DE1545615A1 - Process for the production of penicillins - Google Patents

Description

DR. ELISABETH JUNG ₁ DR. VOLKER VOSSIUS ₁ DIPL.-ING. GERHARD COLDEWEY

PATENT LAWYERS 1 CI Γ C 1 C

8 MÖNCHEN 23 · S I EG ES STRASSE 26 ■ TELEFON 34S0 67. TELEGRAM ADDRESS: INVENJ / MDNCHEN-

2 DEC 3, 1968

u.z .: B 717 (j / Sch / eb)

BBBOHAM GEOUP LIMIl ¹ EI),
Brentford »Middlesex, JBnglsnd

"New penicillins and deadlocks in their manufacture"

Priority: September 3, 1964, Great Britain, Ir. 36206

The invention relates to a novel class of penicillins, which are derived from 6-arainopenicillanic acid and which are known as antibacterial agents, as feed additive in animal feed, as Preparations for the treatment of mastitis in livestock and as therapeutic agents for poultry and animals and in human beings Are of importance, being especially for the treatment of by infectious diseases caused by gram-positive and grama-negative bacteria are suitable.

The new penicillins are made by the general formula

HCOC ~ X «CONHOHCO. NH. CH — Cif '^ N? ^

RI j 1 ' ⁴ CH ₅ C ₀ _ # CH.COOH

characterized in which R is an alkyl, aralkyl, aryl or her'-serooyclieahe group means that if necessary substitutes

Documents (Art. 7 a I Para. 2 -No. I Clause 3 of the amendmenteaa. V. 4. 9. 1f67).

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CHECK ACCOUNT: MUNICH 50175. BANK ACCOUNT: DEUTSCHE BANK A. G. MUNICH. LEOPOLDSTR. 71, KTO. ^ NO. 6Q / 35794,

BATH

and X is a direct bond or a divalent aliphatic, aromatic or heterocyclic, optionally substituted one. Group represents. -.

The process for producing these penicillins is thereby characterized that sin et-aminopenioillin of the general formula

. / B ^ OH, E.CH.CÖ, BH, OH - OH C

fa! I | \ jh, tu)

OO _H _ CH.COOH "

with a reactive compound of an acid of the general .formula

YOG - X · »COOH

is implemented, in which T is a hydroxyl group or the group 01: ⁹ , \ söbei B. ' is a benzyl or substituted benzyl group which is subsequently removed.

Examples of suitable reactive compounds are cyclic anhydrides xC, _s ^ O, mono- and bis-acid chlorides and mono- and bis-mixed anhydrides.

According to one embodiment of the invention, the penicillins by catalytic ^ hydrogenation of a penicillin precursor (III) which contains a protected carboxyl group and has the general formula

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.s

R »000 - X - COIiHCHCO. EH. OH - GH

k II Γ ^0Η 3

CO W CH.COOH

is represented in which E ^{1 is} a benzyl * or substituted Benayl group and R and X have the meanings mentioned above.

The Peniaillinvoratufe (III) is either implemented by dee ci-aminopanicillins (II) with a reactive compound the acid

R «000 -X- COOH (IV)

or by reacting δ-aminopenicillanic acid with a reactive one Compound of acid

R ¹ OOC - X - QOKHCHCOOH (V)

manufactured. About the reactive compounds of acids (IV) and (V) include the chlorides, bromides, asides, anhydrides, mixed anhydride © and those from the acids and a condensing agent, such as dicyelohexyloarbodiimide or carbonyldiimidazole, formed by intermediate products.

The non-toxic salts include non-toxic metal salts such as sodium and potassium. Calcium, aluminum, ammonium and substituted ammonium salts, for example the salts of non-toxic amines v / ie trialky amines. including triethylamine, Prooain, Dibenzylamin, K ~ BGnayl-beta "Phenäthylamin _f 1-JBphenamin, N ^ -Blbenis? min _t Dehydroabietylemln, Ii» Ji ^f -BiS "Äehydroabietyl-

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SAD ORJGiMAL

Ethyleneamine and other amines, which also form acidic cells be used with benzylpenicillin.

The penicillins which can be prepared according to the invention can mostly be used in two epimeric forms occur, and ea is pointed out that the invention has both the S- and L-shape and the DL Mixture includes «.

The invention is illustrated in more detail by the following examples.

example 1

Hatrium-ö-jjb-cM o-carboxybenzamido) ~ phenylacetamidep3- penioilla-

A solution of 3 g of phthalic anhydride in 25 ml of methylene di-chloride is slowly added to a cooled solution, which consists of 7 g of anhydrous 6- £ b (-) - oL-aminophenylao * tamido3-penicillanic acid, 50 ml of methylene dichloride and 8.4 ml of triethylamine is prepared · The mixture is stirred for 2 1/2 hours at room temperature and then diluted with dry ether until the formation of an oily precipitate appears to be complete. The precipitate becomes solid when rubbed with more ether it is then filtered off and dissolved in 25 ml of water. The aqueous solution is coated with 25 ml of methyl isobutyl ketone and treated, with stirring, with dilute Salesic acid to a pH of 1.5. The layers are separated, the solvent phase, which contains the penicillin in the form of the penicillin free. Acid contains »is with 2 χ 2Q ml ^ passer and then with

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Washed 25 ml of a saturated saline solution. By adding a 2n-I »8solution of sodium-2-ethyl-coat in methyl isobutyl ketone, the sodium salt of penicillin precipitated. The precipitate is filtered off and washed first with methyl isobutyl ketone, then with dry a'ther and dry in desiocator under reduced Pressure. The colorimetric test of the product (4 »3 g) with Hydroxylamine gives a purity of 69 # · On paper chromatography Examination one obtains a zone more antibacterial Efficacy whose R ^ value differs from that of the starting material is different.

Example 2

Trium ~ 6- {p-ci- (β-carboxypropionamido) -phenylacetamidoj-penioillanate.

The experiment described in Example 1 is repeated with the modification that 2 g of succinic anhydride are used instead of the phthalic anhydride. The yield of the sodium salt of the desired penicillin is 4.2 gj the colorimetric test with hydroxylamine shows a purity of about 86 $> *

Example 5

Katrium-e-Jp-d-C ß-carboajyacrylamido) -phenylacetamidaj-penicillanate

The experiment described in Example 1 is repeated with .der Modification that there «phthalic anhydride duroh 2 g maleic anhydride, Since there is gölöit in 30 ml of Diozan, it is replaced. The floodplain * The yield of sodium saline from the approximate penicillin is 6.7 g,

BATH ORIGiMAL

the colorimetric test with hydroxylamine reveals a purity of about 90 #.

Example 4

This penioillin is produced according to Example 1, but instead of β-Ο ^ ί ") ^^^^ ⁰ ? ^ ⁰ ^^ ³⁰⁰ * ⁰⁰ ^ ⁰ ^^ ⁸¹¹ ^ ⁰ ^ · ¹ ^ ⁸¹⁰³ ^ ¹ ^ ⁸ 6« {oL-Ämino «-3" »thienylai3etamiclo)« -pe & icillic acid vsrwen & ot.

Example 5

Sodium »j§t- {ß-sarboxypropionamido) -2-f urylacetaraidoJ-penicillanate«

Penicillin is produced according to Example 2, only is instead of the 6- | lb {-) ol-Äaiinoph.8nylaoQt3! aidoJ-p3niöillanäure 6- (db-Amino-2- = ° furylaoetamido) -penicillanic acid used

Example 6

lanat «

A solution of 2.3 g of glutaric anhydride in 50 ml of tetrahydrofuran is stirred to a solution of 8.06 g of 6- £ ί) (-) ο1-attinophenylaeetamidoJ-penicillanic acid trilydrate and 2.84 ml of triethylamine in 50 ml of lasser «. The solution is stirred for 2 hours at room temperature and maintains the pH by adding friethylamine between 7.0 and 7.5. The reaction mixture is at reduced pressure and temperatures below 20 ° 0 to half

Volume constricted. Bs is covered with 25 mV methyl isobutyl ketone and a sufficient amount of 5 η hydrochloric acid is added so that the pH is 2 after shaking. This is brought down once more * The combined organic extracts are washed with 2 100 ml of water then with 2 ζ 100 ml of a saturated salt solution and filtered through a filter treated with 8Uioon. The filtrate is added dropwise with stirring to 2 liters of a 0.01η solution of sodium 2-ätliylhexoat in diethyl ether. A solid product precipitates, which is filtered off after 30 minutes, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. With paper chromatography, one obtains a single zone of antibacterial activity, the R _f value of which is different from that of the initial apenioillin *

Example 7 Hatriutt-6- [D- (Aer (carbozyme thoxyacat amido) -phenylacetamidoJ-pe-

nicillanät.

The experiment described in Example 6 is repeated with the modification 5 that the gum acid anhydride is ereetst by 2.32 g diglycolic anhydride. The yield ah Hatriumeals of gewüneohtea penicillin is 6.8 g, the kolorimetrieche examination with hydroxylamine _t gives a purity of 63 56th

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- BATH

Example 8

5atrium ~ 6-Ij) -dl- (2-carboxypyridine-3 ~ earbamido) -phenylaeetamidoj - penieillanat and sodium-6-Ö> »ÖL- (3-ca5P" boxypyriäin-2-earbaiaido) - phenylacetamidoj-penicillanate.

The experiment described in Example 1 is repeated with the exception that 5 * 0 g of pyridine-2,3-carboxylic anhydride are used instead of phthalic anhydride. The yield of the penicillin mixture in the form of the unpurified sodium eel was questioned 7.0 g.

Boiapittl 9

Hatriu «a-6-fD- <l- (3-carbo ^ r" '"" ^ zin-g-oarbaBidoJ-phenylaoetamidoJ ·

panioillsnat,

The beaohriebene in Example 1 attempt was suppressed obtained with the modification that 2,3-oarboneäureanhydrid Pyrasin-ran be used in place of phthalic anhydride, 3.0 g. The yield of Katriunsalü dee the desired penicillin is 6 _f 9 g; the manometric test with penicillines "gives a unit of 74 i" . A sample examined by paper chromatography shows a zone of antibiotic activity.

Example 10

Iatrium-6-p) -cl .- (ß-carboxy-etjö-dichloroacrylamido) -phanylaoetasüdoj -penicillanat

A solution of 1.7 g of di-chloromaleic anhydride in 2 ml of acetone is slowly stirred into a cooled solution of 4.0 g 6 ~ & (^) - äif-AffiinophenylaöetamidoJ - penicillanic acid trihydrate _{> 50 ml}

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. - BAD ORIGINAL

_ ₉ . ^l 15456U

Added water and 1.4 ml of triethylamine. The clear solution will Stirred for 1 1/2 hours at room temperature and extracted with 3 × 100 ml of diethyl ether. The aqueous phase is diluted with 50 ml Layered methyl isobutyl ketone and treated with stirring with dilute hydrochloric acid to a pH of 1.5 * Dae sodium salt (1.6 g) is then isolated according to Example 1. The colorimetric Examination of the sodium salt with hydroxylamine results a purity of 73 # «

Example 11 ,

Batriura ~ 6- £ p - <& - (o-carboxyphenylacetamido) -phenylaoetamidqjpenicillanat and Hatrium-6-ij) -fi <- (o-carboxymethylbenaamido) -phenylacetamidoj-penicillanate »

The experiment described in Example 10 is repeated with the modification that 1.6 g of homophthalic anhydride are used instead of dichloromaleic anhydride. The yield of the penicillin emisohes in the form of the unpurified Sfatriumealse is 2.8 g,

Example 12

Sodium-6 ~ £ D-oi. ~ C la-Carboxybenzaiiiido ^ phsnylacetamidouf-penioillanat

Mne solution of 2.0 g of isophthaloyl chloride in 50 ml of methyl isobutyl ketone is in a thin even stream to a vigorously stirred aqueous solution of 4.0 g 6-0> (-) oi-aminophenylaoetamidoj-penicillanic acid trihydrate, 50 ml of water and 1 (4 ail of triethylamine are added. After stirring for 2 hours at room temperature v / earth the phases separately, and the organic phase

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is mixed with 3 ac 50 ml! Nasser and then with 2 χ 50 ml a saturated saline solution. Then the Hatrium Sala of Penicillins by adding a 2N solution of sodium 2-ethylhexoate precipitated in methyl isobutyl ketone. The precipitate is filtered off and washed first with methyl isobutyl ketone, then with dry ether and dry in a vacuum desiceator.

The colorimetric test of the product (3.1 g) with hydroxylamine gives a leg fairness of 83 #. In the case of paper chromatography Examination is in need of an antibacterial zone Effectiveness"

Example 13

Sodium «6- £ b-ck- {5 ~ oarboxypyrazole ~ 3-carbamido) -phenylaoetamido] penicillanate.

The experiment described in Example 12 is repeated with the modification * that 1.9 g of pyrazole-3 _t 5-dicarboxylic acid chloride are used instead of isophthaloylochloride. The yield of sodium sala of the desired penicillin is 2.5 g, the manometric test with Penicillinaae shows its purity of 83 #. In the paper chromatograph, there is a single zone of antibalcterial activity.

Example 14

Hodium 6- £ b <"ekr" {S-carboxy - ^ - nitrobenzamido) phenylacetamido penicillanate.

The experiment according to example 1 is repeated with the modification »

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that anateile of phthalic anhydride 3.8 g of 3-nitrophthalic acid - ' anhydride can be used. The yield of sodium sals of the desired Penicillin is 1.4 g, the colorimetric test with hydroxylamine gives a purity of 66 jf.

Example 15

^ atrium-ö-fl-ok-C ß-oarbostyaoryiamido) -m-hydroscyphenylaeetamidq] penicillanat ·

The experiment according to Example 1 is repeated with the modification that instead of phthalic anhydride and 6 "jjb (") 3l-aminophenyl-acetamido} -penioillanic acid, 5 g of maleic anhydride and 1.8 g of G-flt { + H.-Amino- HE-hydroxyphenylaeetamidoJ-penioillänsäiirii are used "In the paper-ear-chromatographic division""the product has a single zone of antibacterial effectiveness"

Example 16

Sodium 6-fjDIi-Ck-i ß-earboxyacrylamido) -valeramidpj -penicillanate β

The experiment according to Example 15 is repeated with the modification that instead of ß- ^ LC + Jd.-Amino-ra-hydroxyphenylacetamide Qj-pe'-nioillanic acid 1.5 g of 6-Q) I- «jLrAminovaleramidoJ-penioillanic acid be used. In the paper chromatography dead test does the product show a single zone of antibacterial effectiveness

Example 17

ITatrium-e-Eb-cL-C carboxy carbamido) -phenylaoetamidoJ-ptnicillanate.

A solution of 25 ml of oxalyl chloride in 80 ml of dry SPoluene

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BATH ORIGINAL

is stirred vigorously at -10 to -5 ° C, while a solution of 27.7 ml of benzyl alcohol in 20 ml of dry toluene dropwise is admitted. The mixture is then without external cooling Stirred for 2 hours and filtered * The filtrate% ird under reduced Pressure (bath temperature 80 °) on a volume of 70 ml constricted.

14.7 ml of the concentrate, which contains Benzylöxyoarbonylearboxylohlorid, are dissolved in 100 ml of methyl isobutyl ketone.This solution is cooled to 0 ° and all at once with vigorous stirring to an ice-cold solution of 20.15 g 6- | ~ D (-) oC- Amine / phenylaoetamido / penicillanic acid trihydrate is added to 100 ml of 0.5N aqueous sodium hydroxide solution. Stirring is continued so vigorously for 40 minutes that the two phases are intimately mixed. The two layers are then separated and the aqueous phase is covered with 25 ml of methyl isobutyl ketone. Ssufficient 5N hydrochloric acid is added so that a pH value of the aqueous phase of 2 is established after shaking. The layers are then separated and a second solvent extraction is carried out in the same way. The combined solvent extracts are washed with 4 × 100 ml of water and then with 2 × 100 ml of a saturated salt solution and filtered through a filter treated with silicone. The clear solution is added dropwise with vigorous stirring to 1.51 ml of an O, O33N solution of sodium 2-ethylhexoate in ether. The precipitate obtained is filtered off, "washed with ether and dried under reduced pressure, giving sodium 6-fjB ^^ Beneyloxycarbonylearbamido) - pheny! Acetamido} -psnicillanate", Pie yield diener & e ~

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^BAÖ

protected penicillin precursor "is 18.3 g> the manometric test with penioillinase reveals a purity of 75 Ά · 5 g of this precursor v / earth dissolved in 50 ml of water and 75 ml of an aqueous suspension of 5% of a catalyst of 5 % palladium added to calcium carbonate, which was previously shaken under hydrogen for 1 hour. The mixture is shaken under hydrogen for a further hour at room temperature and pressure and then filtered. The filtrate combined with the wasoh water is concentrated at low temperature and low pressure and dried the solid Bfinkstanä finally with reduced bridge over Phoaphorpentoxyd. The yield of sodium 6- (J) -Ot-C carboxycarbamido) -phenylaeetamidoj -penioillanat amounts to 4.0 s, the manometric test with penicillines «shows a height of 68 ¹ P. The paper chromatographic examination reveals a single zone of antibacterial effectiveness, the R _f value of which differs from that of the starting penioillin and the Penicillin precursor is different.

Example 18

Sodium * 6- £ iD- <Ä .- (carboxyacetamido) -phenylacetamidoj-penicillanate.

5.82 g of monobenzyl malonate (melting point 50-51 °) and 5 ml of shionylchloride are heated together to 80 ° for 1 hour, then the volatile fraction is removed under reduced pressure (bath temperature 70 °). The remaining oily acid chloride is in 50 ml Dissolved ethyl isobutyl ketone and at once with vigorous stirring to a solution of 12.1 g of 6- | p (-) c (l-aminophenylacetamidoJ-penicillanic acid trihydrate in 50 ml Ο, δη aqueous sodium hydroxide solution

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given. The mixture is then stirred vigorously for 40 minutes, removed any solid matter and separates the layers. You watery Phase is carried out according to the procedure described in Example 17 extracted twice with methyl isobutyl ketone to a pH value of 2. The clear extracts become an ethereal solution of sodium 2-ethylhexoate given, whereby 6 g of HatritauM ^ - £ b-oL ~ (benzyloxycarbonylacetamidoj-phenylacetamidoj-penieillaoat receives. The calorimetric test with hydroxylamine shows a purity by 49 #

4.1 g of this protected penicillin precursor are produced according to the in Method described in Example 17 using 25 g of prehydrogenated catalyst composed of 5 $ palladium on calcium carbonate catalytically hydrogenated. The resulting Katriim-6 ~ £ l} ~ a- <cexboxyacetamido) -> phenylacetamidoj | -penicillanate (2.8 g) shows a purity of $ 34 when colorimetrically tested with hydroxylamine. The paper chromatographic examination shows one single zone of antibacterial effectiveness, the H ^ value of which of that the initial apenicillin and the penicillin precursor are different.

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* ^Aö

Claims (1)

pata ntans t> r ü ο h β 1. Penicillins of the general formula HCX) C- X - COKHOHOO. KH. OH OH CO- H ·. CH.OOOH and their nontoxic salts, where R is an alkyl, aralkyl, aryl or heterocyclic group, which is optionally substituted, and Z is a direct bond or an 8-valent aliphatic, aromatic or heterocyclic, optionally substituted group « 2. Hatriim-6- [i) -dt- (o - carboxyl3ensaraido) -phenylaoetaniidoJ »peni · - oillanat. 3. Hatrii »^ - £ i) - dtr» ß-carboxypropionamido) - "phenylacetainidq7 ~ penicillanate. 4. Katriua - ^ - fD-tir-C ö-carboxyaorylamido) -pheny laoetamidoj -penicillanate. 5. Natriu «-6- ^ i- {o-carboxybenaamido) ~ 3-thienylaeetamido] penioillanate. 6 "Eatrium ~ 6-ßvi ß-oarboxypr opionaraido) -2-f urylacetamidoj-penj.cillsnat · .. ,, ^ _, 909832/1530 hme Unterlaoen (An.7gt /. ·· = ,. £ .-. ^, _{Sentence3 (lesÄnderunggS3sv4gie67} . nicillanat 8 · Natri * ua-6- £ i) "<iw" (carboxymethoxyaeetamido) -phenylacetamidqj penicillanate » 9. Natrim-6- «Ö) - <& - (2-carboxypyridine-3-carbamido) -phenylaoetamidoj penicillanate. XO · Hatrium-6 «- £ D ~ oü- (^ -carboxypyridine-S-carbamido) -phenylaoetamidoj-penicillanate · 11 Hatrium-6-u> -etr> (5-cai * urpyra2in-2-earbamido) -phenylaoetamide <2J-panicillanate. 12. Hatrluia ~ 6- / l} - ^ r (ß-carboxy-otsß-dichloroacrylamido) -phenylacet am £ d <0 «psnieilla & at · 13 · Sodium 6- {l) - ^ i "(o-carboxyphenylacetamido) phenylacetate & midojpeniolilanate. 14 Hatriua-6-f * D- <i- (o-carboxymethylbenzamldo) -phenylacetaaidoj penloillaaat. 15 · Katriuto-6 ~ £ D-oL- (me arboxybensamido) pheiiy laoetaaioj -penicillanate. 16. Hatrium-.6-CD-eir- (5-carboxypyrazole-3-carbamido) -phenylacet- 9 0.9832 / 1 5 3-D '. amidoj-penioillanate * penicillanate 18, Nat r ium-6-f L-d- (B-carbo ^ acijlasni do) -m-hyäroscyphenylaes t · amido] penicillanate. 19th cillanat » 20. Katriuai «6 ~ IJ) - ^ - Cearboxycar & amido)« phenylaeetamidoj cillanat · cillanat. 22. A method for the production of penieillines according to claim Formula I, characterized in that a) © in Οί-Άπιΐηορβηίοϋΐΐη the general ». formula R. CH. CO. KH. OH —CH CH.COOH ittit with a reactive compound of an acid of the general formula YOC -χ- COOH 909832/1530 BATH ORIGINAL in the Y © ine hydroxyl group or the group OR · "denotes, wherein R * is a Benayl or substituted beneyl group will or that ' b) 6-aminopenicillanic acid with a reactive compound an acid of the general formula R ¹ OOO - Σ - CQBHCHCOOH is reacted, where. "B ^{1 is} a benzyl or substituted benäylgruppe, and & 3 H ^{1 is} then removed by catalytic hydrogenation. 23 «Method according to claim 22, characterized in that di? reactive compound, if the substituent Y is a hydroxyl group, a cyclic® anhydride X ^ T JQ * a ^ GO ^ Mono «or bis-säureehlü ^ id or a mono- or bis-gemisehtea Anhydride is * 24 * The method according to claim 22, characterized in that di ι reactive compound, when the substituent Y is an OR ¹ group, is an acid chloride, bromide, azide, anhydride or mixed anhydride. 25. The method according to claim 22, characterized in that the reactive compound, if the substituent Y is an OR ¹ «(J group, is a precursor formed from the acid and a condensation agent» 909832/1530 ^ 26. The method according to claim 25, characterized ge demise Ichnet that the Condensation agent is dlcyclohexylearfaodilmid or carbonyldiimidazole 909832/1530 ^ ^ "■