to 5 carbon atoms in each alkyl group or the triphenylmethyl group, as well as their salts with pharmaceutically acceptable acids and processes for the preparation of these compounds.

- 2 309842/1133

In the above formula A preferably stands for an aliphatic hydrocarbon group with 1 to 6 carbon atoms and a straight or branched and saturated or unsaturated carbon chain, for example _o for methyl, ethyl, propyl, isopropyl, butyl, sec _e -butyl and tert-butyl, pentyl or hexyl group or the like; for an alicyclic, carbocyclic group with 5 - 10 carbon atoms in the ring, in which the ring (s) is (are) saturated or contains 1 or 2 double bonds, depending on the number of carbon atoms, e.g. for the cyclopentyl , Cyclohexyl, 1-adamantyl, 1-bicyclo- (2,2,2) octyl, gyclopentenyl or cyclohexenyl group with the double bond in 2,3- or 3,4-position among others more; for an aromatic group, e.g. a monocyclic carbocyclic aryl group such as the optionally substituted phenyl group, a bicyclic carbocyclic aryl group, e.g. _e the optionally substituted 1- or 2-naphthyl group j for a heterocyclic aryl group containing 5-10 carbon atoms in the ring, e.g. the pyridyl , Pyrazinyl, pyrimidyl, thienyl, furyl or ghinolyl groups in which the heteroatom can occupy any available position and which are furthermore optionally substituted in one or two of the remaining positions. The group A can, as already stated, carry further substituents, for example a lower alkyl group such as methyl, ethyl, propyl, isopropyl or butyl group, etc. menrj a lower alkoxy group such as methoxy or ethoxy group, etc. more? a lower alkylthio group, for example the methyl mercapto or ethyl mercapto group; a lower halogenated alkyl group, for example the mono-, di- or trifluoromethyl group, the mono-, di- or trichloromethyl group or the ethyl homologues and the corresponding bromine derivativesj halogens such as fluorine, bromine or chlorine; or nitro groups. The substituents can be arranged in all possible positions. - ο -

309842/113 3

- 3 - 1A-41 811

Me compounds of the formula I are new and interesting intermediates in the synthesis of important pharmaceutically acceptable penicillin esters. These are made by reacting the 6-aminopenicillanic acid ester with <X-substituted phenylacetic acid derivatives obtained the the formula

in which R is a protected amino group or a group which can be converted into an amino group, for example an azido or a nitro group or a halogen atom and in which the group GO-Y ¹ with the group X'-HK * to form a GO -HH bridge responds. For example, -GO-Y'- can be the residue of an acid halide, e.g. an acid chloride or bromide; an anhydride; a mixed anhydride with an alkyl carbonic acid such as isobutyl carbonic acid, a carboxylic acid, an inorganic acid or a sulfonic acid; or a group which is obtained by reacting the «^ -substituted phenylacetic acid with a garbodiimide or!, iJ'-carbonyldiimidazole or a similarly functional compound

The new compounds are prepared by treating 6-aminopenicillanic acid in the form of its salt, for example its alkali salt or triethylammonium salt, with a halomethyl _{ester of the formula R-GH 2} -OGO (GH ₂ ) _n -A (II) in which R is a halogen atom, preferably a Chlorine atom or bromine atom or a sulfonyloxy group, for example a methylsulfonyloxy or toluenesulfonyloxy group, and η and A have the meanings given above. The 6-aminopenicillanic acid can or can be used as such

* of the formula I _ 4 _

309842/1133

- 4 - 1A-41 811

the 6-amino group can be protected during the esterification. Only such protective groups come for this in embossing that can easily be split off again, without destroying the lactam ring or the ester group, e.g. the iriphenylmethyl group or a "Trialkylsilyl group whose alkyl radicals are not more than Have 5 carbon atoms, for example the trimethylsilyl group. The reaction is carried out in an inert organic solvent such as acetone, dimethylformamide or Methylene chloride and at room temperature or below or made at slightly elevated temperatures. If the amino group was protected beforehand, it can The protective group can be split off in various ways, e.g. by hydrogenolysis or hydrolysis under neutral or acidic conditions involving the ß-lactam ring and the Do not attack the ester group. The reaction products are expediently in the form of their acid addition salts with e.g. p-toluenesulfonic acid or other inorganic or organic salts such as sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, maleic acid, and tartaric acid like isolated.

According to a modification of the production process, any technically accessible penicillin, preferably its salt ^{, is esterified with a compound of the formula II (} under similar conditions as already described, and the side chain of the penicillin ester obtained is then split off) I or its corresponding salt.

The cleavage of the amide bond can be carried out according to a modification of the procedure described in Belgian patent specification No. 698 596

_ 5 _ 309842/1133

- 5 - 1A-41

procedure described are carried out by the 6-acylaminopenicillanic acid ester with an acid halide in the presence of an acidic acceptor such as ghinolin or pyridine and more is implemented. Phosphorus pentachloride is preferably used for this reaction because the reaction in this case Can be carried out at low temperatures, which increases the stability of the intermediate product formed is believed to be an iminohalide. The reaction can take place in various solvents, preferably become chloroform and methylene chloride.

The intermediate product is not isolated, but with a primary alcohol in excess to form an imino ether implemented. The reaction temperature and reaction time depend on the alcohol used; in most cases are Temperatures from -20 C to +20 C are advisable.

The imino ether is not isolated, but subjected to acidic alcoholysis or hydrolysis, whereby the carbon-nitrogen double bond is cleaved and the corresponding 6-aminopenicillanic acid ester of the formula I is formed. It is surprising that the lactam ring and the acyloxymethyl ester group are sufficiently stable under these conditions. Using the customary procedures, the esters of 6-aminopenicillanic acid are then isolated from the reaction mixture as such or in the form of its salt with an inorganic or organic acid, ζ.B _{0 of} the hydrochloride or the tosylate.

309842/1 133

6 - 1A-41 811

example 1

p-toluenesulfonate of acetoxymethyl-ö-aminopenicillanate.

A acetoxymethyl-o-tritylaminopeniciUanate "

A solution of 11.5 g of 6-tritylaminopenicillanic acid in 65 enr acetone was ^{cooled to 0} ° C., treated with 4.2 cm of triethylamine and then with 2.45 cm of acetoxymethyl bromide; the reaction mixture was kept with stirring at ⁰ ° C. for 2 h and finally at room temperature for 1 h. The precipitated triethylammonium bromide (3.5 g) was filtered off, the mitrat was evaporated, the residue was taken up in 175 cm of ethyl acetate, the solution was washed twice with cold aqueous 2% NaHGO solution and with ice water and finally the ethyl acetate layer over MgSO . dried. After evaporation, the desired pure acetoxymethyl ester remained as an amorphous powder _{or the like}

Ber. for G ₅₀ H ₅₁ N ₂ O ₅ S: C 67.77 H 5.87 N 5,, 27 S 6.04 # Found 67.73 5.91 5.22 6.00

° ^: +109.8 (c = 2j CHCl ₅ )
Thin layer chromatography (TLC) on silica gel (Merck showed the product to be pure.
R _f = 0.71 (butanol-ethanol-H ₂ 0 8 + 2 + 2) Rj ₁ = 0.78 (butanol-acetic acid-HgO 8 + 2 + 2)

B p-Toluenesulfonat des Acetoxymethyl-ö-aminopenicillanatSe

1, 3.71 g of acetoxymethyl-b-trltylaminopenicillanate in 120 cm of acetone (0.2 $ HpO) was made anhydrous with 1.21 g Treated p-toluenesulfonic acid. After 1 1/2 hours of standing-

_ 7 309842/1133

- 7 - U-41 811

leave, 0.14 cm of water was added at tree temperature and the p-toluenesulfonate by adding 300 cm of petroleum ether failed. The crude salt was filtered off and washed successively with acetone / petroleum ether, ethyl acetate and Ether washed.

After recrystallizing twice from acetone-ether, a colorless crystalline product with a melting point of ^{132.5-134 0} G (decomp.) Was obtained.

3 series. for O ₁₃ H ₂₄ N ₂ OgS ₂ S 0 46.95 H 5.25 N 6.08 S $ 13.92> Sci. 46.84 5.17 5.86 13.79

lEJ ² ^ ¹ + 127.5 ° (c = 1j ethanol)

R _F = 0.51 (3utanol-ethanol-H ₂ 0.8 + 2 + 2) R ₁₃ = 0.53 (3utanol-CH, C00H-H "0 _f 8 + 2 + 2)

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

2. A dispersion of 4.32 g of 6-aminopenicillanic acid

3 0 3

in HO cm acetone was stirred at 0 C with 6.3 cm Triethylamine added. 3.92 enr acetoxymethyl bromide added dropwise and the mixture was kept at room temperature for 4 h with constant stirring. The unusual one Triethylammonium bromide (3.5 g) was filtered off, the piltrate was evaporated to dryness in vacuo and the residue with 140 cnr ethyl acetate and 110 cm cold 2% sodium bicarbonate solution offset. After shaking and separating, the ethyl acetate solution was shaken with ice water and dried over magnesium sulfate,

- 8 309842/1133

- 8 - 1A-41 811-

When the solution evaporated, 5.2 g of substance remained. The crude ester, dissolved in 200 cm of acetone, was mixed with 3 »5 g of anhydrous p-toluenesulphonic acid and the p-toluenesulphonic acid salt was precipitated by adding 750 cm of ether. The salt was filtered off and washed with ethyl acetate and ether. The complete identity with the product obtained after 1 _o product was detected by comparison of the melting points, IR spectra and TLC values.

The IR spectrum (KBr) showed strong bands at i

1785 cm " ¹ 1758 cm"" ¹

1370 cm " ¹ 1325 cm" ¹

1225 cm "" ¹ 1170 cm " ¹

1123 cm " ¹ 1030 cm" ¹

1006 cm " ¹ 972 cm" ¹

811 cm " ¹ 681 cm" ¹

Reaction with ^ -amino-phenylacetyl chloride hydrochloride led to acetoxymethyl-oC-aminobenzylpenicillinate, which was identified by its IR spectrum (OHG1-) bands at 3300 cm "* ¹ (HH); 1875 cm" ¹ (ß-lactam), 1760 cm " ¹ (ester carbonyl) and 1680 cm" (amide).

Example 2

p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate.

First 1.08 cm of triethylamine and then 1.6 cnr of chloromethyl pivalate and 2.3 g of triethylammonium iodide were added to a solution of 5.6 g of triethylammonium-6-tritylaminopenicllanate in 25 cm of acetone at ^{0 ° C. with stirring.} It was another half hour at. O ⁰ O and then stirred for 20 h at room temperature. The precipitated triethylammonium chloride was filtered off,

- 9 309842/1133

- 9 - 1A-41 811

the filtrate evaporated and the residue with 75 cm Athyiaeetat added. The solution was shaken with cold aqueous 1 J & iger NaHCO-, solution and with ice water, the Ethyü / is separated, over MgSO. dried and evaporated in vacuo. The pivaloyloxymethyl ester remained behind of b-irityiaminopenieillanic acid as amorphous

3 ■ · Powder. The crude ester was dissolved in 40 cm of ethyl acetate and the solution at ⁰ ° C. with a solution of 1.90 g

3 ■ · p-jPoluenesulfonic acid hydrate in 20 cm Ethyiaeetat added. After stirring for two hours at room temperature, the desired tosylate collected on a filter and washed with Athyiaeetat and ether. *-acetate-

Recrystallization from acetone-ether gave the pure; all:
(Decomposition) ο

crystalline compound with a melting point of 138-139 ° C

Ber. for O ₂₁ H ₃₀ N ₂ OgS ₂ IG 50.18 H 6.01 N 5.57 S 12.76 aef. 50.46 6.15 5.36 12.57

^ ": + 131 ° (c = 1; ethanol).

IR spectrum (KBr) i strong bands at 1795, 1768, 1750, 1545, 1485, 1465, 1375, 1365, 1315, 1210, 1160, 1115, 1030, 1010, 980, 815 and 680 cm "" ¹ .

Iodometrically determined purity, with 6-aminopenicillanic acid as reference 99 $ <>

Thin-layer chromatography on silica gel (Merck, R = 0.66 (n-butanol-ethanoi-H ₂ 0, 4 + Ί + 1) Rp = 0.12 (cyclohexane-ethyl acetate, 1 + 1)

- 10 309842/1133

- 10 - 1A-41 811

Example 3

p-l'oiuolsulfonat des pivaloyloxymethyl-ö-aminopenicillanat. 4.32 g of 6-aminopenicillanic acid dispersed in 140 cm

Acetone, was ^{treated at 0} ° C. with 6.4 cm ^{5 of} triethylamine.

ο "5

With constant stirring at OC, 5.9 cm of chloromethyl pivalate were added and 4 »6 g triethylammonium iodide added and that The mixture was left to stand at room temperature for 20 h. 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 dissolved in 45 cm ethyl acetate and 3.4 g of anhydrous p-toluenesulfonic acid in 50 cm of ethyl acetate were added. That immediately precipitated crystalline tosylate was filtered off and washed with ethyl acetate and ether. The pure colorless one The substance was found to be identical in every respect with the analytically pure compound from Example 2..

Example 4

p-toluenesulfonate of pivaloyloxymethyl-ö-aminopenicillanate.

A dispersion of 2.16 g of 6-aminopenicillanic acid in 70 cur ⁵ acetone was mixed with 3.22 cur ^{5 trietiiylamine at 0} G and then with 3.92 g bromomethyl pivalate (Ep 50-51 ° G / 10 mm Hg), which had been obtained from pivaloyl bromide and paraformaldehyde according to the preparation of chloromethyl pivalate described in JA »GS 89, 5442 (1967),

After stirring for 20 hours at room temperature, the Precipitation of triethylammonium bromide (1.63 g) on a Filter collected, the filtrate evaporated and the residue worked up according to Example 2. The crude pivaloyloxymethyl ester was dissolved in 45 cm 'ethyl acetate and in the form of his pure tosylate by adding 1.72 g of anhydrous p-

- 11 309842/1133

- 11 - 1A-41 811

• χ

Toluenesulfonic acid precipitated in 25 cnr ethyl acetate. That Salt was filtered off, washed with ethyl acetate and ether; it was completely identical to the compound from Example 2.

Example 5

p-Toluenesulfonat des PivaloyloxymethyT-ö-aminopenicillanat. 2.16 g of 6-aminopenicillanic acid dispersed in 60 cm

Acetone was at ^{0 0} G successively with 1.8 cm of triethylamine

■ 5
and 10 enr of an acetone solution of 3.2 g of pivaloyloxymethyl p-toluenesulfonate were added. The mixture was stirred 1 / 2Ii at 0 0 and 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 of ethyl acetate and treated with 1.7 g of anhydrous p-

3 ··

Toluenesulfonic acid in 25 cm of ethyl acetate added · The crystalline Precipitate was filtered off and washed with ethyl acetate and was found to be identical to that according to Example 2 produced compound.

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

5 ° G

Ber. for C ₁₃ H ₁₈ O ₅ St C 54.53 H 6.33 S 11.20 # Gef. 54.73 6.3i '11.09 #

Example 6

p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate To a dispersion of 2.16 g of 6-aminopenicillanic acid

3 3

and 1.0 g of potassium bicarbonate in 70 cnr acetone were 1.76 cnr

- 12 309842/1133

- 12 - 1A-41 81.1

Chloromethyl pivalate and 280 mg potassium iodide were given. That The mixture was stirred and refluxed for 5 hours. The solids were filtered off and the acetone solution evaporated in fakuum. The residue was 80 cm Stir ethyl acetate, filter and the cooled ethyl acetate solution with 1.72 g of anhydrous p-toluenesulfonic acid in 40 cnr ethyl acetate added ^ the precipitated tosylate ' was collected on a filter and washed with ethyl acetate and ether. Melting point IR spectrum and thin layer chromatography the colorless crystalline substance proved to be identical to that of the previous examples obtained connection.

Example 7

Pivaloyloxymethyl-o-aminopenicillanate hydrochloride.

3 A solution of 2.1 g POl ₁ - in 20 cm dry,

3 alcohol-free chloroform was mixed with 2.26 cm of dry ghinolin while stirring. The resulting suspension was cooled to -3O ⁰ C and treated with 4.0 g Pivaloyloxymethylbenzylpenicillanat staggered After 30 minutes stirring at -5 ⁰ C to -10 ⁰ G, the solution was cooled to -30 ⁰ C and once with 6.7 cm dry n ~ propanol added. The temperature rose to -15-1O ⁰ G. ^{Then the reaction temperature was increased to 0} ° C. in the course of 15 min and kept at this temperature for 30 min.

the solution then turned to ice cold with stirring

3 3

Mixture of 25 cur water and 40 cm hexane added. the The aqueous phase was separated off and the organic phase was extracted three times with 25 cm of ice-cold 1N HCl Aqueous phases were combined and stirred at 0 C with 90 cm ethyl acetate, the pH being adjusted to 7.5 with IaHCO 3 was discontinued. The organic phase was separated off, dried and evaporated in vacuo. It was left with an oil

- 13 - 309842/1133

- 13 - 1A-41

the Dei O ⁰ G was dissolved in 50 cm of isopropanol. The desired hydrochloride was precipitated by adding 1.75 cm of an 8N 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 156-16O ⁰ C with decomposition.

Ber _e for G ₁₄ H ₂₃ ClN ₂ O ₅ S s G 45.84 H 6.32 9.66 N 7.63 S Gl $ 8.74. Found: 45.60 6.39 9.76 7.54 8.83 / »

/ UJ ² P + 183 ° (c = 1j 0.1 η HGl).

The IR spectrum had characteristic strong carbonyl bands at 1790, 1767 and 1756 cm " ¹ .

In the reaction with D (-) - (-) <ai-Phenylglycylchloridhydrochiorid pivaloyloxymethyl D was - get aminobenzylpenicillinat hydrochloride, Pp (from isopropanol) ~ (*; ⁰ C 155-6 (dec)..

The starting material can be produced in the following ways:
Pivaloyloxymethylbenzylpenicillinate «To a suspension of 19.0 g of potassium benzylpenicillinate

3 3

cillinat in 200 cm acetone were successively 8.3 cm Chloromethyl pivalate and a solution of 1.25 g of sodium

3
iodide added to 5 cm of water. The mixture was refluxed for 5 h, after cooling the potassium chloride was filtered off. The filtrate was admixed with water and the desired compound was precipitated as a colorless crystalline substance with a melting point of 114-115 ° C.

Ber. for U ₂₂ H ₂₈ I ₂ O ₆ Si C 58.91 H 6.30 N 6.24 # found 58.82 6.33 6.28 ^s / _a

- Ί4 -

30934 2/1133

- 14 - U-41

- • 720 ₊₂₅₆ o ^ _{0 = 1} . _Methanol ) _e

Thin layer chromatography on silica gel (Merck showed that the substance was pure.

^R p = O »45 (cyclohexane-ethyl acetate, 1 + 1) R ₁ , = 0.86 (butanol-ethanol-H ₂ 0, 4 + 1 + 1)

In an analogous way, the pivaloyloxymethyl-6— aminopenicillanate obtained if phenoxymethylpenicillin was used instead of benzylpenicillin,

Example 8
Pivaloyloxymethyl-6-aminopenicillanato

A suspension of 24.0 g of p-toluenesulfonate of pivaloyloxymethyl-6-aminopenicillanate in 1.1 l of ethyl acetate was 760 cm aqueous with vigorous stirring 2 ^ iger sodium bicarbonate solution added. The layers were separated and the ethyl acetate solution was washed thoroughly with 600 cm ^ of ice water, mixed with 25 ml of 2% sodium bicarbonate solution shaken.

The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was mixed with 200 cm ⁵ petroleum ether (b.p. <5O ⁰ C). added} after stirring for 2½ hours, the analytically pure ester, mp 60-65 ⁰ G, crystallized out.

3 series. for C ₁₄ H ₂₂ N ₂ O ₅ Si G 50.90 H 6.71 H 8.48 S 9.71 $> Gef. 51.15 6.77 8.36 9.63 #

IT) '<- \ t ι ι η λ O In 4. Π Τ3

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

Patent claims

72XXII

309842/1133

Claims (4)

Claims GH-COOGH ₂ OGO (CH ₂ ) _n -A in the η is an integer from O to 5, A is an optionally substituted aliphatic ^ means alcoholic, aromatic or heterocyclic group and X ¹ is a hydrogen atom, an ^r friphen; ylmethyl group or a trialkylsilyl group having up to 5 carbon atoms in the alky! chain, as well as their salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that 6-aminopenicillanic acid with a halomethyl ester of the formula: R-CH ₂ -OCO (GH ₂ ) _n -A, in which R is a halogen atom or an alkylsulfonyloxj- or Is arylsulfonyloxy group and η and A are those in claim 1 have given meaning, brings to implementation. 3. The method according to claim 2, characterized g e k e η η ζ e i ch η e t that the 6-aminopenicillanic acid in Form of one of their acid addition salts is used. 4. The method according to claim 2 or 3, characterized geke η η ζ ei ch η et that a 6-aminopenicillanic acid with temporarily protected amino group is used. 309842/1133