SE412392B - PROCEDURES FOR PREPARING DERIVATIVES OF 6-AMINO-PENICILLANIC ACID - Google Patents

Description

7401380-6 2 radical, such as a mono- or bicyclic aralkyl radical, e.g. benzyl, fen ~ ethyl, 1- or 2-naphthylmethyl: and R 1 and R 2 in combination with the nitrogen atom may represent the above-mentioned heterocyclic radicals, e.g. during the formation of fully or partially hydrated ring systems, e.g. pelvis piperidyl, morpholinyl, hexahydro-1H-azepin-1-yl, hexahydro-1- (2H) azocinyl or octahydro-1H-azonin-1-yl. , The compounds of formula I may be isolated as "zwitterion" or such as a salt, e.g. alkali metal salts and ammonium or amine salts, or salts with strong acids, such as hydrochloric acid, phosphoric acid, nitric acid acid, p-toluenesulfonic acid, tartaric acid or maleic acid.

Salts can also be prepared with other antibiotics with acid or alkaline nature, and fi in particular with acidic antibiotics with which compounds form synergistic mixtures, such as penicillins.

It is particularly convenient to use acids, as with the compounds I forms salts which have desirable absorption properties and use in clinical practice. Examples of such salts are the pamoate or the naphsylate or salts containing probenecid; this last said compound delays the excretion of those intended only for the invention: the compounds, resulting in prolonged presence of them in the blood.

The compounds of the invention are suitably used for parenteral treatment. 7 7 Thus, the compounds are conveniently administered by injection of a aqueous, sterile solution or suspension of the "zwitterion" itself or of a suitable salt thereof, alone or in combination with a buffer. ' The compounds of formula I have previously been prepared as described in British Patents 1,293,590 and 1,315,566 by turnover of a reactive derivative of an amide or thioamide with the general formula II (II) in which R1, RQ and R; has the above significance and RR denotes O or S, e.g. a compound of f0rme1n ~ ïI1 J 1 nl * 3 \ ._ _ _ Rl / .n c- (o Alma : _ (III) 1 which file, H2 lower alkyl radical, with a 6-amine penicillanic acid derivative with the general formula IV - and R; has the above meanings and Alk denotes one . - .., 7401380-'6 \, ~ I É ä HENÄê% / S \ C / CH3 1 d: PCH; 0 = c --- N --- QH CooR4 in which R a represents an unsubstituted or substituted U alkyl or aralkyl group, or with a silyl ester of 6-aminopenicillan acid. When -COORQ represents an ester group, the reaction must be accompanied by a cleavage of the ester group to give the compounds of the invention. _, _ It has now been found that the compounds of formula I may suitably prepared by reacting a reactive specified below derivative of a compound II with a salt of 6-aminopenicillanic acid (6-APA), preferably a salt with a strong tertiary amine, in a suitable solution means and at temperatures in the range of about room temperature down to about -5o ° c.

Said reactive derivatives of compounds of formula II are acidic amide acetals of formula III, di-lower alkyl sulphate complexes with compounds II. or acid amide halides, obtained by reacting a compound II with a halogenating agent.

It is surprising that the present process results in non-toxic yields (about 70-90%) of high-purity products, as is well known, that reactive derivatives of amides often react with rnr. The acid amide halides can thus react with acids to form of acid analogues, while acid amide acetals can form esters der this reaction. _ Furthermore, the present process is simpler than the prior art processes. farandena. It is carried out in one step, while the previous the process involved the preparation of e.g. a silyl ester or a sylester of 6-APA, followed by conversion to the amidinopenicillanic acid ester and subsequent cleavage of the oyster group.

The reaction is carried out in one step by dissolving or suspending ring of the reactants in an organic solvent, suitably in the absence of water due to the fact that the reactive derivatives of nn II is hydrolyzed when water is present.

The reaction conditions depend on the reactants used and be5kr1veS.d therefore not in detail in the following. -: af sym; "V" -v 'vrIrm-a- ___ .. fs-gßuwgfw-mi. . I .. ,. x. _. f. P, § ...._., .. .-,.,. ,, .....-.... ~ .. =.-.-_ »- = .-. ~. 7 _... 7491380-6 .one n When in the present process an acid amide acetal was used as reactant, the preferred reaction media are methylene _.-. “N \ chloride, chloroform, acetone with a small amount of formamide, methanol and methyl-. formate. In the first three reaction media, the presence of a strong necessary amine for the purpose of obtaining the desired yields of the compounds of formula I with high purity, while e.g. and methanol the reaction can be carried out without the addition of a separate tertiary amine - due to the fact that the weakly acetic acid amide acetal is able to form å an edit with 6-APA 1 this medium. ' As an example of strong tertiary amines that can be used on March * - above can be mentioned triethylamine and N, N-diisopropylethylamine, while, for example, pyridine, N-methylmorpholine or triethanolamine then for the weak rar this purpose. ' The above reaction can be carried out using equivalents amounts of the reactants, but it is preferred that use a small excess of the acid amide acetal and of the tertiary amide nen (in both cases ea 20-30%. It is of course possible to såxm1m; using a salt of 6 ~ APA and the tertiary amine, either by using a salt previously prepared or by allowing 6-APA to partially react with the tertiary amine before adding syraamidaeetalen. The reaction is carried out at or below room temperature. ratur; preferably at a temperature between 0 and 5 ° C, but the reaction can still be carried out at lower temperatures, e.g. around -2500.

The reaction time depends on the temperature and the reaction medium used and whether or not a tertiary amine is added, but usually amounts to 1-6 hours. f ' When a di-lower alkyl sulfate complex is used as a reactant, in the present process: the preferred reaction media are methylated len chloride or methanol. In this case, however, it is necessary to use at least 1 equivalent of a strong tertiary amine for the purpose of .-._ .. ....... ~, .. \. .- lactam ring in the final compound of formula 'I and in 6-APA against the di-lower alkyl sulphate complex, as otherwise the β-lactam ring would open up nas. It is preferred to use about 1.5-3 equivalents of the tertiary the amine and an excess of the di-lower alkyl sulphate complex (about 20-30%).

When using methylene chloride as the reaction medium, it is suitable to allow most of the 6-APA to dissolve as a tertiary amine salt before adding the di-lower alkyl sulphate complex. The preferred The action temperature is 0 ° C, but also higher (approx. room temperature) and lower temperatures (approx. -IOUC) can be used. Reaction times depend on the temperature, the reaction medium and the reactants but amounts usually to 1-6 hours.

W »» w 7401380-6 5 i, l _. ___ l, When an acid amide halide is used as a reactant in religious procedure can only methylene chloride, chloroform and the like inert reaction media are used depending on the acid amide halide are very reactive. In this case, it is appropriate to use 2-3 equivalents of a tertiary amn for the purpose of protecting the β-lactam ring in the final product and in 6-APA. It is appropriate to allow the majority of 6-APA to dissolve as a tertiary amine salt before addition of the acid amide halide. The reaction should be carried out at low temperatures » starts at about -50 ° C. The reaction temperature is allowed to rise to about 0 ° C and the reaction is completed within about 3/4 hour.

The reaction mixture thus obtained, which contains the stable tertiary amine salt of one of the compounds of formula I, or 1 certain case itself "zwitterjoncn", filtered to remove any residue of unreacted 6-APA, and the clear solution is then evaporated in vacuo.

The residue is dissolved in a suitable solvent, from which the acid of the formula In precipitated lice by adding another solvent, in which it is only slightly soluble, or preferably by release of "zwitterion" by the addition of an inorganic or organic acid.

» IN Especially when producing large quantities, it is preferable to remove any residues of the reaction medium by adding a high-coconut, the solvents, e.g. methyl ethyl ketone, optionally with it acid, which was used to release the "zwitterion", and then evaporate the solvent mixture in vacuo. The combination of terti- amine, solvent and acid can be suitably selected so that "zwitter- the ion precipitates and that the amine salt formed during the neutralization remains in solution in the solvent. t For the release of the "zwitterion" p-toluenesulfonic acid can be used, dissolved in acetone or methyl ethyl ketone, but other acids and solvents can be used depending on the operating components used. now ntgñngnmnterinl, used in the above embodiments, I are known compounds or can be prepared according to known methods for L preparation of analogous compounds.

The present process results in a high purity crude product (97-98% (determined by iodometric filtration).

For stability reasons, it is important that the end product contains as little pollution as possible, as even small amounts of significantly reduces stability. l The crude product can thus be further purified by recrystallization a ... from a suitable solvent or mixture of solvents.i In some cases it may be appropriate to convert the crude product to it , ..._ ..._ 2-9- -P-v- Å -a-q-fw-y-uvqw .. 57 -..- 7401380-6 hydrate, which is then recrystallized from any suitable solvent or a mixture of solvents, e.g. formamide-acctone, during formation, of the desired anhydrous compound of formula I.

The compounds of formula I can be isolated as such or in form of, ctt salt, e.g. an alkali metal salt, ammonium ointment or amine salt, or as salts with pharmaceutically acceptable strong acids, such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, acid and malic acid.

The invention encompasses all possible isomeric forms of the compounds with formula I, depending on the different substituents, while The 6-aminopenicillanic acid moiety has the configuration obtained in fermentation procedure. ' The compounds of formula I possess valuable antibacterial activity and the toxic effect is extremely low, as described in the British patents documents 1,293,590 and 1,315.56 (.

The invention is further illustrated in the following, non-limiting example.

Example 1. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillan SVT8. 48 g of 6-aminopenieillanoic acid, 1.62 ml of triethylamine and 2.98 g 1-Hexamethyleneimine carboxaldehyde dimethyl acetal is stirred in 40 ml of methylene chloride at 0-500 for 2.5 hours. After filtration, the filtrate is evaporated. in vacuo and the residue was taken up in 50 ml of acetone. was prepared by adding 1.0 g of p-toluenesulfonic acid monohydrate for 25 ml The mixture held The solution neutralizes acetone while stirring and inoculating at room temperature; v1a o, 5 ° e 1 1.5 hours eeh.f11urera fl ~ n.

Temperature of the title compound: 82%; purity 97 rad 97%.

Example 2. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillan S VFU. .

A suspension of 2,8 H8,6-aminopenicillanic acid in 40 ml of chloroform 4.5 hours at o-5 ° C with 1.62 ml of crystalline amine and 2.25 g of 1- The so obtained weak was stirred -hcxamethyleneiminecarhoxaldehyde dimotylacetal. the cloudy solution is filtered with "Diealite". The filtrate was evaporated vacuum to give an oil which was taken up in 50 ml of acetone. The pure of 1.9 g of p-toluene hour at room; the compound is precipitated by the addition of a solution snl fo! xsjowunonohyclrai. i? 5 l aewcm under 'or1 | 1 ~ ï3pf1inß »'] _ 2 “The crystallized product : c temperature and then one hour at 0-5 ° was filtered off, washed down ac Yield of the title compound:? H%; degree of purity 98, §% / fl / d / MR / a POUR fl UALlTY www-H »53." ma: -m _ --- .- ..,. 1 - »......_-- f, r = r, v _-; ..-_...._, F., _ ,. __. 7401380-6 7 .i _i_o o_ i _ ”_ Example 5. 5. 6- (Hecanydro-1H-azepin-1-yl) -methylene-7-penicillan- acid. 2.48 g of 6-aminopenicillanic acid were suspended in a mixture of 0.5 ml formamide and 25 ml of acetone (Merck p.a.). 1.02 ml of triethylamine and 2.57 ml 1-Hexymethyleneimine carboxaldchyddimethylicctal was added. Mixed nuts A solution of 1.9 g of p-toluenesulfonic acid monohydrate in 25 ml of acetone was added. tons during stirring and inoculation. The formed filling was filtered off and washed with acoton.

Lt change of ticel compound: 67%; rennetsqred 98%.

Example Gel 4. 6 - [(Hexahydro-1H-azepin-1-yl) -methyl] -penicillan- Eïï fi; 2.48 g of 6-aminopenicillanic acid, 1.95 ml of N, N-diisopropylethylamine and 2.57 ml of 1-hexylmethyleneimine carboxaldehyde dimethylacetal were stirred 3 1/2 hour at 0-5 ° C in 40 ml of methylene chloride} After filtration with "Dicalite" and evaporation of the filtrate, the oily residue was dissolved in 50 ml of tert-butyl nol. While stirring, 1.44 ml of 8 N hydrogen chloride in isopropanol was added at room temperature followed by an additional 20 ml of tcrt.butanol. The precipitation of was filtered, washed with tert-butanol and ether and dried.

Yield of the title compound: 69%; purity 97%. f Example 5. 5. [[Hexahydro-1H-azepin-1-yl] -methyleneamino] -penicillan- ålïš; è, 48 g of 6-aminopenicillanic acid, 1.62 ml of triethylamine and 2.57 ml 1-Hexamethyleneimine carboxaldehyde dimethyl acetal was stirred for 5 hours at 0-500 i 40 m1 methyienxioria. After filtration with "mee1ite" was evaporated the filtrate 1 vacuum. To the residue in 50 ml of acetone was added with stirring 0.66 ml glacial acetic acid. The precipitate formed was triturated and dried. yield of the titanium compound: 57%; renneeegrea 98%.

Example 6. '(6-(hexahydro-1H-azepin-1-yl) -methyleneamine-97-penicillar-E! s ra.

By following the procedure of Example 5 but substituting the acetic acid to 1,4'g benzoic acid, a good yield of the desired one is obtained Association! 2 Yield of the title compound: 70%, purity 97%. v _. fe-ew-nsxfng-gg-.ee: Mm w, - 7401380-6 8 å öcâ "f Example 7. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamine] penicillan-E E, 48 g of 6-aminopenicillanic acid, 1.62 ml of triethylamine and 2.57 ml 1-Hexamethyleneimine carboxaldehyde dimethyl acetal was stirred in 40 ml of methylene 'chloride at 0-500 for 5 1/2 hours. After filtration with "Dicalite" the filtrate was evaporated in vacuo. To the residue in 15 ml of acetone was added Q. 60 ml of ether while stirring at room temperature. The mixture was kept at "Z 0-5 ° C for 1.5 hours and filtered to give the desired compound r . in was obtained in crystallized form. ä Yield of the title compound: 70%; purity 97.5%. in Example 8. 6 - [(hexahydro-1H-azepin-1-yl) -methyleneamine] -penicillan-; EMEE; _ 2 10.0 g of 6-aminopenicillanic acid, 7.0 ml of triethylamine and 1-hexamethylamine Lenimine carboxaldehyde dimethyl acetal (1.0.9 ml) was stirred in 50 ml of methanol at O-500 for 1.5 hours. After filtration, the filtrate was evaporated in .sgpe-.g-w-w. ß- vacuum and the residue was taken up in 55 ml of methyl ethyl ketone, containing 8.0 g of V p-toluenesulfonic acid monohydrate. The solvent was removed in vacuo and 50 ml of methyl ethyl ketone was added to the residue. The apparent pH value is adjusted to 7.2 by the addition of triethylamine. After stirring in a Q hour at 0-5 ° C the crystals were filtered off and washed with methyl I ethyl ketone.

Yield of the title compound 85%; purity 99%. "gen w» vy v Example 9 - [(hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillan- fi ïïl; 10.0 g of 6-aminopenicillanic acid and 10.9 ml of 1-hexamethyleneiminecarboxylate aldchyddimethylacetal was stirred in 50 ml of methanol at 20-2500 for 5 hours. mar. After filtration, the filtrate was evaporated in vacuo and the residue was suspended. was suspended in 45 ml of methyl ethyl ketone. The solvent was removed in vacuo and 50 ml of methyl ethyl ketone was added to the residue. The apparent pH value P was adjusted to 7.5 by the addition of p-toluenesulfonic acid monohydrate.

After stirring for one hour at 0-5 ° C, the crystals were filtered off and washed. Wa- taken with methyl ethyl ketone.

Yield of the title compound: 78%; purity 99.5%. .. .mf- Example 10. 6-Thexahydro-1H-azepin-1-yl-methyleneamine-7-penicyl- lansyra. ~ - 21.6 g of 6-aminopenicillinic acid, 25.6 ml of triethylamine and 52.9 g N-Formylhexamethylcinnimine dimethyl sulfate complex was stirred in 85 ml of methanol at 0-500 for B hours. After filtration evaporate the filtrate i - was made with filter aids. The filtrate was evaporated in vacuo. The rest is 7401380-6 v »-_.> -. ~. ,,, ... 9 vacuum and the residue was taken up in 10 ml of methyl ethyl ketone containing 14.3 g p-toluenesulfonic acid monohydrate. The solvent was removed in vacuo and 110 ml of methyl ethyl ketone was added to the residue. The apparent pH value is was regulated to 7.3 by the addition of triethylamine. After stirring one hour at 0 DEG-5 DEG C., the crystals were filtered off and washed with methyl ethyl ketone.

° Yield of the title compound: 74%; purity 98%. 6 - [(hexahydro-1H-azepin-1-yl) -methyleneamine] -penicil- lansvra. 21.6 g of 6-aminopenieillanoic acid and 17.8 ml of triethylamine were stirred in 85 ml of methylene chloride at Of5 ° C for 2 hours. After the addition of 22.4 g 1-Hexamethyleneimine carboxaldehyde dimethylene metal continued stirring until The reaction mixture was then filtered and Example 11. for 2 hours at 0 ° C. the filtrate was evaporated in vacuo. The residue was taken up in 110 ml of methyl ethyl ketone containing 19.0 3 p-toluenesulfonic acid monohydrate.

The solvent was dissolved in vacuo and 110 ml of methyl ethyl ketene was added to the rest. The lower pH value is adjusted to 7.3 GGHOM addition of_triethylnmin. After stirring for one hour at 0 ~ 5 ° C, filter 1 the crystals were washed and washed with methyl ethyl ketone.

Yield of the title compound: 84%; purity 99%.

Example 12. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamine] -7-penicyl- lansyra. 21.6 g of 6-aminopenicillanic acid and 31.1 ml of triethylamine were stirred in 85 ml of methylene chloride at 0-500 for 2 hours. After the addition of 32.9 g of N-formylhexylmethyleneimine dimethylnilphate complex were continued to stir. at the O-500 for 2 hours. Then the reaction mixture was filtered. and the filtrate was evaporated in vacuo. The residue is taken up in 110 ml of methyl ethyl ketone containing 19.0 g of p-toluenesulfonic acid monohydrate. Solution means in vacuo and 110 ml of methyl ethyl ketone was added to the residue. The The apparent pH was adjusted to 7.2 by the addition of triethyl amin. After stirring for 1 hour at 0-5 ° C, the crystals were filtered off and washed with methyl ethyl ketone. _ Yield of the title compound 68%; purity 97.5%.

Example Gel 15. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamine] -penicil- lanslra. 2.2 g of 6-aminopenicillanic acid, 0.81 ml of pyridine and 5.5 ml of 1-hexamene Tylenimine carboxyldehyde dimethyl oil was stirred in 30 ml of methanol at 0 DEG-5 DEG C. for 1.5 hours. The thus obtained, slightly turbid solution filter- § The solution was cooled to -45 ° C. 7401380-6 i 10 I M- H * _w_ ~ _____ The solution was neutralized by adding 1.9 t while stirring and inoculating at 0-5 ° C. and washed with 10 ml of acetone tes 1 50 ml acetone. g p-toluenesulfonic acid monohydrate The crystals formed avfii and 20 ml of ether.

Exchange of the title association: 6 - [(hexahydro-1h-azopin-1-yl) lansyra. 2.2 g of 6-aminopenieillanoic acid. and H, 2 ml of triethylamine was stirred in rm for one hour at room temperature. It formed 1.82 g of an acid amide chloride, prepared ylenimine and oxalyl chloride in 15 n ' 65%; purity 97%.

Example IH. -methylenamino7-penicil- 25 ml dry chlorophyll by reaction between the N-formylhexam dry chloroform, was added slowly, whereby the temperature rose ~ 25 ° C. During the course of 3/4 hour, the temperature rises to 0 ° C.

The solution is evaporated in vacuo. The residue was stirred with 25 ml of acetone The filtrate was evaporated in vacuo and the residue was taken up in By the addition of 1.7 p-toluenesulfonic acid precipitated and filtered. methyl ethyl ketone. "zwitterjonen".

Yield of the title compound: 62%; purity 97%.

Example 15. 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicil- lansyratrihvdrat. 27 g of a product prepared according to Examples 1-14 were suspended in 50 ml of acetone and dissolved by adding 32 ml of water. , GenQm addition of 200 ml of acetone precipitated the pure trihydrate. The filtered, washed with acetone and air dried.

Example 16-6 * / (hOK-hYdPO-1H-azepin-1-yl) -methyleneamino7-penyl ]- lancic acid p-toluenesulfonate. A solution of 9.5 ß p-toluenesulfonic acid monohydrate in 50 ml of isopropa nol was added with stirring at room temperature to a suspension of 19 G 6 “Å (h @ X fl hYdF0 ~ 1H ~ azepin ~ l ~ yl) -methyleneam7-penicillanic acid trihydrate: 5 in 100 ml of isopropanol. The solution thus obtained was filtered and the salt U fi precipitated by adding 100 ml of isopropyl ether, followed by inoculation °° h Addition of surface flux 50 ml isopropyl ether. The crystals are damaged and washed with isopropyl ether.

Yield of the title compound 78%; purity 100% (Analysis of C, H, N: k ° PPect: / ß / D = + l82 ° (c = 1, o, 1N Hcl). 2 ~. g- »gv fl-. wm ._ m.-_ v = ~ _._ ~ __v .... .g-.v -. \ ... v-w. s .. 7401380-6 11 ' Example IIL 6 - [(hexahydro-1H-azopin-1-yl) -methyleneam] -7-penicyl- rabensonsulfonate. 1295 19 g of 6- [fhexanydro-1H-azepin-1-yl) -methyleneamine-phenyl] -anoic acid trihydrate in 125 ml of acetone was dissolved with the slow addition of 8 g of benzene. sulfonic acid in 125 ml of acetone with stirring at 04590, then benzenesul the phopate precipitated spontaneously. It was chewed, washed with 25 ml of acetone and 25 ml of ether and were recrystallized from methanol / ether (110-200 ml).

Yield of the title compound: 80%; purity 100% (analysis of C, H, N: correct); ¿&] Š ° = + 192 ° (c = 1, o, 1N Hcl).

Example 18. 6 - [(Hexahydro-1H-azupin-1-yl) -methyleneamino] -penicil- boric acid maleate monohydrate.

To a stirred suspension of 19 g of 6 - [(hexahydro-1H-azepin-1-yl) - Methylenum 7-penicillanic acid trihydrate in 125 ml of acetone was added to a solution 6 g of maloic acid in 125 ml of acetone at room temperature. The educational the solution was filtered and the salt precipitated by adding 100 ml of cyclohexane. The solubility of maloate in water (5%) is lower than the solubility of the similarity of the p-toluenesulfonate and the benzenesulfonate.

Yield of the title compound: 87; 5%; purity 100% (analysis of C, H, N: correctc); ¿@ 7š ° = + 2oo ° (c = 1, o, 1N Hcl).

Example Gel 12. 6- (Hexahydro-1H-azepin-1-yl) -methyleneamine-7-phenicyl- lancic acid 2-naphthalene sulfonate.

A filtered solution of 3.8 g of 6 - [(hexahydro-1H-azepin-1-yl) -methyl- lenamingy-penicillanic acid trihydrate and 2.6 g of 2-naphthalenesulfonic acid trihydrate hydrate in 50 ml of acetone was evaporated in vacuo. and crystallized by trituration with 25 ml of ethyl acetate. The salt is the answer soluble in water. : Yield of the title compound: 60%; purity 100% (analysis of C, H, N: k @ rrexc); ¿§] § ° = + 169 ° (c = 1, o, 1N Hcl). _ Example 20. Sodium 6 - [(hexahydro-1H-azepin-1-yl) -methyleneamine ]- -poniciQÿgy¿g¿ 11, g 6- [hexahydro-1H-azepin-1-yl) -methyleneamine7-penicillanic acid trihydrate in 50 ml of isopropyl ether was dissolved by adding a solution of 5.1 g of sodium 2-ethylhexanoate in 45 ml of acetone with stirring at room temperature: temperature, at which point the salt precipitated spontaneously. 75 ml of isopropyl ether The salt was recrystallized from was added and the precipitate was nv filtered. 95% n-propanol cter.

Yield of title compound 81 ßenz 81%; purity level 98%.

The residue was grated with 75 ml of ether:> ~ 7401380-6 12 'W, _ p p Av q * _ § ter .. ... _, Example 21. 6- (N, N-dimethylformamidino-N ') -penicillanic acid. 2.48 g of a suspension of 6-aminopenicillanic acid in 40 ml of methylene The mixture was stirred for 2 swims at 0 DEG-5 DEG C. with 1.62 ml of crystalline amine and 1.55 g. www-_ .. ... n-fn The resulting solution, slightly cloudy and the filtrate was evaporated in vacuo. On 014 The residue was dissolved in 50 ml of acetone and 2.14 g of p-toluenesulfonic acid monohydrogen. was added with stirring at 0-5 ° C. The precipitate was filtered off, washed with acetone, and recrystallized from acetone / water / acetone (10/8/30 ml). The analytically pure product thus obtained had a melting point. point "of, l73-17400 (decomposition). ' ' Yield of the title compound: 90%; / αf +: + 318 ° (c = 1, H 2 O). 1,1-dimethoxytrimethylamine. filtered with "Dioalite" .wafv-g-ys; ... f- Example 22. 6- (N, N-dipropylformamidino-N ') -penicillanic acid.

A suspension of 5.0 g of 6-aminopenicillanic acid in 80 ml of methylene chloride was stirred for 5.75 hours at 0-5 ° C with 5.24 ml of triethylamine and 5.25 g N- (dimethoxymethyl) dipropylamine. After evaporation of the filtrate 1 vàküum “ the oily residue was dissolved in 50 ml of acetone. Addition of 5, Éwg p-tolu- ensulfonic acid monohydrate caused precipitation of a solid, which crisis ~ numbered from 96% ethanol / ethyl acetate (50/125 ml), the analyte The purely pure compound was obtained, m.p. 154-15600 (söñüeräeïhing) Yield of the title compound: 64%; Åäjâoá + 505 ° (c = 1, H 2 O). in f . Example 23. 6- (N-Benzyl-N-methylformamidino-N ') -penicillic acid. 4.96 g of 6-aminoponicillanic acid, 3.24 ml of triethylamine and 5.84 g N- (dimethoxymethyl) -N-methylbenzylamine was stirred for 2 hours in 80 ml of methylene-E kioria at o-5 ° c. After filtration with filter medium, n the filtrate in vacuo. The oily residue was taken up in 75 ml of acetone and The "zwitterion" was precipitated by the addition of 3.8 g of p-toluenesulfonic acid mono- hydrate. " 2.8 g of the crude product were dissolved in 30 ml of 60% hot ethanol.

Addition of 60 ml of acetone gave the analytically pure compound with a melt punk of 165-167 ° C (dec.).

Yield of the title compound 83%; jäjšoz + 280 ° (c., 0.1 N HCl). ¥ Example 24. 6- (N-pyrrolidinoformamidino-N ') -penicillanic acid.

A mixture of 4.96 g of 6-aminopenioillanoic acid, 5.24 ml of triethylamine and 3.78 g of 1-dimethoxymethyl-pyrrolidine in 80 ml of methylene chloride were stirred 1 4.75 hours at 0-5 ° C. After filtration, the filtrate was evaporated in vacuo. to give an oil which was dissolved in acetone (100 ml). By appointment of 5.8 g of p-toluenesulfonic acid at room temperature, the above 14 precipitated ...__ vn ". r- -l '"* ° 1 =» § °: § IN Association. After half an hour at O-500, the precipitate was filtered off and recrystallized from water / acetone and 90% isopropanol-acetone, each in the analytically pure compound was obtained with a melting point of 172.5-173.5 ° C (solar unit).

Yield of the compound1 = 76%; / @ 7š ° = + 3o6 ° (e = 1, H2o) ¿ Example Gel 25. 6 - [(hexahydro-1- (2H) -azocinyl27-methyleneamino-penicyl- lansyra. 7.4H g of 6-aminopenicillanic acid, 4.86 ml of triethylamine and 9.7 g of 1-hep- tamethylenimine carboxaldehyde dimethyl acetal was stirred in 120 ml of methylene chloride for 2.5 hours at O-500. After filtration, the filtrate was evaporated in vacuo vacuum and the residue was taken up in 150 ml of acetone. The solution was neutralized E n by adding 5.2 g of p-toluenesulfonic acid monohydrate in 75 ml of acetone while stirring at O-500 for 1.5 hours. The precipitate was filtered off, washed ~ was taken with acetone and recrystallized from water / acetone to give: The lytically pure compound was obtained with a melting point of 169-170 ° C (dec. sharing). l 5 Yield of the compound = 73.5%; , ¿@] Â ° = + 5o9 ° (e = 1, H20). ' Example 26. 6- (N-Morpholinoformamidino-N ') -penicillanic acid. 2.48 g of 6-aminopenicillanic acid, 1.62 ml of triethylamine and 2.10 g 4-Morpholinecarboxaldehyde dimethyl acetal was stirred for 4 hours in 40 ml of methylene chloride. ride at 0-5 ° C. After evaporation of the filtrate in vacuo, the residue was taken up in 75 ml of acetone. Appointment. of 2.14 g of p-toluenesulronic acid monohydrate caused precipitation of a solid, which crystallized from acetone / ¿ / water / acetone (5 / 3.5 / 15 ml), the analytically pure compound being 1 kept with a melting point of 172.5 ~ 744 ° C (dec.) - “i Yield of the compound = 69.5%; / @ 7š ° = + 275 ° (e = 1, H 2 O). § Exemeei 27. 6- (N, N-dimethylšehšámíäíñdïüïlleeñie111šheyreI '"“ "" “'" o By following the procedure of Example 1 and substituting 1 lenimine carboxaldehyde dimethylacetal against N, N-dimethylbenzamide dimethylacetal number is prepared 6- (N, N-dimethylbenzamidino «N ') - penicillanic acid as a Q white amorphous powder, which is soluble in water. Thin layer chromatography F (Merck silica gel HF2 n) was performed in the following solvent systems: n-butanol / ethanol / water (8/2/2), Rf = 0.1Q, and n-propanol / water (7/3), Rf = 0.24.

Yield of title compound 87%; -w-É '

Claims (7)

7401380-6 14 .pa- - v..,. NM spectrum (10% w / v D 2 O) cakc c a a:: a:: än g Nea: a i z 1: a 2: a; § c: An ms at 4.30 '_ own ln ¶ a at 5.01 (J = 4) ä c (5) H "' ._. Ln ¿_. _. A at 5.24 (J = 4 ) 'Q 5H m vid 7,4-7,9 ~ =. - _ ~, -. ~ V_ _-¿_. ,, -._-_-.:.-..- .- Patentkrav { 1. Process for the preparation of derivatives of 6-aminopenicillanic acid f of the general formula I R. 3 R1 \ I H H N-c N E š i /: L- - / S \ / CH3 R C --- C C. 2 I I \ CH (I) .L 3! O = C --- N --- C 1 -C 10 H hydrogen, and R 1 and R 2 together with the nitrogen atom to which they are attached may represent a heterocyclic ring system of 5-10 atoms, which optionally comprises in addition to said nitrogen atom an additional nitrogen or oxygen atom, hence, characterized in that a reactive derivative of a compound having the formula II l5_ 74Û138Û'5 -_ R i_o_I ___ i, I ___. R 1 / R 1 / * n -cine: (II) L 1 which R 1, R 2, and H 5 have the meanings given above, and O or S, which derivative is. a) a compound of formula III R 1, N-c = (o-Alk) p R 5 denote: "1 (III) \ // .H 2 in which R 1. H2 and H3 have the above meanings and Alk represents a lower alkyl radical, b) a lower alkyl sulphate complex with compound II or É o) an acid amide halide obtained by reacting a compound II with a halogenating agent, salt with a strong tertiary anin, the reaction being carried out in a solvent and at a temperature in the range of from about room temperature down to about -5000. Process according to Claim 1, characterized in that the reactive derivative of compound II is a compound with. , formula III, wherein Alk represents methyl. 5. A process according to claim 1, characterized in that the reactive derivative of compound II is a di-lower alkyl sulphate complex and that the reaction temperature is about 0-5 ° C. 4. A process according to claim 3, characterized in that lower alkyl means methyl. 5. A process according to claim 1, characterized in that the reactive derivative of the compound II is an acid amide halide and that the reaction temperature is below 000. - - 6. A process according to claim 5, characterized in that the reaction is carried out using an initial temperature of about -5000. 7. A process according to any one of claims 1-6, characterized in that the reactive derivative of the compound II is reacted with 6-aminopenicillanic acid triethylamine salt. e ANFÖRoA PUBLICATIONER: Sverige 392 723 (com iver / oz), 397 355 (cow 499/02) ..- n-- u ...