DE2312041A1 - PENICILLIN, THE METHOD OF MANUFACTURING THEIR PRODUCTS AND THE PHARMACEUTICAL PRODUCTS CONTAINING IT - Google Patents

Description

Priority · Grofl-Sritannien Kr. It 692/72 of March 13, 1972

The present invention relates to new penicillins and processes for their preparation. The invention also relates to the production of pharmaceutical preparations which contain these penicillins , as well as methods for the pharmacological use of these penicillins

In particular, the invention relates to new mono- and diesters of «{-carboxy-substituted penicillins of the formula I.

R - CH - CO - KH - CH - CH, 2

• CH

: oor

CO - N-

CH - COO - R

(D

and the pharmaceutically acceptable salts thereof; in the formula mean:

R is a phenyl, thienyl or furyl group, R is a hydrogen atom, the group

ch-o-ILr ⁴

or

309841/1 185

and

Ffaniefurt / Mjiti 6765

ank Driäiner Bank AG. Wiesbaden. Koato no. 276 Bü7

8th ,. Γ «

the group -CH-OIR ^{4 or} -CH-XCOR * ¹ "is a water s to ff atom, an alkyl group with 1 to 8 carbon atoms, an ary group or an aralky group, where the alkyl, aryl and Aralkyl groups can be unsubstituted or substituted by one or more of the following groups: amino groups, substituted amino groups, such as methylamino, diethylamino or acetamido groups, halogen, nitro and alkoxy groups with 1 to 4 carbon atoms,

X -O- or -WH-,

R is a hydrogen atom, a methyl group or an ethyl group

R is a saturated or unsaturated alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an aryl, aralkyl or heterocyclic group, the alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups which can be unsubstituted or substituted by one or more of the following groups: Amino groups, substituted amino groups such as methyl, amino, diethylamino or acetamido groups, halogen, nitro and alkoxy groups having 1 to 4 carbon atoms, where

2
R the group,

R ⁵ Ö

-CH-X-C-O-R means, R is a hydrogen atom

^r3 'η

or the group -CH-O-C-R means.

Characteristic examples of radicals falling under the definitions given above and included in the definitions of Radicals within the present application include:

Alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl,.

Pentyl, hexyl, heptyl, octyl, 2-ethylhexyl Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl

309841 / Π a5

Alkoxy: methoxy, ethoxy, propyloxy, isopropyloxy, butoxy,

Isobutoxy

Halogen: F, Cl, Br

Aryl: phenyl, naphthyl, naphthylmethyl, 5-indanyl aralkyl: benzyl, naphthylmethyl, 5-indanyl Heterocyclic groups:

■ - * - y-

The above characteristic examples explain - so far

1 4 applicable - all radicals R to R and other radicals that are mentioned in the description, in the Ausinas s of the definition given for each radical and within the limits of the number of given for each radical Carbon atoms.

The invention relates in a further embodiment - such chemical intermediates which are new and which are useful in the preparation of the compounds of formula I.

The compounds according to the invention are valuable remedies for infectious diseases in humans or animals caused by Bacteria. Can they be isolated and used as such? depending on whether basic or acidic " Groups are present in the molecule, however, they can also be in the form of salts with pharmaceutically acceptable organic or inorganic acids or bases are used. Examples of suitable acids are hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid and fumaric acid. Examples of suitable bases

309841/1185

231204Ί.

are sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, Ammonium hydroxide, non-toxic amines, such as for example trialkylamines, preferably triethylamine, procaine, dibenzylamine, N-benzyl-beta-phenylethylamine, 1-ephenamine, N, N -Dxbenzylethylenediamine, dehydroabietylamine, N, N -Bis-dehydroabietylethylenediamine, N-lower alkylpiperidine (e.g. N-Ae thy lpiperidin) 'and other bases that have been used to make salts with penicillin.

The side chain of the penicillin structure in formula I contains an asymmetric carbon atom in the Λ position. Depending on Due to the configuration at this carbon atom, the compounds come in two different diastereoisomeric forms both of which are biologically active. Similarly, the ester groups may contain asymmetric carbon atoms, e.g. when R denotes the methyl or ethyl group, whereby different diastereoisomeric forms arise which also are all biologically active. It goes without saying that the invention includes both the pure diastereoisomers and Mixtures of the same.

It is known that substitution of benzylpenicillin and analogous compounds in the © (position of the side chain with a carboxyl group or certain esterified carboxyl groups compounds of the formula II gives:

R - CH - CO - NH - CH.- CH GC '

■ COOR ⁵ CO -N CH-COOH

wherein R has the same meaning as above and R denotes hydrogen, alkyl or aralkyl groups; Compounds of the formula II have good antibacterial activity against gram-positive and gram-negative bacteria, for example against Pseudomonas aeruginosa (Dutch patent 6,404,384, South African patent 67/2804,

309841/1185

South African patent 67/6472, Dutch patent 6 805 524, U.S. U.S. Patent 3,142,673 and Dutch patent 6,913,416).

Such compounds, however, are poorly or only moderately well absorbed when administered orally, and so are the carboxy compounds (II, R = H) must be injected. It is an object of the present invention to provide esters of these compounds which are well absorbed when administered orally and which are then hydrolyzed within the body are, so that blood and organ levels of the "compounds of the formula II are obtained which are used for the treatment of Infectious diseases caused by bacteria sensitive to penicillins of general formula II are suitable.

The carboxyl group of the oc-carboxy! Penicillins (II, R = H) is quite unstable and is partially split off during connection and storage, whereby the corresponding non-carboxylated penicillins are obtained which are resistant to gram-negative bacteria and are particularly less effective against Ps. aeruginosa. By converting the carboxyl group into an ester group this decomposition is avoided and compounds are obtained which can be easily made and stored. To get the full antibacterial effectiveness of the oC-Carboxypenicillins To obtain, however, it is necessary to choose those ester groups that are released in vivo with the Carboxypenicillins are rapidly hydrolyzed. It is an essential feature of the present invention to add esters create that under manufacturing and storage conditions are stable, but are quickly hydrolyzed after resorption in the organism, so that high levels of blood and organ mirroring of carboxypicillins.

309841/1185

The compounds of the formula I mentioned are well tolerated, have a low frequency of side effects and can easily be used in pharmaceutical preparations either as such or in the form of their salts, furthermore they can with solid carriers and / or auxiliaries be mixed. In such preparations, the ratio of therapeutically active substance to carrier substances and Excipients can be varied in the range from 1 to 95%. The preparations can be processed into tablets, pills or coated tablets or can be filled into medical containers, e.g. capsules, in the form of - ^ - Mirs-ch-ungen - k-önn-en them be bottled. Pharmaceutically acceptable, organic or inorganic, solid or liquid carrier substances, which are suitable for oral or enteral administration or for topical application, can be used for the manufacture of the preparations are used. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and Oils, vegetable gum and polyalkylene glycol and other known carriers for pharmaceuticals are all used in the manufacture of Preparations of the compounds mentioned are suitable. The preferred salt of the compounds according to the invention is the hydrochloride, However, salts with other inorganic or organic acids can also be used, including with antibiotic acids can be used, for example phosphates, acetates or salts with phenoxymethylpenicillin. In addition, it can Preparation containing other pharmaceutically active compounds for administration together with the invention Compound for the treatment of infectious diseases are suitable. For example, other antibiotic may be effective Substances such as gentamicin and polymyxin can be added.

In the treatment of bacterial infections in humans, the compounds according to the invention can, for example

30984 1/1185

administered in amounts that are 5 to 200 mg / kg / day, preferably in the range from 10 to 100 mg / kg / day, in divided doses, e.g. two, three or four times a day. They can be administered in dosage units containing, for example, 175, 350, 500 or 1000 mg of the compounds.

Examples of preferred compounds according to the invention are:

309841/1185

(Π O O O

Κ \ I O — ΟΙ

CM

Η3

πι

• Ο

Ό ι

Oi = O

I O

do

-O I

HJ

VD O

IfY

HJ

CM Ο—

CM O, I CM

»Ή

O I

-CH

• in

O.

CM O

M-I K -O Ο— I.

• 309841/1185

in

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CM O

O O O

O 1

CM O

231204

in in ΙΓ \ HJ HJ VD VD CM ο O O

CM O

CM O

O O O

O I

ο-u

(M O

ω.

O-O I

M-I O

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CM

CM

K O

O O O

CM tlj

Ü — O

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• s

CM iU O

CM O I

_._. O I

ο — ο

υ 131 2041 « O = O ακζπο I. ι pi K ί3 I. I. CM CM ¹ T ¹ O Ü I. I. CM CM JU O O I. I. O O O O O O I. I. O . O I. I. CM
* T * CM O O I. I.

in in in ΙΙΛ in n:
vo K
VO lrl
H-*
vo K
CM VO CM O O ü O O ο-

309841/1185 ORfGiNAl, «NSPECIH)

-. 10

pi

O O

ti

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ο ι

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pci O O

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i CM O ϋ I. I. CM O do O O O t * I. . I. ο O ο O ι I. CM W. O O I. I.

CM

ιη ιη . ιη m ιη Jt) ve VO VD νο O ο O O O

309841/1 λ 85

CM

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ir!
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CM

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CM
O
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O = O
I.

in

in in KY in CM Jr! irl O U ic O CM CM —Ι— CM I. O O O O I. I. I. O O O = O O O O O I. ¹ I. § O O 1 1 I. CM
ir!
O I.

IfN

in

CM O

O O O

tn

ο — ο ι

in

vo ο

in ir!

CM O

O O O

CM

in K

CJ

309841/1185

^w g

ir; O ο — ο

■ f -

M. pi

- 12 -

CM

Cv) O

CM O

O O O

O I

K ο

in

¹ T ¹ IM,

CM O

O = O

I O

CM

IfY

CM O

O I

CM KO

O O

ο ι

O = XD

I O

in
ίχί

CM m

O O

CM O Il

K ϋ

CM • τ

O O O

ο — ο j__ j.

in

CM O

O O O

■ ο

2312P4T

CM

CM

CM • τ ¹

M-I

O I

O!

Ο

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3 0 9 8 4 1/1 1 8 5

μΓ CM O

O = O I

O IA I

O

1-

S ¹ ^

O.

in ιη
VD
O ιη . ιη ιη ιη VD
ο VO
ο VO
ο VO
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O

O (M O O O ί - Ο O

OJ

pi

pi

O — Ο — O I.

ιη

νο O

O OJ

O I

OJ

O I

- 13 -

ο-

ιη

OJ

I O

! O = O

! O

-ο

ιη

■ Ι-Γ *

ο ο 309841/1185

ιη

VD

CQ = O ι

»Τ *

OJ O ιη I. OJ O OJ I. O ο i I. O O O = O O 1 I. O O ι ! OJ OJ δ B. I. I.

(M KN Hi. M-I O
ΪI ο — ο Il
K O CM O IA fr] - S. CM O O O O O = O O I. Ί O ■ ο I. ι ο — ο

CM O O

CvJ

O
O

• ο

CvI
pi

O O

O I

O I

CM

O
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O = O

O O

O O

ο — ο

CO

CO

CO

Α1 / 1 1.8 5

O CVJ CM O pi pi O I. O ~ o ω - O I. pi

pi

pi

- 15 -

CVJ

O O

I O = O

I O

O O

in

<M O O

O 1

0 9841/1185

O CM CM O Ph Ph O I. O -O Ph Ο Ι ■ Ρί

Ph

- 16 -

HO CM

O I

CM

»Τ *

• t-M

O Ί CM

O I

O O O

O I

CM Pi O

O
I. CM CO = TO 1 1 CM Ph CM O Ph I. O CM
pH I. O CM I. B. O I. O O O O I. O O I. ΝΛ I O Ph Ph I. . O O_ CM K O I.

CM

W. CM I. O . CM O O __. · W I. I. CM O • o = o Ph O O
■ O I. O I. O a O O ! I. O I. CM I CM Ph Ph ir! JxJ Ph O O O- -O • O I. I. I.

3 0 9841/11

Preferred classes of compounds of the invention are those compounds of the formula I in which R is phenyl, 2- or 3-thienyl

or 2- or 3-furyl, R hydrogen, lower alkyl, benzyl, phenyl, 5-indanyl, lower alkoxycarbonyloxymethyl, 1'-lower alkoxycarbonyloxyethyl, 1'-lower alkoxycarbonyloxypropy1, lower alkoxycarbonylaminomethyl, 1'-lower alkoxycarbonylaminoethyl, 1'-lower alkoxycarbonylaminoethyl, 1'-lower alkoxycarbonylaminoethyl, 1'-lower alkoxycarbonylaminoethyl acyloxyethyl , 1'-lower acyloxypropyl, phenoxycarbonyloxymethyl, 5-indanyloxycarbonyloxymethyl, 1'-phenoxycarbonyloxyethyl, 1 '- (5-indanyloxy) -carbonyloxyethyl / 1'-benzoyloxy-ethyl, lower-benzoyloxy-ethyl, lower-alkoxy-1'-oxymethyl, Λ' -benzoyloxy-1'-oxymethyl, Λ '-benzoyloxy-1'-oxymethyl, Λ'-benzoyloxy-1'-oxymethyl,1'-benzoyloxy-1'-alkyloxy-ethyl,Λ'-benzoyloxy-1'-roxy-1-alkyloxy-1'-benzoyloxy-propyl'-Lower alkoxycarbonyloxypropyl, lower alkoxycarbonylaminomethyl, 1'-lower alkoxycarbonylaminoethyl, 1'-lower alkoxycarbonylaminopropyl, phenoxycarbonyloxymethyl, 5-indanyloxycarbonyloxymethyl, 1'-phenoxycarbonyloxyethyl, 1'loxy) -ethyl-indbanyxyethyl.

Further classes of preferred compounds of the invention

1 2

are obtained when R is hydrogen and R Niedrigalkoxycarbonyloxymethyl, 1 * -Niedrigalkoxycarbonyloxyäthyl, 1'-Niedrigalkoxycarbonyloxypropy1, Niedrigalkoxycarbonylaminomethyl, 1'-Niedrigalkoxycarbonylaminoäthyl, l'-lower alkoxycarbonylaminopropyl _t Phenoxycarbonyloxymethyl, 5-Indanyloxycarbonyloxymethyl, 1'-Phenoxycarbonyloxyäthyl, 1 '- ( 5-indanyloxy) carbonyloxyethyl means.

Still other classes of preferred compounds are obtained when the acyloxy moieties or the alkoxycarbonyloxy, the acyloxycarbonyloxy, the alkyloxycarbonylamino or the acyloxycarbonylamino groups of the substituents R and

R by amino, methylamino or di (lower alkyl) amino groups are substituted. The compounds according to the invention can be prepared in various ways.

309841/1185

- Xö -

Manufacture of esters, the penicillins A. ^ S ^

COOR "
III

R-CH-CO-NH-CH - CH, 2 '

C00R ^£

CO-N

CH,

.CH,

. , R-CH-CO-Z +. H ₂ N-CH-CH

CO-N -CH-COOR

IV

CH - COOR

7 '

R-CH-CO-NH-CH-CH, 2

COOR

CO - N

CH

CH ~ COOR ¹

According to this method, an activated malonic ester derivative III with an ester of 6-aminopenicillanic acid (6-APA) IV to form a Penicillin ester V implemented.

2 * 2 7 '7

If R = R and R = R, then the product V is one

■ 2 "7 ^!

connection according to the invention. If R or R contains groups, which are protected, then the protective groups in a manner known per se in at least one · additional • Step removed in order to obtain the compounds of the formula I A.

In the formula scheme above are the different radicals defined as follows;

R has the meaning given above ,

2 2 2

R is R , which is as defined above or - if R is a hydrogen atom or if R contains amino groups or substituted amino groups - a protected derivative

2
vat of R,

-CO-Z is a reactive group that can react with an amino group to form an amide group, e.g. an acid chloride or a functional equivalent

^therefor '30 9841/1 1 85

₇ , _{7 7} 231204

R is R or - when R is amino groups or substituted

Contains 7 amino groups - a protected derivative of R,

R ⁷ is

-CH-OCR or -CH-XCOR ⁴ / where R ² '

-CH-XCOR ⁴ means when R ^{7 is} "CH-OCR ⁴ "

3 4
R, R and X have the meanings given above.

As protective groups for the carboxyl group, groups can be used which act as carboxyl protective groups Penicillin syntheses have been applied. In particular, the protective group can be benzyl, p-nitrobenzyl or Be diphenymethyl; these groups can be catalytic Hydrogenation are cleaved, or the protective group can be an alkyl or acyl group, which by mild alkaline hydrolysis can be split off or the protective group can be a / 3-trichloroethyl group which can be split off by treatment with zinc in acetic acid or the protective group can be a / 3-iodoethyl, a (X-p-Tolylsulfohyläthyl- or a mono- or dxhalobenzyl groups cleaved by treatment with a basic agent such as sodium thiophenolate can be.

Such protecting groups can be used as protecting groups for the amino and substituted amino groups that can be removed without destroying the penicillin ring system. Such protective groups are known for example the benzyloxycarbonyl, the o-nitrophenylsulfenyl, the 2-p-Tolylsulfonyläthoxycarbonyl-, the ß-Trichloräthoxycarbonyl- and the l-methoxycarbonylpropen-2-yl group.

309841/1185

The reaction is an acylation of an ester of penicillanic acid; it can be carried out in the manner described for the acylation of other esters of 6-aminopenicillanic acid (for example as described in French patent specification No. 1,576,027). The acylating group -CO-Z in III can be an acid chloride group or a group - which acts in the same way, for example an acid bromide, an acid acid, an anhydride, a mixed anhydride which is formed with an inorganic or an organic acid, such as For example an alkyl carbonic acid, for example isobutyl carbonic acid, a carbonic acid, a sulfonic acid and in particular an alkoxyformic acid, or it can be a radical obtained by reacting the ^ -substituted phenylacetic acid and a carbodiimide or N, N -carbonyldiimidazole or another compound, which reacts in a similar way.

The reaction can be carried out in organic solvents, such as diethyl ether, Tetrahydrofuran, acetone, ethyl acetate, chloroform, methylene chloride, dimethylformamide, dimethyl sulfoxide, or hexamethylphosphoramide, in water or in aqueous organic solvents in the presence of organic or inorganic bases such as triethylamine, quinoline, pyridine, N-methylmorpholine, sodium hydroxide, sodium bicarbonate or Potassium carbonate can be carried out.

The compound of formula V can be extracted from the Reaction mixture can be isolated, if necessary, after

Dilution with water and neutralization. The compounds of the formula V (R ² = R ² \ R ⁷ = R ⁷ ) are compounds of the general formula I.

The esters of 6-aminopenicillanic acid with the general "structure IV can be prepared by treating 6-APA with compounds.

7 «7 ι

R -Y, where R has the meaning given above and Y

30984 1/1185

Halogen or a functionally equivalent derivative thereof, such as an organic sulfonic acid residue is prepared will. The reaction is preferably carried out in organic solvents such as dimethylformamide or dimethyl sulfoxide.

Optionally, ö-acylaminopenicillanic acids with acyl groups, which are removed without destroying the penicillin ring system

7 «
can, reacted with R -Y to esters of δ-acylaminopenicillanic acids, from which the acyl groups are then removed, the esters of 6-aminopenicillanic acid of the formula IV being obtained. A preferred method consists in the implementation of a salt, for example the sodium, potassium or tetra

7 '

alkylammonium salt of benzyl penicillin, with R -Y in an organic solvent such as dimethylformamide, dimethyl sulfoxide, Acetone, chloroform, methylene chloride or hexamethylene phosphoramide or in a mixture of an organic Solvent and water, e.g. aqueous acetone or dioxane, whereby the corresponding ester of benzylpenicillin is obtained. The phenylacetyl side chain is then made according to the method described in Dutch patent specification no. 6 401 421 or the South African patent specification No. 67/2927 by treatment with phosphorus pentachloride split off in the presence of a tertiary organic base, an iminochloride being obtained with an alcohol such as propanol is converted to the corresponding imino ether, which in turn is converted by adding water hydrolyzed or alcoholized by the addition of alcohol, whereby the ester IV is obtained. Optionally, the phenylacetyl side chain by enzymatic hydrolysis according to that described in French Patent No. 1,576,027 Removed method using an E. coli acylase will.

309841/1185

According to another method, N-protected 6-amino

7 «.

penicillanic acids with R -Y to the corresponding ester sets from which the protective groups are removed, whereby the compounds of the formula IV are obtained. at games for protective groups that can ■ be used are the benzyloxycarbonyl group catalyzed by ^ Hydrogenation is removed, the o-nitrophenylsulfenyl group, which are removed by treatment with nucleophilic reagents at acidic pH (Japanese Patent Publication No. 505 176) den can and the trityl group, which can be removed by weak acid hydrolysis. .__.. ——- _ ..

B. A natural or biosynthetic penicillin of the formula

R ° ~ CONH-CH - CH C ^ '.

II I ^CH 5 (VI) _co " _N CH - COOM

where R CO is the acyl group in the side chain of the natural or biosynthetic penicillins and M hydrogen or an alkali atom such as sodium, potassium or calcium, is obtained by reaction with a compound of

7 '7'

Formula VII, R -Y, wherein R and Y are those given above Have meanings, esterified, whereupon the ester of the formula VIII obtained in this way

^ "S j CH-?
R ° -C0NH-CH-CH- "^ C <^ ^

^CH 3 (viii) CO - N - CH - COOR '.

in an inert solvent and preferably in the presence of a tertiary amine with a phosphorus halide an iminohalide compound is reacted, which in turn with a lower alcohol to an iminoether derivative is implemented. The imino ether is then with a compound of formula III

30 9 841/1185

R-CH-CO-Z

1 2 ' COOR

2 '
in which R, R and Z have the meanings given above, reacted and the reaction product is converted into a compound of the formula V with water or an alcohol

■ ^ S "CH, R-CH-CO-NH-CH-CH CC

• CH, (V)

COOR ^ CO - N CH - COOR '

implemented, which is then, as described above under A, converted into a compound of formula I. at this method is the imino ether compound obtained as an intermediate acylated directly without isolating any intermediates.

The group R CO- in the compound of formula VI is a organic acyl group that is found in known natural or bio-synthetic Penicillins is included. Accordingly, the group R can optionally with a heterocyclic Group substituted alkyl, aralkyl or methyl group or a derivative thereof. Examples of "suitable groups R ° are Heptyl, phenoxymethyl, 2-thienylmethyl, 2-furylmethyl and Benzyl. Examples of suitable phosphorus halides include phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, Phosphorus trichloride, etc. Phosphorus pentachloride is preferred. Examples of suitable alcohols with which the imino halide can be reacted are lower alky! Alcohols, such as with- " for example methanol, ethanol and n-propanol.

3 Q 98-4 1/1 185

H-CH-CO-NH-CH - CH> 2 '

■ COOR '

CO-N.-

IX

.CH

CH - COOH

7 '+ R' Y

R-CH-CO-NH-CH-CH CC ^J

■ COOR CO-N CH - COOR '

R-CH-CO-NH-CH-CH C ^^ ^J

CH,

COOR '

CO-N CH - COOR '

ΙΑ '

.The. Compounds of the formula 'IX can by reactions with

7 "i" 7> Compounds of the formula R -Y, in which R is the above Has meaning and Y is halogen or a functionally equivalent group such as a sulfonylic acid residue, means to be converted into a compound of formula V. If Y is halogen, preferably chlorine, bromine or iodine, or if it is a sulfonic acid residue, e.g. a p-tolylsulfonyloxy group, means, the reaction is preferably carried out with a salt, e.g. sodium, potassium or trialky ammonium or tetraalkylammonium salt, the compound IX in an organic solvent such as dimethylformamide, dimethyl sulfoxide, acetone, Chloroform or methylene chloride or a mixture of

309841/1185

Water and an organic solvent, e.g. aqueous dioxane or acetone.

2 · ο 7 * 7 If R = R and R = R, the product V represents a

2 ¹ 7 '

Compound according to the invention. If R · or R is protected Contain groups, the protective groups are removed in a manner known per se in at least one additional stage, whereby the compounds of the formula I A are obtained.

2 «penicillins of the formula IX, wherein R is the above Has meaning, are prepared by acylation., Of 6-aminopenicillanic acid according to methods known per se.

R-CH-CO-NH-CH-CH

COOH - CO -

CH - COOR

+ R ⁶ Ύ

R-CH-CO-NH-CH-CH COOR ⁶ 'CO

- N-

XI

R-CH-CO-NH-CH-CH, 6

.CH, CH,

CH - COOR

CH CH,

• r

COOR CO - N CH - COOR

IB

8th'

309841/1185

The compound of the formula X can with a compound of Formula R -Y are converted to a compound of the formula XI. When R = R and R = R, the product represents

6 '8' XI is a compound of the invention. When R or R contains protected groups, the protective groups removed in a manner known per se in at least one additional stage, whereby the compounds of formula I B can be obtained.

In the formula scheme above, the different radicals have the following meanings: - - -

R has the meaning given above R is R or - when R is amino groups or substituted

Contains amino groups - a protected derivative of R, R means the group

ψ OR ^ O

-CH-OCR ⁴ , or -CH-XCOR ⁴ ,

an alkyl group with 1 to 8 carbon atoms, an aryl group or an aralkyl group, where the alkyl, aryl and aralkyl groups can be unsubstituted or substituted by one or more of the following groups: amino groups, substituted amino groups, such as methylamino, diethylamino or acetamido groups, halogen, nitro and alkoxy groups with 1 to 4 carbon atoms,
R is R or - when R is amino groups or substituted

Contains amino groups, - is a protected derivative of R, R ⁸

-CH-OCR ⁴ or -CH-XCOR ⁴ where R ⁶ 'means -CH-XCOR ⁴ , if R ⁸ j means _H _ ₀ _ | _ _R 4,

309841/1185

_ O "7 _ Δ ι

4th

R, R and X have the meanings given above.

The protective groups mentioned under A can be used as protective groups.

The reaction conditions described under C can be found in applicable parts can also be applied to this method.

-CHC = O + H ₉ N-CH- - CH

I I

COOK'
XII

CO-N CH - COOR

IV

R-CH-CO-NH-CH-CH

ι, ι ι

COOR ^ CO-N .V

CH -COOR

R-CH-CO-NH-CH-CH

COOR ^ CO - N. CH - COOR

IA

309841/118

Instead of the activated carboxylic acid derivative of the formula III, used in Method A may be a ketene derivative of formula XII can be used in the acylation reaction as described in Belgian patent 726,421 has been.

-RC = C = O + H ₀ N-CH - CH

C-Cl

■ J

XIII

CO-N

CH ~ COO

Ah χ ϊ-

O-R

■ - XIV.

'R-CH-CO-NH-CH-CH

CO-N

COOH

- CH ~ COOCH-X-C-O-R

XV

R-CH-CO-r NH-CH'-CH "C

COOH CO - N

IC

CH-COOCH-X-C-O-R ^

A ketene acid chloride of the formula XIII is made with the 6-APA ester of formula XIV implemented, whereupon the compound obtained

4 ″ is hydrolyzed to a compound of the formula XV. When R

4th
= R is the product, XV is a compound according to the invention,

4 «
If R contains protected groups, the protecting groups are removed in a manner known per se in at least one additional stage, compounds of the formula IC being obtained.

3 4 In the formula scheme above, the radicals R, R, R and have

4 '4 X has the meanings given above and R is R or

309841/1185

- if R is amino groups or substituted amino groups

4 holds - a protected derivative of R. As protective groups

the protective groups mentioned under A are applicable. The manufacture of penicillins

R-CH-OO-Z

+ H ₂ N-CH

.GH *

• COO-CH-XCOR '
R ^
XVI

R-CH-CO-NH-CH -

4 '

CO - N-

COO-CH-X-C-O-R

R-

4 '

R-CH-CO-NH-CH-CH

CH - CH CC ^

I I I CH ^

CO - N -: CH - COOH

CH, CH,

CH - COOH

XVIII

CO - N

COO-CH-XCOR ⁴

ID

.CH ₇ CH.

CH - COOH

XVII

According to this method, an activated malonic ester derivative is made XVI reacted with 6-aminopenicillanic acid (6-APA) XVII to form a penicillin of the formula XVIII.

3 4 '

In the formulas, the symbols have R, -CO-Z, R, R, R and

X has the meanings given above.

309841/1185

The reaction conditions are the same as those for preparation of penicillins can be applied by acylation of 6-APA. The production of the appropriate Esters (method A) described conditions for applicable parts can also be used for this method.

R-CH-CO-NH-CH-CH

's:

+ Y-CH-XCOR ⁴

CH

COOH CO-N -: - CH - COOA

XIX

R-CH-CO-NH-CH-CH

CO-N

COOCH-X-C-O-R '

4 '

CH -

COOA

R-CH-CO-NH-CH-CH

H-CH - CI CO - N-

COOCH-X-C-O-R

I D

CH - COOH

According to this method, a compound of the formula XIX, wherein R has the meaning given above and A is protecting group means with a compound of the formula.

RfI
Y-CH-XCOR ⁴ '

3 4 4 'wherein Y, R, R, R and X are those given above Have meanings to a compound of the formula XX

309841/1185

implemented; this connection then becomes a connection of the Formula I D implemented by the group A by a. Hydrogen

4 · atom is replaced and by replacing the protective group of R in a manner known per se.

Groups which have been used as carboxyl-protecting groups in pehicillin syntheses can be used as A. In particular, A can be benzyl, p-nitrobenzyl or diphenylmethyl. These groups can be split off by catalytic hydrogenation, or A can be an alkyl or aryl group which can be split off by weak alkaline hydrolysis, or A can be a β- trichloroethane group which can be split off by treatment with zinc in acetic acid, or A can be a 3-iodoethyl, a 2-p-tolylsulfonylethyl or a mono- or dihalobenzyl group, which can be split off by treatment with basic agents such as sodium thiophenolate.

I. A natural or biosynthetic penicillin of the formula XXI

R ° -CONH-CH - Cif ^ CC "

' (XXI)

CO - N - CH - COOA

where R -CO is the acyl group in the side chain of the natural or biosynthetic penicillin and A has the meaning given above, is in an inert Solvent and preferably in the presence of a tertiary amine with a phosphorus halide to form an iminohalide compound reacted, which is then reacted with a lower alcohol to form an imino ether derivative; the imino ether is then with a compound of the formula XVI

R-CH-CO-Z
309841/1185 \ f

f ,

COOCH-X-C-O-R ^ '

3 4 4 '
worm R, R, R, R, X and Z have the meanings given above, reacted, and the reaction product obtained is treated with water or an alcohol, a compound of the formula XXII

• _, CJ ρττ

.R-CH-CO-NH-CH - CH ■ * ^ "*

I I 13

CO - N ^ -CH - COOA (XXII)

- COO-CH-XCOR ⁴ '-.

which is then converted into a compound of the formula I D as described above under H. At this Method is the imino ether compound obtained as an intermediate acylated directly without isolation of any intermediates.

The group R CO- in the compound of Formula XXI is a organic acyl group found in known natural or biosynthetic penicillins is included. Accordingly, the group R can optionally with a heterocyclic Group substituted alkyl, aralkyl or methyl group and derivatives thereof. Examples of suitable groups R ° are heptyl, phenoxylmethyl, 2-thienylmethyl, 2-furylmethyl and benzyl. Examples of suitable phosphorus halides are phosphorus pentachloride, phosphorus pentabroinide, phosphorus oxychloride, Phosphorus trichloride, etc. Phosphorus pentachloride is preferred. Examples of suitable alcohols with which the Iminohalide can be treated include lower alkyl alcohols such as methanol, ethanol and n-propanol

309841/1185

J.

R-C = C = O

+ H ₂ N-CH

CH

COO-CH-XCOR ⁴ '

co -

2Ϊ - COOA

XXII

.XXIII

R-CH-CO-NH-CH-Cif ^ "CC ^J

CO-N

COO-CH-X-C-O-R ^

I ₃ - Il

R ^ 0 .XX

• CH - COOA

-R-CH-CO-NH-CH-CH

CO - N-

COO-CH-X-C-R

I D

.CH, CH,

CH - COOH

Instead of the activated carboxylic acid derivative XVI according to Method G can use a ketene derivative of the formula XII in the acylation S reaction used as it is in the belgian "Patent No. 726,421.

Production of esters of penicillins (additional method)

R-CH-CO-NH-CH-CH

■ I I I

COOH CO - N-

.CH, CH,

CH - COOH

+ Y-CH-X-C-O-R

XXIV

R-CH-CO-NH-CH - CiT

I I

CO - N-COOCH-XCOR ⁴ '

I ₃ Il

R ^ 0

CH,

CH

CH - COOH

309841/118

XVIII

R-CH-CO-NH-CH - CH COOH CO-N-

XXV

CH

COO-CH-X-C-Q-R '

4 '

^ S CH ₃

R-CH-CO-NH-CH-CH C-C

I 1 1 ^c % 4-

CO-N- ^: CH-COO-CH-XCOR ^

COO-CH-XCOR ⁴ '■ A3 I

I ₃ Ii ■ - • ^{R ö}

R ^ O. · XXVI - ■

Treatment of carboxypenicillin of the formula XXIV, in which R is as defined above, with a compound

Y-CH-XCOR ⁴ '

h J

3 4 «
where R, R, X and Y have the meanings given above, results in a mixture of two monoesters XVIII and XXV

4 '4 and the Diester XXVI. In the cases where R = R, ask all these esters according to the invention compounds of structure I and they can be used in the form of their mixture.

4 «■ ■ _: ■

If R contains protected groups, the protecting groups are removed in a manner known per se in at least one additional stage.

If desired, however, the pure compounds XVIII, XXV and XXVI can be prepared from this by methods known per se Can be separated mixture, for example by extraction, fractional precipitation or crystallization. The preferred one The way to produce the diester XXVl '... that carboxypenicillin XXIV with at least two equivalents

3098 4 1/118 5

3 Q
Y-CH-XCOR

to treat.

In the reaction between the carboxypenicillin and the compound of the formula

R ^{3 n}

CH-XCOR ⁴ '

the first-mentioned — connection in the form of its salt with

inorganic or tertiary organic bases, e.g. as sodium, potassium, calcium or triethylamine salt, used, and the reaction is carried out in organic solvents such as dimethylformamide, dimethyl sulfoxide, acetone, tetrahydrofuran, Hexamethylphosphoramide or in mixtures of organic solvents with water, e.g. aqueous acetone or dioxane.

As described above, the starting material can be used for some routes for the preparation of the compounds according to the invention be in the form of a salt, for example in the form of a sodium, potassium, calcium or trialkylammonium salt,

In addition, tetraalkylammonium salts and other analogues can be used Salts, such as salts in which the cation has the

1 2 "3 4 Φ 1
Formula AAAAN, where A is a straight or branched alkyl group having 3-6 carbon atoms, a substituted or unsubstituted aryl group or a substituted one

2 3 4 or unsubstituted aralkyl group and A, A and A, the are the same or different, a straight or branched one

Denote an alkyl group with 1-6 carbon atoms, where A,

3 4

A and A are alkyl groups with 3-6 carbon atoms, v / if A is an alkyl group, can be used ..

309841/1185

Characteristic examples of suitable combinations of

1 2 "·? 4 ~ 1 2 ^ 4 ffl

A, A , A and A in the quaternary ammonium ion AAAAN are given in the table below.

Table I - Examples of suitable combinations of radicals A through A in the AAAAN ion

n-propyl i-propyl n-butyl i-butyl n-pentyl n-hexyl phenyl

Phenyl

p-tolyl p-chlorophenyl

n-propyl

i-propyl

n-butyl

i-butyl

n-pentyl

n-hexyl

methyl

Ethyl

EthyI

Ethyl

n-propyl

i-propyl

n-butyl

i-butyl

n-pentyl.

n-hexyl

methyl

Ethyl

Ethyl

Ethyl

n-propyl i-propyl n-butyl i-butyl n-pentyl n-hexyl methyl ethyl ethyl Ethyl

14 If the radicals A -A are all different from each other, the resulting ion contains an asymmetric center and can exist in two enantiomeric forms. Epimeric forms

12 3

can occur if A, A, A and / or A is an or contain several asymmetric carbon atoms.

Examples of quaternary ammonium ions containing an asymmetric center are given in Table II below.

309841/118

Table II - Examples of quaternary ammonium ions

■ ι ρ ο Α ffi

AAAAN having an asymmetrical center contain

A '

Benzyl

Benzyl

Benzyl

n-propyl

n-propyl

n-propyl

n-propyl

n-propyl

n-propyl .n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl n-propyl

i-propyl

i-propyl

n-butyl

n-butyl

n-propyl

n-propyl

n-propyl

n-butyl

n-butyl sec-butyl sec-butyl sec-butyl

sec-butyl sec-p en ty I sec-hexyl sec-hexyl

The use of a quaternary salt form described above the starting material for the preparation of the compound according to the invention is not yet in the relevant Literature described. In this method, the preferred cation is the tetraalkylammonium ion, especially the tetrabutylammonium ion. The preferred solvents are chloroform, methylene chloride and acetone.

The quaternary ammonium salt form of the starting material described above can be obtained by reacting the starting material in question with a quaternary ammonium salt of the formula A Α ² Α ³ Α ⁴ Ν ^Φ Β ^Θ , wherein A, A, A and A are the above

have given meanings and B is a suitable anion,

θ θ θ

such as HSO, Cl or CH ₃ COO, means,

to form a quaternary salt of the starting material getting produced.

309841/1185

The salts of the above formula that contain B as an anion, can be done in a known manner / for example analogously to the method described in Belgian patent specification No. 751 791 getting produced. According to a preferred embodiment

Cl Ci

The lead form is the anion B, the ion HSO. .-

Preferred embodiments are given below on the basis of examples ungs forms of the invention explained in more detail.

Example 1 - Preparation of 6- (o ^ -Carboxyphenylacetamidö) -

-. "-Penicillanic acid-oCr.Xäthoxycarbonyloxymethyl) -----

monoester sodium salt

a) According to method A

1) By reacting 38.7 g (0.30 mol) of chloromethyl chloroformate with stirring with 13.8 g (0.30 mol) of ethanol in 500 ml of dry ether in the presence of 23.7 g (0.30 mol) of pyridine Chloromethylethyl carbonate produced. Stirring was continued at room temperature for 3 hours. After filtration and evaporation, the residue was distilled to give a colorless liquid (33.0 g, 79%; b.p. ₁₄ = 48-50 ⁰ C.)

2) To an ice-cold suspension of 43.5 g (0.25 mol) of potassium phenyl acetate in 80 ml of dry dimethyl sulfoxide, 27.7 g (0.20 mol) of chloromethyl ethyl carbonate were added dropwise with stirring. Stirring was continued at room temperature for 18 hours. The mixture was ice-cooled in 500 ml. 0.5 η sodium bicarbonate solution was poured and, after stirring for 20 minutes, the mixture was extracted three times with 150 ml of ethyl acetate each time. The combined organic phases were washed with cold water, dried over anhydrous magnesium sulfate and evaporated. The crude oil (44 / ° g, 94%) was used in the next stage.

309841/1185

3) A 1.5 μm solution of n-butyllithium in hexane (40 ml, 60 mmol) was added (N ₃ atmosphere, -78 ° C). After 15 minutes, a solution of the ethoxycarbonyloxymethylphenyl acetate obtained above (13.0 g; 54.5 mmol) in 40 ml of dry tetrahydrofuran was added dropwise over a period of one hour, and then an excess of powdered dry ice was added and stirring was continued Continued for 15 minutes. The solution was added dropwise to ice-cooled ~ 2 η hydrochloric acid (-ΙΟΰ-κιΙ) - and after stirring for 15 hours, this mixture was extracted three times with 75 ml of chloroform each time. The combined organic phases were washed with cold water, 100 ml of water were added, and the pH was adjusted to 7.5 with 1 η sodium bicarbonate solution. The organic phase was washed with water and, after washing with chloroform, the combined aqueous phases were added to diethyl ether and the pH was adjusted to 1.0 with 2η hydrochloric acid. The aqueous phase was washed with ether and the combined organic phases were washed with water and dried. Evaporation gave a crystalline residue (9.7 g; 63%) which was identified as Phenylmalonsäureäthoxycarbonyloxymethylmonoester.

The infrared spectrum (potassium bromide pellet) had absorption maxima at the following wave numbers (cm): At 3700-2150 (carboxyl-OH): 1755 (ester and carbonate C = 0); 1690 (carboxyl-C ~ 0). Nuclear Magnetic Resonance Spectrum (NMR) in deuterochloroform showed absorptions (ppm ((T) of tetramethylsilane) at 9.50 (s, COOH); 7.33 (s, CgH ₅ ); 5.79 (s, OCH _n O ); 4.70 (s, C, -H ₁ -CHCO); 4.19 (q, OCH ₀ CH ₀ ); 1.23 (t, OCH ₀ CH-.).

09841/1185

4) The phenylmalonic _{acid ethoxycarbonyloxymethyl monoester (1.13 g, s} 4.0 mmol) was stirred with thionyl chloride (1.67 g, 14 mmol) for one hour at 65.degree. C. and then the reaction mixture was stirred four times with dry benzene (25 ml) Evaporated to dryness.

The crude acid chloride (1.20 g; 4.0 mmol) was dissolved in 5 ml of dry methylene chloride and, with stirring, dropwise to an ice-cooled solution of 2.22 g (4.0 mmol) of benzhydryl 6-aminopenicillanate-p-toluenesulfonate in 35 ml given dry methylene chloride. Stirring was continued at 0 ^° C. for 90 minutes, then 40 ml of cold water were added and the pH was adjusted to 2.0 with 2η hydrochloric acid. The organic phase was separated off and washed successively with saturated sodium bicarbonate solution and sodium chloride solution. After drying and evaporation, the residue (2.4 g) was chromatographed on a silica gel column (40 g) prepared in dry benzene. The residue was dissolved in the smallest possible amount of benzene, applied and eluted by the gradient elution method, using isopropyl ether-acetone (8: 2) as the second solvent. was turned. The collected fractions were analyzed by thin layer chromatography (TLC) on silica gel plates using the same mixed solvent. In this way, a white foam (1.30 g; 50%) was isolated from one of the middle fractions of the eluate. It showed only one spot on thin layer chromatography.

IR (Kbr): 1780-1740 (β-lactam-, ester- and carbonate-C = 0); 1680 (amide-C = O). NMR (CDCl ₃ ): 7.38 (s, 3 CgH ₅ ); 6.94 (s, CH (C ₆ H _{5) 2);} 5.79 (s, OCH ₂ O; 5.80-5.40 (m, 5-H and 6-H); 4.66 (d, CcH ₁ -CHCO); 4.51 (d, 3-H ); 4.20 (q, OCH ₀ CH ₀ ); 1.60-1.10 (m, OCH ₂ CH ₃ , and according to CH ₃ ).

Analysis calculated for C ₃₄ H ₃₄ O ₉ N ₂ S (646.73): C 63.14; H 5.30; O 22.27; N 4.33; S 4.96. Found: C 63.28, H 4.32-, 0 22.17; N 4.18; S 4.86.

309841/1185

5) The 6- (oC-Carboxyphenylacetamido) -penicillanic acid-oC- (ethoxycarbonyloxymethyl) obtained above -3- (benzhydryl) -diester (1.15 g, 1.8 mol) was in a 1: 1 mixture of ethyl acetate and ethanol (10 ml) dissolved and converted to a pre-hydrogenated palladium-activated carbon catalyst (1/0 g; Pd content 10%) in a mixture of 5 ml of ethanol and 5 ml of water containing 0.15 g (1.8 mmoles) of sodium bicarbonate. the Hydrogenation was carried out at normal pressure and room temperature for 2 hours, then the catalyst was filtered off, Ethanol and ethyl acetate were distilled off under reduced pressure and the mixture obtained was treated with ___ Washed ethyl acetate. 10 ml of ethyl acetate were added and the pH was adjusted to 2 η hydrochloric acid set to 2.0. The organic phase was dried and a 2 η solution of sodium 2-ethylhexanoate (1.0 ml; 2 mmol) was added. The solution was evaporated to the smallest possible volume, and the sodium salt was' mit precipitated dry ether. The filtered product (0.50 g, 55%) showed in thin layer chromatography in one Butanone-pyridine-water-acetic acid system (70: 15: 15: 2) only a spot and was with that prepared according to method E. Identical product, but purer than this one.

IR (Kbr): 1780-1740 {^ -lactam-, ester- and carbonate-C = 0); 1675 (amide-C = O); 1610 (carboxyl-C = Q). NMR (D ₀ O): 7.40 (s, C ₆ H ₅ ); 5.80-5.60 (m, 5-H, 6-H and OCH ₂ O); 4.30 (d, 3-H); 4.10 (q, OCH ₂ CH ₃ ); 1.51 (d, gem, CH ₃ ); 1.12 (t, OCH ₂ CH ₃ ). Analysis calculated for C ₂₁ H ₃₃ O ₉ N ₃ SNa (502.49): N 5.58; S 6.38? Na 4.58. Found: N 5.45; S 6.22; Na 4.68.

The degree of hydrolysis of all 6- (c <carboxyphenylacetamido) -penicillanic acid derivatives described here was in Sörensen's buffer solution (B), in 25% human serum (H) and in 5% rat serum (R) in the presence of 10%

309841/1185

- 42 - ■. '

Dimethyl sulfoxide examined, the pH of each mixture was adjusted to 6.8. The mixtures were incubated at 37 ° C. , samples being taken at various time intervals after 3 (B 3 and H 3) or 2 (R 2) hours. Aliquots were applied to paper strips, and the components of the reaction mixture were separated by chromatography using butanol-ethanol-water (.4: 1: 1) as the solvent system. The concentration of the released 6- (o <-Carboxypheny! Acetamido) -penicillinate was determined by microbiological. Detection (Bacillus subtilis) against simultaneously determined — standards quanti-ta-fei-v —- determination rate ^ The degree of hydrolysis of the substance described in this example was: B3 = 24.2%, H3 = 37.5%? R2 = 95%.

b) According to method G

The Phenylmalonsäureesteräthoxycarbonyloxymethylmonoesterchlorid (3.0 g; 10 mmol) in 5 ml of dry ether was mixed with thorough stirring to form an ice-cold solution of sodium 6-aminopenicillate prepared by suspending 3.24 g (15 mmol) of 6-aminopenicillanic acid in 50% acetone (50 ml) and adjusting the pH to 7.0 with 2N sodium hydroxide. During the addition of the acid chloride, the pH maintained at 7.0 by adding alkali. That Stirring was continued for one hour at 0 ° C, then the organic solvents were reduced at Distilled off pressure, and the remaining aqueous phase was washed with ether. The pH was with 2 η hydrochloric acid adjusted to 4.5, the precipitate was filtered off and the filtrate was in the presence of 50 ml Ether acidified to a pH of 2.2. The organic Phase was washed with water and then by adding 50 ml of water and adjusting the pH with 2 η sodium hydroxide solution extracted to 7.0. The ethereal

309841/1185

free aqueous phase was freeze-dried to give a colorless powder (3.1 g; 62%) which on thin layer chromatography (Butanone-pyridine-water-acetic acid) resulted in a major stain in addition to a smaller amount of 6- (° C ~ carboxyphenylacetamido) disodium penicillinate. This substance was according to spectral analysis, elemental analysis and hydrolysis data identical to the substance prepared according to method A.

Example 2 - Preparation of 6- (© (-Carboxy-S-thienylacetamido) penicillanic acid-oC- (ethoxycarbonyloxymethyl) monoester sodium salt "-

1) Chlormethyläthylcarbonat (6.9 g; 50 mmol) was added dropwise to an ice-cooled suspension of potassium ~ 3-thienylacetat (10.8 g- _T 60 mmol) in 20 ml of dry dimethyl sulfoxide was added and the reaction mixture was for 20 hours at room temperature stirred and then worked up in a manner similar to that described in Example Ia. The remaining oil (11.1 g; 91%) was uniform on the basis of thin-layer chromatography in isopropyl ether-acetone (8: 2).

2) A solution of the ethoxycarboxyloxymethyl (3-thienyl) acetate obtained above (7.1 g; 29 mmol) in 20 ml of dry tetrahydrofuran was added dropwise (-78 C; N “atmosphere) within one hour to a solution of lithium -N-iso- • propylcyclohexylamide given, prepared as in Example Ia by reacting N-isopropylcyclohexylamine (4.2 g- _f 30 mmol) with n-butyllithium (30 mmol). Powdered dry ice was added and after 10 minutes the reaction mixture was worked up as in Example Ia and gave a product (6.1 gj 73%) which was identified as 3-thienylmalonic acid ethoxycarbonyloxymethyl monoester.

309841/1185

IR (KBr): 3700-2100 (carbonyl-OH); 1760 (Ester and Carbonated); 1690 (carboxyl-C = 0). NMR (CDCl ₃ ): 9.51 (s, COOH); 7.35-7.05 (m, C ₄ H ₃ S); 5.80 (s, OCH ₂ O); 4.83 (s, C ₄ H SCHCO); 4.19 (q, OCH ₀ CH-); 1.23 (t, OCH ₀ CH ₀ ).

3) S-thienylmalonic acid ethoxycarbonyloxymethyl monoester chloride was prepared as in Example Ia from the acid obtained above (1/73 g; 6.0 mmole) and thionyl chloride (1.67 g; 14 mmole). After the usual work-up (codistillation with dry benzene), the crude oil was 41/84 g; 6 _r 0 mmol) —- dissolved in 5 ml of ether and added dropwise to an ice-cold 50% strength acetone solution of sodium 6-aminopenicillinate, which is obtained from 6-aminopenicillanic acid (1.95 g; 9 mmol) according to the method given in Example Ib Description had been made. Work-up and freeze-drying as in Example Ib gave a powder (1.8 g; 59%) which, in thin-layer chromatography (butanone-pyridine-water-acetic acid), showed a major stain in addition to a smaller amount of 6- («.-Carboxy-3 thienyl acetamido) disodium penicillinate. IR (KBr): 1780-1740 (β-lactam, ester and carbonate C = 0); 1680-1670 (amide-C = 0); 1610 (Carboxy1-C = O). NMR (D ₂ O): 7.35-7.05 (m, C ₄ H ₃ S); 5.80-5.60 (m, 5-H, 6-H and OCH ₂ O); 4.30 (d, .3-H)? 4.11 (q, OCH ₂ CH ₃ ); 1.50 (d, according to CH ₃ ); 1.12 (t, OCH ₂ CH ₃ ). Analysis calculated for C ₁₉ H ₃₁ O ₉ N ₂ S ₂ Na (508.52): N 5.51; S 12.61; Na 4.52. Found: N, 5.38; S 12.52; Na 4.62.

The degree of hydrolysis of this compound was: B3 = 11.5%; H3 = 32.8%; R2 = 104%.

309 8 U T / 1185

Example 3 - Preparation of 6- (<* - Carboxyphenylacetamido) -penicillanic acid-οζ- (phenoxycarbonyloxymethyl) monoester sodium salt

1) Chloromethyl chloroformate (38.7 g; 0.30 mol) 'in dry Ether (150 ml) was added dropwise to a stirred and ice-cold one Solution of phenol (28.2 g; 9.30 mol) and pyridine (23.7 g? 0.30 mol) in 400 ml of dry ether. That Stirring was continued for 16 hours, then the pyridine hydrochloride was filtered off ^ the filtrate was evaporated, and_ the residue (45.3 g) was distilled and gave chloromethylphenyl carbonate as a colorless liquid (40.7 g? 73%; bp = 65-68 ° C).

2) Phenylacetic acid phenoxycarbonyloxymethyl ester was similar In the same way as in Example 1 a) from chloromethylphenyl carbonate and potassium phenyl acetate, and the crude ester was obtained at -78 ° C under a nitrogen atmosphere with lithium-K-isopropylcyclohexylamide implemented, and then as described in Example 1 a), treated with dry ice. The usual Working up gave phenylmalonic acid phenoxycarbonyloxymethyl monoester, which was converted into its acid chloride by heating with thionyl chloride has been converted; Excess reagent was removed by redistillation with dry benzene.

3) A solution of phenylmalonic acid phenoxycarbonyloxymethyl monoester chloride (1.74 g? 5.0 mmol) in 5 ml of dry methylene chloride was added to an ice-cooled solution of 1.21 g (12.5 mmoles) of triethylamine and 2.77 g (5.0 mmoles) of benzhydryl 6-aminopenicillanate p-toluenesulfonate given in 45 ml of dry methylene chloride. After stirring for 90 minutes at 0 C, the reaction mixture was made up as in Example 1 a)

309841/1185

operates and gave a yellowish foam (3.34 g) which was chromatographed on a silica gel column (50 g) prepared in dry benzene. Elution according to the gradient elution method using isopropyl ether-acetone (8: 2) as the second solvent gave a main fraction, the 6 - (* <.- carboxyphenylacetamido) -penicillanic acidöC- (phenoxycarbonyloxymethyl-3-benarydryldiester (1.84 g; 53% ) -, isolated as white foam; according to thin-layer chromatography, this was pure.

IR (Kbr): 1780-1740 (/ 3-lactam, ester and carbonate ~ C = 0); 1675 (amide-C = O). NMR (CDCl3): 7.45-7.10 (m, 4 CH); 6.95 (s, (C _c H _r ) “CH); 5.80 (s, OCH..O); 5.80-5.40 (m, 5-H and 6-H);

OJ Z £ ■

4.67 (d, C, H _C CHCO) •; 4.51 (d, 3-H); 1.40 (s, according to CH_).

Analysis calculated for C ₀₀ H ₀ .O _n NS (694.78): C, 65.69; H 4.93;

jo. J4 y ζ

0 20.73; N 4.03; S 4.62.

Found: C, 65.75; H 4.96; 0 20.62; N 4.00; S-4.58.

4) The diester (1.60 g; 2.30 mmol) was as in Example 1 a) hydrogenated in the presence of palladium-activated carbon, and the sodium salt (0.82 g; 65%) was in the usual way with sodium 2-ethylhexanoate failed. In thin-layer chromatography, the substance showed only one spot.

IR (Kbr): 1780-1740 ( β- lactam-, ester- and amide-C = O); 1680 (Amide-C = O) 1610 (Carboxy1-C = O). NMR (D ₃ O): 7.45-7.10 (m, 2 C ₅ H ₅ );

5.80-5.60 (m, 5-H, 6-H and OCH ₂ O); 4.30 (s, 3-H); 1.50 (d, according to CH ₃ ) -.

Analysis calculated for C ₃ H ₃₃ O ₉ N ₃ SNa (550.52): N 5.9; S 5.83; Na 4.18.

Found: N, 4.96; S 5.62; Na 4.48.

30 9841/1185

Degree of hydrolysis: B3 = 29.2%; H3 = 42.5%; R2 = 117%.

Example 4 - Preparation of 6- (oC-carboxyphenylacetamido) -

penicillanic acid o (- (acetoxymethyl) -3- (1'-ethoxycarbonyloxyethyl) diester

1) Chloromethyl acetate (2.72 g; 25 mmol) was added with stirring to an ice-cold suspension of 5.23 g (30 mmol) in 10 ml of dry dimethyl sulfoxide and the mixture was Stirred for 16 hours. Working up as in Example 1 a) gave 4.77 g (92%) of acetoxymethylphenyl acetate, which as in the Examples described above, with lithium N-isopropylcyclohexylamide and carbon dioxide in phenylmalonic acid acetoxymethyl monoester (1.97 g; 34%) was converted. Treatment of this acid (1.51 g; 6.0 mmoles) with 1.67 g (14 mmoles) of thionyl chloride nitrate work-you — the usual way — resulted in — acid chloride in the form of a crude oil (1.73 g; 6.0 mmol) which is directly was used in the acylation stage.

2) 6.9 g (33 mmol) of phosphorus pentachloride were added within 5 minutes with vigorous stirring to a solution of 13.5 g (30 mmol) of e-phenylacetamido-penicillanic ^{acid S- (I 1} -ethoxycarbonyloxyethyl ester and 12.3 ml ( 97 mmol) of N, N-dimethy1-aniline in dry methylene chloride (135 ml), kept under nitrogen at -25 C of dry was added. After l _f 5 hours, 120 ml of dry methanol was added while maintaining the temperature at -25 G to -30 ° C. After a further 2.5 hours, a solution of 12.0 g of sodium chloride in 60 ml of water was added at -10 ° C. The mixture was allowed to warm to room temperature and the organic phase was separated off and evaporated. After repeated treatment of the remaining oil with petroleum ether

3 0 9 8 41/118 5

this dissolved in tetrahydrofuran and with 5.7 g (30 itiMol) Replaced p-toluenesulfonic acid monohydrate. After adding Ethers push themselves crystals of 6-aminopenicillanic acid (l'-ethoxycarbonyloxyethyl) ester p-toluenesulfonate (9.4 g; 62%).

IR (Kbr): 1785-1745 ( β- lactam, ester, and carbonate-C = 0). NMR (in deuterated dimethyl sulfoxide): 9.50-8.10 (s, very broad, NH_ ⁺ )? 7.36 (g, CH_C H.SO,) } 6.83 (q, OCH- (CH ₀ ) O)? 5.50 (d, 5-H); 5.09 (d, 6-H); 4.41 (s, 3-H); 4.20 (g, OCH ₀ CH.); 2.26 (3, CH ₃ C ₆ H ₄ SO _3); 1.45-1.15 (m, according to * CH ₃ , OCH (CH ₃ ) O and OCH ₂ CH ₃ ).

Analysis calculated for ^c ₂ o ^H 28 ° 9 ^N 2 ^S 2 < ^{504 '59} ) ^{: N 5} ' ⁵⁵ ? ^s 12.71. Found: N, 5.36; S 12.52.

3) 3.03 g ("6.0 mmol) of the substance obtained above in the presence of 1.52 g (15 mmol) of triethylamine as described in Example 1 a), with 1.73 g (6.0 mmol) of phenylmalon. acid acetoxymethyl monoester chloride acylated. After chromatography on 60 g of silica gel, using the usual method and the usual solvents were used, the desired product was in the form of a foam (1.56 g; 46%) from the middle fractions of the eluate isolated.

IR (CHCl ₃ ): 1780-1740 (/ 3-lactam-, ester- and carbonate-C = 0); 1680 (amide-C = 0). NMR (CDCl.): 7.38 (s, C _t H _c ) γ 6.77 (g, OCH (CH) O) 5.76 (s, OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 4.60 (d, C ₁ -C H 1 -CHCO); 4.43 (d, 3-H); 4.20 (q, OCH ₀ CH.); 2.06 (s,

CH ₃ CO); 1.60-1.110 (m, OCH ₂ CH ₃ , OCH (CH ₃ ) O and according to CH ₃ ).

Analysis calculated for C ₂₅ H ₃₀ O ₁₁ N ₃ S (566.59): C, 53.00;

H 5.34; O 31.06; N 4.94; S 5.66.

3.09841 / 1 185

Found: C, 53.4Oj, H, 5.62; O 31.00; N 4.78; S 5.58. Degree of hydrolysis: B3 = 3.2%; H3 = 11.15%; R2 = 43.5%.

Example 5 - Preparation of 6- (oC-Carboxyphenylacetamido) penicillanic acid-τΧ, - (ethoxycarbonyloxymethyl) -3 (1 * -acetoxyethyl) -diester

3.78 g (9.0 mmol) of 6- (phenylacetamido) penicillanic acid 3- (I ¹ -acetoxyethyl) ester were dissolved in methylene chloride solution at ~ 25 ° C in the presence of 3.7 ml (29.1 mmol) of N. , N-dimethylaniline treated with 2.07 g (9.9 mmol) of phosphorus pentachloride, then 36 ml of methanol and water were added as described in Example 4. The crude, oily 6-aminopenicillanic acid 3- (I ¹ -acetoxyethyl) ester was dissolved in 80 ml of methylene chloride and treated with 2 in the presence of 1.36 g (13.5 mmol) of triethylamine in the same manner as in Example 1a , 70 g (9.0 mmol) of phenylmalonic acid ethoxycarbonyloxymethyl monoester chloride acylated. Work-up and chromatography on 100 g of silica gel was carried out in the usual manner and the desired product (1.78 g; 35%) was isolated from one of the middle fractions of the eluate.

IR (CHCl ₃ ): 1780-1740 (β-lactam, ester and carbonate C = 0); 1680 (AmId-C = O). NMR (CDCl ₃ ): 7.39 (s, CgH ₅ ); 6.87 (q, OCH (CEU) O) f 5.78 (s, OCH ₀ ); 5.80-5.40 (m, 5-H and 6-H); 4.60 (d, C ₆ H ₅ C H CO); 4.40 (d, 3-H); 4.20 (q, OCH ₂ CH ₃ ); 2.02 (s, (CH ₃ CO)); 1.60-1.10 (m, gem, CH ₃ , OCH ₂ CH ₃ and

OCH (CH-) O). Analysis calculated for C ₀₁ -H _0n O ₁₁ N ₀ S (566.59): 5 2.O JU JLx ζ

C 53.00; H 5.34; O 31.06; N 4.94; S 5.66. Found: C, 53.22; H 5.46; O 30.82; N 4.82; S 5.62. Degree of hydrolysis: B3 = 1.2%; H3 = 8.8%; R2 = 38.2%.

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_ ς η _

Example 6 - Preparation of 6- (o <.- Carboxyphenylacetamido) -

penicillanic acid-3- (1'-ethoxycarbonyloxyethyl) - • monoester sodium salt ■

a) According to_Methgde_A _x _indirect_way

1) To a solution of 3.24 g (8.0 mmol) of 6-aminopenicillanic acid 3- (1'-aethoxycarbonyloxyethyl) ester p-toluenesulfonate in 70 ml of dry methylene chloride, which is 2.01 g (20.0 mmol) Containing triethylamine, 2.31 g (8.0 mmol) of phenylmalonic acid monobenzyl ester chloride were added dropwise with stirring and cooling with ice given in 10 ml of dry methylene chloride. Stirring was continued at 0 C for 90 minutes and then the mixture was worked up as in Example la and on 100 g of silica gel chromatographed. The diester (3.03 g; 65%) was isolated in the form of a foam which, according to thin layer chromatography was pure.

IR (CHCl ₃ ): 1780-1740 (ß ~ lactam, ester and carbonate C = 0):

1680 (AmId-C = O). NMR (CDCl ₀ ): 7.28 (d, 2 C _r H _r ); 6.77 (q, OCH (CH ₀ ) O) } 5.80-5.40 (m, 5-H and 6-H) ·, 5.16 (s, C 1 H ₁ -CH ₀ O); 4.61 (d, C ₆ H ₅ C H CO); 4.42 (d, 3-H); 4.20 (q, OCH ₂ CH ₃ ); 1.60-

1.10 (m, mixed, CH-., OCH ₀ CH ₀ and OCH (CH ₀ ) O).

Analysis calculated for ^C 29 ^H 32 ^N 2 ^S 9 ° ^{(584 '66): c,} 59.58; H 5.52-,

0 24.63; N 4.79; S 5.49. Found: C, 59.66; H 5.60; O 24.34; N, 4.64; S 5.32.

Degree of hydrolysis: B3 = «£ 1%; H3 = ^ 1 %; R2 = 47.5%.

2) 2.92 g (5.0 mmol) of the diester obtained above

dissolved in 10 ml of ethanol and converted to a prehydrogenated palladium-activated carbon catalyst (3.0 g; palladium content 10%) in a mixture of ethanol and sodium bicarbonate (0.42 g; 5.0 mmol). The hydrogenation was carried out at normal pressure and room temperature for 2 hours, then the catalyst was filtered off and the ethanol was

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distilled off at reduced pressure. There were 25 ml of ether added, the pH was adjusted to 2.2 with 2η hydrochloric acid, and the organic phase was separated and washed with water. 25 ml of water were added, the pH was adjusted to 7.0 with 2 η sodium hydroxide solution, and the ether-free aqueous phase was freeze-dried, whereby a white powder (1.60 g; 62%) was obtained according to Thin layer chromatography (butanone-pyridine-water-acetic acid system) was pure.

IR (KBr): 1780-1760 (β-lactam, ester and carbonate ~ C = 0); 1675 (amide-C = O); 1615 (Carboxy1-C = O). NMR (D ₂ O): 7.35 (s, C ₆ H ₅ )? 6.71 (g, OCH (CH ₃ ) O); 5.70-5.60 (m, 5-H and 6-H); 4.42 (s, 3-H); 4.15 (q, OCH ₂ CH ₃ ); 1.50-1.10 (m, gem, CH ₃ , OCH ₀ CH ₀ and OCH (CH-) O).

Analysis calculated for C ₃₃ H 5O ₉ N ₃ SNa (516.51): N 5.42; S 6.21; Na 4.45. Found: N, 5.36; S 6.16; Na 4.74. Degree of hydrolysis: B3 = 3.5%; H3 = 13.5%; R2 = 83.5%.

b) According to_Methode_A _x _direct_way

Crude 6 ~ aminopenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester, according to Example 4 from 6-phenylacetamidopenicillanic acid 3- (l'-ethoxycarbonyloxyethyl) ester (2.70 g; 6.0 mmol) was dissolved in 20 ml of 50% acetone and washed with 0.80 g (4.0 mmol) of phenylmalonic acid monochloride acylated, whereby the same reaction conditions and the same work-up procedure as in Example Ib were used. Freeze-drying of the ether-free aqueous phase gave the compound named in the heading in the form of a powder (0.74 g; 36%). According to spectral analysis, elemental analysis and hydrolysis data, this substance was with that on indirect Identical product prepared by way (6a), but had a lower degree of purity.

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c) According to_Methode_A _x -Ke-th-Weg

A solution of 0.45 g (2.5 mmol) of phenyl (chlorocarbonyl) ketene, prepared from phenylmalonic acid and phosphorus pentachloride (CA. Ί3_, 25451 t, 1970), in 5 ml of dry methylene chloride was added dropwise at -20 C. Stir to a solution of 1.01 g (2.0 mmol) of 6-aminopenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester p-toluenesulfonate in 10 ml of dry methylene chloride containing 0.22 g (2.2 mmol) Contained triethylamine, given. Stirring was continued at 0 C for 90 minutes, then 20 ml of water were added and the pH was adjusted to 2.2 with 2η hydrochloric acid. The methylene chloride solution was then extracted with 15 ml of water, the pH was adjusted to 7.0 with 2 η sodium hydroxide solution. The aqueous phase was freeze-dried and gave the compound given in the heading in the form of a powder (0.66 g / 64%); According to the spectral analysis, elemental analysis and hydrolysis data, the substance was identical to the substance obtained indirectly (6a), but had a lower degree of purity.

d) According to_Methode_C

To an ice-cold solution of 17.0 g (50 mmol) of tetrabutylammonium hydrogen sulfate 50 ml of chloroform were added to 25 ml of water with stirring, and the pH was adjusted to 2 η sodium hydroxide solution adjusted to 7.0. There were 25.3 g (50 mmol) of 6- (o ^ -carboxyphenylacetamido) -penicillansätire-e ^ -benzylmonoester potassium salt added in portions, then the organic phase was separated and, after drying, with anhydrous Magnesium sulfate were 7.6 g (50 mmol) of oC-chlorodi- "ethyl carbonate admitted. The solution was .la · .cj. For 16 hours

leave.

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left to stand at 40 C.

The reaction mixture was evaporated, 150 ml of water were added, and the product was extracted three times with 100 ml of ether each time. The combined organic phases were washed successively with water, saturated sodium bicarbonate solution and water. Drying and evaporation gave an oily residue (17.4 g) which was chromatographed according to the usual method using 250 g of silica gel. The diester (8.9 g; 30.5%) was isolated in the form of a foam and this was identical in all respects to the diester prepared by the usual route (6a). - - '- -

2) Hydrogenation of this substance, as described above in this example, gave the compound given in the heading (5.4 gj 69%) which, according to spectral analysis, elemental analysis and hydrolysis data, was identical to the substance mentioned under 6a.

Example 7 - Preparation of 6- -carboxy-3-thienylacetamido) -penicillanic acid-3- (1'-ethoxycarbonyloxyethyl) -monoester sodium salt

7.1 g (50 mmol) of 3-thienyl acetic acid became a at 40 ° C Stirred for one hour with 12.0 g (100 mmol) of thionyl chloride and then codistilled four times with 50 ml of dry benzene each time. The crude acid chloride (50 mmol) was added dropwise with stirring to an ice-cold solution of 5.4 g (50 mmol) Benzyl alcohol was added to 30 ml of pyridine and the mixture was stirred for 18 hours.

The reaction mixture was poured into 50 ml of ice water, and after acidifying with hydrochloric acid, it was extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and water, dried and evaporated. The residue was distilled and gave pure benzyl (3-thieny1) acetate (6.75 g; 58 % -, bp _n , = 143-144 ° C)

309841/1185

This ester (4.65 g; 2.Q. mmol) was prepared in a manner similar to Described in Example 1a, lithium N-isopropylcyclohexylamide is used and carbon dioxide converted into the 3-thienylmalonic acid monobenzyl ester (4.20 g; 67%).

Its acid chloride (1.92 g; 6.5 mmol) was used using the same method as described in Example 6a to obtain e-aminopenicillanic acid-S- * (I ¹ -ethoxycarbonyloxyethyl) -ester-p- toluene sulfonate (3.28 g; 6.5 mmol) to acylate. Chromatography on 60 g of silica gel gave pure 6- (oc-carboxy-3-thieny / acetamido) -penicillanic acid-Ä-benzyl-3- (1'-ethoxycarbonyloxyethyl) -diester (2.23 g; 58%). IR (CHCl ₃ ): 1780-1740 (^ -lactam-, ester and carbonate-C = 0); 1680-1670 (AmId-C = O). NMR (CDCl ₀ )? 7.45-7.05 (m, CgH ₅ and C ₄ H ₃ S); 6.77 (q, OCH (CH ₃ ) O); - '" 5.80-5.40 (m, 5-H and 6-H); 5.16 (s, C ₆ H ₅ CH ₃ O); 4.77" (d, C ₄ H ₃ SCHCO) ; 4.42 (d, 3-H) ί 4.20 (q, OCH ₂ CH ₃ ); 1.60-1.10 (m, "according to CH ₃ , OCH ₂ CH ₃ and OCH (CH ₃ ) O). Analysis calculated for C ₂₇ H ₃₀ O ₉ N ₂ S ₃ (590.69): C 54 , 90; H 5.12; 0 24.38; N 4.74; S 10.86. Found: C 54.85; H 5.22; 0 24.54; N 4.62; S 10.82. Degree of hydrolysis: B3 = «£ 1%; H3 = < 1%; R2 = 39.8%.

4) The diester (2.09 g, 3.5 mmol ·) was prepared as in Example 6a "" described hydrogenated in the presence of palladium-activated carbon (2.0 g). The freeze-dried product (1.17 g; 64%) showed in thin layer chromatography (butanone-pyridine-water-acetic acid system) just a stain.

IR: (KBr) 1780-1760 φ-lactam-, ester- and carbonate-C = 0); 1675 (AmId-C = O); 1610 (carboxyl-C = 0) NMR (D ₂ O): 7.35-7.05 (m, CHS); 6.71 (q, OCH (CH2) O); 5.70-5.60 (m, 5-H and 6-H) 4.43 (s, 3-H); 4.15 (q, OCH ₂ CH ₃ ); 1.50-1.10 (m, gem, CH ₃ , OCH ₂ CH ₃ and OCK (CH ₃ ) O).

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Analysis calculated for C ₂₀ H ₂₃ O ₉ N ₂ S ₂ Na (522.53): N 5.36? S 12.27; Na 4.40. Found: N, 5.22; S 12.08; Na 4.62. Degree of hydrolysis: B3 = 4.9%; H3 = 15.3%; R2 = 92.6%.

Example 8 - Preparation of 6- (eC-Carboxyphenylacetamido) penicillanic acid-ft- (ethoxycarbonyloxymethyl) -3- (l'-ethoxycarbonyloxyethyl) diester

a) According to_Methode_A_ _t _direkter_AcYlierungswe2

Crude 6-aminopenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester, as in Example 6b from 6-phenylacetamidopenicillanic acid 3- (l'-ethoxycarbonyloxyethyl) ester (4.05 g; 9.0 mmol) was prepared as described in Example la, with Phenylmalonic acid ethoxycarbonyloxymethyl monoester chloride (2.70 g; 9.0 mmol) acylated in methylene chloride solution (70 ml). After working up, the crude oil was attached to 100 g of silica gel chromatographed, the specified in the heading Connection was obtained; this was in the form of a foam (0.75 g; 14%) from one of the middle fractions of the eluate isolated.

IR (CHCl ₃ ): 1780-1740 φ-lactam-, ester- and carbonate-C = 0); 1685-1675 (AmId-C = O); NMR (CDCl ₃ ): 7.40 (s, C ₆ H ₅ ); 6.80 (q, OCH (CH ₃ ) O); 5.81 (s, OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 4.61 (d, C ₆ H ₅ C H CO); 4.41 (d, 3-H); 4.23 (q, OCH ₂ CH ₃ ); 1.60-1.10 (m, gem, CH-, OCH ₀ CH ₀ and OCH (CH ₀ ) 0). Analysis calculated for ^C ₂ ^H 6 32 ° 12 ^N 2 ^{S 596} ^ ^'67) - ^c, 52.34; H 5.41; O 32.18; N 4.70; S 5.38. Found: C, 52.44; H 5.48; O 31.88; N, 4.62; S 5.44. Degree of hydrolysis: B3 = 3.8%; H3 = 12.7%; R2 = 46.5%.

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b) According to_Method A _, _ additional_We2

2/07 g (9.9 mmol) of phosphorus pentachloride were at -25 ° C under dry nitrogen within 5 minutes with vigorous stirring to a solution of 4.05 g (9.0 mmol) of δ-phenylacetamidopenicillanic acid-S- (1 '-äthoxycarbonyloxyäthyl) ester and 3.7 ml of Ν, Ν-dimethylaniline in 40 ml of dry methylene chloride. After 1, "5 hours 36 ml of dry methanol was added while the temperature was maintained at -25 C to ⁰ C -3.0. After a further 2.5 hours, 5.4 ml of Ν, Ν-dimethylaniline were added, and then 3.25 g (10.8 mmol) of phenylmalonic acid ethoxycarbonyloxymethyl monoester chloride in 10 ml of methylene chloride were added dropwise over the course of one hour. The mixture was then stirred for 16 hours at -20 ⁰ C. 27 ml of water were added, the pH was adjusted to 2.0 with 2η hydrochloric acid, and the organic phase was separated off and washed successively with saturated sodium bicarbonate solution and sodium chloride solution. After drying and evaporation, the residue (8.70 g) was chromatographed on 100 g of silica gel. The compound given in the heading was isolated in the form of a foam (2.30 g; 43%) from one of the middle fractions of the eluate. It showed the same spectral, analytical and hydrolysis data as the sample prepared under a.

Example 9 - Preparation of 6- («xL-Carboxy-3-thieny! Acetamido) penicillanic acid -« * - (ethoxycarbonyloxymethyl) -3- (1'-ethoxycarbonyloxyethyl) diester

0.92 g (3.0 mmol) of 3-thienylmalonic acid ethoxycarbonyloxymethyliuonoesterchlorid was with 1.51 g (3.0 mmol) of 6-aminopenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester ptoluenesulfonate in methylene chloride solution in the presence of

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0/76 g (7.5 mmol) of triethylamine in a manner similar to that in Example la produced described. After working up and chromatography on 40 g of silica gel in the Compound given in the heading in the form of a foam (0.99 g? 55%) from one of the middle fractions of the eluate isolated.

IR (CHCl ₃ ): 1780-1740 (β-lactam, ester and carbonate C = 0); 1680 (AmXd-C = O). NMR (CDCl ₃ ) I 7.35-7.05 (m, C ₄ II ₃ S); 6.78

(q, OCH (CH-JO); 5.81 (s, OCH ₀ O); 5.80-5.40 (m, 5-H and 6-H); j ζ

4.78 (C ₇₁ H ^ SCHCO)? 4.41 (d, 3-H)? 4.23 (q, OCH ₀ CH,); ItSO-I-,

* i J - ZJ

(m, according to CIKr OCH ₀ CH-. and OCH (CH ₀ ) O). Analysis calculated for ^C ₂ 4 ^H 3O ° l2 ^N 2 ^S 2 ^{<602 '66)} · ^c, 47.62; H 4.88; 0 31.58; N 4.44; S 10.28. Degree of hydrolysis: B3 = 2.8%; H3 = 13.6%. R2 = 51.5%.

Example 10 - Preparation of_6- (CK-carboxyphenylacetamido) penicillanic acid-oC-phenyl-S- {1 '- ethoxy car bony 1-oxyethyl) -diester

1.26 g (2.5 mmol) of δ-aminopenicillanic acid S- (1'-ethoxycarbonyloxyethyl) ester p-toluenesulfonate were as described above in methylene chloride solution with 0.69 g (2.5 mmol) Phenylmalonic acid monophenyl ester chloride acylated. Work up and chromatography on 30 g of silica gel gave that in the heading t specified compound in the form of a foam (0.87 g; 61%) from one of the middle fractions of the eluate.

IR (CHCl ₃ ): 1780-1740 (β-lactic acid, ester and carbonate-C = 0); 1680 (amide-C = O). NMR (CDCl ₃ ): 7.40-7.10 (m, 2 CgH ₅ ); 6.78 (q, OCH (CHOO); 5.80-5.40 (m, 5-H and 6-H); 4.60 (d, CcH ₁ -CHCO) y 4.42 (d, 3- H); 4.22 (q, OCH ₀ CH-.); 1.60-1.10

D D ——ZO

(m, according to CH ₃ , OCH ₂ CH ₃ and OCH (CH ₃ ) O.

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Analysis calculated for C ₀₀ H _0n O ₀ N ₀ S. (570.64): C, 58.94;

to Ju y ζ

H 5.30; O 25.23; N 4.91; S 5.62. Found: C, 58.72; H 5.16; O 24.92; N 4.84; S 5.55. Degree of hydrolysis: B3. = -.

^ l%; H3 = 4.2%; R2 = 58.5. %. .-. , ■ · ■.

EXAMPLE 1 1 - Preparation of 6- (d-Carboxyphenylacetamido) -penicillansäure-OC (5'-indanyl) -3- (l'-äthoxycarbonyloxyäthyl) .- ^_diester:: .- ■: ■■

2.02 g (4.0 mmoles) of 6-aminopenicillanic acid 3- (1'-ethoxycarbonyloxyethyl) ester p-toluenesulfonate was obtained using the same method as in that. previous example with 1.26 g (4.0 inMol) phenylmalonic acid-5'-indanyl- ■■; acylated monoester chloride. After chromatography on 50 g of silica gel, the compound given in the heading was isolated in the form of a foam (1.51 g; 62%) from one of the middle fractions of the eluate. ....: - ^ \ <

IR (CHCl ₃ ): 1780-1740 φ-lactam, ester and carbonate C 1 O); 1680 (Amid-C = 0). NMR (CDCI-): 7.40-6.90 (m, CgII ₅ and indanyl-H) ; 6.78 (q, OCH (CH ₀ ) O; 5.80-5.40 (5-H and 6-H); 4.61 (d ,. '

CH _C CHCO); 4.41 (d, 3-H); 4.20 (q, OCH ₀ -CH ^) ;: 2.86; (t.,

bj - ζ ο ■ _.

Indanyl-H); 2.30-1.90 (m, indanyl-H); 1.50-1.10; (m, acc.

_{CH 1} , OCH 0 CH ₀ and OCH (CH ₀ ) O);

Analysis calculated for C ₃₁ H ₃₄ O ₉ N ₂ S (610.70): C, 60.97; ·

H 5.61; 0 23.58; N 4.59; S 5.25. Found: C, 60.52; H 5.38; 0 23.72; N, 4.62; S 5.18. Degree of hydrolysis: B3 = ^ T1%;

H3 = 12.3%; R2 = 65.8%. , 'r ...

Example 12 - Preparation of 6- (CK-Carboxyphenylaeetamido) -penicillanäure-i ^ v-3- (ethoxycarbonyloxyrnethyl) -diester · - ·, -

To an ice-cold suspension of 1.51 g (3.0 mmol)

309841/1185 ^

- ZiQ -

6- (oC-Carboxyphenylacetamido) -penicillanic acid-Ä- (ethoxycarbonyloxymethyl) -monoester sodium salt in 6.0 ml of dry dimethylformamide containing 0.01 g of potassium iodide with stirring, 0.49 g (3.5 mmol) of chloromethyl ethyl carbonate dropwise given.

The mixture was stirred at room temperature for 16 hours, then the reaction mixture was saturated in 10 ml Sodium bicarbonate solution was poured, and after stirring for 10 minutes the mixture was washed three times with 10 ml of ether each time extracted. The combined organic phases were with - water washed, dried and evaporated to give an oily residue (1.4 0 g), which in conventional Way was chromatographed on 40 g of silica gel. The compound named in the heading was in the form of a foam (0.26 gj 15%) from one of the middle fractions of the eluate isolated.

IR (CHCl ₃ ): 1780-1740 (β-lactam, ester and carbonate C = 0); 1680 (amide-C = O). NMR (CDCl ₃ ): 7.39 (s, CgH ₅ ); 5.80 (s, OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 4.60 '(d, C ₆ H ₅ CHCO)? 4.42 (d, 3-H); 4.21 (q, OCH ₀ CH-); 1.50-1.10 (m, according to CH _{3 , OCH 9} CH 2) Analysis calculated for ^C 25 ^H 3 O ° 12 ^{N 2 S} ( ^{582 '60} > ^{: c} 51.54; H 5.19; O 32.95; N 4.81; S 5.55. Found: C 51.46; H 5.08; 0 32.72; N 4.72; S 5.36. Degree of hydrolysis: B3 = 13.8% ; H3 = 29.2%; R2 = 88.2%.

Example 13 - Preparation of 6- (oC-Carboxyphenylacetamido) peiiicillanic acid 3- (ethoxycarbonyloxymethyl) monoester sodium salt

1) To an ice-cold suspension of 20.2 g (40 mmol) 6- (oQ-Carboxypheny! Acetamido) -penicillanic acid-o ^ -benzyl monoester potassium salt in 32.5 ml of dry dimethyl sulfoxide, 5.5 g (40 mmol) of chlorine thy läthyl-

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carbonate given.

After stirring for 16 hours at room temperature, the reaction mixture was poured into 150 ml of ice-cold saturated Poured sodium bicarbonate solution. After stirring for 10 minutes, this mixture was washed three times with 75 ml of ethyl acetate each time extracted. The combined organic phases were washed with water, dried and evaporated, whereby 18.5 g of an oil were obtained; the OeI was chromatographed on 250 g of silica gel using the usual solvent system. In this way, the Main fraction of the eluate 9.8 g (43%) 6- (cK-Carboxyphenylacetamido) -penicillanic acid-tK-benzyl-S- (ethoxycarbonyloxymethyl) -diester isolated.

IR (CHCl ₃ ): 1780-1740 (β-lactam-, ester and carbonate-C = 0); 1680 (amide-C = 0). NMR (CDCl ₃ ): 7.30 (d, 2C ₅ H ₅ ) J 5.78 (s, OCH ₀ O); 5.80-5.40 (m, 5-H and 6-H); 5.16 (s, C, _H, -CH _o 0); 4.60 (d, C ₆ H ₅ CBCO); 4.42 (d, 3-H); 4.22 (q, OCH ₂ CH ₃ ); 1.60-1.10 (m, according to CH ₀ and OCH ₀ CJ ₀ ). Analysis calculated for C _{0n OÜ} H O N _{0 n} S (570.64): C, 58.98; H 5.30; 0 25.23; N 4.91; S 5.62. Found: C, 58.76; H 5.14; O 25.42? N 4.82; S 5.46. Degree of hydrolysis: B 3 = <£ 1%; H3 = ■ <£.! %; R2 = 64.5%. ·

2) The diester (9.7 g; 17 ml-lol) was over palladium-activated charcoal (10.0 g; palladium content 10%) hydrogenated using the method described in Example 6a. That Freeze-dried product (6.0 g; 70%) was a white powder that was found in thin-layer chromatography (eutanone-pyridine-water-acetic acid system) showed only a stain.

309841/1 185

IR (KBr): 1780-1740 (# -lactam-, ester- and carbonate-C = 0); 1685-1675 (AmId-C = O); 1615-1605 (carboxyl-C = 0). NMR (D ₂ O): 7.33 (s, CgH ₅ )? 5.70-5.60 (m, OCH ₂ O, 5-H and 6-H); 4.45 (s, 3-H); 4.17 (q, OCII ₀ CH ₀ ); 1.50-1.10 (m, according to CH ₀ and OCH ₂ CH ₃ );

Analysis calculated for C ₀ .. HON-SNa (502.48): N 5.58? S 6.38; Na 4.58. Found: N, 5.31; S 6.38; Na 4.88. Degree of hydrolysis: B3 = 18.2%; H3 = 37.5%; R2 = 109%.

Example 14 - Preparation of 6- (cK-Carboxyphenylacetamido) -

-. penicillanic acid-3- (ethoxycarbonylaminomethyl) - .._ monoester sodium salt

1) According to the description given in Example 13, 1.87 g (3.7 mmol) of 6- (c <~ carboxyphenylacetamido) -penicillanic acid-oc-benzyl monoester potassium salt treated with 0.55 g (4.0 mmol) of 'N- (chloromethyl) -äthy! urethan. After working up the residue was chromatographed on 40 g silica gel, the pure diester (0.57 g; 27%) was isolated from one of the middle fractions of the eluate in the form of a foam.

IR (CHCl ₃ ): 1780-1750 (β-lactam- and ester-C = O), 1720-1680 (amide- and urethane-C = O). NMR (CDCl ₃ ): 7.30 (d, 2 CgH ₅ ); 5.80-5.40 (m, 5-H and 6-H); 5.17 (C 1 H _n CH ₀ O); 4.85 to 4.55 (m, C H _{c r} CHCO and OCH NH); 4.41 (d, 3-H); 4.19 (q, OCH ₀ CH ₀ ); 1.60-1.10 (m, according to CH ₀ and OCH ₀ CH ₀ ).

Analysis calculated for C ₀₀ H ₀₁ O ₀ N ₀ S (569.65): C 59.04; H 5.49;

ZQ Jl ö Δ

0 22.47; N 7.36; S 5.63.

Found: C 58.88; H 5.36; 0 22.36; N 7.42; S 5.58.

2) The diester (0.40 g? 0.70 mmol) was hydrogenated using the method described in Example 6a over palladium-activated carbon and after freeze-drying gave the compound given in the heading (0.19 g; 54%) in the form of a white powder.

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IR (KBr): 1780-1750 (β-lactarn- and ester-C = O)? 1720-1880 (amide and urethane C = O)? 16.10 (Carboxy 1-0 = 0}. NMR- (D ₂ O): 7.35 (s, C ₆ H ₅ ? 5.70-5.60 (m, 5-H and 6-H)? 4, 85-4.65 (m, OCH ₇ NH)? 4.43 (s, 3-H)? 4.15 • (q, OCII ₉ CK-)? 1.50-1.10 (m, according to CH ₃ and OCH ₂ CH). Analysis calculated for ^C 2i ^H 24 ° 8 N ₃ SNa (501.50): N 8.38; S 6.39? Na 4.58. Found: N 8.28; S 6, 18? Na 4.72., Degree of hydrolysis: B3 = 3.6%? H3 = 9.8%? R2 = 73.5%.

Example 15 - Preparation of 6- (K-carboxypheny / acetamido) penicillanic acid 3- (2'-methylaminoethoxycarbonyloxymethyl) ester salt

1) From benzyl chloroformate (34.12 g; 0.20 mol) and 2-methylaminoethanol (37.55 gy 0.50 mol) in dry ether (300 ml), N-benzyloxycarbonylmethylaminoethanol (40.3 g? 96 ■%) ■ produced.

2) Chloromethyl chloroformate (10.2 g? 72 mol) in 50 ml dry ether was added dropwise with stirring to an ice-cold solution of 15.0 g (72 mm mol.): N-benzyloxy-carbonyimethylaminoethanol and 5.7 g (72 mm mol.) ) given dry Pyridiii in 100 ml of dry ether. Stirring was continued for 5 hours 1 _A, and the solution would then filtered. The filtrate was washed with 50 ml of 1N hydrochloric acid, 50 ml of water and 50 ml of 0.5 η sodium bicarbonate solution. The organic phase was dried and evaporated. The residue consisted of a colorless one. OeI (12.8 g?. 59%) - .. NMR (CDCl.) 7.35 (s, '.C ^ Äi-)? 5.73 fs _r Cl CH "O)? 5.10 Cs _r OCH ₀ C 1 H ₁ -) ν 4,33 (t _t .. < 0GH., CH _o N)?, 3, 53 (t, QCBI “CiOT) ^; j; 2.92 (S, NCII ₃ ). : 'ο- ... .- ■

9841 / t

3) To an ice-cold suspension of 25.25 g (50 itiMol) 6- (oC-Carbonylphenylacetamido) -penicillanic acid-öt-benzyl monoester potassium salt in 80 ml of dry dimethylformamide, 15.1 g (50 mmol) of chloromethyl 2-N-benzyloxycarbonylmethylaminoethyl carbonate were added dropwise with stirring given in 20 ml of dry dimethylformamide. After stirring for 16 hours, the reaction mixture became in the usual manner worked up, and the residue (26.8 g) was on a silica gel column (400 g) using an isopropyl ether-acetone (7: 3) -Solvent system chromatographed. Repetition of the chromatography of 14.3 g of isolated Substance in a similar manner gave the desired compound in the form of a white foam (10.7 g; 27.8%), according to Thin layer chromatography was uniform.

IR (KBr): 1785-1765 (β-lactam, ester and carbonate C = 0); 1680 (Amid-C = 0). NMR (CDCl-.): 7.40 (s, C, H _C ; 7.25 (s, C ^ H ₁ -); 5.78 (s, OCH ₂ O); 5.65-5.40 ( m, 5-11 and 6-H)? 5.16-5.10 (2s, COOCH ₂ C ₆ H ₅ ); 4.60 (COCHC ₆ H ₅ ); 4.40 (d, 3-H); 4.25 (t, OCH ₀ CH ₀ N); 3.60 (t, OCH ₀ CH ₀ N); 2.95 (NCH-.); 1.50 (s, according to CH ₃ ). Analysis calculated for CHO ₁₁ N ₃ S (733.81): C, 60.56, H, 5.36, 0-24.00, N, 5.73, S, 4.37. Found: C, 60.72, H, 5.42, 0.23 , 82; N 5.52; S 4.25.

4) The N-benzyloxycarbonyl-o <-benzyl ester derivative prepared as above (1.5 g; 2 mmol) was at room temperature and normal pressure in 150 ml of 50% dioxane over palladium-activated carbon (3.0 g; palladium content 10%) hydrogenated. After 3 hours the catalyst was filtered off and the pH value the filtrate was adjusted to 2.8 with 2 η hydrochloric acid. The solution was evaporated to a small volume (approx. 20 ml), extracted several times with ether, and then the pH was adjusted to 4.8. After several days of refrigeration

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a yellow-white powder is deposited, which is filtered off and washed with a few drops of cold water.

IR (KBr): 2750-2530 (ammonium); 1780-1740 (0-lactam, Ester and carbonate C = 0) .; 1670 (amide-C = O). Degree of hydrolysis: B3 = 23.8%; H3 = 54.6%; R2 = 87.5%.

Example 16 - Preparation of 6- (c <-Carboxyphenylacetamido) penicillanic acid-oC- (ethoxycarbonyloxymethyl) 3- (2'-aminoethoxycarbonyloxymethyl) diester hydrochloride

1) According to the method given in Example 13, 4.09 g (9.2 mmoles) of 6- (o <.- Carboxyphenylacetamido) -penicillanic acid-K- (ethoxycarbonyloxymethyl) -monoester sodium salt were obtained treated with 1.80 g (10.0 mmol) of chloromethyl (2-acidoethyl) carbonate. Chromatography on 100 g of silica gel gave the diester in pure form as a foam (1.41 g; 25%).

IR (CHCl-,): 2150 (azido); 1780-1740 (β- lactam, ester and carbonate-C = 0) 1680 (AmId-C = O). NMR: 7.29 (d, 2 CgH ₅ ); 5.80 (s, OCH-O); 5.80-5.40 (5-II and 6-H); 5.17 (s, CAI ^ CIUO) ; 4.61 (d, CgHt-CHCO); 4.45-4.20 (m, 3-H and OCH ₂ CH ₂ N ^); 3.49 (t, OCH "CH"N_); 1.42 (s, according to CH ₀ ). Analysis calculated for ^C 28 ^H 29 ° 9 ^N 5 ^S (611.65) s C 54.99; H 4.78; 0.23.54; N 11.45; S 5.24. Found: C, 55.16; H 4.94; O 23.42; N 11.36; S 5.17.

2) The azido diester, (920 mg; 1.5 mmol), prepared as described above, was hydrogenated at room temperature and normal pressure in 55 ml of ethyl acetate over palladium-activated charcoal (0.5 g; palladium content 10%). After 7 hours, the catalyst was filtered off, the filtrate was admixed with 10 ml of cold water, and the pH was 2 η

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Hydrochloric acid adjusted to 2.7, and the organic phase was separated off and washed twice with 5 ml of water each time. The combined aqueous phases were washed with isopropyl ether extracted and then the aqueous phase was freeze-dried. The white, microcrystalline residue was Uniformly according to thin-layer chromatogram.

IR (KBr): 3050 (ammonium); 1790-1775 (β-lactam, ester, and carbonate-CO) j 1685 (AmId-C = O); 1510 (ammonium). Degree of hydrolysis: B3 = 28.5 % - _T H3 = 62.5%; R2 = 92.5%.

Example 17 - Preparation of 6-GK-carboxyphenylacetamido) penicillanic acid 3- (1'-cyclopentyloxycarbonyloxyethyl) ester sodium salt

1) A stream of dry chlorine (220 g, 3.14 moles) was added at a temperature of 25 to 35 ° C for 30 hours passed through 450 g (417 mol) of ethyl chloroformate. During the reaction, the mixture was with a 250 lamp (white light) irradiated.

Fractional distillation of the product (the fractions were checked with GLC) gave a fraction which was pure (greater than 95%) © C-chloroethyl chloroformate (114 gj 25.6%) contained.

2) The substance obtained above (50.0 g; 0.35 mol) was in the presence of the method described in Example la of 27.7 g (0.35 mol) of pyridine reacted with 30.1 g (0.35 mol) of C.yclopentanol. After stirring for 19 hours the reaction mixture was filtered and the filtrate was successively with 2 η hydrochloric acid, saturated sodium bicarbonate solution and washed water. After drying

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and evaporation, the crude .OeI (60/3 g-; 89%) became direct used in the next stage. . ■ .- ·:. "■ -. ■■

3) 2.89 g (15.0 mmol) of C ^ -Chloräthylcyclopentylarbonat was added dropwise with stirring to an ice-cold suspension of 5.07 g (10.0 mmol) 6- (cK-Carbqxyphenylacetamido) -penici 11 ans acid oc-benzy Imönoe s terkaliums al ζ given in 10 ml of dry dimethyl sulfoxide. After stirring for 18 hours, the mixture was worked up as in Example 13 and chromatographed on 100 g of silica gel. From one of the middle fractions of the eluate were 2/06 g (33%) of pure 6 - ( "X-Carboxyphenyläcetamido) -penicillansäure-öt-benzyl-3- (1 ^r -cyclopentyloxycarbonyloxyäthy 1) diesters isolated. "·

IR (CHCl ₃ ) -. 1780-1740 (β-lactam, ester and carbonate-C = 0) 1680 (AmId-C = O) ν NMR (CDCl ₃ ): 7.28 (d, 2 CgH ₅ ); 6.78 (q, OCH (CIIo) O); 5.80-5.40 (m, 5-H and 6-Ή); 5.35-5.05 (m, C 1 H ₁ -CH ₀ O and cyclopentyl); 4.6.0 (d> C _c H, -CHCO-) ■; ■ 4.41 (d, 3-H)? 2.00-1.70 (m, cyclopentyl) _τ 1.60-1.10 (m, according to CH ₃ and OCH (CH-) O).

Analysis calculated for C ₃₂ H ₃₆ O ₉ N ₂ S (-624.73): C, 61.53; .Η 5.81? 0 23.05; ^: N, 4.48; S 5.13. Found: -C 61.62; H, 5/88; O 22.92; N 4.24; S 5> 08. "'"

4) The diester (1.87 g; 3.0 mmol) was hydrogenated and worked up in the same manner as in Example 6a. The "freeze-dried product" (1.07 % q-, 64%) was pure according to thin-layer chromatography (butanone-pyridine-water-acetic acid system).

IR (KBr) -: 1780-1740 (β-lactam-, ester- and carbonate-C = 0); 1680-1670 (AmXd-C = O); 1610-1600 (Carboxy1-C = O). NMR (D ₂ O): 7.35- (s, C 1 H ₁ -); 6.71 (q, OCH (CH-JO; 5> 70-5 / 60 (m, 5-H and 6-H) .; 5.35-5.05 (m, cyclopentyl); 4.43 (s , 3-II)? 2.00-1.70 (m, cyclopentyl); 1.50-1.10 (m, according to CH ₃ and OCH (CH ₃ ) O).

309 841/1185

Analysis calculated for C ₂₅ H ₂₉ O ₉ N ₃ SNa (556.57): N, 5.03; S 5.76; Na 4.13T Found: N 4.92; S 5.58; Na 4.52. Degree of hydrolysis: B3 = 5.8%; H3 = 15.6%; R2 = 73.5%.

Example 18 - Preparation of 6- (GC-Carboxyphenylacetaraido) penicillanic acid-pC-benzyl-3- (benzyloxycarbonyloxymethyl) -diester

According to the method given in Example 17, 5.07 g (10.0 μmol) were reacted. After chromatography on 100 g of silica gel, the title compound (2.02 gi 32%) was obtained in pure form as a foam.

IR (CDCl ₃ ): 1780-1740 (β-lactam, ester and carbonate C = 0); 1680 (AmId-C = O). NMR (CDC1.J: 7.28 (d, 2 CH, -); 5.78 (s,

OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 5.18 (d, 2 C ₆ H

4.61 (d, 0, -HrCHCO); 4.42 (d, 3-H); 1.42 (s, according to CH-,). ο ο— j

Analysis calculated for C 1-4 H 0 N S (632.70): C, 62.65; H 5.10; 0 22.76; N 4.43; S 5.07; Found: C, 62.75; H 5.24; 0 22.62; N 4.36; S 5.02. Degree of hydrolysis: B 3 = <1%; H3 = <1%; R2 = 36.5%.

Example 19 - Preparation of 6- («K-Carboxyphenylacetamido penicillanic acid-o (-benzyl-3- (2-furfuryloxycarbonyloxymethyl) diester

Using the same method as used in the Examples 17 and 18 described were 5.07 g (10.0 mmol) of 6- (oC-carboxyphenylacetamido) -penicillanic acid oCr-benzyl monoester potassium salt treated with 1.91 g (10.0 mmol) of chloromethyl (2-furfuryl) carbonate. Chromatography gave the pure diester (1.68 g; 27%) as a foam.

09841/1185

IR (CHCl ₃ ): 1780-1740 (β-lactam, ester and carbonated); 1680 (amide-C = 0). NMR (CDCl ₀ ): 7.50-7.30 (m, C _C H _C and C ₄ H ₃ O); 6.55 to 6.35 (m, C ₄ H ₃ O); 5.78 (s, OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 5.18 (s, 0, -H ₁ -CH ₀ O and C ₄ H ₃ OCH ₂ O);

Analysis calculated for CHONS (622.66): C, 59.80; H 4.86; 0 25.70; N 4.50; S 5.15. Found: C, 60.02; H 4.78; 0 25.54; N 4.32; S 5.04.
Degree of hydrolysis: B3 - ^ 1%; H3 = <1%; R2 = 41.5%.

Example 20 - Preparation of 6- (c ^ -Carboxyphenylacetamido) -penicillanic acid-3- (cis-2-methyll, 3-dioxanyl-5-oxycarbonyloxymethyl) -monoester sodium salt

Chloromethyl 5- (cis-2-methyl-1,3-dioxanyl) carbonate (1.68 g; 8.0 mmoles) were treated with 6- (oC-carboxyphenylacetamido) -penicillanic acid-tert-benzyl monoester potassium salt (4.05 g; 8.0 raMol) reacted, as described above. Chromatography gave the pure diester (1.44 g; 28%) as a foam.

IR (CHCl ₃ ): 1780-1740 (p-lactam, ester, and carbonate C = O); 1690-1680 (AmId-C = O). NMR (CDCl.,): 7.29 (d, 2 C 1 H,.); 5.80 (s, OCH ₂ O); 5.80-5.40 (m, 5-H and 6-H); 5.19 (s, C ₆ H ₅ CH ₂ O); 4.69 (q, OCH- ^ (CH ₂ O) ₂ > CHCH ₃ ); 4.65-4.40 (m, 3-Ή, OCH <(CH ₀ O) "> CHCH_ and CcH ₁ -CIlCO); 4.20-3.90 (m, OCH ■ - ^ (CH ₉ O) ₂ > CHCH ₃ ); 1.60-1.10 (m, according to CH ₃ and OCH < (CH ₀ O) _> CHCH_).

Analysis calculated for C ₃₁ H ₃₄ O ₁₁ N ₂ S ^{(642 'C9): C} 57.94; H 5.33; O 27.38; N 4.36; S 4.99. Found: C, 57.82;

H 5.24; 0 27.42; W 4.30; S 4.72. /

309841/1185

The diester (1.22 g; 1.9 mol) was transferred in the usual manner Palladium-activated carbon hydrogenated and yielded after freeze drying the compound given in the heading (0.72 g; 66%) in the form of a white powder.

IR (KBr): 1780-1740 φ-lactam, ester and carbonate-C = 0) 1690-1680 (amide-C = O); 1620-1600 (carboxyl-C = 0). NMR (D ₂ O): 7.35 (s, C ₆ H ₅ ); 5.80-5.60 (m, OCH ₂ O, 5-H and 6-H); 4.70 (q, OCH <(CH ₂ O) ₂ ;> CHCH ₃ ) j 4.65-4.35 (m, 3-H, CgH ₅ CHCO and OCH ^ C (CH ₂ O) ₂ > CHCH ₃ ) ί 4.20-3.90 (m, OCH * C (CII ₂ O) ₂ > CHCH ₃ ); 1.60-1.10 (m, - mixed CH ₃ and OCH «£ (CH ₂ O) ₂ ^ CHCH ₃ ). Analysis calculated for C ₂₄ H ₂₇ O ₁₁ N ₂ SNa (574.54): N 4.88; S 5.58; Na 4.00. Found: N, 4.66; S 5.42; Na 4.18. Degree of hydrolysis: B3 = 7.6%, H3 = 21.5%; R2 = 88.5%.

Example 21 - Preparation of 6- (cv-Carboxyphenylacetamidopenicillanäure-ö <, 3- (1 * -athoxycarbonyloxyethyl) -diester

A suspension of 15.1 g (180 mmol) sodium dibicarbonate and 15.5 g (30 mmol) 6- (oC-Carboxyphenylacetamido) -penicillanic acid-3- (1 · -athoxycarbonyloxyethyl) rmonoester sodium salt in 50% dioxane (30 ml) was added dropwise with stirring in 13.7 g (90 mmol) of ice-cold oC chlorine diethyl carbonate given.

The reaction mixture was stirred for 64 hours, then it was filtered and the filtrate was added with 100 ml Added chloroform. The organic phase was separated and successively with water, saturated sodium bicarbonate solution and washed water. After evaporation, the residue was left under high vacuum for 12 hours (0.01 Torr) kept to remove residual dioxane and o (-chlorodiethyl carbonate to remove. Chromatography on 150 g

309841/1185

Silica gel using the usual solvent " systems resulted in the connection given in the heading (1/50 g; 8.2%) in pure form; the connection went off one of the two main fractions of the eluate in the form of one Foam isolated "The other main fraction contained 6- (phenylacetamido) -penicillanic acid-3- (1 * -äthoxycarbonyloxyäthyl) -ester"

IR (CHCl ₃ ): 1780-1740 (^ -lactam-, ester- and carbonate-C = 0); 1690-1670 (AmM-C = O). NMR (CDCl ₃ ) .: 7.39 (s, C ₆ H ₅ ; 6.78 (q, OCH (CH ₀ JO) f 5.80-5.40 (m, 5-H and 6-H); 4.60 (d, C.B.CHCO) ·, 4.41 (d, 3-H); 4.20 (q, OCH ₂ CH ₃ ); 1.60-1.10 (m, according to CH ₃ , OCH ₂ CH ₃ and OCH (CH ₃ ) O) Analysis calculated for C ₂₇ H ₃₄ O ₁₂ N ₂ S (610.65): C 53.11, H 5.61, O 31.44, N 4 , 59; S 5.25. Found: C 53.25; H 5.72; O 31.28; N 4.46; S 5.15. Degree of hydrolysis: B3 = <£ 1%; H3 = 8.5% ; R2 = 32.5%.

Example 22 - Preparation of 6- (i <- Carboxyphenylacetamido) - penicillanic acid-pC- (1'-ethoxycarbonyloxyethyl) -monoaster sodium salt -

To an ice-cold suspension of 40.5 g (0.15 mol) Phenylhialonic acid monobenzyl ester and 88.2 g (1.0 5 mol) Sodium bicarbonate in 150 ml of 50% dioxane were under Stir dropwise 68.6 g (0.45 mol) of OC-chlorodiethyl carbonate given. Stirring was continued at room temperature for 64 hours.

The precipitate was filtered off and _r 500 ml of chloroform was added to the filtrate. The organic phase was separated and successively saturated with water

309841 / 1IiS

Washed sodium bicarbonate solution and water. After evaporation the residue (98.5 g) was kept under high vacuum (0.01 torr) for 16 hours to remove residual dioxane and O ^ -Chlorodiethylcarbonat to remove. This residue (46.3 g) was chromatographed on a silica gel column (300 g) made in carbon tetrachloride. The substance was applied without dilution and was eluted by the gradient elution method using dry chloroform was used as the second solvent.

The second main fraction was 9.7 g (16.5%) of phenylmalonic acid benzyl (1 * -athoxycarbonyloxyethyl) diester isolated as a colorless oil.

2) The diester (9.5 g; 24.6 mmol) was dissolved in 100 ml of ethyl acetate dissolved and at room temperature and under normal pressure over palladium-activated carbon (4.25 g; palladium content 5%) hydrogenated until an equivalent of hydrogen had been absorbed. The catalyst was filtered off, and that Piltrate was evaporated, whereby 5.8 g (80%) phenylmalonic acid (1'-athoxycarbonyloxyethyl) monoester as a colorless one Syrup were obtained.

IR (film): 3500-3200 (hydroxyl); 1760-1740 (ester and carbonate C ^ O); 1690 (carboxyl-C = 0). NMR (CDCl ₃ ): 10.20 (s, COOH); 7.32 (s, CgH ₅ ); 6.78 (q, OCH (CH ₃ ) O); 4.65 (s, Cc-H ₁ -CITCO); 4.12 (q, OCII ₀ CH-.); 1.60-1.10 (m, OCH ₀ CH., And OCH (CH-JO).

3) 3.15 g (10 mmol) phenylmalonic acid (1'-athoxycarbonyloxyethyl) monoester chlorid, prepared in the manner described above from the corresponding acid (2.96 g; 10 mmol) , were by the method described in Example Ib for the acylation of NatriuiTr - 6 - ciini.noperiicii.l inat

3 09 841/1185

used. The freeze-dried product (3.10 g; 60%) showed in thin layer chromatography (butanone-pyridine - water-acetic acid system) a major stain next to a minor amount of disodium 6- (^ -carboxyphenylacetamido) penicillinate.

IR (KBr): 1780-1740 (β ~ lactam-, ester- and carbonate-C = 0); 1680 (amide-C = O) ι 1610 (carboxyl-C = 0). NMR (D ₂ O): 7.40 (s, C ₅ H ₅ ); 6.70 (q, OCH (CH ₃ ) O); 5.70-5.60 (m, 5-H and 6-H); 4.30 (s, 3-H); 4.12 (q, OCH ₂ CH ₃ )? 1.60-1.10 (in, OCH ₂ CH ₃ ) O and according to CH ₃ ).

Analysis calculated for C ₂₂ H ₃₅ O ₉ N ₂ SNa (516.51): N 5.42; S 6.21; Na 4.45; Found: N 5.28; S 6.12; Na 4.58. Degree of hydrolysis: B3 = 4.8%; H3 = 13.8%; R2 = 85.3%.

b) According to_Methode_H

1). A suspension of 17.0 g (30 mmol) 6- (c <-Carboxy phenyl acetamido) -penicillanic acid-S-benzhydryl monoester sodium salt (produced by acylation of 6-amihopenicillanic acid-3-benzhydryl ester-p-toluenesulfonate with Pheriylmalonsäuremonochlorid) and 15.1 g (180 mmol) sodium bicarbonate in 30 ml of 50% dioxane v / urde in a similar manner as. in Example 21 is described with 13.7 g (90 mmol) of c <-chlorodiethyl carbonate treated. After working up and chromatography on silica gel, the second main fraction was obtained of the eluate 1.74 g (8.8%) 6- (oi-carboxyphenylacetamido) -penicillanic acid-iX- (1 ' -äthoxycarbonyloxyäthyl) -3-benz-

£ * hydryldiester isolated.
to

-C "* IR (CHCIo) ϊ 1780-1740 (^ -lactam-, ester- and carbonate-C = 0);

^ 1680 (AmId-C = O). NMR (CDCl ₃ ): 7.38 (d, 3 C ₆ H ₅ ); 6.95

_ »(S, (C ₁ ^ Hp) ₀ CH); 6.78 (q, OCH (CH ₀ ); 5.80-5.40 (m, 5-H and

_m 6-H); 4.66 (d, C, II _r CHCO); 4.51 (d, 3-H); 4.20 (q, OCH ... CIU);

1.60-1.10 (m, OCH ₂ CH ₃ , OCH (CH ₃ ) O and according to CH3). Analysis calculated for C ^ H _n O _n N ₀ S (660.76): C 63.62; II 5.49; O 21, .79;

o ~> 36 y /

N 4.24; S 4.85. Found: C, 63.78; II 5.62; 0.21.68, N 4.16; S 4.32.

2) The diester (1.65 g; 2.5 mmol) was made according to that in Example la hydrogenated method described, and the product was worked up by the same method. The product (0.92 g; 71%) was, according to its spectral, analysis and hydrolysis data, identical to the substance produced according to method E, However, it has a greater degree of purity.

Example 23 - Preparation of 6- (oC-Carboxyphenylacetamido) ~ penicillanic acid-oi- (5'-indanyloxycarbonyloxymethyl) -monoester sodium salt

Sodium 6-aminopenicillinate in 50% acetone solution was made with 1.17 g (3.0 mmol) of phenylmalonic acid (5'-indanyloxycarbonyloxymethyl) monoester chloride acylated using the same method and work-up procedure as in Example Ib was applied. The freeze-dried product (1.05 g; 59%) showed on thin layer chromatography (Butanone-pyridine-water-acetic acid-systeine) a major stain besides a smaller amount of disodium-6 - (^ - carboxyphenylacetamido) -pen-icillinat.

IR (KBr): 1780-1740 (£ -lactam-, ester- and carbonate-C = 0)? 1690-1680 (amide-C = O); 1610-1600 (carboxyl-C = 0). NMR (D ₂ O): 7.40-6.90 (m, C ₅ H ₅ and indanyl-H); 5.80-5.50 (m, OCH ₂ O, 5-H and 6-H) f 4.30 (s, 3-H)? 2.89 (t, indanyl-H)? 2,3o-1.90 (m, indanyl-H); 1.50 (s, according to CH ~).
Analysis calculated for C ₂₈ H ₂₇ O ₉ N ₃ SNa (590.59): N 4.74 S * 5.43; Na 3.89: Found: N 4.66; S 5.32; Na .4.12. Degree of hydrolysis: B3 = 17.2%; 113 = 35.4%; R2 = 83.6%.

0 9 8 4 1/1 1 85

Example 24 - Pharmaceutical Preparations

The following were used to make tablets
Mixes prepares:

a) Sodium 6 - / pi- (ethoxycarbonyloxymethoxy) carbonylphenylacetamido7 ~ penicillanate 350 mg starch 100 mg magnesium stearate 10 mg

b) Sodium 6 - / pi- (ethoxycarbonyloxymethoxy) carbonyl ~ 3-thienylacetamido / penicillanate 400 mg starch 100 mg magnesium stearate IO mg

c) Aethoxycarbonyloxymethyl-o-ZoC- (ethoxycarbonyl-. oxymethoxy), - carbonylphenylacetamido / -

penicillanate calcium carbonate magnesium stearate

d) 1'-ethoxycarbonyloxymethyl-6- (<* .- carboxyphenylacetamido) -penicillanate sodium salt
Lactose

Magnesium stearate

e) Sodium 6- / κ- (1'-ethoxycarbonyloxyethoxy) -carbonylphenylacetamidoZ-penicillanate
Microcrystalline cellulose '- ^
Magnesium stearate

500 mg 100 mg 10 mg 400 mg 100 mg 10 mg 400 mg 100 mg 10 mg

3098-1 / 1185

f) ethoxycarbonylaminoinethyl-6- (oc-car boxy-

pheny! acetamido) penicillanate sodium sal 350 mg

Calcium carbonate. 100 mg

Lactose 100 mg

Magnesium stearate 10 mg

For filling into capsules, the following mixture was prepared:

g) Sodium δ- ^ oc- (ethoxycarbonyloxymethoxy) carbonylphenylacetamido / penicillanate 350 mg magnesium stearate 5 mg

For suspensions to be administered orally, the following mixture was prepared:

h) Sodium-e- ^ tK- (1 '-äthoxycarbonyloxyäthoxy) -carbonyl-

phenylacetamido / penicillanate 35 g

Sodium benzoate 0.48 g

Sodium chloride 0.75 g

Flavor Corrections 4.7 g

0.3 g

Antifoam ^ / 0.0375 g

Alkali salts of polysaccharide sulfates 4.0 g

Sodium saccharinate 0.4 g

Sorbitol ad 100.0 g

309841/1185

Claims (3)

PATENTANS. PRUE-C-HE 1. Compounds of the formula R-CH-CO-NH-CH-CH COOR ² CO - N - CII - COO - R ¹ and pharmaceutically acceptable salts thereof, in which formula R is a phenyl, thienyl or furyl group R is a hydrogen atom, R ⁵ QR ³ Q -CH-OCR ⁴ or -CH-XCOR ⁴ and κ ² - R ⁵ 0 R ⁵ 0
-CH-OCR ⁴ , -CH-XCOR ⁴ , a. Hydrogen atom, an alleyl group having 1 to 8 carbon atoms, an aryl group or an aralkyl group, the alkyl, aryl and aralkyl groups unsubstituted or substituted by one or more of the following groups: amino groups, substituted amino groups, such as ^ ethylamino, diethylamino or acetamido groups, halogen, nitro and alkoxy groups having 1 to 4 carbon atoms; mean, where 3
R is a hydrogen atom, a methyl group or a X 0 or NH,
a water
Ethyl group and R is a saturated or unsaturated alkyl group having up to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon & n ~ »ier> _l« «*«; ^ / i-, aralkyl- or heterocyclic uuao. ,,,, »ο 309841/1185 Group, where the alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups are unsubstituted or by one or more of the following groups can be substituted: amino groups, substituted amino groups, like methylaminoT, diethylamino or acetamido groups, Halogen, nitro and alkoxy groups with 1 to 4 carbon material atoms; mean, where R is the group R ³ O _±
-CH-XCOR means if_R ejuQ_W_assjerstoffatom or f 9 4
-CH-OCR is. 2. A compound according to claim 1, having one or more asymmetric centers in the form of a substantially pure one Stereoisomers. 3. A compound according to one of claims 1 or 2 with the formula CH-CO-NH-CH-CH CO - N CH - COOH COOCIi ₀ -OCOC ₉ Hj or a therapeutically acceptable salt thereof. 4. A compound according to one of claims 1 or 2, having the formula 309841/1185 CH-CO-NH-CH-CH C co CH - COOH COOCH ₀ -OCOC ₀ H _n ■ _{2 |} -ζ, or a therapeutically acceptable salt thereof. 5. A compound according to one of claims 1 or 2, having the formula ■ S. ..CH, CH-CO-NH-CH-CH # X '. CI 3. CO CH-COOH COO-CH-OCOC ₀ H ₁ : or a therapeutically acceptable salt thereof. 6. A compound according to any one of claims 1 or 2, having the formula .., "■"^{'-.';; 1 l} ^ S - CH-CO-NH-CH - CH ι r ^ ίί · Ζ GO; -Β ^ CH - COOCH ₂ -OCOC ₂ H ₅ COOCH ₀ -OCO-CpHp- or a therapeutically acceptable salt thereof. 30984 1/1185 ORfGiNAL A - 7. A compound according to one of claims 1 or 2, having the formula "Λ yCH-CO-NH-CH - CH ^ C ^ ' COOH CO - N CH - COOCH ₂ -OCOC ₂ H ₅ or a therapeutically acceptable salt thereof. 8. A compound according to its own of claims 1 or 2, having the formula Λ-CH-CO-HH-CH - CH CT v III ^CH H C COOH CO - N CH - COOCHp-NH-C-O-CpHt si. - or a therapeutically acceptable salt thereof. 9. A pharmaceutical preparation which contains at least one compound according to one of the claims as an active ingredient 1 or 2 in association with a pharmaceutically acceptable carrier. 309841/1185 <Ό, Process for the preparation of a compound of the formula R-CH-CO-NxH-CH ~ CH ^CH 5 (DA (I.
.--- COOK ² CO .-. N_ ~ ^ —CH - COOR ⁷ or a therapeutically acceptable salt thereof, where in the formula " R is a phenyl, thienyl or furyl group, -CH-O-C-R, · -CH-X-C-O-R ^, _a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an aryl group or an aralkyl group, the alkyl, aryl and aralkyl groups being unsubstituted or substituted by one or more amino groups, such as ethylamino, diethylamino or acetamido groups, calogen _r nitro or alkoxy groups with 1 to 4 carbon atoms can be substituted / .r5 · 0 R ^ 0. ■ "" ■ -CH-OCR ⁷⁺ or -CH-XCOR ⁴ "mean, where furthermore X 0 or IJH,
R is a hydrogen atom, a-- ·· methyl group or a Aethy! Group and
R ^{4 is} a saturated or urs. ;;.-... saturated alkyl group 1 to 8 carbon atoms: ^, a cycloalkyl group nit 3 to 7 'carbon atoms, an "aryl, aralkyl or heterocyclic group, v / obe'i the alkyl, cycloalkyl-- · 3 09 841/1185 BAO ORIGINAL Aryl, aralkyl and heterocyclic groups unsubstituted or substituted by one or more amino groups Amino groups, such as methylamino, diethylamino or acetamido groups, Halogen, nitro or alkoxy groups can be substituted with 1 to carbon atoms; mean, 2
where R R ³ OR ³ O t A. "7 I Il A -CH-X-C-O-R means when R is -CH-O-C-R, thereby marked that a) a compound of the formula
R-CH-CO-Z COOR ² ' with a compound of the formula H ₉ N-CH-CH C ² II I ■, _r CO - Ν CH - COOR ' to a compound of formula (I) A is reacted, in certain cases via an intermediate with protective Groups, where in the formulas R are those given above 2 «2 Has meaning, R = R _f as defined above, or 2 2 when R is a hydrogen atom or when R contains amino groups or substituted amino groups - a protected derivative of R, -CO-Z is a reactive group that is linked to an amino group under BiI- 7 ¹ 7 formation of an amide bond can react, R = R or if R is amino groups or substituted amino groups " contains - is a protected derivative of R or 309841/118 5 b) an ester of a natural or biosynthetic penicillin of the formula R-CONH-CH - CH CO - N- .CH, CiL CH - COOR ¹ wherein R-CO- denotes the ayl group of the side chain of the natural or biosynthetic penicillin, in an inert solvent with a phosphorus halide reacts that the iminohalide compound thus formed is reacted with a lower alcohol and that the imino ether thus formed with a compound of the formula R-CH-CO-Z toOR ² '. 2 ' wherein R _f R and Z have the meanings given above, is reacted, whereupon the protective groups of the compound of the formula R-CH-CO-NH-CH «CH, 2 ' COOR CO-N CH ₅ CH .-. CQOR ¹ split off with formation of a compound of formula (I) A. be or c) a compound of the formula R-CH-CQ-NH-CH- 'Cfi CO-N 3Q9841 / 1185 CH - COOH with a compound of the formula 7 ¹
RY to a compound of the formula (I) A is reacted with _# in certain cases via an intermediate 2 ' protecting groups, where in the formulas R, R and R has the meanings given above and Y denotes a halogen atom or a functionally equivalent group thereof or. ~ - d) a compound of the formula R-C = C = O COOR ² ' with a compound of the formula H ₂ N-CH-CH C _ υ -CH-COOR ' is reacted to form a compound of formula (I) A, in certain cases via an intermediate with protected groups, being in the formulas 2 '7' R, R and R have the meanings given above, whereupon the compound of formula (I) A, if desired, converted to a therapeutically acceptable salt thereof. 309841/1185 11. Process for the preparation of a compound of the formula R-CH-CO-NH-CH - Cl-f ^ C <" ⁵ ■■■■ - ■■ ·" ^CH ₅ - ^{(I) B} COOR ⁶ CO - N CH - COOR ⁸ or a therapeutically acceptable salt thereof, wherein R is a phenyl, thienyl or Fury! Group, * 'R ⁶ -CH-O-C-R, -CH-X-C-O-R ^, an alkyl group with 1 to • carbon atoms ,. an aryl group or an aralkyl group, where the -alkyl, aryl and aralky groups are unsubstituted or with one or more amino groups, substituted amino groups, such as methyl! amino or acetamido groups, halogen, Nitro or alkoxy groups can be substituted with 1 to 4 carbon atoms, »'■ • 7. -X -CH-OCR ⁴ or -CH-XCOR ^ mean, where-further R is a hydrogen atom, a methyl group or a X O or KH,
a water: Ethyl group and 4 - R is a saturated or unsaturated alkyl group with 1 up to 8 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an aryl group _{for an} aralkyl group or a heterocyclic group, the alkyl, cyclo, aryl, araljiyl and heterocyclic groups being unsubstituted or substituted by one or more amino groups or anino - 309841/1185 8ADOBtGiNAL groups such as methylamino, diethylamino or acetamido groups, halogen, nitro or alkoxy groups with 1 to 4 Carbon atoms can be substituted, mean where R R ³ OR ³ O l ii 4 8 * »'4 -CH-X-C-O-R means when R is -CH-O-C-R, characterized in that a compound of the formula --41-GH-CO-HH-GH-CH ^ CC " ⁵ COOH CO-N CH - COOR ⁸ with a compound of the formula is converted to a compound of formula (I) B, in certain cases via an intermediate with protective groups, where in the formulas R are those given above QI O Has meaning, R = R, as defined above, or when R contains amino groups or substituted amino groups - is a protected derivative of R, R = R, as defined above, or - if R contains amino groups or substituted amino groups - a protected one Is derivative of R and Y is a halogen atom or a functionally equivalent group thereof, whereupon the so formed compound of formula (I) B, if desired, converted into a therapeutically acceptable salt thereof will. 309841/1186 231204T ι ?. , - = ancestor for establishing a connection -der ' Foriael R-CH-CO-NH-CH-CII I] 'j 3 R ^: COOH CO - N OH - COO-CH-XCOR ⁴ " ^CH 3 R ³ or a therapeutically acceptable salt thereof, wherein R is a phenyl, thienyl or furyl group / R is a hydrogen atom, a methyl group or an ethyl X 0 or NH, a water group and R is a saturated or unsaturated alkyl group with 1 to 8 carbon atoms, a 'Gycloalkylgruppe having 3 to carbon atoms, "a" Ary group?, An aralkyl group or a heterocyclic group, wherein the alkyl, cycloalkyl _f Äryl-, Äralkyl- and heterocyclic groups unsubstituted or substituted by one or more amino-substituted, Amino groups, vzie methylamino, diethylamino or acetamido groups, halogen, nitro and alkoxy groups can be substituted with 1 to 4 carbon atoms, characterized in that a compound of the formula R-C = C = Q C-Cl - ■■■■ "I! • ο ■ with a compound of the formula - I I CO - N CH - COO - CH ~ X ~ C ~ 0 - 309841/1185 ^R - Yi - is converted to a compound of formula (I) C, in certain cases about an intermediate with protective 3 groups, whereby in the formulas R, R and X the above 4 '4. have given meanings, and R = R, as defined above, 4th
or - if R amino groups or substituted amino Contains 4 groups - is a protected derivative of R, whereupon the compound of formula (I) thus formed is C, if desired, converted to a therapeutically acceptable salt thereof. Process for the preparation of a compound of the formula - R-CH-CO-NH-CH-CH CO - N CH - COOH COO-CH-XC-Ö-R ⁴ _(I) or a therapeutically acceptable salt thereof, wherein R is a phenyl, thienyl or furyl group, R is a hydrogen atom, a methyl group or a XO or KH,
a water
Ethyl group and R is a saturated or unsaturated alkyl group with 1 to 8 carbon atoms, cycloalkyl groups with 3 to 7 carbon atoms, an aryl group, an aralkyl group or a heterocyclic group, the alkyl, cycloalkyl, aryl, Aralkyl and heterocyclic groups unsubstituted or 309841/1185 (ftf by one or more amino groups, substituted amino groups, such as methylamino, diethylamino or acetamido groups, Halogen, nitro and alkoxy groups with 1 to 4 Carbon atoms can be substituted, mean, characterized in that a) a compound of the formula R-CH-CO-Z -XCOR "
3 COO-CH-J R ' with a compound of the formula 'H ₂ N-CH-CH
CO- N- CH CH - CO COOH to a compound of formula (I) D is reacted, in certain cases via an intermediate with protecting groups, where in the formulas R, R and 4 '4 X have the meanings given above and R = R, 4 as defined above, or - if R is amino groups or contains substituted amino groups - is a protected derivative of R, and -CO-Z is a reactive one Is a group capable of reacting with an amino group to form an amide moiety or b) a compound of the formula R-CH-CO-HH-CH ~ CH
I. QtT COOH CO - N - CH - .COOA 309841 / T185 23120A1 with a compound of the formula R ⁵ 0
Y-CH-XCOR ^ to a compound of the formula S 'PH R-CH-CO-NH-CH - CiT' ^ cT " ³ CO - N - CH - COOA is reacted and that the compound thus obtained is then converted into a compound of the formula (I) D by the group A by a hydrogen atom 3 4 ¹ -, where in the formulas R, R, X and R have the meanings given above, Y is a halogen atom or a functionally equivalent group thereof and A is a protective group or c) a natural or biosynthetic penicillin of the formula R-CONH-CH -CH C <T ° CH ₃ CO-N CH - COOA where R ° -CO- is the acyl group of the side chain of the natural or biosynthetic penicillin, in an inert solvent with a phosphorus halide is implemented that the iminohalogen compound thus formed is reacted with a lower alcohol and that imino ethers thus obtained with a compound of the formula 30,984.1 / 1 185 R-CH-CO-Z CQO-CH-X-C-O-R I ₃ Il R- "0 4 ' 3 4 ' wherein R, R, X, R and Z have the meanings given above have, whereupon the protective groups of the compound of formula R-CH-CO-NH-CH-CH CO - N - 4 '. COO-CH-X-C-O-R CH, CH - COOA with formation of a compound of the formula (I) D are split off or d) a compound of the formula TD ft «ι - ft. ,,,, f \ COO-CH-XCOR ^/ I ₃ HR ^ O with a compound of the formula ■ 'H ₂ N-CH CO - N- CH - COOA is converted to a compound of the formula (I) D, in certain cases via an intermediate product with protect- 3 4 «the groups, where in the formulas R, R, X, R and A 30984.1 / 1 185 have the meanings given above, whereupon the so educated. Compound of formula (I) D, if desired, into a therapeutically acceptable salt thereof will. 14. Process for the preparation of a mixture of the compounds of the formulas " R-CH-CO-NH-CH - CO-: N COO-CH-XCOR ⁴ R- CH ~ COOH (XVIII) A. R-CH-CO-NH-CH-CH COOH , CEL CIL (XXV) A. .CO - K CIi-COO-CH-XCOR ^{4 and} nd R-CH-CO-NH-CII - ClT CO - N COO-CPI-XCOR ⁴ 3 CH-COO- CiI-XCOR ⁴ R ^ 0 (XXVI) A. or their therapeutically acceptable salts, where R is a phenyl, thienyl or furyl group, 309841/1185 X O or NH, R is a hydrogen atom, a methyl group or an ethyl group and 4 ' R is a saturated or unsaturated alkyl group with 1 to 8 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an ary group, an aralkyl group, or a heterocyclic group, the alkyl, cycloalkyl, aryl, aralkyl and heterocyclic groups being unsubstituted or by one or more amino groups, substituted amino groups, such as methylamino, diethylamino or Acetamido groups, halogen, nitro and alkoxy groups can be substituted with 1 to 4 carbon atoms, mean characterized in that a compound of the formula R-CH-CO-NH-CH-CH COOH CO - N CH-COOH with a compound of the formula
R ⁵ 0 Y-CH-XCOR ⁴ ' 3 4 ¹
where R, R, X and R have the meanings given above and Y is a halogen atom or a functionally equivalent group thereof, to compounds of the formulas (XVIII) A, (XXV). A and (XXVI) A, is reacted, in certain cases via intermediates with protective groups, whereupon the various compounds of the mixture thus obtained, if desired, are separated from the mixture by methods known per se and the various compounds, if desired, converted into their therapeutically acceptable salts,, 309841/1185