DE1946089A1 - Penicillin derivatives and their manufacture - Google Patents

Description

DR. BERG DIPL.-ING. STAPF

8 MUNICH 2, HILBLESTRASSE 2O

Dr. Berg Dipl.-Ing. Stopf, 8 Munich 2, Hllblestra8e 20 Your sign Our sign date ia - · _Α Μ |

J6. Sep 1969

A nwalts file 1 8 820
ße / Sch

American Home Products Corporation, New York / USA

"Penicillin derivatives and their production"

This invention relates to the manufacture of penicillins and cephalosporins and, more particularly, to their manufacture of 2-Amidopeniclllinen and 2-Amidocephalosporinen, as well as these new products with antibiotic action and their hydrolysis to their corresponding acidic forms. The invention further relates to the preparation of these 2-amido compounds by amidation of penicillins

009817/1855

(OSl)) '5 16 20 8) Teleorctmmti PATENTEULE Munich Bank, Bayerisch · Verclnibank Munich 433100 Postscheck, Munich 653

or cephalosporins or by acylation of a 2-amido-6-aminopenicillanic acid or a 2-Απιίάο-7 · ~ 8 · πιΐηοοθρΙΐΒΐο-sporic acid. The invention also relates to production the aforementioned 2-amido-6-aminopenioillanic acids and 2-amido-7 "-aminocephalosporic acids, as well as these novel products themselves, over 2;: amido-6-haloimidopenicillins, 2-Amido-6-alkoxyimidopenicillins, 2- Afflido-7-halogenimidocephalosporins and 2-Amido-7-alkoxyimidocephalosporins and it also relates to the production of 6-aminopenicillanic acid and 7-aminocephalosporic acid, as well as these products themselves by appropriate hydrolysis of 2-amido-6-aminopenicillanic acids or 2-amido-7-aminocephalosporic acids.

The invention therefore relates to a method for producing a penicillin or cephalosporin or one 2-amido derivative of the same of the general formulas

where R is a penicillin or cephalosporin amide group is, X · is an electron withdrawing group (electrophilic group), Ϊ o an optionally electron withdrawing group Can be group or X and Y. with formation of an electron withdrawing cyclic group can be connected

-3-009817 / 185S

and R is a methyl, hydroxymethyl, N-pyridiniumylmethyl or alkanoyloxymethyl group, in which a penicillin or cephalosporin, if desired, after first converting the 2-carboxy group to a functional derivative group, is reacted with a reactive amine derivative with replacement of the hydroxyl radical of the starting 2-oxy group by an amido group. of the formula -1ST ^. γ, if desired, the 2-amidopenicillin or 2-amidocephalosporin obtained is reacted in a reactive non-protonic solvent with a phosphorus pentahalide in the presence of a base to form a corresponding 2-araido-6-haloimidopenicillin or 2-araido-7-haloimidocephalosporin, the is reacted with an alkanol to form the hydrohalide of a corresponding 2-amido-6-alkoxyimidopenicillin or 2-amido-7-alkoxyiraidocephalosporin, which in turn is hydrolyzed with water to form a 2-araido-6-aminopenicillanic acid or 2-araido-7 -aminocephalosporic acid hydrohalide, which, if desired, is neutralized and the ^ -amido-ö-aminopenicillanic acid or 2-amido-7-aminocephalosporic acid or an acid addition salt thereof is reacted with an acylating agent to form a further 2-amidopenicillin or 2wimidocephalosporin, if desired , to the corresponding penicillin or cephalosporin hydrolysi will be.

-4- 009817/1855

The novel 2-amidopenicillins created by the invention and 2-amidooephalosporins are antibiotically active 2-amidopenicillins and 2-amidocephalosporins, and their pharmacologically acceptable acid addition salts, in which the amido group of the formula.

-GN ^, where X is an electron withdrawing Q ^Y

Is a group, Y is an optionally electron withdrawing group, or X and Y join together to form a Form electron withdrawing cyclic group (along with the nitrogen atom to which they are attached). The invention also provides the corresponding 6- or 7-amino, -halogenimido or -alkoxyimido derivatives of these Links.

The invention therefore provides a 2-amidopenicillin or 2-amidocephalosporin and its 6- or 7-amino-, -halogenimido- or alkoxyimido derivatives of the general formulas

J— *

where R is a penicillin or oephalosporin amide group, an amino group or a haloimido or alkoxyiraido group is that of a penicillin or cephalosporin-

009Ä17 / 1855

18th
araidgruppe originate, R .a methyl, hydroxymethyl, N-Pyridiniumylmethyl- or Alkanoyloxyraethylgruppe, X is an electron withdrawing group, Y may be an optionally electron withdrawing group or X and Y together form an electron withdrawing group are connected cyo metallic or an acid addition salt thereof. '

Penicillin or Cephalosporinamidgruppen are the raann known both as natural and synthetic ^ penicillins and cephalosporins and include example as ι the subsequent general formulas

I Υ

00S817 / 1855

2 -5
wherein the radicals R and R ^ are hydrogen or lower alkoxy groups, R is hydrogen, lower alkyl or

5 6 7

Is phenyl, R- ^ and R are hydrogen or halogen, R '

and R- hydrogen, halogen, lower alkyl, lower

Q. / IQ

Alkoxy, phenyl, or phenoxy, R ⁷ and R 'when separated are hydrogen or lower alkyl, or when taken together with the carbon atom to which they are attached, an cycloalkyl ring having from about 4 to about 8 carbon atoms and a piperidine ring complete, a is an integer from 0 to 1, b is an integer from 0 to 5t c is an integer from 1 to 3 , with the restrictions that if a is »O, ο is greater than 1 and if a »■ is 1, c is less than 3 and X and Y have the meaning defined above.

The term "natural penicillins" used here Not only those who fall through lermentation produced, but also the biosynthetic

—7—

009817/1855

. -7- 1946Q89

put penicillins! by adding certain precursors to the fermentation broth; Examples of these types of penicillins are: Penicillin O, dae the type according to the 2-carboxy derivative of the compound of

20th

the following formula (VI), wherein R is allyl meroapto-

20 ν

is methyl, penicillin S, wherein .R · -Chlorcrotylmer-

20 '

oaptomethyl, penicillin V, where R is phenoxyraethyl,

ρω? o

Penicillin G, in which ΈΓ benzyl, penicillin F, in which R 2-pentenyl, dihydropenicillin F, in which R is amyl, penicillin

20 20

cillin K, where R is heptyl '., and penicillin X, where R p-Hydroxybenzyl is. Under the term "synthetic Penicillins, as used here, include all penicillins produced by the acylation of 6-aminopenicillanic acid can be produced. Examples of these types of penicillins are: Ampicillin, which is by type is the 2-carboxy derivative of the compound of formula (VI),

20 20

where R is cxr-aminobenzyl, nafcillin, where R 2-

20 athoxynaphthyl and dicloxacillin, wherein R $ - (2,6-dichlorophenyl) -5-methyl-4-isoxazole is. It should be emphasized that while most desirable it is "natural" To use penicillins "as starting materials in the process according to the invention, the process with regard to his ability to work does not depend on these raw materials is limited and works equally well when "synthetic penicillins" are used as reactants.

-8-0ÜS81 7/1855

As known to those skilled in the cephalosporin art, the compounds of this invention include such Compounds of the formula (II) in which the 3-position "Acetoxymethyl" group R by known chemical process is modified with the formation of

18 bonds in the 3-position with other R substituents are substituted, for example with N-pyridiniumylmethyl, methyl, hydroxymethyl or other alkanoyloxymethyl groups.

The term “cephalosporins” includes derivatives of cephalosporanic acid, such as cephalothin, but also such compounds to understand wherein the 3-position "acetoxymethyl" group is modified as explained above is.

As known to those skilled in the art, when X and Y are separated, electron withdrawing groups include, for example Cyano, nitro, trifluoromethylsulfonyl, 2,4,6-tri-methylbenzoyl, 2,3,5,6-tetramethylbenzoyl-, carb (lower) -alkoxy, Di (lower) -alkylcarbamyl-, lower alkylsulfonyl-, di (lower) -alkylsulfamyl-, di (lower) -alkylamino- (lower) -alkylsulfonyl-, lower alkanoyl-, for example tert-butyryl-, cyclo (lower) -alkanoyl-, aroyl-, for example Naphthoyl and furoyl, substituted aroyl, arylsulfonyl, for example naphthylsulfonyl, pyridylsulfonyl,

- 9 -009117/18 55

1 ^ 6089

Furylsulfonyl, substituted arylsulfonyl groups and the following groups

• 11 12
in which the radicals R and R are, for example, hydrogen, lower alkyl ,, halogen, CCrifluorraethyl, lower alkoxy ,, phenyl, phenoxy, nitro, lower alkylsulfonyl, di (lower) -alkylsulfamyl and the radicals R, R and R. * hydrogen, Nitro, halogen, trifluoromethyl, lower alkyl, lower alkoxy, lower alkylsulfonyl, lower alkylthio, di (lower) -alkylsulfarayl, di (lower) -alkyl-. _(Oarbamyl, cyano and carb (lower) alkoxy and may be an integer of 0. d to 'about 6 ·

It is also known to those skilled in the art that when X and X are together, for example, belong to the oyo-metallic electron withdrawing groups

• ι

CH ₃

009 (17/1855

-10-

wherein the radicals R and RV. separated "Masseratoff, lower Alkyl, lower alkoxy, halogen, phenyl, I? Hen (lower) alkyl, lower alkoxyphenyl, aryl, heteroyclic groups * for example 2-pyridyl-, "4-pyridyl-, ffirihalogenraethyl · ·, for example 'jrifluoromethyl-, nitro-, bi (lower) -alkylaraino-, SuIfamido-, Oarb (lower) -alkoxy-, "Cyano-, lower Are alkylthio or lower alkylsulfonyl groups and if.

16 1 * 7 ■

R and R 'are connected, they complete a benzene ring, which is fused with the existing benzene ring to form a naphthalene ring, S sulfonyl or carbonyl, W is sulfonyl, carbonyl or methylene, V. Oxygen, sulfur or methylene, ai. Carbonyl or methylene and the broken line "indicates a single or double bond between these two positions * While Y can be any organic residue that is not one. Electron withdrawing group is, for example a Alkyl, alkenyl, cycloalkyl, aryl, heterooyclic or aralkyl radical is ι κ / o.b at any of these with. Halogen, trifluoromethyl, nitro, carb-lower-alkoxy, ' lower alkyl, lower alkylsulfonyl, di-lower alkylsulfamoyl, Di-lower-alkylamino-lower-alkyleulfonyl-, Cyano, sulfamido, di-lower alkyloarbamoyl, lower alkoxy-, di-lower-alkylaioino-, lower alkyl · · sulfonyl or lower alkylthio or an aoyl radical, ■ for example lower alkanoyl, aralkanoyl, aroyl »alkyl · sulfonyl or arylsulfonyl substituted soaps, canoe, »is'

-11-

009817/1855

it is preferred that Y, like X, be an electron donor Group is.

\
As known to those skilled in the art, the groups defined as "haloiraidoyl" (such as chloriraidoyl and brominidoyl) include those haloimido substituents derived from natural and synthetic penicillins and oephalosporins. originate, where for example R, as used in penicillin formula (I), can be defined as ,, 2-allylmercapto-1-haloäthylidenaniino, 1-halo-2- (V-chlorocrotylmercapto) -äthylidenamino, 1-halo-2-phenoxyäthylidenamino , a-Halogenphenethylidenaraino, I-Halogen-J-hexenylidenamino, 1-Halogenhexylidenaraino, 1-Halogenootyl-

idenamino and a-Ohlor-p-hydroxyphenethylidenamino. and R, as used in oephalosporin formula (II), i-halo-2- (2-thienyl) ethylideneamino can be. It is also known that the groups defined as "alkoxyimido" those with lower alkoxyimido substituents include the

of natural and synthetic penicillins and oephalo

1 originate from sporins. Examples of such groups when R in the penicillin formula I is used are: 1- (lower) -

Alkoxy-2-allylmercaptoäthylidenaraino ,. 1- (lower) -alkoxx ** 2- (T * -chlorcrotylmeroapto) -äthylidenaraino ,. 1- (lower) -alkoxy-2-phenoxyäthylidenamino, a- (lower) -alkoxyphene * ethylidenamino, 1- (lower) -alkoxy-5-hexenylideneamino,

1- (lower) -alkoxyhexylideneamino, 1- (lower) -alkoxyootylideneamino and ai- (ni, ederes) -alkoxy-p-hydroxyphenethylJ

009817/1855

denamino and R, as used in gephalosporin formula (11), can be 1- (niöderes) -alkoxy-2- (2-thienyl) -äthylidenamino be*

Preferred compounds created by the invention sind'solche of formula (III) wherein X and Y are ver chains to form a substituted or tiadcharyl- Saccharylgruppe. These compounds are duroh in the demand ^, the following formula

(in)

as well as the acid addition salts thereof, in which the radicals

1 16 17
R, R and R 'have the meanings defined above. Among the cephalosporins, the corresponding 2-aoocharyl or substituted saccharyl cephalosporins (IXIa) are similarly preferred »

They designate "lower alkyl" as they are used here alone

-15-009817 / 1855

or used in conjunction with other designated groups includes straight and branched chain alkyl groups and also those containing from 1 to about 6 carbon contain atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 2-ethylpropyl, hexyl, 2-propylpropyl and the like. Similarly, are the terms "lower alkoxy" and "lower alkanoyl", as used here alone or in conjunction with other designated groups to be construed as straight or branched chain groups containing from 1 to about 6 carbon atoms. The designation "Halogen" as used herein either alone or in conjunction with other designated groups includes Chlorine, bromine, iodine and fluorine. It will also be understood that the ring substituents, either carbocyclic, for example Phenyl, benzyl, etc. or heterocyclic, for example 2-pyridyl ,. 4 — pyridyl, and the like as well one or more such common substituents as liie

16 17
listed above for R and R 'may be substituted., Likewise, the naphthalene ring, the results can

16 17
when R and R 'are linked as indicated above, they also carry one or more similar substituents as indicated above. The term “electron withdrawing group” is to be understood as an electrophilic group which inductively withdraws electrons from the carbonyl part of the 2-amido groups of the compounds according to the invention and

00SÄ17 / 1855

This causes these groups to be split by a nucleophile With / with, for example, water, alkali metal hydroxides, tertiary amines, quinoline and the like, making a carboxylic acid group more inclined. .

The novel 2-amidopenicillins and 2-amidocephalosporins created by this invention can generally be prepared by adding a starting penicillin or cephalosporin, for example, a 6- 'acylated penicillanic acid or 7- € loylated cephalosporanic acid with an appropriate one reactive nitrogen compound converts the hydroxyl radical of the carboxyl group of penicillin or cephalosporin by a group of the formula

^Q Y

-C-N

wherein X and Y have the meanings defined above, can replace. Such reactions are known to the person skilled in the art and several solo processes are described below, those for making 2-amidopenicillins of this invention are suitable, explained schematically. It should be emphasized that the new and novel 2-amidocephalosporins of this invention can also be prepared by these reactions, using only instead of the Starting penicillins the appropriate cephalosporin is used.

-15-009817 / 1855

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00S917 / 1055

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For example, the preferred compounds (III) of this invention are generally prepared by preferably in the cold a 3-halosaccharin derivative, for example 5-chloro-1,2-benzisothiazole-1,1-dioxide or an appropriately substituted derivative thereof with a penicillin or an alkali metal salt the same in an organic solvent such as anhydrous methylene chloride, which is an acid acceptor ', for Example- contains triethylamine if the starting penicillin is in the acid form. When the condensation reaction is over, the 2-saccharimidopenicillin obtained using standard procedures, e.g. the reaction mixture is washed, dried and concentrated, for example under vacuum at temperatures higher than room temperature. The residue can then again dissolved and from a suitable organic solvent system, e.g. ether (e.g. 25 #) in benzene are crystallized out.

The 3-chloro-1ι2-benzisothiazole-1,1, dioxide-starting ma-

16 19 material is commercially available while the R and R 'substituents can be introduced to the benzo radical of the saccharin derivatives according to known conventional processes The penicillins and cephalosporins are either commercially available or they can be found in the literature described processes are produced «Only in at ·»

$ 00 β17 / 1855

In a playful way, the U.ß. patent specification should be mentioned here 2 996 501, 5 157 659, 3 159 61? and 3 239 507 j the conventional method of “manufacture describe various penicillins used as starting materials. Similarly, the are reactive Nitrogen compounds that contribute to the formation of the

amido groups designated above are used, are also commercially available, or if they are not available, they can be readily prepared by standard organic methods described in the chemical literature. The preferred 2-saccharyl or substituted saccharyl cephalosporins (purple) can be prepared in a similar manner.

The invention also provides a method of manufacture of 2-amido-6-aminopenicillanic acids (IV) or 2-Amido-7-aminocephalosporic acids (V) of the general Formulas

U ^y ο

for) Ca) °

18th
wherein H has the meaning defined above, X is an electron withdrawing group, Y is an optionally electron withdrawing group or X and Y together

008817/185 5

- 21 -

rait the nitrogen atom to which they are attached complete cyclic electron withdrawing group, taking a phosphorus pentahalide, such as phosphorus entachloride and phosphorus pentabromide, with a 2-amido derivative of a natural or synthetic penicillin (VI) or cephalosporins (VII) of the general formulas

ta)

18th
wherein R, X. and Y ^{- have} the meanings defined above

20th
have, R a substituent contained in natural and synthetic penioillins, such as allyl mercaptomethyl, Y-chlorocrotyl mercaptomethyl, phenoxymethyl, benzyl, 2-pentenyl, arayl, heptyl and p-hydroxy

benzyl and R is a substituent contained in natural and synthetic oephalosporins, for example 2-Thienylmethyl is, in a reaction-inert, not brings protonic solvent into contact in the presence of a base to form a 2-amidohaloimido compound, one of the corresponding general formulas

OTWQ8817 / 185S

PO 2Ί
wherein R, R, X. and X have the meanings defined above, And Z is a halogen atom, for example chlorine or bromine. The new and novel ^ -emidohaloimido compounds of this invention, in particular the 2-amido-6-haloimidopenicillins (VIII) and the 2-amido-6-haloimidocephalosporins (IX), which were prepared by the above reaction, can be prepared by the usual recovery methods separated, for example the reaction mixture is filtered and the collected solid is dried to form the product (VIII or IX). Optionally, the unseparated product is used immediately in the subsequent reaction.

The 2-amidohaloimido compound (VIII or IX) prepared above is brought into contact with an alkanol, whereby the corresponding 2-amidoalkoxyimidohydrohalide compound, for example the hydrochloride or the hydrobromide of one of the corresponding general formulas

«Ίί J— Ω- κ«

Cr). ·· CH) & ^y

20 21

wherein H ₁ R, X, Y and Z have the meaning defined above

-23-009817 / 1855

and R is lower alkyl is obtained. The new and novel 2-amidoalkoxyimidohydrohalide compounds of this invention, in particular the 2-amido-6-alkox3ri.midopenicillin hydrohalides (X) and the 2-amido-7-alkoxyimidocephalosporin hydrohalides (XI), which were prepared according to the substitution reaction described above, can be used directly in the subsequent reaction or they can be used according to standard separation procedures, for example by filtering and drying the collected precipitate.

The 2-amidoalkoxyimidohydrohalide compound (X or XI), as prepared above, is then hydrolyzed according to routine methods, for example by contact with water, whereby the corresponding hydrohalide of the 2-amidoamine compound is obtained. This hydrohalide. for example hydrochloride or Hydrobroraid, is then easily converted to its corresponding basic form (IV. or V) by neutralization ion processes which are known as such to the person skilled in the art are known ... For example, the hydrohalide is briefly treated with water, which contains a base such as triethylamine, Contains sodium bicarbonate or the like, preferably treated in the presence of a water-miscible solvent.

The term "reaction-inert" non-protonic solvent "includes liquids that do not contain any Protons deliver and which the reactants without in their

009817/1855

Reaction to occur, - dissolve, such as methylene chloride, chloroform, Dioxane, tetrahydrofuran, ether, dimethoxyethane, benzene, xylene and toluene * Under the name "Base" are both organic and inorganic proton acceptors, which are suitable for proton uptake, too understand, with these for example Ohinolin,

Dimethylaniline, pyridine, N-ethyl morpholine and potassium carbonate. While many of the compounds (I and II) created by the invention are basic are, the water solubility of the salts formed from these compounds with acids during isolation and purification of the above compounds and in the preparation of aqueous solutions thereof in more advantageous manner Way to be evaluated. Such known acids include, for example, hydrochloric acid, hydrogen bromide, sulfuric acid, Nitric acid, phosphoric acid, benzenesulfonic acid, Toluenesulfonic acid, methylsulfonic acid, ethylsulfonic acid and similar. These salts can be prepared by commonly used methods, for example the compound reacts with one equivalent of the selected acid in an aqueous solution and the solution concentrated. Other known methods can also be used. ·

Another method according to the invention relates to Production of 6-aminopenicillanic acid (XII) and 7-aminocephalosporanic acid (XIII) with the following

17/1855

speaking 2-carboxyamine compound of the general formulas

COOH

in which one "2-amidoamine compound (IV or V.) the Formulas'

/ JQ

wherein E, X, and Y have the meanings defined above, brings with water in the presence of a hydrolytic catalyst in contact, until the hydrolysis terminated · The term "hydrolytic catalyst" refers Si ₁ Oh at Bubstanzen that the hydrolysis of 2-Amidorests The 2-amidoamine compounds of this invention can support many such substances are known to the person skilled in the art, for example quinoline, pyridine, imidazole and alkali metal acetates such as sodium acetate.

The starting diaraide compounds, for example 2-amidopenicillins and 2-Ämidocephalosporins can be prepared in such a way that imidoyl halides with natural

-26-009817 / 1855

'- 26 -

lichen or synthetic penicillins and cephalosporins converts. "For example, the starting 2rsacoharitnidopenicillins for the preparation of the preferred compounds (III) in which, R is an amino group, prepared by that you can get a penicillin with a 3-halosacoharine derivative or a suitably substituted derivative as indicated above. The natural or synthetic penicillins or cephalosporins used in the manufacture of the starting materials described above are commercially available or they can be easily prepared by known methods. The imidoyl halides are also commercially available available or in those cases where they are not available, they can be easily looked up in the chemical literature and standard organic processes known to those skilled in the art.

A preferred method created according to the invention relates to the manufacture of those identified above 2-saccharimidoamine compounds such as the 2-saccharimido-6-aminopenioillanic acids (III). These compounds (III) are prepared by first using the saccharimide one, natural or synthetic penioillina, for Example benzylpenicillin, phenoxymethylpenicillin and. the like, as described above, produces.

The 2-saocharimidoamido compound is used in one reaction

-27-008917 / 1855

inert, non-protonic solvent, for example methylene chloride, in the presence of a base, for example Ohinoline, dissolved "and then mixed with phosphorus pentachloride, whereby the corresponding 2-saccharimidochlorimido compounds, for example 2-sacoharimido-6-chloriraidopenicillin, obtained, which then with an alkanol, for example methyl alcohol, ethyl alcohol. Propyl alcohol, Butyl alcohol and the like, is reacted so that the chlorine atom of the imidochloride residue is replaced by that of the used Alkanol delivered alkoxy group with formation a suitable hydrochloride salt of a 2-saccharimidoalkoxyimido compound, for example 2-saocharimido-6-alkoxyimidopenicillin hydrochloride is replaced.

Thereafter, the reaction mixture to hydrolyze the salt described above so W & si ^ .v? admitted that a Hydrochloride of a 2-saccharimidoamine compound such as that Hydrochloride of 2-saccharimido-6-aminopenicillansäuΓβ-, is obtained, which is then converted to its corresponding base by treatment with an aqueous base, for example Triethylamine ,. Sodium bicarbonate and the like, preferably in the presence of a water-miscible solvent can be converted.

The 2-saccharimidoamine compound prepared above then readily becomes the corresponding 2-oxyamine compound duroh contact with water in the presence of a hydrolytic isohen

009817/1855

-28 *

BATH

Catalyst converted .. For example, 2-saccharimido-6-aminopenicillanic acid at a pH of about 1.5 to about 9 in water or a mixture of water and a water-miscible solvent treated until hydrolysis to form 6-aminopenioillanic acid is finished.

The preferred method of the present invention for making the 2-sacoharimido-6-aminopenicillanic acids (III) and 6-aminopenicillanic acid (XII) described above can proceed through the subsequent reaction being represented·

-29- 008 * 17/1855

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009817/1855

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1346089

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009817/1855

Furthermore, an alternative method of making the new and novel 2-amidopenioillins and 2- 'amidooephalbsporins of the present invention is available. This new and novel alternative process is particularly useful in preparing the novel compounds of this invention which are derivatives of synthetic oc-amino and 1-aminopenioillins and oeptiaiosporins which contain an additional reactive group which will react with the haloimine derivatives of the other reactants as well can connect ·. In this V. erfah *. ren is the 2-amido group at the exit v6- ^; '"

Aminopenicillanic acid is present, with Ban then usually aoylated in the 6-position. In general, in this process, a 2-amido derivative of a penicillin, for example benzylpenicillin, phenoxypenioillin, penicillin K or the like, is produced first The respective starting penioillin is mixed with a suitable organic solvent, for example methylene chloride, and then an acid acceptor, such as triethylamine, trimethylamine and the like, is added to form a solution, this solution is mixed with a suitable amino isohalide derivative, preferably under cold conditions When the amidation has ended, the solution is washed, dried and concentrated under vacuum, resulting in the 2-aido derivative of the starting penioillin being obtained as the residue

009 17/1855

then from a suitable organic solvent system, for example ether in benzene, can be crystallized out can. Thereafter, the 2-amido derivative of penicillin is either as a residue or in the crystallized form in Methylene chloride, which is an organic base, for example Ν, Ν-dimethylaniline, ohinoline, N-ethylmorpholine and the like, contains, dissolved and then with a phosphorus pentahalide, like phosphorus pentachloride or phosphorus pentabromide, to form the corresponding 6-haloimide implemented. Optionally, the organic base is preferably added immediately to the starting reaction mixture after the addition of the iminohalide derivative was added, thereby achieving the isolation and crystallization process described above is bypassed. This 2-amido-6-haloimido derivative The penicillin is then mixed with a lower alkanol, for example methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol and the like mixed to form a hydrohalide acid addition salt of e-alkoxyimido - ^^ amido derivative of penicillin, wherein the halogen atom of the 6-imido radical through the alkoxy part of the lower used Alkanol was substituted. The reaction mixture is then subjected to aqueous hydrolysis, whereby the corresponding 2-amido-6-aminopenicillanic acid as the hydrohalide salt receives. The basic form of this salt is obtained by briefly treating the hydrohalide with an acid acceptor such as triethylamine, sodium bicarbonate

-33-

001817/1855

- 53 -

and the like, in a solvent, preferably What s he will get.

The acylation of this 2-amido-6-aminopenioillanic acid can can then be continued according to conventional methods, as mentioned above, whereby the antibiotic effective

seed 2-amidopenicillins of the present invention.

These conventional methods generally relate to the reaction of the 6-amino group of 6-aminopenicillanic acid either as such or as a functional derivative such as an organosilyl derivative or a salt thereof or the corresponding oephalosporin series with an acylating agent to form the desired penicillin or oephalosporin amide group and include in this specification and the terms reaction with an aoylating agent or "acylation" include all of such reactions. It is also known to those skilled in the art of peptides and penicillin that if the penicillinamide residue contains a further reactive functional group, this: is conventionally protected in the acylation reaction and the masking group is removed by methods known per se Proton attachment can be protected as an acid addition salt or as N-oxy-anhydride and only the conventional stages are, insofar as they are necessary, in

-34-009117 / 1855

For example, a 2-atnido-6-aminopenioillanic acid can be mixed with an acid chloride to form the 2r-amido derivatives of 2-ethoxynaphthylpenicillin or an N-carboxy anhydride to form the 2-atnido derivatives of D (-) - a- Aminobenzylpenicillin are converted, both of which have strong and sustained antibiotic effectiveness in warm-blooded animals. When using gelioher methods, eynthe- ^ tisohe 2-amidopenioillins and -cephalosporins are obtained, the valuable uninterrupted activity both against gram-positive as well as In some cases, where it is desirable to retain the acid forms of the penicillins as such, ie without the 2-avoro substituent, the acid forms can be obtained by simple hydrolysis. For example, the 2-amidopenioillin, after it is treated for a sufficient time with water or a mixture of water and miscible organic solvent, for example at a pH of about 1.5 to about 9, gives the deaerated penicillin. For example, the amido derivatives of nafoillin can be mixed with water or a mixture of water and a miscible organic solvent at a pH of about 1.5 to 9 for a sufficient time. be treated. Ampicillin can be prepared from amido derivatives of ampicillin by similar processes «Ea. let here emphasize that although the above

009 * 17/1855

Procedure has been described in relation to 2-amidopenioillins, it applies in the same way to the 2-amidocephalosporins this invention is applicable.

Thus, the novel 2-amido-6-aminopenicillansäuren, 2-amido-6-halogenimidopenicilline, 2-amido-6-alkoxyimidopenicilline, 2-amido-7-aniinocephalosporansä ^J acid, 2-amido-7-halogeniraidocephalosporine and 2-Araido- 7-e.lkoxyimidocephalosporins and their acid addition salts are particularly brewable as intermediates for the preparation of 6-aminopenicillanic acid and 6-aminocephalosporanic acid, which in turn can be acylated by methods known to the person skilled in the art to form synthetic penicillins and cephalosporins, for example 6-aminopenicillanic acid with an acid chloride by the methods described in US Pat. No. 3,248-386 to form 2-ethoxynaphthylpenicillin or nafcillin or an N-oxy anhydride as described in US Pat. No. 3,206,455 to form D (-) - oc-aminobenzylpenicillin or ampicillin are acylated. These two penicillins have potent antibiotic activity in warm-blooded animals. Using the same process, many synthetic penicillins and cephalosporins are produced which have valuable activity against both gram-positive and gram-negative bacteria.

-36-

009817/1855

- 56 .-

scher 2 "amidopenioillins and 2-amidooephalospor'ins Using conventional acylation procedures outlined above.

The antibiotic 2-amidopenicillins and 2-amidooephalosporins of the present invention have valuable biological activity. In particular wise these compounds in standard and especially specific biological studies effectiveness against gram-positive and gram-negative bacteria. In this regard, these compounds are therefore useful as antibacterial agents Nutritional additives in animal feed, as agents for treating mastitis in cattle and as therapeutic agents in poultry and other animals, in the treatment of infectious, gram-positive and gram-negative bacteria caused diseases, both after parenteral and also effective for oral administration. Furthermore, parenteral, For example, intramuscular follow-up of the compounds of this invention is a sustained antibacterial Effectiveness through the slow in situ hydrolysis of the same with the formation of the corresponding deamidated penicillins, which are then easily absorbed.

It is clear that the 2-amidopenicillins and 2-amidocephalosporins of this invention can be used as such or in the cases of such compounds of the

-37-

009817/1855

They can be of the ar-amino or 1-amino type in the form of pharmacologically acceptable acid addition salts thereof can be used, these being produced by the reaction of the selected antibiotic active substances Compound with a suitable organic or inorganic acid, for example hydrochloric acid, hydrogen bromide, Fumaric acid, citric acid and the like, as is common in pharmacology.

Furthermore, the antibiotically active synthetic penicillins and cephalosporins, 2-amidopenicillins and 2-Araidooephalosporins made available by this invention can be used in pharmacologically acceptable preparations together with a pharmacologically acceptable carrier, for example in a suitable injectable form, including solutions and suspensions or orally as tablets, . Capsules and the like can be used using conventional solvents, suspension colloids, excipients and the like. As indicated previously, the compounds of this invention can be administered orally or parenterally. Of course, the dosage of these compounds will vary somewhat with the mode of administration and the particular compound selected. Furthermore, it will change with the patient under treatment. In general, the compounds of this invention are conveniently administered in dosages

-38-0 01017/1855

those of the commercially available penicillins and Cephalosporins correspond .. Although modifications of these dosages will generally provide effective results without causing any adverse or harmful side effects.

The following examples, in which the temperatures in

O are given, explain the invention without the scope of the invention to restrict.

example 1

The saccharimide of phenoxymethylpenicillin 3,3-dimethyl-7-oxo-6- {2-phenoxyacetamido) -4-thia-1-azabicyclo- ^ 3,2,07-heptane-2-carboxylic acid (phenoxymethylpenicillin) (17 »5 g »0.05 mol.) Is added to anhydrous methylene chloride (750 ml), then triethylamine (5.05 g, 0.15 mol) to form a solution. The solution, stirred with a magnetic stirrer, is cooled to 3 ° in ice water. 3-chloro-1,2-benzisothiazole-1,1 _T dioxide (10.05 g, O _1, 05 mol) is added all at once, woduroh to obtain a light yellow solution. After stirring in ice water for half an hour, the solution is kept at room temperature overnight, then _{washed with cold water (700 ml), cold 0.13 M / pH7, V (K 2} HPO ₄ ZKH ₂ PO ₄ ) (500 ml) and washed with sodium sulfate dried". The filtrate is dried over GaIo ium sulfate and then with

«39-

00 * 117/1855

concentrated under vacuum to give a foam (24.2 g). The foam was dissolved in 25 # ether in benzene (approximately 80 ml) to give the title compound as crystals (18.6 g,, melting point I7I ⁰ decay (uncorrected).

Analysis: calculated for C ₂₅ H ₂ ^ N ₅ OyS ₂ .0 ₂

00: 52.30 0, 4.27 H, 7.96 N, 12.14 S, 2.38 H ₅ O found (#): 52.22 0, 3.91 H, 7.89 N, 12, 18 S, 2.35 H ₃ O.

Example 2

The baccharimide of 6- (2 _< 2-dimethyl - ^ - o: xo - 4 - phenyliinidazolidin-1-yl) -penicillin

6- (2,2-Dimethyl-5-oxo-4-phenylimidazolidin-1-yl) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo / 3 _i 2, o7-heptane-2- carboxylic acid / 6- (2,2-Dimethyl ^ 5-oxo-4-phenylimidazoliidin-1-yl) penicillin7 (3.90 g, 0.01 mol) is converted to anhydrous methylene chloride (150 ml), then triethylamine (1, 01 g, 0.01 mol) was added to form a solution. The m ± t magnetic stirrer stirred solution is cooled to 3 ° in ice water. 3-0hlor-1,2-benzisothiazole-1 _T 1-dioxide (2.02 g, 0.01 mol) is added all at once and the resulting solution is reacted and prepared in a manner similar to Example 1, whereby the Compound designated in the heading 'obtained as a light yellow solid (3.7 6, 67 #), melting point 182 ° decay (uncorrected)

-40- 009817/1855

T9T6089

Analysis: calculated for ^G 26 ^H 26 ^N 4 ° 6 ^S 2

• W i 56.30 0, -4.72 H, 10.10 N, 11, .57 S found (#): 56.08 G, 4.52 H, 10.21 N, 11.78 S.

Example 3

Following the procedure described in Example 1, a number of penicillins can be obtained with different Saccharin chloride derivatives are implemented, whereby the corresponding Sacchariraide of the penicillins with strong maintains antibiotic effectiveness. The reactants and the resulting saccharimides of penicillins are given in Table A below.

Tabel Ju

Saccharin chloride saccharimides of penicillins derivatives penicillins

Phenoxymethyl-3-chloro-4-ethyl-1,2-4-iithylsacchar imid penicillin benzisothiazole-1,1- from phenoxymethyl-

penicillin dioxide

6- (2,2-dimethyl-3j5-BiChIOr ^ -PrOPyI-4-propyl-5-chloro-5-oxo-4-phenyl1,2-benzisothiazole saccharimide of 6-imidazolidine-1-1,1-dioxide (2,2-dimethyl-5-oxo-

yl) -penicillin 4-phenylimidazolidine-

1-yl) penicillin

2,6-Dimethoxy— 3-chloro-5 »6-diamono- ^» ö-Diamonosaccharphenylpeni-1,2-benzisothiazole- imide of 2,6-dioillin, 1,1-dioxide methoxyphenylpeni-

cillin

2-Ethoxy-3-0hlO3? -4-nitro-1,2-4-nitrosaccharimide

naphthyl-benzisothiazole-1,1- of 2-ikthoxynaphthyl-

penioillin dioxide penicillin

Phenoxyprop-1-3-chloro-4,5-dibromo- 4,5-dibroraeaochariaiid ylpenioillin 1,2-benzisothiazole- from phenoxyprop-1-

1,1 -dioxid ylp eni ο illin

008817/1855

Penicillins

saccharin chloride derivatives of accharimides of Penicillins

3- (2,6-dichloro-3-chloro-4-hexyl-1,2-4-hexyl saccharimide
phenyl) -5-methyl-benzisothiazole-Ί, 1- of 3- (2,6-dichloro-4-isoxazoylpenidioxide phenyl) -5-methyl-4—

cillin isoxazoylpenicillin

3-phenyl-5-methyl-4-isoxaz oylp enic illin

3-OhIor-4-but oxy-5-phenyl-1,2-benzisothiazole-1,1-dioxide

3-p-Chlorophenyl-3-chloro-5- (p-5-methyl-4-isoxmethoxy) phenylazoyl penicillin 1,2-benzisothiazole

1,1-dioxide

Benzylpenicillin 3-0hlor-4-phenyl-

1,2-benzisothiazole-1,1-dioxide

Phenoxyethyl penicillin

2-methoxy

naphthyl

penicillin

3-chloro-5-benzyl-1,2-benzisothiazole-1,1-dioxide

3-chloro-7- (mpropoxyphenyl) -1,2-benzisothiazole-1,1-dioxide

3-o-Chlorophenyl-3-chloro-4-butyl-5-5-methyl-4-isoxfluoro-1,2-benzisoazolyl penicillin thiazole-1,1-dioxide ^ -butoxy- ^ - phenyl saccharimide of 3 ~ phenyl-5-raethyl-4-isoxazoylpenibillin

5- {p-methoxy) phenyl saccharimide of 3-p-chlorophenyl - ^ - niethyl-4-isoxazoylpenicillin

4-phenyl saccharinide of benzyl penicillin

5-benzyl saccharimide of Phenoxyäthylpeni-'cillin

7- (m-Propoxyphenyl) saccharimide of 2-methoxynaphthylpenicillin

4-butyl-5-fluorosaccharimide of 3-θτ-chlorophenyl-5-diethyl-4-isoxazolylpenicillin

3> 5-

isoxazolyl

penicillin

cc-phenoxybenzylpenioillin

a-Phenoxyethylpenioillin

2,6-Dira ethoxy-
benzylpenicillin

3-chloro-4,5-dimethyl-4,5-dimethylsacchar- 1,2-benzisothiazole-iniide of 3 »5" diphenyl-1,1-dioxide 4-isoxazolylpenioillin

3-chloro-4- (2-pyridyl) -1,2-benzisothiazole-1,1-dioxide

3-chloro-5-dimethylamino-1,2-benzisothiazole-1,1-dioxide

3-chloro-6-trifluorraethyl-1,2-benzisothiazole-1,1-dioxide 4- (2-pyridyl) -saooharimide of ar-phenoxybenzylpenicillin

5-uimethylaininosaccharimide of a-phenoxyethylpenicillin

6-Trifluoromethylsacoharimid von 2,6 ~ Dim et hoxybenzylpenioillin

009817/18 -42-

example Jas saccharimide of ampicillin

The salt of 2- (6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo - /! ^, Oy-heptane ^ -ylcarbonyl ^ i ^ -benzisothiazol-3 (2H) -one -1,1-dioxide of p-toluenesulphonic acid (saccharide of δ-aminopenicillanic acid, p-toluenesulphonic acid salt) (5 »5 S» O »» O "I mol) is dissolved in $ 80. Acetone-water (230 ml) at 0 ° to form a solution of pH 2.2. Then, D - (-) - a-Arainophenylaoetylchloridliydrochlorid (3 »1 g» 0.015 mol) of the magnetically stirred solution is added in about 10 increments for half an hour 0 ° was added, the pH being maintained with 50% sodium hydroxide at 2 to 3. The solution is stirred for a further 15 minutes at 0 and the pH is adjusted to 4.5 with 50% sodium hydroxide ⁰ removed under vacuum and the volume of the remaining water "adjusted to 100 ml. The pH value is adjusted to 6.8 with 50 # igera sodium hydroxide at 0 °, whereby the compound named in the title is a light yellow solid (3, 2 s, 62 #), melting point I70 ⁰ decay (uncorrected) received.

Example 5

If the procedure of Example 4 is followed, in this case a number of sacoharimides of 6-aminopeni oillanic acid are reacted with various acylating agents,

008817/1855

whereby one the saccharimides of the penicillins with antibiotischef Effectiveness. The reactants and resulting saccharimides of the penicillins are in the Table B given.

baccharimide of 6-aminopenicillanic acid

4- (4-pyridyl) -5-methyl saccharimide. from 6-APA

5-trichloromethyl saccharimide from 6-APA.

6-dimethylamino-7-methyl saccharimide from 6-ÄPÄ.

6-sulfamidosaccharimide from 6-APA

4-carbethoxy- saccharimide of 6-APA ".

4-gyanosaccharimide of 6-APA

4- (Prop-2-yl) thiosaccharimide of 6-APA.

Table B.

acylating agent

N-carboxyanhydride
of 1-aminocyclopentanecarboxylic acid

N-carboxyanhydride
of 1-aminocyclohexanecarboxylic acid

Phenylglycine chloride hydrochloride

N-carboxyanhydride
of 1-amino-1-indanecarboxylic acid

üaocharimide of the penicillins

4- (4-pyridyl) -5-methyl saccharimide of 1-aminocyclopentane penicillin

5-trichloromethyl saccharimide of 1-aminocyclohexane penicillin

δ-dimethylamino-ymethyl saccharimide of 1-aminobenzylpenioillin

6-sulfamidosaccharimide of amino-1-indan- ^ penicillin "

N-carboxyanhydride 4-carbethoxy- of 1-amino-1,2,3,4-saccharimide'von totrahydronaphthoe-1-amin'o-1, 2,3 »4-acid tetrahydronaphthyl

penicillin

N-carboxyanhydride 4-cyanosaccharimide. from 1-amino- from i-amino-1,2,3, ^ - 1, / 2,3,4-tetrahydro-tetrahydro-7-7-ethpxy-1-naphethoxy-1-naphthylthoic acid penicillin

N-carboxyanhydride.
from 1-amino-4—
phenyl-1-indan-
carboxylic acid

4- (prop-2-yl) thiosaccharimide from 1-

^ y indanpenioillin

009 # 17/1855

-44-

üaccharimide of

6-aminopenicillan acylation saccharimide der

acid · '_ .means of penicillins

5-ethylsulfonyl- N-oxy anhydride 5-ethylsulfonyl-

saccharimide of from 2-amino-3-saccharimide of 2-

6-APA. phenoxy-2-indan-amino-3-phenoxy-2-

carboxylic acid indanpenicillin

, 5 N-carboxyanhydride 4,5-benzosacchar-

imide of 6-APA of 1-amino imide of 1-amino

1,2,3,4-t-etrahydro-1,2,3,4-tetra-3,6-diraethyl- ^/ 1-hydro-3,6-dimethylnaphthoic acid 1-napb.thylpenicillin

Example 6

The dimethylcarbamoyldimethylsulfamoylimide of ampicillin 6-Amino-313-diraethyl-N-dimethylcarbamoyl-N-dimethylsulfamoyl-7-oxo-4-thia-'1-azabicyclo / 3 »2, o7-neptan-2-carboxamide (the N-dimethylcarbamoyl -N-dimethylsulfamoylimide of 6-aminopenicillanic acid) (7.81 g, 0.02 mol) is in 60 $ water-tetrahydrofuran (200 ml), the N-Garboxy-D-phenylglyoin anhydride (5.32 g, 0.03 mol) contains, dissolved at 0 to 5 ^a , the pH being adjusted to 5 with glacial acetic acid. The solution is stirred for a further 3 hours at 0.5 ° and filtered. The tetrahydrofuran is the aqueous residue adjusted to approximately ⁰ .for O at 0 ° removed under vacuum and the pH. The mixture is filtered to give the title compound as a light yellow solid.

Example 7

Using the general procedure of Example 6

-45-009817 / 1855

but a different series of amides of 6-aminopenicillanic acid than that of Example 6, for acylation by the N-arboxyanhydride of phenylglycine, the corresponding Amido derivatives of ampicillin, as indicated in the table, obtained, the substituents X and Y being the Amido derivatives are given below. ,

Table O

NH-

ο ^ν γ

-CN

-CN -CN -CN -CN -CN -CN

-NO ₂

-NO ₄

-CN -NO,

-SO ₂ C ₂ H ₅ .

-SO ₂ N (C ₂ H ₅ ).

-S0 "CF"

-46-

009117/1855

-NO,

-SO ₂ CF ₅

-SO ₂ CF,

-SO ₂ CF ₅ -SO ₂ CF ₅ -CO ₂ CH ₅ -CO ₂ CH ₅ -CO ₂ CH ₅ -CON (CH) ₂ -CON (CH) ₂ -CON (CHj) ₂ -C0N (CH _{5) 2}

-SO ₂ CF ₅

-CCL

-CON

-SO ₂ C

-so.

₂ N (CH ₅ ) _J

-CON -SO

-SO.

-SO ₂ C ₅ H _n

-CN

-CN

-CN

009817/1855

-so.

-SO ₂ CH ₅ -CO- /

-CO-f .. VBr

-Cl

W ^

-CON (CH ₃ ).

-CO ^

-NO.

-cojn *

^? - ° ^6H ₅

NO, NO «

NO ₂

// Λ

009817/1855

/ ^C 2 ^H 5

-CO

-CN

-CN Cl

CF,

-SO ₂ CF ₃

-CON (CH ₃ ), -SO.

Br

Cl

CON (CHj) ₂

009817/1855

-SO ₃ CP- Cl

-CN «

CH,

-CH ₂ CH ₅

-50-

009817/1855

CH,

CH ₃ CHj

-COC (CHJ ₃

CH ₃ CH ₃ -CH ₂ CH ₂ N (CH ₃ ) ₂

-COCiCEL) -C

6 * 13

-C0C (CH _{3) 3}

CBL

NO.

-CN

-C.

009817/18 5 5

-SO ₂ CH ₃ .CH ₂

-SO ₃ CF- 4 j

-CH-

Example 8 The maleic acid imide of I-aminocyclohexylpenioillin

heptan-2-ylcarbonyl) - ^ \ ^ '-pyrroline-2,5-dione (the maleic acid imide of 6-arrainopenicillanic acid) (5-90 g _t 0.02 mol) is dissolved in 60 $ water-tetrahydrofuran (200 ml), since it contains N-carboxylaminocyclohexanecarboxylic anhydride (5 »O7 S» 0.03 mol), dissolved at 0 to 5 ° and the pH adjusted to 5 with glacial acetic acid. The solution is stirred at 0 bis for 3 hours and filtered. The tetrahydrofuran is removed at 0 ° under vacuum and the pH of the aqueous re-

-52-009817 / 1855

stood set to about 7 at O ⁰ . The mixture
is filtered, whereby the compound named in the title is obtained as a light yellow solid.

Example 9

Are you following the general procedure of Example 8, by mistake? but now a number of amides of 6-amidopenicilanic acid, which have cyclic amido radicals, see above the amides with N-carboxyanhydride of 1-aminocyclohexanecarboxylic acid acylated to form the corresponding amidopenicillin derivatives given in Table D. are.

. Table D.

—C — NH-

LJf

z>

-53-

0-09017 / 185

Z N-

ο-

* N-

SO,

.Il

SO.

.Λ

ι.

0098 ^ 7/1855

ZJS-

Z N-

so.

⁰ ^

S.

N-

.CH ₈

N-

CH.

SO,

N-

SO.

N-

80.

ZV ,, "

■ f

009817/1855

Example 10 VI -: .. «.- ■

Saccharimide of 1-aminocyclohexylpenioillin . 6- (α-aminocyclohexanecarboxaraido) -5,5-dyne] ethyl-7-oxo - ^ - «thia-1-azabicyclo / 5,2,27-neptane-2-carboxylic acid (1-aminocyclohexylpenicillin) (23.4 g , 0.0685 mol) is added to methylene chloride (11), then triethylamine (6.93 Si 0.1685 mol) to form a solution. The magnetically stirred solution is cooled to 3 ° in ice water. 3-Ohlor "-" 1,2-benzisothiazole-1,1-dioxide (13.8 g, 0.0685 mol) is added all at once and the resulting solution is reacted and worked up in a manner similar to Example 1, whereby the compound referred to in the title is obtained as a pale yellow solid (16.5 g »48 #), melting point 174 ° decomposition, (uncorrected).

Analysis: calculated for

(#): 52.16 0, 5.17 H, 11.06 N, 12.66 S.

found (#): 51.12 0.51.06 0.506, 4.90 H, 10.82 N,

11.28 S.

Example 11

oaccharimide of dicloxacillin

6- / F- (2,6-dichlorophenyl) -5-diethylisoxazole-4-carboxamide _; o7 "3,3-dimethyl-7-oxo-4-thia-1-azabicyclo / 5,2, o7-heptane-2-carboxylic acid (dicloxacillin) (47.03 g, 0.1 mol) turns into anhydrous methylene chloride ( 1.5 1), then triethylamine (10.1 g, 0.1 mol) was added to form a solution.

-56-Q09817 / 1855

The magnetically stirred solution is cooled to 5 ° in ice water and J-Ohlor-1,2-benzisothiazole-i, 1-dioxide (20 »2 g _t 0.1 mol) is added all at once. The resulting solution is reacted and worked up in a manner similar to Example 1 to give a raw, pale yellow Sohaura. The foam is crystallized from ethyl acetate with formation of white crystals of the compound named in the heading (10 g, 16%), melting point 192 ° decay (uncorrected). \ ""

Analysis: calculated for O ₂₆ H ₂₀ Cl ₂ N ^ A ₇ S ₂

Wi 49.14 0, 5.1? H, 8.81 N ₁ 10.09 β, 11 "16 Found (#) i: 49.15 0.5.50. H, 8.72 N, 9.83 ö, 11 "15

Example 12 .

Sacoharimide of benzylpenicillin

Triäthylammoniura-3 _t 5-dimethyl-7 ~ oxo-6- (2-phenylaoetamido) -4-thia-1 -azabicyclo / ^ »2, Oy'-heptane-2-carboxylate (benzylpenicillin) (105 s, 0.222MoI) is dissolved in methylene chloride (2.5 l) and the solution is cooled to 3 ° in ice water. Then 3-chloro-1,2-benzisothiazole-1,1-dioxide (44.8 g “0.222 mol) is added to the magnetically stirred solution admitted at once. The resulting solution is reacted and worked up in a similar manner as described in Example 1 »then concentrated at 40 ° under vacuum, whereby white crystals of the compound named in the title are obtained (70 g" 62 $), melting point 193 ° decay, (incorrect

-57-

00 9817/1855

yaws), the mil; cold methylene chloride and anhydrous in Ether to be washed. The filtrate of the crystals gives an additional amount of crude yellow solid (19.5 g)

Analysis: calculated for ° 23 ^H 21 ^N 3 ^Ö 6®2

»(#): 55.30 O ₁ 4.23 H, 8.4-1 N, 12, β4 S found (#): 55.21 0.4 ·, 12 H, 8.41 N, 12.65 S, 0.16 H ₂ Q

♦ '
Example 13 ^ - • - '

Sacoharimid von Phenoxymethylpenicillin The salt of 2- (6-amino-3,3-dimethyl-7-oxo-4-thia-1-aza-bioyclo / 3,2, Ö7-heptan-2-ylcarbonyl) -1,2 -benzisothiazol-3 (2H) -one-1,1-dioxide of p-toluenesulfonic acid (saocharimide of ö-aminopenicillanic acid-p-toluenesulfonic acid salt) (2.21 g, 0.004 mol) is added to a mixture of ethanol (15 ml) , Methylene chloride (15 ml), water (8 ml) and sodium bicarbonate (1.01 g, 0.012 mol) were added and the mixture was stirred at 0-3 °. Phenoxyacetyl chloride (1.36 g * 0.008 mol) in methylene chloride (3 ml) is then added over a few minutes, then more sodium bicarbonate (1.01 g, 0.012 mol) and the mixture is stirred at ° to 3 ° for one hour. Water (25 nil) is added and the mixture is extracted twice with methylene chloride. The methylene chloride solution is then washed twice with water, once with saturated salt and dried over sodium sulfate. The. Solution is then evaporated to a small volume under vacuum at 20 ° and anhydrous ether (approximately 25 ml)

-58-00S8t7 / 1855

■ - 58 -.

admitted what, one referred to in the heading Compound as a white solid (0.75 S »35 #) is obtained. The infrared spectrum is with the authentic connection of Example 1 identical.

Example 14-

Phenoxymethy! Penicillin
2- / 3 »3-Dimethyl-7-oxo-6- (2-phenoxyacetamido) -4-thia-'1- ^ azabicyclo / 3,2, oy-heptan - ^ - ylcarbonyl ^ i, 2-benzisothiazol-3 (2H) -one-1,1-dioxide (saccharimide of phenoxymethylpenicillin) (5.16 g, 0.01 mol) is dissolved in tetrahydrofuran (30 ml) and then a solution of sodium bicarbonate (1.68 g, 0.02 Mol) in water (20 ml) was added. The mixture is stirred magnetically at room temperature for 2 1/2 hours under nitrogen and water (15 ml) is added. Some tetrahydrofuran is removed under vacuum at 30 ° until a cloudy solution is obtained. The solution is stirred for an additional half an hour and then all of the tetrahydrofuran is removed at 30 ° under vacuum. The mixture is washed twice with methylene chloride and all of the methylene chloride is removed at 30 ° under vacuum. Glacial acetic acid (2.4 ml) is then added and the mixture is stirred in ice for 20 minutes and a brown resin is filtered off and washed with water (15 ml). After allowing it to stand for about 2 hours at room temperature, white crystals are formed in the mother liquor (1.2 g, $ 4%). The infrared spectrum

-59-009S17 / 1855

is that of an authentic phenoxymethylpenioillinic acid identical.

Example 15

Sac'jharimide of e-aminopenicillanic acid hydrochloride 2- / 3,3-Uimethyl-7-oxo-6- (2-phenoxyacetamido) -4-thia-1-azabiöyclo / 5 »2,07-heptan-2-ylcarbonyl7- '1,2-Benzisothiazol-3 (2H) -one-1,1-dioxide (the saccharimide of phenoxy ^ ..- * methylpenicillin) (10.3 S »0.02 mol) is dissolved in anhydrous methylene chloride (75 ml ) and Ν ,, Ν-dimethylaniline (8.5 Sj 0.07 mol) added. The solution is cooled to -40 ° by an Acetori dry ice bath and phosphorus pentachloride (4-, 5 ^ S »0.218 mol) is added over a few minutes under nitrogen. The solution is kept at -35 to -40 ° for 3 hours while stirring mechanically. After about 1/2 to 1 hour at this temperature, the saccharimide of 6-Ohlorimidophenoxymethylpenioillin forms as a white crystalline material. Then 1-butanol (75 ml) is added over approximately 1 hour at -35 to -4-0 ° and this temperature is maintained for 3 hours, whereby the saccharimide of 6-butoxyimidophenoxymethylpenicillin hydrochloride is obtained. Then water (40 ml) is added to the rapidly stirring mixture added, the temperature being allowed to rise to 0 to 5 °. The mixture is stirred at this temperature for 1 hour and then left to stand overnight at 0 ° without stirring.

-60-009817 / 1855

permit. The mixture is filtered and the solid .mit. · Washed with anhydrous ether, forms a white pest of the compound named in the heading (2.5 s, $ 29), melting point 172 °, decay (uncorrected)

Analyzes calculated for O ^^ cNxQcSg.Ή01.1 / 2H ₂ O (#): 42.20 0, 4.01 H, 9 * 84 N, 15.02 S, 2, ^ 0 H ₂ O

found (#) ι 42.57 0.399 H, 9.14 N, 13.40 S, 1.99 H ₂ O ..

- «■■ · '

Example 16 6-aminopenicillanic acid

2- (6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo / 3,2, O7-hept-2-ylcarbonyl) -1,2-benzisothiazol-3 (2H) -one Dissolve -1 _{t of} 1-dioxide (the saccharimide of 6-aminopenicillanic acid) (7.64 g, 0.02 mol) in tetrahydrofuran (60 ml) and add a solution of sodium bicarbonate (3.36 g, 0.04 mol) in Water (40 ml) was added all at once. The mixture is stirred at room temperature for 3 1/2 hours to give a solution. The tetrahydrofuran is then stripped off at 30 ° under vacuum and the resulting mixture washed with methylene chloride. The aqueous fraction is then placed in a rotary evaporator at 30 ° and the dissolved methylene chloride is removed. The solution is filtered and the pH is adjusted to 3.8 with glacial acetic acid. The mixture is stirred in ice water for 20 minutes and then filtered, whereby 6-aminopenicillanic acid is obtained as white crystals .

-61-00S817 / 185 5

19460B9

Example 17 . -.

The procedure of Example 15 is followed using a series of saccharimide derivatives of phenoxymethylpenicillin as Precursors for the formation of the corresponding ßacchariraide. of 6-aminopenicillanic acid can be used as described in Table E below is given. The saccharin chloride as such (for example 3-chloro-1,2-benzisothia-ζοΐ-ΐ, ΐ-dioxide, that is required to make the sacoharimid. ©, of penicillin) is commercially available.

2. 5

The benzene ring substituents R and R ^ are condensed in the Saccharin chloride benzene residue introduced using conventional methods.

Table E.

Saccharimide derivative of phenoxymethylpenicillin

4-ethyl saccharimide of Phenoxymethylpenicillin

4-propyl-5-chlorosaccharimide of phenoxymethylpenicillin

M-- Nitrosaccharimide of phenoxymethylpenicillin

4,5 - uibromosaccharimide of Phenoxyraethylpenicillin

4-hexyl saccharimide from Phenoxymethylpenicillin

4-butoxy-5-phenylsac ο hariraid of phenoxymethylpenicillin

5- (p-methoxy) phenyl saccharimide of phenoxyniethylpenioillin

Oaccharimide derivative of 6- aminopenicillanic acid

4-iithyl saccharimide of 6-aminopenicillanic acid

p ^
of 6-aminopenicillanic acid

4-nitrosaccharimide of 6-aminopenicillanic acid

^ i-, 5-dibromosaccharimide of 6-aminopenioillanic acid

4-hexylsacohariraid of 6 ~ aminopenioillanic acid

4-butoxy-5-phenylsaooharimide of 6-aminopenioillanic acid .

5- (p-Methoxy) -phenylsaoohar imide of 6-aminopenioillanic acid

00S817 / 1855

.62 «

Sacchariniide derivative of Ptienoxymet hy! Penicillin

4-phenyl saccharimide from Phenoxymethylpenicillin

5-benzyl saccharimide of phenoxyniethylpenicillin

7- (m-propoxy) phenyl saccharide of phenoxyraethylpenicillin

M- butyl-5-fluoro saccharimide of phenoxymethylpenicillin saccharimide derivative of 6- aminopenicillanic acid. ., «. ·

^ - phenyl saccharimide of 6-aminopenicillanic acid

5-benzyl saccharimide from 6-arainopenioillanic acid

7- (ra-propoxy) phenyl saccharimide of δ-aminopenicillanic acid

• ^ -Butyl - ^ - fluorosaooharimide. of 6-aminopenioillanic acid

Example 18 . .

The procedure of Example 15 is followed again, but in this case a number of saooharimide derivatives of benzylpenicillin are used as precursors and the corresponding ones are obtained. Saccharimide derivatives of 6-aminopenioillanic acid, as indicated in ^{Table i 1 below.}

! Table Έ

öacchariniidderivat benzylpenicillin

4- (2-pyridyl) -5-methyl saccharimide of benzyl penicillin

5-trifluoromethyl saccharimide of benzyl penioillin

6- (Diraethylamino) -7-methyl saccharimide of benzyl penicillin

7- (Diethylaraino) -saoohariraid of benzylpenicillin iäaccharimide derivative of 6-aminopenicillanic acid

4- (2-pyridyl) -5-methyl sacoharimide of 6-aminopenicillanic acid

5-trifluoromethylsacoharimide of 6-aminopenicillanic acid

6- (dimethyl) amino-7 ~ ¹ nethylsaccharimid of 6-Aminopenioillansäure

7- (dimethyl) aminosaccharimide of δ-aminopenioillanic acid

00SÄ17 / 1855

Saccharimide derivative of benzyl penicillin

4-Garbaraoyl saccharimide of benzyl penicillin

6-sulfamidosaccharimide of benzyl penicillin

4-, Carbethoxysaccharimide of benzylpenicillin

4-cyanosaccharide of Benzyl penicillin

4- (I »ropyl-2) -thiosaccharimide of benzyl penicillin

5-ethyl sulfonyl saccharimide of benzyl penicillin

4- (4-pyridyl) saccharimide of benzyl penicillin

4,5-benzosaccharimide of benzylpenicillin saccharimide derivative of e-aminopenicillan acid ""

4-Oarbamoyl saccharimide of 6-aminopenicillanic acid

6-sulfamidosaccharimide from 6-aminopenicillanic acid

4-carbethoxysaccharimide of δ-aminopenioillanic acid

4-Oyanosaccharimide of 6-aminopenicillanic acid

4- (Propyl-2) -t hio sao chariinid of 6-aminopenicillanic acid

^ -Ethylsulfonylsaccharimide of 6-aminopenicillanic acid

4- (4-pyridyl) saccharimide of 6-aminopenicillanic acid

4,5-benzosaocharimide from 6-aminopenioillanic acid

Example 19

Following the general procedure of Example 15 a number of amidophenoxymethylpenicillins, others used as the accharimides thereof are the corresponding Acyl-protected derivatives of 6-aminopenicillanic acid, as indicated in the formula (I), whose separate substituents X. and Y. in the foregoing ! Table O. and cyclic substituents -NC in the

Y
Table S of Examples 7 and 9 are given.

Example 20 Hacc'harimid of cephalothin

Triethylammonium-3-acetoxymethyl-8-oxo-5-thia-7- (thiophene

009817/1855 -64-

2-acetamido) - ^f l-azabicyclo / ^z f _f 2, o7-oot-2-en-2-oarboxylate (3 »3 S» 0.00663 mol) is dissolved in methylene chloride (100 ml) and the solution is dissolved 3-chloro-1,2-benzisothiazole-1,1-dioxide (1.33.6, 0.00663 mol) is then added all at once to the magnetically stirred solution, and the solution is left to stand overnight Warm up to room temperature, whereby white crystals are obtained, which are washed with cold methylene chloride to form 2- / C3-

bicyclo _i / 4,2 _i o7-oct-2-en-2-yl) -carbonyl7-1 ».2-benzisothiazol-3 (2H) -one-1,1-dioxide acetate, which is also referred to as the sacoharimide of cephalothin will (1.8 g, $ 48), melting point 160 ° decay, (uncorrected) ..

Analysis «calculated for CgxH ^ gN ^ OgSx

'(#): ^ 9.19 0, 3.41 H, 7.48 N, 17.13 S found (%) i 49.49 0, 49.52 0, 4.07, 3.99 H, 7i .? 6 N,

17.01 p.

If the above process is repeated and the triethylammonium salt of Cephalothin.mit a suitable substituted saccharimide is used, the following are Get connections:

5-methoxysacoharimide of cephalothin, • 5,6-diohlorsaccharimide of cephalothin, •. , 4-chloro-6-ciodosacqharimide of cephalothin ,, 7-S ¹ luor-5-phenethylsacoharimid of cephalothin,

-65 *

009817/1855

'. ₆₅ - 194608a

5-ethoxyphenyl saccharimide of cephalothin, 5- (N-ethyl-N-methylaraino) -saccharimide of cephalothin » ö-carbomethoxysaccharimide of cephalothin, 5-chloro-6-methylthiosaccharimide of cephalothin,

6-carbethoxysaochärimide of cephalothin and ι

5-methylsulfonyl saccharimide of cephalothin.

Example 21

'ill I. - _- Λ ·· '· <*

Saocharimid of 2-ethoxynaphthylpenicillin 6- (2-ethoxy-1-naphthamido) -5 * J-dimethyl-y-oxo - ^ - thia-iazabicyclo / 5,2,07-heptane-2-carboxylic acid (20.7 g » 0.050 mol), also known as 2-ethoxynaphthylpenicillin, is added to methylene chloride (750 ml), then triethylamine (5 »O5 6» 0.050 mol). ^ -Chlor-i ^ -benzisothiazol-i, '! - dioxide (10 , 1 g, 0.050 mol) is added to the cooled solution (approx. 5 °) in a single addition with stirring and the reaction mixture is processed in a manner similar to that given in Example 1. The product obtained as a foam is converted to a resinous solid after heating with absolute ethanol (approximately 500 ml) and cooling and scratching. The crude product is uracrystallized from ethyl acetate-hexane (charcoal), resulting in white crystals of 2- / T6- ^ 2 "-ethoxy-1-naphthamido7-5i3-dimethyl-7-oxo-4-thia-i-azabicyolo ^ 5,2,07-hept-2-yl) -carbonyj ^ - '^ l -benzisothiazolin-J-on-ijji-dioxide is obtained, which also as öacoharimid of 2-Ä £ hoxynaphthylpenioillin

-66-

00M17 / 186S ν

is designated (1.5 g), melting point 180 ° disintegration (un corrected).

Analysis: calculated for O ₂₈ H ₂ CNvOr ₇ S ₂

(#): 58.02 0, 4.34-H, 7.25 N, 11.07 S found (#) «. 58.17 O ₁ 4.51 H ₁ 7.50 N, 10.90 Su,

22nd

Following the in Examples 1, 2, 20 and 21 besohrie ¹ - surrounded method, and identifying a legs of penicillins with different Saccharinchloridderivaten to, one obtains the corresponding Saccharimide of penicillins with strong antibiotic activity. The reactants and the resulting saccharimides of the penicillins are given in Table G below.

Table G.

Penicillins saccharin chloride saccharimides from . derivative penicillins

Phenoxymethyl-3-chloro-5-ethyl-1,2-5-ethyl saccharimide penicillin benzisothiazole-1,1- of phenoxymethyl-

penicillin dioxide

6- (2,2-Dimethyl-3,5-dichloro-6- ^ -propyl-ip-chloro-5-oxo-4-phenylpropyl-1,2-benz saccharide of 6-imidazolidine-1-isothiazol-1,1- (2,2 ~ Mraethyl-5-yl) -penioillandioxid oxo-4-phenylimidazo

acid lidin-1-yl) -peni-

cillanic acid

2-ethoxy-J-chloro- ^ nitro- 5-nitrosacbharimide naphthyl-1,2-benzisothiazole- of 2-ethoxynaphthylpenioillin 1,1-dioxide penicilllin

-67-Ö0S817 / 1855

Penicillins

Phenoxyprop-1-ylpenicillin

3- (2,6-dichlorophenyl) -5-methyl-4risoxazoyl penicillin

3-phenyl-5-

inethylf4-isox-

azoylpenieillin

3- (p-Chlorophenyl) -5-methyl-4-isoxazoylpenicillin

Benzyl penicillin

Phenoxyethyl
penicillin

2-methoxy

naphthyl

penicillin

3- (o-chlorophenyl) -5-4-isoxazoyl
penicillin

Accharin chloride derivatives

3.5 ~

ißoxazoylpeni-

oillin

ar-phenoxybenzyl
penicillin

1,2-benzisothiazole 1,1-dioxide

1,2-benzisothiazole 1,1-dioxide

6-butoxy-3-chloro-5-phenyl-1,2-benzisothiazole-1,1-dioxide

3-chloro-5- (p-ynethoxyphenyl) -1,2-benziaothiazole-1,1-dioxide

3-chloro-6-phenyl-1,2-benzisothiazole " 1,1-dioxide

5-benzyl-3-chloro-1,2-benzisothiazole-1,1-dioxide

3-chloro-7- (m-propoxyphenyl) -1,2-benzisothiazole-1,1-dioxide

fluoro-1, 2-benzisothiazole-1,1-dioxide

3-chloro-5,6-diraethyl-1,2-benzisothiazole-1,1-dioxide

3-chloro-4- (2-pyridyl) -1,2-benzisothiazole-1,1-dioxide

Saccharimides of penicillins

4,5-dibromosaccharimide of phenoxyprop · 1-ylpenioillin

5-hexyl saccharinide of 3- (2,6-dichlorophenyl) -5-raethyl-4-isoxazoylpenicillin

6-butoxy-5-phenyl saccharimide of 3 ~ phenyl- 5-ni et hy 1-4-isoxazoylpeniciliin

^ - (p-methoxyphenyl) - sacchariraid of 3- (p-chlorophenyl) -5 ~ methyl-4-isoxazoyl penicillin

δ-phenyl saccharimide of benzyl penicillin

^ -Benzylsaochariiiiid of phenoxyethyl penicillin

7- (m-Propoxyphenyl) * »saccharimide of 2-methoxynaphthylpenioillin

6-butyl-5-fluorosaccharimide of 3- (o-chlorophenyl) -5-diethyl-4-isoxazoylpenicillin

5, δ-dimethyl saccharide of 3t5-diphenyl 4-isoxazoyl penicillin

4- (2-pyridyl) sacchariraid of a-phenoxybenzylpenioillin

009117/1855 -68-

Saccharin chloride saccharimide.yp.n ... Penicillin derivatives penicillins

a-phenoxyethyl- 3-chloro-5-di ~ 5-dimethylamino-

penicillin methylamine- ^, 2- saccharimide by oe-

benzisothiazole- phenoxyethylpeni-

1,1-dioxide oillin

2,6-dimethoxy-. 5-chloro-6-trifluoro-6-trifluoromethyl- benzylpenicillin methyl-1,2-benzisosaccharimide of 2,6-

thiazole-1,1-dioxide dimethoxybenzyl

penicillin

Example 23

Saccharimide of I-Aminooyclohexanpenicillin ² ~ Zr6-Amino-5 _i 5-dimethyl-7-oxo-4-thia-1-azabioyclo / 5,2, o7-hept-2-yl) -oarbonyl7-1,2-benzisothiazole- 3 (2H) -one-1,1-dioxide (1.91 S, 0.005 mol) is dissolved in methylene chloride (100 ml) and the stirred solution is cooled at -5 ° in an ice bath ^. Pyridine (0.403 ml, 0.005 mol), then 1-aminooyclohexanecarboxylic acid chloride hydrochloride (1.02 g, 0.005 mol) are added and the mixture is stirred at -5 ° 20 minutes. The resulting solution is allowed to warm to room temperature and then stirred for two hours to give a white solid precipitate. The mixture is cut in half and filtered one half. And washed with methylene chloride to give 2 -_ ^ C6- (1 -Aminooyolohexanecarboxamido) -3,5-dimethyl-7-oxo-4-thia-1-azabicyolo / 5,2, o7-hept-2-yl) -carbonyl7-i _t 2-benzisothiazol-3 (2H) -one- 1, i-dioxidhydrοChlorid, also known as uaocharimid of 1-Aminooyolohexanpenicillinhydroohlorid, obtained as a white solid (1.15 g, 85 #, based on the

009.117 / 1855

Half of the total yield β), melting point 153 ^ 'decay., (Μη-corrected). .

Analysis: calculated for 0 ₂ 2

(#): 48.65 O, 5.01 H, .10.32 N, 11.81 S, 5 * 01 01

found (#) »48.71 0.5.12 H, 10.14 N, 10.25 S, 9.83 01. ι

The other half of the mixture is left to dryness under vacuum evaporated at 30 ° to give a white solid (1.7 s). The solid is pulverized and turned into water (15 rol) added at 3 °, the constant at pH 9 »4 with 1 N sodium hydroxide is held. The mixture is filtered 10 minutes after the final addition and washed with water, which gives 2- / C6- ^ fr-aminocyclohexanecarboxaraid £ 7 ~ 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo ^ »2,07-hept-2-yl) -oarbonyl7-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide , also referred to as the saccharimide of I-aminocyolohexanpenioillin, obtained as a white solid (1.25 g, 99 #, based on half the total yield), melting point 145 ° decomposition (uncorrected).

Analysis: calculated for öp2 ^H 26 ^N 4 ^ 6 ^S 2 * ^fl '2 ^O *

Wx 50.37 0, 5.38 H, 10.68 N, 12.23 S, 3.44. H ₂ O found ($) i 49.78 O ₁ . 5.54 H, 11.11 N, 12.59 S, 3.34 HgO.

Example. 24

When 4 and 23 using the methods of Examples and a series of Saooharimiden the east-Äminopenioillansäure

008817/1855

(6-APA) reacts with various acylating agents, so one obtains Saceharimide of penicillins with strong antibiotic Effectiveness. The reactants and the sac char imide of the penicillins obtained are in the -naöhfol-? Table H given below.

Saceharimide of 6-aminopenicillanic acid (6-APA)

5y (pyridyl) saccharimide from 6-APA

5-trifluoromethyl saccharimide from 6-APÄ

6-dimethylamino-7-methyl saccharimide from 6-APA *.

6-sulfamidosaccharimide by 6-APA-

5-carbethoxysaccharimide of 6-APA.

5-oyanosaooharimide of 6-APAl

6- (Prop-2-yl) -thio «sacohariraid of 6 APE.

Table H.

acylating agent

N-carboxy anhydride of 1-aminocyclopentanecarboxylic acid

N-oxy anhydride of 1-aminocyclohexanecarboxylic acid

Phenylglycine chloride hydrochloride

W-Oarboxyanhydride of i-amino-1-indanecarboxylic acid

N-carboxyanhydride; of 1-amino-1,2, 3,4-tetrahydronaphthioic acid

N-Oarboxyanhydride of i-Amino-7- ethoxy-1,2,5,4-tetrabydro-inaphthoic acid

N-carboxyanhydride of i-amino-4-phenyl-1- indanoarboxylic acid

Sac charimid— ' penioilline

5y (pyridyl) saccharimide of Ί-aminocyclopentane penicillin

5-trifluoromethyl saccharimide of Λ— aminocycloliexane penicillin

6-dimethylaraino-7-methyl saccharimide of 1-aminot> enzylpenicillin

6-sulfamidosacchariraide of 1-amino-1-indanp eni cillin

5-carbethoxysaccharimide from 1-

tetrahydronaphthylpenicillin

5-öyaiio sac c herimid of i-amino-7-ethoxy-1,2,3,4- ^ tetrahydro-1-naphthatylpulphilin

6- (prop—
i

Amino-4-phenyl-1-indanpenioillin

009817/1855

Saccharimides of 6-aminopenicillanic acid (6-APA)

5-ethyl sulfonyl saccharimide from 6-APA

5 _f 6-Benzosacchariraid from 6-APA

Acylation

roittel

N-carboxy anhydride. of 2-amino-3-phenoxy-2-indanecarboxylic acid

N-carboxyanhydride of 1-amino-1,2,3 ,. tetrahydro-3,6-dimethyl-1-naphthoic acid sacchariniid - penicillins

5-ethyl sulfonyl saccharimide of 2-amino-3-phenoxy-2-indanpenicillin

5,6-benzosaccharide of 1-amino-1,2,3,4-tetrahydro-3 »6-dimethyl-1-naphthylpenicillin

Example 25

Repeating the procedure of Examples 6 and 7 and the 2-amido-6-aminopenicillanic acid and 2-amido-7-aminocephalosporanic acids are acylated by reaction with appropriate N-carboxyanhydrides, the compounds become of Tables I, J, K, L and M are obtained.

Table I.

where X and Ϊ are defined separately as follows »

X p-nitrophenylsulfonyl

p-'frifluoromethylphenyleulfonyl

m-nitrobenzoyl p-methylsulfonylbenzoyl

009S17 / 1855 -72-

2,4-dinitrophenylsulfonyl p-chlorophenylsulfonyl Irifluoromethylsulfonyl

m · »· (N, N-diethyl sulfamyl) -benzoyl

Garboniethoxy.

Cyano

Oyanp

Trifluoromethylsulfonyl · N | N ~ dimethyloarbamyl p-toluyl
p-methoxybenzoyl

p- (N, N-dimethylsulfamyl) -benaoyl

p-trifluoromethylbenzoyl

p-trifluoromethylbenzoyl o-Chlorophenylsulfonyl ^ vm-Trifluorraethylphenylsulfonyl p-nitrophenylsulfonyl 2-broin-4-chlorophenylsulfonyl

Table J

-NH

OH ₂ OCOCH ₃

wherein X and Y- _{t are} separately defined as follows: ";

Methylsulfonyl N, N-dimethylsulfamyl

Oarbohexoxy
Oarbethoxy

iErifluoromethylsulfonyl 2-bromo-4-nitrophenylsulfonyl

m- (N, W-Dira ethyloarbainyl) phenylsulfonyl

p-methylsulfonylphenylsulfonyl

p- (N, N- diethylsulfamyl ) -phenylsulfonyl

4-cyano-2-quodophenylsulfonyl

00SS17 / 1855 -75-

Cyano
Pentylsulfonyl 2-: fluoro-4- nitrophenylsulfonyl p-Oarbobutoxyphenylsulfonyl

Table K

IH— C NH '

Il O

CH ₂ OCOCIL

where X and J are defined separately as follows t

Propionyl

Acetyl

Propionyl

Cyano

2,4,6-triraethylbenzoyl.

2,4-, 6-trimethylbenzoyl N, N-dimethylcarbamyl 2,3,5 »δ-tetramethylbenzoyl

Cyolovaleryl.

p-iodobenzyl sulfonyl butyryl

Benzoyl

Phenylsulfonyl phenethylsulfonyl p-methoxyphenylsulfonyl W, W-Diinethylaiiiinoäthylsulfoiiyl p-methylthiophenylsulfonyl in-nitrophen ethyl sulfonyl

Table L.

CH ₂ OCOCH.

009817/1855

wherein X and Y _{1 are} separately defined as follows: i

N, N-Dipropylarainobutyl- sulfonyl

Cyano

Oyolobutyryl Oyolocaproyl Furoyl * '

N, N-dimethylsulfainylphenpropionyl p-propylphenylsulfonyl 2-naphthylsulfonyl. Phenbutyryl 2-furylsulfonyl 2-naphthoyl

2,4-dimethyldenzoyl p-pluorphenac etyl Trifluoromethylsulfonyl Oyano carbopropoxy

Acetyl p-butoxybenzoyl nitro Oaproyl

Table M.

C-NH

where X and I ₁ are defined separately as follows »

2-pyridylsulfonyl Phencaproyl.

Phenpropylsulfonyl

p-Propylsulfonylphenyl- sulfonyl methylsulfonyl Oyano Trifluorm ethylsulfonyl Oyano

009817/1855 -75-

Nitro p- (N, N-dibutylcarbamyl) -phenyl

sulfonyl

ra-carbomethoxyphenyl-carbethoxy

sulfonyl

p-propoxyphenylsulfonyl methylsulfonyl

Cyano p-pentylthiophenylsulfonyl

Example 26

Following the general procedure of Example 8 and acylating a number of 2-0ycloamido-6-aminopenicillanic acid by reaction with N-carboxyanhydride of 1-aminocyclohexanecarboxylic acid, the corresponding 2-0ycloamidopenicillin derivatives, which are given in Table N below, are obtained are:

Table N.

wherein X and X. together with the nitrogen atom with the they are connected, the following cyclic electron removing groups form ι.

5-ethyl-5-oxo-1 ^ -benzisothiazolin ^ -yl-i, 1-dioxide, 4-methoxyphthalimido,

009617/1855

6,7-Mchlor-3-oxo-4 ·, 1,2-benzodithiazine ~ 2 (3H) -yl-1,1-. . dioxide, -

3-0xo-6-nitro-1,4,2-benzodithiazine-2 (3H) -yl-1,1-dioxide;

diazin-2-yl-1,1-dioxide,

3 »3,4,4-tetramethyl-2-oxo-1-pyrrolidinyl, 6-broin-3 _i 4-dihydro-2 _i 4-dioxo-2H-1,3-benzoxazin-3-yl,

7-irifluoromethyl-3,4-dihydro-2,4-dioxo-2H-1 ₁ 3-benzothiazin _r 3-yl, '

7-ethylsulfonyl-1,4-dihydro- ^/ l-methyl-2, quinazolinyl,

i-2-yl-1,1-dioxide ,, ■ 5-benzyl-1-oxo-2-isoindolinyl,
2-isothiazolidinyl-1,1-dioxide,

6-chloro-3,4-dihydro-7-methyl-3-oxo-2H-1,2-benzothiazin-2-yl-1,1-dioxide,

7-Oarbomethoxy-3, ^ - dihydro-1,3-diGxo-2 (1H) -isoohinolyl ^ o-benzenedisulfonimido and
o- (3-bromobenzene) -disulfonimido ..

Example. 27

The general procedure of Example 8 is repeated, taking a number of i-Cycloamido ^ -aminocephalosporins acylated, being reacted with N-Oarboxyanhydride of I-aminocyclohexanecarboxylic acid and on this © Way the corresponding 2-Oycloamidocephalosporinivate of the following table 0 receives:

-77-009117 / 1855

■ 1946083

Or

Table 0

τΐΛ-

^ J ν J- CH ₂ OCOCiL

I ο

where * Χ and Y. together rait the nitrogen atom with the they are connected, the following cyclic electron-removing To form groups:

5-iithyl-3-oxo-1,2-benzisothiazolin-2-yl-1,1-dioxide, phthaliraido,
öuccinimido,

3-0xo-2-isothiazolidinyl-1,1-dioxide, 3-oxo-4-isothiazolin-2-yl-1,1-dioxide,

6,7-dichloro-3-oxo-4,1,2-benzoxathiazine-2 (5H) -yl-1,1-dioxide,

3-Oxo-i, 4,2-benzodithiazin-2 (JH) -yl-1,1-dioxide,

6-Cyano ~ 3,4-dihydro-4-methyl-3-oxo-2H-1,2,4-benzothiadiazin-2-yl-1,1-dioxide ^

iCetramethylsuccinimido,

3,4 - dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl,

7-1'rifluoromethyl-3,4-dihydro-2,4-dioxo-2H, 1,3-benzothiazin-3-yl,

^, .4-dioxo-3 (2H) -ohinazolinyl, 1, .2-Benzisothia2olin ~ 2-yl-1,1-dioxide, 5-senzyl-1-oxo-2-isoindolinyl,
2 ~ isothiazolid.inyl-1,1-dioxide,

-78-009117 / 1855

2-0x0-1 -pyrroXidinyl ,.

3,4-Dihydro-3-oxo-2H-1,2-benzothiazin-2-yl-1,1-dioxide

7-0arbomethoxy-3 »4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl. and

o-benzene disulfonimido,

Example 28

Saochagimides of I-Aminooycloaliphatic Penicillins In a manner similar to Example 10, suitable I-aminocyoloalkane penicillins are reacted with 3-chloro-1,2-benzisothiazole-1,1-dioxide, whereby the following compounds are obtained:

I-aminooycloheptane penicillin saccharimide, I-Aminooyclooctane penicillin saocharimide and 1-aminocyolononane penicillin saccharimide

Example 29

Saccharin lid of various penicillins If the procedure of Example 13 is repeated, the following compounds are produced using suitable reaction partners:

21ö-Dipropoxybenzylpenioillinsaccharimid, 4-Butoxynaphthylpenicillinsacoharimid, Naphthylpenicillinsacchariroid,
3- (2,6-dibromophenyl) -4-isoxazoylpenioillin saochariraid,

3- (2-E ¹ luoro-4-oodphenyl) -5-propyl-4-ieoxaaoylpenioillinsacchariraid,

0SS17 / 1855

■ -79- 194608a

5-ethyl-3- (p-fluorophenyl) -4-isoxazoylpenicillin- "' saccharimide,. ...

1-Amino-4-chloro-i, 2,5,4-t etrahydronaphthylpenicillin sacchariraid,

1 -Araino - ^ - brora-5-met; hoxy-1,2,3,4-t etrahydronaphthylpenicillinsacoharimid,

6- (2,2 ~ DiT3utyl-5-oxo-4-phenylimidazoiidin-1-yl) -penicillan acid saccharimide,

6- (2-Ethyl-5-oxo-4-phenyliniidaziolidin-1-yl) -penioillan T. acid sacchariinid,

6- / 5-0xo-4-phenyl-2- (4-p ip eridin) -iraidaz olidin-1 penicillan acid saccharimide,

6- (2-0yclobutyl-5-oxo-4-phenylimidazolidin-1-yl) penicillanic acid sacchariraid and

6- (2 ~ 0yclohexyl-5-oxo-4-phenylimidazolidin-i-yl) penicillic acid saccharimide.

Example 30

If the procedure of Example 13 is repeated and 2 / T7-amino-3-hydroxym-ethyl-8-oxo-5-thia- ^/ 1-azabicyclo / 4,2,07-oct-en-2-yl) -carbonyl7 -1,2-benzisothiazol-3 (2H) -one-1,1-dioxidaoetate is reacted with a suitable acylochloride, the compounds given in Table P are prepared:

Table P

CHjPCOCH ₅

-80- 009817/1855

where R has the following meaning:.:, - ,. -, .. '

2-phenoxyacetamido,

2,2-Dimethyl-5-oxo-4-phenylimidazolidin-1-yl _t , thiophene-2-acetamido,

2-Athoxy-1-naphtharaido ₉

2-amino-2-phenylac et amido,

I-aminocyclohexanecarboxamido,

2-phenylacetanido, - · "- '

I-aminocyclopentanecarboxamido,

1-naphthamido and

$ - (2,6-Mchlorophenyl) -5 ~ -niethyl-4-isoxazoloarboxamido.

Example 31 Various penicillins and cephalosporins

If the procedure of Example 14 is carried out and instead of the saccharimides of Examples 1 to 5, 10 to 13, 17, 18, 20 to 24, 26 to 30, 35 to 37 and 41 the corresponding 3-acetoxymethyl-8-oxo are used as starting materials ~ 5-thia-7-substituted-1-azabioyolo ^ 4 ", 2 _f o7-oot-en 2-carboxylic acids are used, 3 _i 3-dimethyl-7-oxo-6-substituted-4-thia-1- azabioyolo ^ B>, 2,07-heptane-2-carboxylic acids.

Example 32 I-aminocyclohexanepenioillin

2- ^ T6-Amino-3 , 3-dimethyl-7-oxo-4-thia-1-azabioyolo / J, 2,

008117/1855

hept-2-yl) carbonyl7-1,2-benzisothiazol-3 (2H) -o, n-'1,1-dioxide hydrochloride (80 g, 0.1725 moles on a 98 # basis Purity) is added to a solution of acetonitrile (1200 ml) and water (300 ml), previously warmed to 35 was added .. The mixture quickly becomes about 30

Stirred seconds, causing the solid to dissolve. The solution is stirred and placed in an ice-salt bath cooled and at 11 ° the pH to 2.5 to 3, Q with 35 # igem Sodium hydroxide set. I-aminocyclohexanoarboxylic acid chloride hydrochloride (43.6 g, 0.22 mole) is added in approximately 10 strokes over a period of approximately 15 minutes admitted. The temperature is kept at 8 to 10 ° and is simultaneously with the addition of the acid chloride Sodium hydroxide added to keep the pH at 2.5-3. After all of the acid chloride has been added, the The mixture was stirred at pH 2.75 at 0 ° to 10 ° for 20 minutes and the pH was then adjusted to 2.0 with concentrated hydrochloric acid. The stirring is stopped and the top layer is removed by decantation. Anhydrous ether (2.4 l) is added to the top layer and the mixture to 5 ° in Ice-salt cooled and stirred for one hour. The solid is filtered and the organic solvents are passed through Evaporation removed. The resulting solid is pulverized, stirred with cold water (140 ml), filtered and washed once with cold water * The pasty filter cake is sprayed onto filter paper, air-

-82- 009817/1855

dried to strength, pulverized and _{vacuum dried over P 0} Qc ^to give a white powder containing 2- / C6- / T ~ aminocyclohexanecarboxamido7-3 $ 3 ~ dimethyl-7-oxo-4-thia-1-azabicyclo2 ^ 5,2,07-hept-2-yl) -carbonyl7-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide hydrochloride and also referred to as saocharimide of I-aminooyol.ohexanpenioillin · 'hydroo.hloride becomes (21 g, 22 $), * ■

- **** * '*' Cold water (1JO ml) is added to the lower layer and the solid filtered using a funnel. The filter cake is washed twice with cold water and the pasty filter cake is sprayed onto filter paper and dried. The solid is pulverized and ^{dried over PpOc ^ m} vacuum to give a white powder which is also the saocharimide of 1-aminocyolohexane penicillin hydrochloride (50 g,

The accharimide of 1-aminocyclohexane penicillin hydrochloride prepared above (4.0 g, 0.00737 mol) is mixed with water (20 ml) until it is completely suspended *. Chino liri (4 ml) is added dropwise over approximately 3 minutes to give a thick white paste. Mixing is continued for an hour, causing most of the solid to dissolve but leaving a resin on the walls of the flask which is scraped into solution. The mixture is filtered and washed with water (5 ml). The filtrate is cooled to 0 ° and the

9 817/1855

pH brought to 7.6 with 25 $ NaOH. The Geraisch is twice with. Ether washed and antipyrine (1.2 g, "0.0064 mol) admitted. The solution is cooled to -3 to -5 ° and the pH adjusted to 1.5 while crystals form .. After 10 minutes the mixture is filtered and the filtrate is removed washed with ethyl acetate. The pH of the aqueous phase is increased to 5.2 with 25 # strength sodium hydroxide and the solution concentrated to 7 »5 ml at 50 °. The solution is made with a few crystals of I-aminocyclohexanepeni- "" cillin dihydrate and a few crystals of anhydrous I-aminocyclohexanepenicillin. Isopropanol (approx 1 ml) is added and after scratching it forms crystals. The crystals will rest at 0 ° overnight let, filtered and washed with a minimum of cold water, giving white crystals of 6- (1-aminocyclohexanecarboxamiäo) -3 »3-dimethyl-7-oxo-4-thia-1-azabicyclo / J ^ jO ^ -heptane ^ carboxylic acid dihydrate (1.37 St 5 ^ #) receives.

Example 33

3,3-Dimethyl-7-oxo-6- (2-phenoxyacetamido) -4-thia-1-azabicyclo _i / 3 »2, o7-heptane-2-carboxylic acid, also known as Ehenoxymethylpenicillin, (15» 1 6 » 0.04-3 mol) is converted to anhydrous methylene chloride (150 ml) »which is stored in a dry 500 ml three-necked round bottom flask equipped with a stirrer, drying tube and thermometer ,

009817/1855

- 8Ί- -

is included, added through a U-shaped nitrogen outlet ''. Then triethylamine (4.54 g _s 0.043 '"mol") ^' is added and the solution is cooled to 5 ° in ice. Pseudosaccharinchlorid (8.7 g ₅ 0.043 mole) is added at once, thus obtaining a canary yellow solution. The solution is stirred for half an hour at 5 ° and kept at room temperature overnight. The solution is then brought to the boiling point for 5 minutes and allowed to cool to room temperature with formation of 2 - / ('3,3-Di'- * - "' methyl-7-oxo-6- / 2-phenoxyacetamide £ 7-4-thia-1-azabicyclo- / 5,2,07-hept-2-yl) -carbonyl7-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide, also as the saccharimide of phenoxymethyl * denotes penicillin.

Then ohinolin (14.5 6, 0.112 mol) is added and the stirred solution, which contains the saccharimide and the mixture, cooled to -30 ° and phosphorus pentachloride (11.6 g, 0.056 mol) added over a few minutes, the Temperature is kept at -30 °. The mixture is stirred for 3 hours at -30 ° with formation of 2- / C6- / T-chlorine ~ 2- phenoxyäthylidenamino7-3> 3-dimethyl-7-oxo-4-thia-1-azabioyclo / 3.2,07-hept-2-yl) carbonyl7-1,2-benzisothiazol-3 (2H) -one-1, i- dioxide, the same as the accharimide of 6-0hlorimidophenoxymethylpenioillin is known. A small part of this Gemisohs is separated and 6-Chlorimid isolated Analyzes calculated for ^ δ ^ Ο ^^ δ ^ δ ^

00: 51.73 O, 3.78 H, 6.6401, 7.87 N, 12.01 S. found (#): 51.92 0, 3.91 H, 6.16 Ql, 7.76 N, 11.69 S.

0 0 9 «17/1855 -85-

- op -

To the rest of the mixture described above containing the 6-Ghlorimid, quinoline (6.6 mL, 0.056 mol), followed by absolute ethanol (100 ml) was added over a few minutes and the temperature at -30 - ■ 3 0 maintained. After the mixture has been stirred at -JO for one hour, the temperature is allowed to rise rapidly to + 20 ° with hot water and then immediately brought back to -JO ⁰ and stirred for a further hour. Then the temperature is brought to + 20 ° with hot water and immediately cooled again to -10 ° and the mixture is stirred for a further hour, whereby 2- / C6- / T-ethoxy-2r ^ henoxyäthylidenamino7-5t5- · dimethyl- 7-oxo-4-thia-1-azabicyolo _i / 5,2, o7-hept-2-yl) -oarbonyl7-1,2-benzisothiazol-3 (2H) -one-1, ί-diaxide hydrochloride, as well called fcJaocharimid of 6-ethoxyimidophenoxymethylpenicillin hydrochloride.

Then water (75 ml) is added to the mixture described above, which contains 6-ethoxyimide hydrochloride, and the temperature is lowered to 0 ° and then stirred for 20 minutes. The mixture is kept at 0 ° overnight and filtered. The solid is washed with cold water (5 ° 0) (30 ml) without the solid being suspended in the water and then sucked dry. The solid is then washed with cold (5 ° ö) methylene chloride (2 χ 30 ml) , slurried in absolute ether and sucked dry over the funnel, then dried in a vacuum over ^ p ⁰ S to form

-86- 00 9 817/1855

white crystals of 2 .- / Jß> - amino-3,3-dimethyl-7ro ^xo ~ ^ "" thia-1-azabicyolo / 3,2, o7-hept-2-yl) -carbonyl7-1,2-benzisothiazole -3 (2H) -one-1,1-dioxide hydrochloride, also known as the saccharimide of δ-aminopenicillanic acid hydrochloride (11.1 to 12, .6 g, 62 to 75 #), melting point decay (uncorrected).

Analysis calculated for Ο,] ^, -N ₅ Q ₅ S ₂ . HOl

(#): 42.40 0, 4.01 H, 9.84 N, 15.02 S, found (JIi): 42.25 0, 3.83 H, 9.73 N, 15.11 S, 11.4 Q

Example 34

2- / C6-Amino-3,3-diraethyl-7-oxo-4-thia-1-azabioyclo _i / 3,2,07-hept-2-yl) -carbonyl7-1,2-benzisothiazole-3 (2H ) -one-1,1-dioxide hydrochloride (8.6 g, 0.0206 mol), prepared as in Example 33, is pulverized, added to water (75 ml) in four portions and stirred at 0 °. The adjustment to pH 6.9 is carried out after each addition with a 60 # strength saturated sodium bicarbonate solution. After the second addition, a little ether is added to control the foam formation. After the final adjustment to pH 6.9, the Gemisoh is stirred at 0 to 2 ° for 10 minutes and the pH is slowly allowed to run to 7 »1. The solid is filtered, washed with cold water (2 x) and ^{dried in a dryer over Pp ^ 5; he götrooknet} vacuum at 5 °, whereby a white solid is obtained, the 2- / C6-amino-3,3- diraethyl-7-oxo-4-thia-1-azabioyolo / 3,2, ^ 7-hept-2-yl) -

-87-QQSM7 / 1855

carbonyl ^, 2-benzisothiazol-3 (2H) -one-1,1-dioxide is that as well as the saccharimide of 6-aminopenioillanic acid (7.0 g, 90 #), melting point 158 ° disintegration (uncorrected).

Analysis: calculated for ^c i5 ^H i5 ^N 3 ^ 5 ^S 2

: 47.25 0, 3.97 H, 11.02 N, 16.81 S.

found (#) .: 47.45 0, 3.94 H, 11.21 N, 16.60 S.

Example 35

Following the procedure of Examples 15 »16, 33 and 34 becomes Phenoxymethylpenicillin with a number of saccharimide derivatives reacted to form the saccharimide derivatives of phenoxymethylpenicillin given below, which are brought into contact with phosphorus pentachloride to form the corresponding saccharimides of 6-Ghlorimidophenoxymethylpenioillin, which in turn with an alkanol are reacted to form the suitable öaccharimide of ö-Alkoxyiraidophenoxyraethylpenioillinhydrohalogeniden, which are then hydrolyzed and neutralized to form the following üaochariraide of 6-aminopenicillanic acid:

Table Q,

Accharimide derivatives of saccharimide derivatives of phenoxymethyl penicillin 6-aminopenicillanic acid

5-ethylsaccharimide of 5- £ thyls & cohariniid of 6- * Phenoxymethylpenicillin aminopenicillanic acid

-88- 000817/1855

Sacchariraide derivatives of Phenoxym efhylp enic illin

5-chloro-6-propylsaccharimid of phenoxymethylpenicilin

6-nitrosaccharimide of phenoxymethylpenioillin

5,6-dibromosaccharimide of pfrenoxymethylpenicillin

5-hexyl saccharimide of phenoxymethylpenicillin

♦ '

Jp-butoxy-o-phenyl saccharimide of phenoxymethylpenicillin

5- (p-Methoxyphenyl) -saocharimide of phenoxymethylpenicillin

5-phenyl saccharimide of phenoxymethyl penicillin

6-benzyl saccharimide of, phenoxymethylpenicillin

7- (m-Propoxyphenyl) saccharimide of phenoxyraethylpenioillin

A-butyl-5-fluorosaccharimide of phenoxymethylpenicillin saccharimide derivatives of 6-aminopenicillanic acid, - ·

^ -Ohlor-ö-propylsacchariraid of 6-aminopenicillanic acid

6-nitrosaccharimide of 6-aminopenicillanic acid

5t6-dibromosaccharimide of 6-aminopenioillanic acid ©

5-hexylsacoharimide of 6-amihopenioillanic acid

5-butoxy-6-phenyl saccharimide of 6-aminopenicillanic acid

5- (p-M © thoxyphenyl) -sacchar imide of 6-aminopenicillanic acid

5-phenyl saccharimide of 6-aminopenicillanic acid

6-benzyl saccharimide of 6-atninopenicillanic acid

7- (m-Propoxyphenyl) -sacoharimid of 6-aminopenicillanic acid

4- butyl-5-fluoro-aooharimide of 6-aminopenicillanic acid

Example 36

Repeating the procedure of Examples 15, 16, 33 and 34 to react a number of saccharimide derivatives with benzylpenicillin, the following saccharimide derivatives of benzylpenicillin are prepared, which are then brewed in contact with phosphorus pentabromide to form the corresponding saccharimides of 6-bromo

-89-

009817/1855

194608a

iraidobenzylpenicillin, which in turn are brought into contact with an alkanol to form the appropriate saocharimides of 6-alkoxyimidobenzylpenioillin hydrobromide, which are then hydrolyzed and neutralized to form the following saccharimides of 6-aminopenioillanic acid:

Table R.

üaccharimidderivate benzylpenicillin

5-MethyX-6- (2-pyridyl) saccharimide of benzyl penicillin

5-'l ¹ rifluorraethylsacchar- • imide of benzylpenicillin

6-dimethylamino-7-diethyl saccharimide of benzyl penicillin

7-diethylaminosaccharimide of benzyl penicillin

^ -Carbomethoxysaccharimide of benzyl penicillin

6-sulfamidosaccharimide of benzyl penicillin

5-carbethoxysaccharimide of benzylpenicillin

6-Oyanosacchariuiid of Benzyl penicillin

5-propyl thiosaccharimide of benzyl penicillin

5-ethyl sulfonyl saccharimide of benzyl penicillin

6- (4-pyridyl) -saooharimide of benzylpenicillin saccharimide derivatives of 6 ~ aminopenicillanic acid

5-methyl-6- (2-pyridyl) sacchariraide of 6-aminopenicillanic acid

5-trifluoromethyl saocharimide of 6-aminopenicillanic acid

6-dimethylamino-7-roethyl- saccharimide of 6-arenopenicillanic acid

7-bioethylaminosaccharimide of 6-aminopenicillanic acid

^ -öarbomethoxysaccharimid of 6-aminopenicillanic acid

6-sulfamidosaccharimide of 6-aminopenicillanic acid

5-carbethoxysaccharimide of 6-aminopenicillanic acid

6-ayanosacoharimide of 6-aminopenioillanic acid

5-propylthiosac charimide of 6-aminop © nigillanic acid

5-ethyl sulfonyl saccharimide of δ-aminopenicillanic acid

6 - (^ - Pyridyl ) -sao oharimide of 6-aminopenioillanic acid

-90-

00S817 / 1855

saccharimide derivatives of saccharimide derivatives of

Benzylpenicillin 6-aminopenicillanic acid ..

5,6-Benzosaccharimide von ^ »ö-Benzosaocharimid von

Benzylpenicillin 6-aminopenioillanic acid

Example 37 · ■

6v (3-hexenamido) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo- _i / 3,2,07-queptan-2-cartonic acid, also referred to as 2-eentenylpenicillin "" , (0.040 mol) is added to anhydrous methylene chloride (150 ml) contained in a dry three-necked flask equipped with a stirrer, drying tube and thermometer through a U-shaped nitrogen inlet. Then triethylamine (0.040 mol) is added and the solution is cooled to 5 ° in ice. Pseudosaocharine chloride (0.040 mol) is added all at once to give a yellow solution. The solution is stirred for half an hour at 5 ° and held overnight at room temperature, then brought to the boiling point five minutes, allowed to cool to room temperature, filtered, the collected solid 2- / T6 - ^ - Hexenamido7-3 "3-dimethyl- 7-oxo-4-thia-1-azabicyolo / 3 »2,07-hept-2-yl) -carbonyl. 7-1,2-benzisothiazol3- (2I $ -one-1,1-dioxide, which is also is referred to as Saocharimid of 2-Pentenylpenioillin.

If the above procedure is repeated, using suitable penicillins with different Saooharinohlorid «

817/1855

derivatives are implemented, so are the following Penioillinsacchariraide obtain:

2- / r6- / 2-Allylmercaptoacetamido7-3 »3-dimethyl-7-oxo-4— thia-1-azabicyclo ^ _f 2, o7-tiept-2-yl) -carbonyl7-5-chloro-1 _f 2- benzisothiazol-3 (2H) -one-1,1-dioxide, also known as 5-chlorosaccharimide from Allylraercaptome'thylpenioillin,

- ⁴ / ci- ( Y -Chlorcrotylmeroapto) -acetaniido7-3i3-diniethyl-

7-oxo-4-thia- ⁱ l-azabicyclo / 5,2, Ö7-hept-2-yl) carbonyl7-1,2-benzisothiazol-3 (2H) -one-1,1-dioxide, also described as Saccharimide of Y-chlorocrotylraeroaptoniethylpenioillin »

2- / Γ31 ^ -Tue

azabicyolo _i / 3,2, Ö7-hept-2-yl) -carbonyl7-'1 »2-benzisothiazol-3 (2H) -one-1,1-dioxide, also referred to as saooharimide of benzylpenicillin,

2- / T6-hexanamido-3,3-diethyl-7-oxo-4-thia-1-azabicyclo- / 3,2,07-hept-2-yl) carbonyl7-1 »2-benzisothiazole -3 (2H ) -on 1,1-dioxide, also described as the saccharimide of amylpenicillin,

2- / C3,3-Dimethyl-6-octanamido-7-oxo-4-thia-1-azabicyolo-Z ^ » ² » 27-hept-2-yl) -carbonyl7 - '' »2-benzisothiazole-3 ( 2H) .- on 1,1-dioxide, also known as saooharimide of heptylpenicillin and

-92 "

00β «17/1855

-92-. "■ ■

^ -thia-1-azabicyclo / j »2,07-hept-2-yl) -carbonyJ ^ i-1,2-bf n? - isothiazol ~ 3 (2H) -one-1, .1-dioxide, also referred to as the saccharimide of hydroxybenzylpenicillin.

Example 38

The saccharimide of 2-pentylpenioillin as in Example 37 is prepared with methylene chloride (150 ml) and Ohinoline (0.110 mol) mixed, the stirred mixture to .., -10 ° cooled and Riosphorpen.tachlorid (0.055 mol) during added a few minutes. The resulting mixture is stirred at -10 °, then the precipitate is filtered off separated, whereby the Saooharimid of 6 "Ohlorimido-2-pentenylpenioillin is obtained.

The other penioillin sacoharimides are acted in a similar manner of Example 37 reacted with phosphorus pentahalide with the formation of:

5-chlorosaccharimide of e-chloritnidoallyl-meroaptomethylpenicillin,

Saccharimide of G-bromimido-Y-chlorocrotylmercaptoinethylpenicillin ,,

Saccharimide of 6-chloroimidobenzylpenicillin, öaccharimide of ö-Ohlorimidoamylpenicillin ,. Saooharimid from 6-Ohlor: ünidoheptylpenioillin and Saocharimid of 6-0hloriraidohydroxybenzylpenicillin *.

-95-009817 / 18 55

Example 39

The saccharimide of 6-chlorimido-2-pentenylpenioillin, prepared as in Example 38, is mixed with methylene chloride (150 ml), ghinoline (0.055 mol) and absolute methanol (100 ml), the (temperature at -50 ° - $ ° Q. After the mixture has been stirred at -20 ° for 1 hour, the temperature is allowed to rise to + 20 ° with hot water * and then the mixture is brought back to -0 ° and stirred for a further hour the temperature was brought up to + 20 ° with hot water and then quickly cooled to -10 ° and stirred for a further hour, whereby the saccharimide of 6-methoxyimido-2-pentenylpenicillin hydrochloride is formed, which is separated off by filtration.

Similarly, the 6-haloimidopenicillin saccharimides of Example 38 reacted with various alkanols to form:

Sacchariraid of 6-ethoxyimido-2-pentenylpenicillin hydrochloride ,.

Saccharimide of 6-pentoxyiroido ~ 2-pentenylpeniaillinhydro chloride,

5-chlorosaccharimide of 6-methoxyimidoallylmeroaptomethylT penicillin hydrochloride,

5-chlorobacchariraid of ö-ethoxyimidoallyliaeroaptorcethylpenioillin hydrochloride ,:

0QM17 / 1855

5 ~ chlorosaccharimide of 6-butoxyimidoallylmeroaptoraethylpenicillin hydrochloride,

Saocharimide of ö-methoxyimido-V-chlorocrotyliiiercaptomethylpenicillin hydrobromide, _%

Saccharimide of e-ethoxyimido-YTChlorcrotylmeroaptoniethylpenicillinhydrobromid,

öaochariraid of ö-hexoxyimido-Y-ohlorcrotylmercaptoinethylpenicillin hydrobromide,

Saocharimid of e-Athoxyiinidobenzylpenioillin hydrochloride, Saccharimide of o-butoxyiraidobenzylpenicillin hydrochloride, Sacoharimide of ö-ethoxyimidoamylpenicillin hydrochloride, Saooharimide of ö-propoxyimidoainylpenioillin hydrochloride, Saocharimide of e-methoxyiraidoamylpenicillin hydrochloride, Saooharirnid of e-Me-bhoxyimidoheptylpenioillin hydrochloride, Saccharimide of e-ethoxyimidolieptylpenicillin hydrochloride, Saocharimide of e-butoxyimidoheptylpenioillin hydrochloride,

• Saocharimid of ö-methoxyimidohydroxybenzylpenioillin hydrochloride,

Saccharimide of 6-ethoxyimidohydroxyben25ylpenioillin hydrochloride and.

Saooharimid of ö-Butoxyiraidohydroxybenzylpenioillinhydro- ohlorid ..

-95-

009117/1855

Example 40 "·

The saccharimide of 6-methoxyimido-2-pentenylpenicillin hydrochloride, prepared as in Example 59, is added to methanol (100 ml), water (75 ml) and the temperature is reduced to 0 ° while stirring for one half hour. The mixture is ^{kept at 0 0} overnight and filtered. The solid is washed with cold water (5 ° 0 »30 ml) without slurrying the solid in the water and dried. The solid is then washed with cold methylene chloride (5 ⁰ Gj 2 χ 30 ml), slurried in absolute ether and then dried over the funnel, then over Ep. ^ 5 in a vacuum to form crystals of saocharimide of e-arainopenicillanic acid hydrochloride ^.

Similarly, the other 6-alkoxyimidopenicillin are saccharimide hydrohalides of Example 39 to the corresponding saccharimide of the 6-aminopenioillanic acid hydrohalides converted·

When the above prepared hydrohalides by the process of Example 34 are neutralized, the corresponding saccharides of 6-aminopenioillanic acid obtain.

Example 41

Triethylamraonium-3-acetoxymethyl-8-oxo-5-thia-7- (thiophene-2-aoetaraido) -1-azabicyolo ^, 2, pJ? -OGt-2-en-2-oarboxylate

-96-009817 / 1855

(0.040 mol) is added to anhydrous methylene chloride (150 nil), which is contained in a dry 500 ml three-necked round bottom flask equipped with a stirrer, drying tube and thermometer. Thereafter, the solution is cooled to 5 ° in ^ is and pseudosaocharin chloride (0.040 mol) is added all at once, whereby a yellow solution is obtained. The solution is stirred for half an hour * at 5 ° and left overnight at room temperature. The solution is then placed for 5 minutes on the boiling point and allow to cool to room temperature to give 2 - /] ^ - hydroxymethyl-8-oxo-7 (2 «thiophenacetamido) -5-thia-'1-azabicyolo2 ^i:!?, 2, o7-oet-2-en-2-yloarbonyl7-1,2-berizisothiazol-3 (2H) -one-1,1-dioxidaoetat, also known as the sacchariraide of cephalothin, has a melting point of 160 ° decay (uncorrected) .

Then ghinolin (0.110 mol) is added while stirring the saocharimide solution admitted. The mixture is cooled to - $ 0 ° and PhOBphosphorus pentachloride (11.6 g, 0.056 mol) were added over a few minutes, keeping the temperature at -30 will. The Geraisch is stirred for three hours at -50 ° with formation of 2- / 7- (1-GhIor-2- / 2-thienyl7-äthylidenamino) -3-hydr oxyraethyl-8-oxo-5-thia-1-azabioyolo2? 5 · »2» 07-oct-2-en-2-ylcarbonyl7-1,2-benzisothiazoi $ (2H) -one-1,1-dioxide acetate, the same as the saooharimide of 7-olorimidooephalothin is known '

-97-

• 009817/18 55

To the one described above, the designated 7-phlqriinid · "·. Geraisch containing, becomes ohinoline (0.055 mol), after that absolute ethanol (100 ml) was added over the course of a few minutes, the temperature being kept at -30 ° -3 °.

After the mixture has been stirred ^{at -JO 0 for one hour,}

'ο

the temperature is quickly increased to +20 with hot water and immediately afterwards back to -JO. brewed and stirred for another hour. Then the temperature ^ ,. * Is brought to + 20 ° with hot water and immediately afterwards to -1Q ° and stirred for a further hour, whereby 2- ^ 7- (1-ethoxy-2- ^ 2-thienyl7-äthylidenamino) ~ 5-hydroxymethyl-8-oxo-5-thia-1-azabicyclo ^ f, 2, p_7 ^; -oot-2-en-2-yloarbonyl7-1,2-benzisothiazol-5 (2H) -one-1, i-dioxide-acetate hydrochloride, which is also described as the saccharimide of ^ 'Jashox ^ lmlao " cephalothin hydrochloride.

Thereafter, water (75 nil) Clem mixture described above, "the the designated 7-Äthoxyimidhydroohlorid contains added and lowering the temperature to O ⁰ O and stirred for 20 minutes .. The mixture is stirred at 0 ° to stand overnight and then filtered. The solid is washed with cold water (5 ⁰ O; 30 ml), without the Sohlämmebildung Peststoffs in the water, washed and sucked dry ·. Then the solid is washed with cold methylene chloride (5 ° 0; 2 χ 30 ml), soled in absolute ether and dried over the Trook funnel, then over P ₂ O ₅ in a vacuum »

-98-001117 / 1855

Oh, one crystals of 2- ^ 7-amino ~ 3-hydroxyffiet] ayl-8- -thia-i-azabicyclo ^^ i ^ -oot ^ -en ^ -ylcarbonyl ^ -i, 2 benzisothiazol-3 (2H) -one- "1,1-dioxideacetate hydrochloride, the same as the saocharimide of 7-aminoeephalosporanic acid hydrochloride is known ..

Example 42

IT-i, 2-benzisothiazol-3 (2H) -one ~ 1,1-dioxide acetate hydrochloride (0.02 mol), prepared as in Example 1, is pulverized and added to water (75 nil) in four increments and at 0 ° touched·. After each addition, the pH is adjusted to 6.9 with a 60 ^° C. saturated sodium bicarbonate solution. After the second addition, a little ether is added to control the foam formation. After the final adjustment of the pH to 6.9, the mixture is stirred at 0 ° to 2 ° for ten minutes and the pH value changes slowly to 7 | 1 · ^D ®r Solid is filtered, washed with cold water (2 ×) , getrodknet in a SL'rookner on F ₂ Oc.unter vacuum at 5 ° woduroh to obtain a white solid containing 2- £ ^ - & m ± IKO-3 ^'m hydroxymethyl-8-oxo-5-thia-1- azabioyolo _i ^ f, 2, Q7-oot-2-en ~ 2-yloarbonyl7-1,2-benzisothiazol-3 (2H) -one-1,1-dioxidacetat, is that as the Saooharimid of ^7-i Um nooephalosporansäure is described.

example

- ^ "Amino-3-hydroxym et hyl-e-oxo-5-thia-i-azabiöyolo ^ f, 2» £ J7-009817 / 1855 . -99-

• ο «1346089

_oc -b_2-en-2-ylcarbonyl7-1,2-benzisothiazol-5 (2H) -one-1,1-dioxide acetate, prepared as in Example 42, is dissolved in tetrahydrofuran (60 ml) and a solution of sodium bicarbonate (0 0.04 mol) in water (40 ml) was added all at once. The mixture is stirred for three hours at room temperature to form a solution. Then the tetrahydrofuran ^{is removed at 3O 0} O under vacuum and the resulting mixture washed with methylene chloride. The aqueous traction is then treated in a rotary evaporator and the dissolved methylene chloride is removed. The solution is filtered and the pH is adjusted to 5.8 with glacial acetic acid. The mixture is stirred in ice water for half an hour and then filtered to give crystals of 7-amino-3- (hydroxymethyl) -8-oxo-5-thia-1-azabicyclo / ?, 2,07-oct-2-ene -2-carboxylic acid acetate, which is also known as 7 ~ aminocephalosporanic acid.

Example 44

Using the general procedures of Examples 57-40, 2-amido derivatives of the natural penicillins are made

produced, which reacted with phosphorus pentachloride to form their corresponding ^ -araido-ö-chloriraidopenicillins which in turn are then reacted with alkanol to form suitable 2-amido-6-alkoxyimidopenicillin hydrochloride, which are then hydrolyzed and neutralized to form 2-amido-6-aminopenioillan · »

-100- 003817/1855

acids of the formula:

wherein X and Y, separately, have the following meanings: i

Table p.

Cyano-cyano cyano cyano cyano cyano Cyano Nitro Nitro Nitro.

Nitro Nitro Trifluoromethylsulfonyl Trifluoromethylsulfonyl Trifluoromethylsulfonyl ^ Trifluoromethylsulfonyl

Cyano

Nitro

Trifluoromethylsulfonyl carbopentoxy

Ν, Ν-dimethylcarbamyl ethylsulfonyl

N, N-diethylsulfamyl Trifluoromethylsulfonyl carbethoxy

N _t N-dipropylcarbamyl methylsulfonyl N-ethyl-N-methylsulfamyl trifluoromethylsulfonyl carbohexoxy

N-iithyl-N-methyloexbarayl-propyleulfonyl

009817/1855

- 10Π -

Trifluoromethylsulfohyl carbomethoxy

Carboraethoxy

Carbomethoxy

NvN-dimethylcarbamyl NjN-dimethylcarbanjyl.

N, N-MtI et hylcarbamyl N, N-dimethylsulfamyl Cyano

Cyano

Cyano

Methylsulfonyl methylsulfonyl carbethoxy

Garbethoxy

N, N-dimethylcarbaniyl Carbobutoxy

Nitro

p-nitrophenylsulfonyl

p-trifluoromethylphenylsulfonyl

2,4-dinitrophenylsulfonyl p-chlorophenylsulfonyl.

Trifluoromethylsulfonyl

m- (N * N-diethylsulfaoyl) -benzoyl-

N, N-dimethylsulfamyl N, N-dipentyloarbamyl Methylsulfonyl N, N-dimethylsulfarayl Pentylsulfonyl N, N-dimethylsulfamyl.

Ν, Ν-dimethylcarbamyl N, N-dimethylsulfamyl p-butylbenzoyl m -oluyl

p-phenoxybenzoyl o-chlorobenzoyl 2,4-dibromobenzoyl p-chloro-m-toluyl p-iodobenzoyl p-ethylbenzoyl p-methoxybenzoyl p-phenylbenzoyl ra-nitrobenzoyl p-methylsulfonylbenzoyl

p-toluyl
p-methoxybenzoyl

P- (N, N-dimethylsulfamyl) benzoyl.

Methylsulfonyl

009117/1855 -102-

χ Ι -

darbomethoxy p-trifluoromethylbenzoyl

Oyano o-chlorophenylsulfonyl

Oyano m-trifluoroiethylphenyl-

.sulfonyl

Trifluoromethylsulfonyl p ~ nitrophenylsulfonyl.

N, N-Dimethylcarbamyl 2-BroIn-4-ohlophenyl- ·

sulfonyl

example

Using the procedures of Examples 41-45 are a number of 2-amido derivatives of cephalothin made with phosphorus pentahalogenide under formation their corresponding 2-amido-7-haloimidooephalothine are implemented, which in turn then with an alkanol be implemented, whereby one suitable 2-amido-7 ~ e-lkoxy * - imidocephalothin hydrohalide which is then hydrolyzed and are neutralized to form 2-amido-7-aminocephalosporanic acids the formula:

J, N s ^ -raywxäL ■

where X and Y, separately, have the following meanings

to have*

-105-009117 / 1855

'- 103 - X 009817/1855 ■} Y Table T Methylsulfonyl 2-brora-4-nitrophenyl-
sulfonyl N, N-dimethylsulfamyl IH- (N, N-dimethyloarbamyl) -
phenylsulfonyl Carbohexoxy p-methylsulfon ^ henyl-
sulfonyl Oarbätaoxy
* ■ p- <N, N-diethylsulfaniyl) -
phenylsulfonyl Trifluoromethylsulfonyl ***
4-cyano-2-iodophenyl
sulfonyl Cyano 2-! Fluoro-4 ~ nitrophenyl ^: -
sulfonyl Pentylsulfonyl p-carbobutoxyphenylsulfonyl oyano p-iodobenzyl sulfonyl Cyano Butyryl Nitro Acetyl Cyano Benzoyl Propionyl. Phenylsulfonyl 2,4,6-tri-diethylbenzoyl Phenethylsulfonyl 2,4,6-tri-ethylbenzoyl p-methoxyphenylsulfonyl W, N-Diniethylcarbarayl Ν, Ν-dimethylarainoethyl
sulfonyl 2.5 »5 ₁ ö-l'etraraethylbenzoyl ' p-methylthiophenylsulfonyl Cyclovaleryl ra-nitrophenethylsulfonyl N, N-dipropylaminobutyl-
sulfonyl 2-naphthoyl Cyano 2,4-dimethylbenzoyl. Nitro p-Fluorphenao etyl Cyolocaproyl. Trifluoromethyl sulfonyl -104-

χ Oyano Furoyl Carbopropoxy N, N-dimethylsulfamylphene
propionyl Oyclobutyryl p-propylphenylsulfonyl p-butoxybenzoyl 2-naphthylsulfonyl Nitro Phenbutyryl. Oaproyl 2-furylsulfonyl Methylsulfonyl 2-pyridylsulfonyl Cyano. Phenoaproyl. Trifluoroethylsulfonyl Phenpropyisulfonyl Oyano p-propylsulfonylphenyl-

sulfonyl nitro

ia-carbomethoxyphenylsulfonyl, p-propoxyphenylsulfonyl. Oyano

p- (N _t N-dibutyloarbamyl.) - p.henyl sulfonyl

Oarbethoxy

Methylsulfonyl
p-pentylthiophenylsulfonyl

Example 46

Using the procedures of Examples 57 to 40, 2-cycloamido derivatives of the natural penicillins are prepared which are reacted with phosphorus pentachloride to form their corresponding 2-cycloamido-6-chloroimidopenioillins which are then reacted with an alkanol to give suitable 2-Gyoloamido- 6-alkoxyimidopenioillin hydrochloride receives _f . which then

-105-

0.0981-7 / 1855

hydrolyzed and neutralized to form 2-oyoloamido-6-aminopenicillanic acids of the formula «.

where α and Y, together, have the following meanings to have: ·

Table U

3-oxo-i, 2-benzisothiazolin-2-yl-1,1-dioxide, 4-methoxyphthalimido, Maleic acid imido, Succihimido,

3-Qxo-4, 1,2-benzoxathiazin-2 (3H) -yl-1,1-dioxide, 3-0xo-6-nitro-1,4,2-benzodithiazin-2 (3H) -yl-1,1-dioxide »

3,4-dihydro-4-methyl-3-oxo-2H-1,2,4-benzothiadiazin-2-yl-1 _T 1-dioxide,

3,3,4-, 4-tetramethyl-2-oxo-1-pyrrolidinyl, 6-bromo-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl, 3 , 4-Dihydro-2,4-dioxo-2H-1,3-benzothiazin-3-yl _# '7-Ethylsulfonyl-1,4-dihydro-1-methyl-2,4-dioxo-3 (2H) -quinazolinyl ,.

6-i "luoro-1,2-benzisothiazolin-2-yl-1,1-dioxide, 1-0xo-2-isoindolinyl, 2-0xo-3-pyrrolin-1-yl, 4-Ißothiazolin-2-yl-1,1-dioxide, ',

-106-001117 / 1855

6 = chloro-3,4-dih; yuro-7-methyl-5-oxQ-2H-1,2-benzothiazin · 2-yl-1,1-dioxide, '. ^ Mx. - ■

3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl and ο- (3-brorabenzol) -disulfonimido.

Example 47

Using the procedures of Examples 41-43 will result 2-Gycloamido derivatives of cephalothin made the with phosphorus pentabromide to form their corresponding 2-0ycloamido-7-bromimidocephalothine are implemented, di © in turn converted with an alkanol, whereby the suitable 2-Cyoloamido-7-alkoxyimidocephalothinhydrobromide obtained, which are then hydrolyzed and neutralized to form 2-cyoloamido-7-aniinooephalosporanic acids the formula;

CH ₂ OCOCH ₃

wherein X and X, together, have the following meanings have j

Table V-

5-ethyl-3-oxo-1,2-benzisothiazolin-2-yl-1ii-dioxide,

Phthalimido,

Suooiniraido _r "■

-1.07-009817 / 1855

3-oxo-2-isothiazolidiny1-1,1-dioxide, 3-oxo-4-isothiazolin-2-yl-1,1-dioxide,

- ^ ₁ I, 2-benzoxathiazin-2 (5H) -yl-1,1-

dioxide,

3-0x0-1, 4-, 2-benzodithiazin-2 (3H) -yl-1,1 ~ dioxide,

6-cyano-5,4-dihydr o-4-methyl-5-oxo-2H-1,2,4-benzothiadiazin-2-yl-1,1-dioxide,

Tetramethylsuccinimido,

3,4-Dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl,

7-irifluoromethyl-3,4-dihydro-2,4-dioxo-2H-1,3-benzothiazin-3-yl,

1,4-bihydro-1-methyl-2,4-dioxo-3 (2H) -quinazolinyl, 1,2-benzisothiazolin-2-yl-1,1-dioxide, 5-benzyl-1-oxo-2-isoindolinyl,

2-isothiazolidinyl-1,1-dioxide,

2-0xo-1-pyrrolidinyl,

3,4-dihydro-2-oxo-2H-1,2-benzothiazin-2-yl-1,1-dioxide ,.

7-Oarbomethoxy-3 »4-dihydro-1,3- <iioxo-2 (1H) -isoohinolyl and

o-Benzene disulfonimido ..

Example 48 "

3,3-uiraethyl-7-oxo-6- (2-phenoxyacetamido) -4-thia-1-azabicyclo ^ 3,2, C »7-heptane-2-carboxylic acid, also called phenoxymethylpenicillin, (256 g, 0.73 mole) becomes anhydrous methylene chloride (2 1) was added and the mixture was stirred and cooled to 6 ° in ice. Then triethylamine was added (78.8 g, 0.73 mol) were added and water-

-108- 009817/1855

washed free methylene chloride (250 mL) causing the solid to dissolve. The solution is cooled to 5 ° and Y-saccharin chloride (14-7 6 »0.73 mol) added and washed with anhydrous methylene chloride (250 ml). The light yellow solution is ^{stirred at 5 to 0} for half an hour and then left to stand at room temperature overnight. Ohinoline (215 ml, 1 »8 mol) is added to the stirred solution before the internal temperature is increased

quickly lowered to -50 0. Once the temperature has reached -50, powdered phosphorus pentachloride (187 S "0.90. Mol) is added over about three minutes while the temperature is maintained at -28 to -50 ⁰ O * The mixture for three hours at -50 ° stirred and a solution of ohinoline (105 ml> 0 "90 mol) in absolute ethanol (850 ml) is added over about 10 minutes, the temperature being kept at -27 to -50 °. After stirring for one hour at -50 °, the temperature is quickly brought to + 20 ° and then immediately back to -50 °. After stirring for another hour at -50 °, the temperature is quickly increased to + 20 ° and then immediately lowered to -10 °. The temperature at -10 ° is maintained for one hour, then water (65Q ml) is added and that. Geraisch stirred at 0 ° for twenty minutes. The mixture is left to stand overnight at 0 and filtered through a coarse sintered funnel. The white solid is washed three times with cold methylene chloride (5 ° 0) »three times

-109-0C9817 / 1855

cold water (just enough to cover the solid), and slurried twice with anhydrous ither. The resulting white solid is sprayed onto paper in a hood and air dried overnight to give a powdery white solid which is 2- / C6-amino-3 »^ - dimethyl - ^ - oxo - ^ - thia-i-azabioycio ^, 2,07-hept-2-yl) -carbonyl7-1 _{f is} 2-benzisothiazol-3 (2H) -one-1,1-dioxide hydrochloride, but is also known as the saocharimide of 6-aminopenicillanic acid hydrochloride (189 "" έι

Example 49

2- / TD - / ^ - Amino - 2-phenylacetamido7-3,3-diraethyl-7-oxo-4-thia-1-azabicyclo / 3,2, Ö7-hept- "2-yl) -oarbonyl-1 , 2-benzisothiazol-3 (2H) -one-1,1-dioxide, also described as öaochariraid of ampicillin, (0.02 mol) is dissolved in anhydrous methylene chloride (75 ml) and N, N-dimethylaniline (0.07 Mol) is added. The solution is ^{cooled to -4O 0} O by an acetone-Srooke ice bath and phosphorus pentabromide (0.218 mol) is added over a few minutes under nitrogen. The solution is ^{stirred at -35 to -40 0} O for three hours with mechanical stirring Then left to rest for about 1/2 to 1 hour at this temperature, whereby a white crystalline material forms, the 2 / Xlh ° / TU-amino-1-brora-2-phenyläthylidenamino7-3,3-dimetnyi-7 -oxo * 4-thia-i-azabioyolo ^, 2, ö7-hept-2-yl) -oarbonyi7-1 » 2-bena-

00Slt7 / 1855

- 110 -. .

isQthiazol-3- (2H) -one-1,1-dioxide, is also known as the acoharimide of 6-bromimidoampioline. Then 1-butanol (75 ml) is added over about five minutes at -35 to -40 ⁰ O and this temperature is maintained for three hours, whereby 2 / TD- / 2-amino-1-butoxy-2-phenyläthylidenaTnono7-3 ' , 3-dimethyl-7-oxo-4-thia-1-azabicyclo _i / $, 2, o7-hept-2-yl) -carbonyl7-1,2-benzisothiazol-3 (2H) -one-i, 1- dioxide hydrobromide, which is also referred to as the sacoharimide of 6-butoxyiraidoarapicillin hydrobromide. Then water (40 ml) is added to the rapidly stirring mixture, which is allowed to cool to 0 to 5 °. The mixture is stirred for one hour at 0 ° to 5 ° and left to stand at 0 overnight without stirring. It is then filtered and the solid is washed with anhydrous ether to give a white solid which is the hydrobromide of 2- / C6-amino-3, 3 * · diraethyl-7-oxo-4-thia-1-azabicyclo25 »2, 07'-hept-2-yl) -carbonyl7-1,2-benzisothiazol-3 (2H) -one-1fi-dioxide, which is also referred to as the saccharimide of 6-ainopenioillanic acid hydrobroride »

Example 50

2- / C6-Etnino-3,3-dimethyl-7-oxo-4-thia-1-azabioy clo ^ J , 2 , o7- . hept-2-yl) carbonyl7-1,2-benzisothiazol-3 (2H) -one-1 , 1-di oxide hydrobromide, also described as saochariraid of 6-aminopenioillanic acid hydrobromide, (0.02 mol) is in tetrahydrofuran (60 ml ) and a solution of sodium

001 ^ 17/1855

bicarbonate (3.36 g, 0.04 mol) in water (40 ml) is added once admitted. The equipment is stirred for three hours and allowed to stand at room temperature for half an hour to obtain a solution. Then the tetrahydrofuran Stripped at 30 ° under vacuum 'and the resulting mixture washed with methylene chloride. the The aqueous fraction is then placed in a rotary evaporator at 30 and the methylene chloride is removed. The solution is filtered and the pH is adjusted to 3 | 8 with glacial acetic acid · The mixture is stirred in ice water for 20 minutes and then filtered, giving white crystals of 6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo ^ 3,2,07-heptane-2-carboxylic acid, also known as ö-aoinopenioillanic acid, receives.

-112-0Ü9817 / 1855

Claims (1)

. 1 Patent claims: 1 «Process for the preparation of ¹ -a penicillin or oephalo * sporin or a 2-amido derivative of the same of the general formulas: ■ /-OH ■: -. «■ ·. ■ -. ■ ■ 1
where R is a penicillin or cephalosporin amide group, X is an electron withdrawing (electrophilic) group «. Y is an optionally electron withdrawing group or X and X withdraw electrons to form an electron 18 are connected to the cyclic group and R is a methyl, .Hydroxymethyl, N-pyridiniumylmethyl or alkanoyloxyroethyl group is, characterized in that a penioillin or cephalosporin, after one, if desired, first the 2-carboxy group to a functional derivative " group, with a reactive araine derivative is reacted to the hydroxyl radical of the initial 2-oarboxy group by an amido group of the SOrrael - " to replace, if desired, the 2-amidopenioillin or 2-amidooephalosporin obtained in a reaction-inert, non-protonic solvent, with a phosphorus pentahalide in the presence of a base ÖG98I7 / 1855 with formation of a corresponding 2-amido-6-haliraido ~ penicillins or a-amido - ^ - halimidooephalosporins, that > Is reacted with an alkanol, whereby one the hydrohalide a corresponding 2-amido-6-alkoxyimido, penicillins or 2-amido-7-alkoxyimidooephalosporins er—, which in turn is hydrolyzed with water below ' Formation of a 2-amido-6-aminopenioill <* acid or 2-amido * 7-aminocephalosporic acid hydrohalide, which, if desired, is neutralized and the 2-amido-6-aminopeni * oillanic acid or 2-amido-7-aminooephalosporic acid or an acid addition salt of the same with an aoylation " is reacted with the formation of another 2-, amidopenioillin or 2-amidocephalosporin, which, if ge * - wishes to the corresponding penicillin or oephalo ** ' sporin is hydrolyzed. . . 2 *. Process according to claim 1 for the preparation of a penioillin or oephalosporin or a 2-Saooharylroder substituted 6acoharylpenioillin or -cephalosporin of the general formulas. -.! ■ · '· • I i .I ''. '' I, . I. 0ÖS8I7 / 18SS -114 -. "'. 16 17
where R * and R 'have the meaning defined below 18 *
and R a methyl-, hydroxymethyl-, N-pyridiniuraylm ethyl * 1 or alkanoyloxymethyl group and H. is a penicillin or oephalosporin amide group, characterized in that a penioillin or cephalosporin, if desired, after first converting the 2-carboxy group into a functional derivative group, is reacted with a reactive amine derivative which is a Saccharin or substituted saccharin of the general foraal. ·, t'l'-HN Il I, .0. , i, ■ ι or its functional derivative is wherein the radical is H 19th
and R ', when separated, is hydrogen, lower alkyl, lower alkoxy ,, halogen, phenyl ,. Phen (lower8s) -alkyl _t lower alkoxyphenyl, aryl, heterooyolyl, Srihalogen « ,, Nitro ,, Di (lower) -alkylaioino ,. Bulfaaido ». 0arb ~ - , Cyano, lower · Alkgfttbieeod «P lower ·« O038T7 / 1855 Τ9Τ6Ό89 Alkylsu} .fonyX or, when combined, complete the benzene ring, which is fused with the existing benzene ring to form a naphthalene ring and, if desired, the obtained 2-öaccharyl- or substituted öaοcharylverbindungen according to claim 1 is hydrolyzed to a 2-saccharyl or substituted saocharyl-6-aminopenicillanic acid or ^ -aminocephalosporanic acid, which is acylated to form another 2-saccharyl or substituted saccharylpenioillins or cephalosporins, which, if desired, is hydrolyzed to the corresponding penicillin or cephalosporin 3 · Process for the preparation of a 2-amidopenioillin or 2-amidocephalosporins of the general formulas where R is a penicillin or cephalosporin amide group, R is a ethyl, hydroxymethyl, N-pyridiniumylmethyl or alkanoyloxymethyl group, X is an electron withdrawing group, Y is an optionally electron withdrawing group and X and Y are forming an electron withdrawing cyclic group are connected, as characterized by, that a corresponding 2-amido-6- -116-Q0S817 / 1855 me 08 a -.116 - - ·. ' ί aminopenicillanic acid or 7-aminocephalosporic acid der general formulas OßßR or an acid addition salt of the same with an aoylie reacted with the formation of the desired R group will. 4. 2-atnidopenicillin or 2-amidocephalosporin or be 6- or 7-amino, haloimido or alkoxyimido derivative the general formula ¹ '.i « Ki 1
where E. is a penicillin or gephalosporin amide group, an amino or haloimido or aikoxyitnido group, that of a penicillin or cephalosporin amide group 18th
originates from, R is methyl, hydroxymethyl, N-pyridiniumylmethyl or alkanoyloxymethyl, X is an electron withdrawing group, Y may be an optionally electron withdrawing group or X. and Ϊ are linked together under -117- 009817/1855 --W6 - && 9- Formation of an electron withdrawing cyclic group or an acid addition salt thereof. 5. 2-saccharyl or substituted saccharyl penioillin or -cephalosporin or its 6- or 7-amino-, -halogenitnido- or -alkoxyimido derivative of the general formulas -1 where R is a penicillin or oephalosporin amide group, an amino group or a haloimido or alkoxyimido group is that of a penicillin or cephalosporin 16 17
amide group originates, R and R, separately, hydrogen, lower alkyl, lower alkoxy, halogen, phenyl, phen (lower) alkyl, lower alkoxyphenyl, aryl, a heterocyclic group, trihalomethyl, nitro, di-lower alkylamino, bulfamido, Oarb- lower-alkoxy, cyano, lower alkylthio or lower alkylsulphonyl or, when linked, complete a benzene ring that connects with the existing benzene ring to form a naphtha 009817/1855 -118- 194608a 1ö thalinrings is fused and R is methyl, hydroxymethyl, Is N-pyridiniumylmethyl or alkanoyloxymethyl or an acid addition salt thereof. 6. Use of the prepared in the preceding claims or mentioned compounds as medicinal products * 008817/1855