DE2062297A1 - Pemcillanic acid derivatives - Google Patents

Description

. Dr. F. Zumsteln sen. - Dr. E. Assmann Dr. R. Koenlgaberger - Dlpl.-Phys. R. Holzbauer - Dr. F. Zumsteln \ un,

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 225341 ■ ^ 8 MUNICH 2,

TELEX 529979 "'P 20 62 297 * 2 BRÄUHAUSSTRASSE 4 / III

TELESRAMS: ZUMPAT CHECK ACCOUNT: MUNICH 91139.

BANK ACCOUNT: BANK H. HOUSES

95 / zö
DüI-1140

Koninkli ^ ke Hederlandsche Gist- en Spiritusfabriek H.V ·.,

DeIft / Netherlands
Penicillanic acid derivatives.

The present invention relates to new penicillanic acid derivatives, processes for their preparation and their use as intermediates in the production of Ihiopenicilliiien. The present The invention also relates to new, from the Penioillan- " Acid compounds made thiopenicillins and compositions, especially for therapeutic purposes, containing the new Contain thiopenicillins.

It was found that e-isothiocyanatopenicillanic acid of the formula:

- CH C

. ß «C« N - CH

. ''. 0 = C - N ~~ - CH - COOH

esters and salts thereof (eg. as amine, alkali metal and alkaline earth metal salts), which are all new compounds are exceptionally useful intermediates for the preparation of Shiopeni "ciilinen, since the isothiocyanato group can be easily converted into a substituted amino group ₉ which new as well as

well-known! Dhiopenicillins yields. ·

■ BATHROOM

109026/1944

The δ-thiocyanatopenicillanic acid esters according to the invention correspond the general formula:

SbOsJJ-. OH «CH C ^ ^J

% i- Λ- II

O = C- K -GH - C ·· 0 - E «

where E 'an easily separable and forming a free Carboxyl group is replaceable by Viasgerstoff group which - very generally speaking - meet the following conditions should:

a) It should easily be converted into the carboxyl group of 6-aminopenicillanic acid of the formula:

- CH - CH C

CH CH C.

11 I.

N CH - COOH

can be introduced without undesired conversions such as the opening of the ß-lactam ring of the penicillan acid skeleton occurs;

"b) It should be easily separable so that the carboxyl group is wit. which can be produced without affecting the penicillanic acid structure, and

c) it should impart satisfactory stability to the ester itself.

Suitable groups as indicated above by E 'are e.g. B.

1) Sllyl groups, such as those of the general formula (IU) Si-,

wherein R is a hydrocarbon radical, such as a lower alkyl, aryl. (preferably phenyl) or aralkyl (preferably phenyl low, alkyl) group. The term "low" as used herein refers to Alley1 groups is used means that the alkyl group has at most 6 carbon atoms.

109828/19 * 4 ^

Such Silj'lester, which correspond to the formula II, are smoothly and easily hydrolyzed, for. B. by passing a stream of moist air through a solution in which they are contained, and preference is given in particular to the esters in which E ¹ denotes the 'JOrimethylsilylgxup'pe, ie trin: ethylsi] .yl-6 ~ -isothiocyanatopenicillanate.

2. A phenacy group, which may be attached to the benzene ring (preferably in the p-position) is substituted by halogen ", z. B. the p ~ Br oinphenacy! Group. ■

5. A benzyl or benzhydryl group.

According to the present invention, one obtains the '6-1 so thiocyanate? " penicillanic acid compounds of the general formula:

- CH - CH C,

I ™ H IV

O «C - K --— ÖH - COOE

where E has the same meaning as E ^? as indicated above, or denotes a hydrogen atom, "by a process which is characterized in that! thiophosgene is mixed with a penicillin-lanine derivative of the general formula:

(where W is a hydrogen atom or an easily separable group means and E 'has the meaning given above) in one inert organic solvent, converts to the W-HH grouping convert to an isothioeyanatopenicillanato group, without changing the rest of the molecule and one if desired 6-isothiocyanatopenieillanic acid by methods known per se from the resulting δ-isothiocyanatopenicillanic acid ester releases. It is necessary to understand the reaction with Miio-

109826/194 * b «« «« «.

phosgene, which can sometimes be violent, under control keep.

The G-isothiocyanatopenicillanic acid obtained in this way can be converted into the alkali metal and alkaline earth metal salts thereof by methods known per se or reacted with an equimolar amount of an amine to form aln salts of the acid, the reaction preferably being carried out in an organic solvent, e.g. B. ethyl acetate is carried out. Amine salts which can be prepared in this way can be primary, secondary or tertiary amine salts derived from aliphatic, cycloaliphatic amines and heterocyclic amines, e.g. B. the cyclohexylamines, dicyclohexylamine and N-ethylpiperidine salts.

The penicillanic acid starting materials of the formula V, in which ^{V.T is} a hydrogen atom, can be prepared by esterification of 6-aminopenicillanic acid with an alcohol of the formula B'-OH or an ester of the formula E'-Hai, in which Hai is a halogen (preferably a chlorine- ) Denotes atom and E ^{1 has} the meaning given above, is obtained. The reaction is preferably carried out in an inert organic solvent and in the presence of an acid-binding agent. Solvents such as aromatic hydrocarbons, in particular [toluene and Picblormctban, are very suitable, and an organic base such as a tertiary amine is preferably used as the acid-binding agent.

The group ¥ in the starting materials of the formula V can be introduced simultaneously with the esterification of the carboxyl group or subsequently into the amino group of 6-aminopenicillanic acid. Preferably the group W is a silyl group of the formula (R ^) Si-, in which R has the meaning given above and such a group, for example a tri-lower-alkylsilyl (preferably trimethylsilyl) group, is advantageously simultaneously with the Esterification stage introduced into the 6-aminopenicillanic acid, the reaction conditions being chosen so that this is achieved, and a penicillanic acid of the formula V

109826 / mt

BAD ORfGfNAL

in which E 'and W mean the same group. If W in If the starting material of the formula Y is an easily separable group, such as a Triallcylsily! group, the reaction proceeds with Ihiophosgene much smoother under the same reaction conditions as the .Pail is if ¥ eix). Means hydrogen atom.

In an alternative and preferred method of manufacture 'of the ö-lBothiocyaiia-topenicillanic acid compounds of the formula IYj where E is the Phehacyl-, Benzyl- or Benzhydry! group, δ-isothiocyanatopenicillanic acid is obtained according to the above mentioned process, in solution in acetone and ¥ water with sodium bicarbonate neutralized and with an acyl halide under Formation of the phenacyl ester of the acid reacted, or 6-isothiocyanatopeiiicillanic acid is made with Eheny! diazomethane or Diphenyldiazomethane reacted in ethereal solution to give the benzyl or benzhydryl ester of the acid.

In the process for the preparation of the esters of 6-isothiocyanatopenicillanic acid of formula IY, particular care should be taken with the reaction conditions, with regard to both the Sensitivity of 6 ~ aminopenicillanic acid to various influences (e.g. acidic or alkaline medium and higher ! Temperature) as well as the reactivity of the isothiocyariate group: accordingly, the reaction is carried out in a dry, inert organic solvent medium. For this Soluene and dichloromethane or mixtures thereof are particularly suitable for this purpose. It can also be used to facilitate the response an organic base can be added to the chlorine-hydrogen formed to tie; it can be beneficial in certain circumstances e.g. when W is in the starting material of Formula V an IrialkyIsilylgruppe means the acid-binding agent according to the introduction of the ihiophosgene into the solution of the 6-aminopeni-gillanic acid ester reactant admit. Preferably the basic acid binding agent is a tertiary amine such as Triethylamine or li-ethylpiporidine and in particular one whose hydrochloride tends to precipitate in the solvent used than dissolves in it. If the reactant of the formula V bears an 'i'rialkyl substituent on the 6 ~ araino group

-V09828 / 1944 bad

secondary or primary amines, ζ. Β. Aniline, suitable means for Binding of the hydrogen chloride formed during the reaction with thiophosgene, since such amines under the reaction conditions used do not react with the isothiocyanate group.

The processes used to date for the preparation of isothiocyanates use elevated temperatures to bring about the formation of the isoyanate group -N = C = S, but such procedures are unsuitable for the process according to the invention, since they could also lead to a decomposition of 6-aminopenicillanic acid . However, it has been found that the esters of 6-aminopenicillanic acid of the formula V can be converted into the corresponding 6-isothiocyanatopenicillanic acid esters of the formula II by reaction with thiophosgene at very low temperatures, advantageously temperatures at or below -2O ⁰ C and advantageously at -40 ⁰ C can be used. This completely or almost completely prevents the destruction of the bicyclic core.

From the ö-isothiocyanatopenicillanic acid esters of the formula II and their salts, e.g. A wide variety of thiopenicillins, such as amine salts, can be prepared by taking advantage of the well-known reactivity of the isothiocyanato group. This r group can e.g. B. react with amino compounds or compounds with a hydroxyl group.

Thus, according to another object of the present invention 6 -substituted aminopenicillanic acid compounds are prepared by a process which is characterized in that the isothiocyanate radical of a 6-isothiocyanatopenicillanic acid ester of the formula II, according to methods known per se which do not affect the rest of the molecule, in ^{converts a substituted amino group and - if necessary - separates the group E 1} from an ester of a 6-substituted aminopenicillanic acid prepared in this manner in a manner known per se and, if necessary, converts the acid formed into one of its salts, e.g. B. converted into an alkali, alkaline earth or amine salt. By the expression "in itself

109826/1944

BATHROOM 0RK3ÜNAL

. known procedures "are meant procedures that have hitherto used or described in the chemical literature " became. \

Among the Ihiopenicillineii obtained by this new process The iDhioureidopenicillins are the most common Formula: '

- CIi - UJ

s C - N

- N - C - NH - CH - CH

N-CH-COOH

and their esters and salts, especially amine salts and alkali metal and alkaline earth metal salts, of particular interest. In this formula, R ^ means a lower alkyl group, '. Β. a Μ «thy1 -, - ithyl, propyl, η or isobutyl, pentyl or hexyl group, a lower alkeny group, ζ. An allyl group, an aryl group e.g. B. a phenyl or haphthyl group, an alicyclic group, e.g. B. a cyclopentyl, cyclohexyl or cycloheptyl group, an aralkyl group, e.g. B. a benzyl, phenethyl, 1-phenylethyl or phenylpropyl group, a heterocyclic group which is bonded to the specified nitrogen atom via a carbon atom, e.g. B. a 2-piperidyl, I-isoquinq-IyI, 2-pyridyl, 4-pyridyl or 3-morpholyl group, a substituted amino group, e.g. B. a 1-piperidyl, 3-aminoquinolyl, I-aminoisoquinolyl, adenyl, 4-aminomorpholyl, a 6-aminopenicillanyl ester, a phenylamino, acetylamino or benzenesulfonylamino group, and Rp is hydrogen or an I-lower alkyl group or R ^ and R ₂ together with the nitrogen atom to which they are attached represent a mononuclear heterocyclic group, preferably with 5 or 6 ring atoms, ζ . B. a piperidino or morpholino radical. The above-mentioned groups RJ can carry one or more substituents, such as halogen atoms, lower alkyl, IT-lower alkoxy, hydroxy, esterified carboxy1 groups, or have carbonyl groups.

BAD ORSGiNAL

109826/19 44

The mioureidopenicillins of the formula YI can be prepared by reacting an δ-isothioeyanatopenicillanic acid ester of the formula II with an amine of the formula R ^ RgM, in which R ^ and R _{2 have the} meanings given above and, if desired, by procedures known per se, the resulting thioureidopenicillin ester converted into the corresponding acid or a salt thereof or another ester. Examples of suitable amine reactants are 1- or 2-faphthylamine, benzylamine, aniline, N-methylaniline, 2-methoxyaniline, butylamine, 2,2-diethoxyethylamine, allylamine, cyclohexylamine, 6-aminopenicillanic acid or an ester thereof or a protected amino acid such as ethyl glycinate. The reaction is preferably carried out in an inert organic solvent medium, ζ. Β. Ethyl acetate or acetone carried out under anhydrous conditions. The addition of strongly basic compounds such as sodium hydroxide or certain aliphatic amines to the reaction mixture leads to an epimerization of the 6-isothiocyanatopenicillanic acid ester on the carbon atom in the 6-position. In the particular case of a primary or secondary aliphatic amine, further reaction with the isothiocyanato group on the epimerized Og carbon atom can occur, resulting in the formation of isomeric i-dioureidopenicillins. However, Cg epimerization occurs only to a minor extent with most aliphatic amine reactants and cannot keep pace with the relatively rapid addition of the amine to the isothiocyanato group.

It is also possible to use the 6-isothiocyanatopenicillanic acid ester of the formula II or the acid derived therefrom to react with other amines, such as hydrazines, hydrazides or sulfonyl hydrazides.

The e-isothiocyanatopenicillanic acid esters of the formula II and the Free acids derived therefrom can be reacted with compounds which have a hydroxyl group, so that penicillin derivatives are obtained the general formula:

1 0 9 8 2 6/1 9 U

Y ^ OG- JfBT- CH-- CH c ^ " ³

pcH ₃ tu

. / O = C-N-CH-CCX) E.

receives, wherein Y is an optionally substituted hydrocarbon off remainder, such as a lower alkyl group, z. * -B. a methyl, n- or tert-buty group, an aralkyl group, "for example a benzyl group or an alicyclic group, for example a cyclohexy group, and E has the meaning given. \

The compounds of the formula YII can be prepared by reacting δ-isothiocyanatopenicillanic acid or its ester with an alcohol in the presence of a catalyst. Examples of catalysts suitable for this purpose are Friedel-Crafts catalysts, such as aluminum trihalides, e.g. B. Aluminum trichloride »Generally only a small amount of a catalyst is required» The reaction can be carried out in an organic solvent medium and in rare cases where the alcohol reactant is liquid under the reaction conditions, the alcohol itself can be used as the reaction medium. Preferably an ester of isothiocyanatopenicillanic acid is used, e.g. B. a silyl ester, e.g. B. the inrlmethylsilylester. The end product is obtained as a free acid or as an ester of the alcohol used as the starting material. It should be noted, however, that the corresponding esters are obtained with methanol and oxyclohexanol, whereas with benzyl alcohol, n-butanol and tert-butanol are obtained. receives the free acids. The reactions are preferably carried out at slightly elevated temperatures, but room temperatures can also be used in some cases.

The compounds are obtained when, point 6-IsothiQpenicillansäure or esters thereof are reacted with an alcohol a iCautomerie shown _r characterized in that at least in solution an equilibrium between tautomeric forms is present. This relationship can be seen in an HMR spectrum of the solution in veraohie «

■ 1Ο 02-: 8/1 44

2082297

which solvents observe. Another fact that indicates tautomerism is that the compounds obtained as products are easily attached to the S atom, e.g. B. can be alkylated with diazoalkanes _f. This alkylation can give compounds of the following formula:

JP-H-CH-CH C (CHj) _{2 YIII}

0 «C - K CH -COO-

. where R *, R ^ and R, -, which are identical or differ from ν can be, each represent a lower alkyl or aralkyl group.

The formulas which are given in Examples 10 to 14 below and which relate to the compounds obtained by reacting isocyanates with alcohols must therefore be considered from the point of view of possible phoneticism.

New penicillanic acid derivatives, which correspond to the general formulas VI, VII and VIII, have antibiotic properties, which make them particularly valuable as medicines for people and üiere and as additives for animal feed. They are preferably supplied in the form of a non-toxic salt such as the sodium-potassium or calcium salt used for therapeutic purposes. Other salts used in pharmaceutical preparations include the nontoxic, suitably crystallizing salts with organic bases such as amines, e.g. B. with iErialkylamine, Cyclohexylamine, Procaine ,, Dibenzylamine and ! "N-Alkylpiperidines.

When the new penicillins, which correspond to formulas VI, VII and VIII, or their non-toxic salts are used for therapeutic purposes, they can - as they are - or in Form of a pharmaceutical preparation as it is usually used

1C982S / 19U

for the administration of therapeutically active substances, in particular antibiotics, are used. The present The invention therefore also includes pharmaceutical preparations that as an active ingredient of one of the new penicillins according to the invention together with a pharmaceutically acceptable carrier, ' which can be solid or liquid. The penicillins can be used as they are or mixed with a solid or liquid. gen diluents in capsules made of absorbable material, such as Gelatin. The penicillins can be used bound to or incorporated into a carrier substance in such a way that the active substance remains in the course of a prolonged period of time is released after ingestion. Liquid preparations can be in the form of solutions suitable for parenteral administration are available.

The following examples are intended to further the present invention explain. :

example 1

A. Preparation of a solution of the erimethylsilyl ester of the 6-iso « thiocyanatopenicillanic acid from the! driinethy! allyl ester of 6-N-trimethylsily! Aminopenicillanic acid.

A double-walled vessel is used for the conversion. the Cooling is brought about by the circulation of a coolant through a thermostat that operates at any selected temperature can be. The vessel is covered by an iDeflon film that can be mechanically destroyed by adjusting the stirrer, connected to a filter unit so that a cold filtration the reaction products is made possible in the absence of air.

To the flask equipped with a stirrer, a dropping funnel, a P ₂ O ₅ tube and a gas inlet tube through which nitrogen is supplied, 17.2 g (79.5 mmol) of 6-aminopenicillanic acid and 270 ml are added Dichloromethane. Then 25.5 ml (183 mmol) of triethylamine and, in the course of about 15 minutes, 28.5 ml (225.5 mmol) of trimethylchlorosilane are added dropwise

10S826 / 19U

.2O ⁰ C to. Uach completion of the addition is stirred for a further 60 minutes at 2O ⁰ C. Then, the temperature at -55 ⁰ C is placed and 200 ml of toluene and 2 ml (14.5 mmol) of triethylamine and then 9 ml (116 mmol) of thiophosgene was added, whereby the temperature rises to about -47 ⁰ C to about 8 ⁰ C. ' The mixture is stirred v / urther 60 minutes at -45 ⁰ C and then the temperature is brought to -55 ⁰ C. wirderum then added a further amount of 11.5 ml (82.5 mmol) of triethylamine added, whereby the temperature of the reaction medium to at least 10 C rises and the medium itself becomes almost colorless. The mixture is stirred v / urther 4 hours at -45 ⁰ C. At this temperature, the precipitate formed is filtered off under nitrogen and washed three times with cold anhydrous toluene (total 300 ml). From the combined PiItrat and the washing solutions is allowed to GroE · ßeren part of the excess thiophosgene with Triniethylchlorsilan, triethylamine and dichloromethane under reduced pressure, starting evaporate at an internal temperature of -45 ⁰ C.

If only traces of dichloromethane are detected in the distillate 250 ml of cold anhydrous toluene are added to the residue in order to separate off the last traces of thiophosgene. During this procedure the temperature is allowed to slowly rise to room temperature. The resulting faintly colored Solution is filtered at room temperature in the absence of water. The final volume of the clear solution of the trimethylsilyl ester of ö-isothiocyanatopenicillanic acid in toluene, the one represents new compound is 250 ml. The concentration is 0.3 mmol / ml. Yield: 75 mmol ($ 94).

B. Preparation of a solution of the irimethylsilyl ester of 6-isothiocyanatopenicillanic acid from the trimethylsilyl ester of 6-aminopenicillanic acid.

12.9 g (59.5 mmol) of 6-aminopenicillanic acid are dissolved in 100 ml of dichloromethane suspended. 9.1 ml (65 mmol) of triethylarain are added under a nitrogen atmosphere and then added dropwise 7.9 ml (62.5 mmol) trimethylchlorosilane. The mix will Stirred for 60 minutes at room temperature. It will then be published under

109 626/1944

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'- 13 -

gem stirring under St iciest off atmosphere cooled to-'einer mixture of 7 ml (90 mmol)! thiophosgene, 9.1 ml (65 mmol) of triethylamine, 50 ml dichloromethane and 150 ml of toluene, the -vorher to -50 ⁰ C. , given, at such a rate that the reaction temperature does not rise ^{above -40 0 G.} Subsequently, a further 50 ml of dichloromethane are added and stirred for a further 60 minutes at -40 ⁰ O. After-cooling to -45 ⁰ O .dem

are added dropwise 7.5 ml (54 mmol) of triethylamine was added to give, makes sure that the temperature does not rise to "higher than -40 ⁰ O. The reaction mixture is stirred for 3 hours at -40 _v ⁰ G and at this temperature, nitrogen atmosphere and filtered. the precipitate on the filter is washed three times with a total amount of 400 ml of cold anhydrous! washed toluene. While allowing the temperature to slowly rise from -50 ⁰ C, the combined filtrates are evaporated under reduced pressure and the solution is stirred at room tempera door again The final volume of the clear solution of the trimethylsilyl ester of 6-isothiocyanatopenieillanic acid in toluene is 113.5 ml. The concentration is 0.31 mmol / ml. Yield: 35 mmol (59 "/ *). .

Example 2

Isolation and characterization of the trimethylsilyl ester of o-Isothiocyanatopenicillanic acid.

250 ml of the abovementioned solution of the trimethylsilyl ester of e-isothiocyanatopenicillanic acid in toluene (Example 1A) are concentrated to a volume of about 100 ml at room temperature under reduced pressure. A small amount of crystallization occurs, but the crystals essentially disappear when the solution is gently heated, which is then kept at room temperature for a few hours. It is then cooled to ^ ⁰ O for a few hours and then lpted to stand overnight ^{at -18 0} C; the semi-solid product is filtered off under a nitrogen atmosphere at -25 ⁰ O. The crystals are washed three times with cold anhydrous toluene. The remaining toluene adhering to the crystalline product is then min- "

100 * 16/1 * 44

2062197

removed under the current pressure. This gives 16.5 g of the trimethylsilyl ester, the east-Isothiocyanatopenicillansäure, mp. = 102 to 105 ⁰ Cj [a] ^ = + 160.9 ° °° in like Lorin ethane (c = 1). Molecular weight is determined by mass spectroscopy: 330 (calculated 330).

Analysis: C 1 DD
J Λ pXl 18 ^Ν 2 ° 3 2 ^ί H 5, $ 49 N 8, 44 Calculated: C. 43, $ 61> 5 ·, 47 8th, 37 Found: 43, 94

The IR and NMR spectra in toluene (before isolation) and in Chloroform (after isolation) show the structure and / the purity of the initially obtained toluene solution (a Achieved purity of $ 95 or better).

The solutions in toluene obtained first can be ^{stored for weeks at about 0} ° C. without noticeable decomposition. The solid can be stored for months at room temperature, provided that the usual precautions for hygroscopic compounds are observed. The plague

Easily dissolves in solvents such as diethyl ether or dichloromethane.

Analysis of the NMR spectrum of the trimethylsilyl ester of 6-isothlocyanatopenicillanic acid (at 60 Mc; S values in ppm, internal standard: tetramethylsilane):

solvent
(conc.)

Si (OH,),

CH,

C ₂ -H

C ₅ -H and C ₆ -H

AWAY

(Quartet; J = 4.0

+0.2 ops

[Toluene (approx
105 mg / ml)

ODCl, (approx
110 Aeg / ml)

0.17
0.33

1.27 1.35 1.56 1.70

4.37 4.52

3.95 4.02 4.87 4.94 5.08 5.15 5.54 5.61

Partial analysis of the IR spectrum of the trimethylester of 6 ~ isothiocyanatopenioillanic acid, recorded in chloroform, concentration

109826/1944

tion about 10 mg / ml, fourth in "cm" *:

H = G = SC = Oβ-lactam C = O-ester

2060 1788 1720 850

Example 3

Isolation and characterization of δ-isothiocyanatopenicillanic acid. .

, _{|| i i;} - , ] ι ι i r ■ _ 1 m uni ill 1 · "I .Il ι · -I- '■ ii M ill Ii ■ ι ι' 11 - ι ι 1: - - -

2 g of trimethylsilyl! Ester of G-Isotliiocyanatopenicillansäure were added portionwise contained at a temperature of -8 ⁰ C with stirring, to 35 ml of acetone containing about 3% of water. After stirring for 10 minutes, the solution is concentrated to about 5 ml. 25 ml of cold anhydrous acetone are then added with stirring at a temperature of ^{0 ° C.} The solvent is again evaporated under reduced pressure and 25 ml of anhydrous ethyl acetate are added to the slightly moist pale yellow oil. After evaporation of the solvent, a further amount of 10 ml of anhydrous, purified / Lthy3.aeetat is added to the essentially anhydrous oil. According to the thin-layer chromatogram, the quality of the e-isothiocyanatopenicillanic acid had not suffered as a result of this treatment. The solution is concentrated under reduced pressure at ⁰ ° C., as a result of which spontaneous crystallization occurs. After cooling to -18 ⁰ C and _; v filtration / ground the crystals at -18 ⁰ C and the small volume Äthylacet and dichloromethane in succession, then dried. The colorless crystalline product is pure according to thin-layer chromatography, which is confirmed by characterization using spectroscopic methods. The δ-isothiocyanatopenicillanic acid can be recrystallized from dichloromethane.

In an analogous manner, the e-isothiocyanatopenicllanic acid can be used in The form of an oil or a solid can be obtained directly from solutions of their trimethylsilyl ester in toluene.

Both the oil and the solid can be in an aqueous

109826/1944 _BAD original

■. - 16 -

Buffer solution (pH = 7) can be dissolved without noticeable decomposition. The compound can be isolated from acidified aqueous solutions by extraction with solvents such as diethyl ether or ethyl acetate. In such cases the decomposition can be limited to a maximum of 5%.

The new compound 6-isothiocyanatopenicillanic acid is as follows characterizes:

Thin-layer chromatography: Rf = 0.48 (silicon dioxide; diethyl ether / formic acid = 98/2).
[a] J3 °° = 199 ° in dichloromethane (c = 1).

Behavior when heating.

The compound shows no characteristic melting point. Above 11O ⁰ C enters a yellowish color and 15O ⁰ C uses a more discoloration to brown. Melting, which is accompanied by a significant decomposition occurs above 170 ⁰ C.

Calculated: C 41.84 % H 3.90 ° /> N 10.85 i S 24.83 ^c β>

0 18.58 56.

\ Found: C 41.71 % H 3.98 # N 10.70 $ S 24.72 f>

0 18.89 jS

Partial analysis of the IR spectrum (recorded in chloroform, concentration: about 10 mg / ml; Values in cm "):

OH (carboxyl) N = C = S C = O (ß-lactam) C = O (carboxyl)

around 3500 around 2055 1790 1725 (probably the dimer)

around 265Ö 1765 shoulder (probably around 2550 monomers)

Analysis of the NMR spectrum of a solution of 6-isothiocyanatopenicillic acid in CDCl, (taken at 60 Mc; ei values in ppm,

10 * 8 2? / 1944

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under use ° 2 from '. Detramethylsilane as internei AB quartet
cps. • Default: CH ₃ 4, -H C ₅ -H and C ₆ -H
J = 4.0 + 0.2 55 5.62 -COOH 1.62 1.74 61 5.12 5.19 5, at 10

The position of the four absorption lines, which _{can be assigned to the protons bound to the C 1} or Cg atoms, depends heavily on the concentration and the choice of solvent.

Stability and solubility of 6-isothiooyanatopenoillanic acid.

The compound is easy in diethyl ether, acetone, ethyl acetate and chloroform soluble; whereas the solubility in dichloromethane is somewhat lower. The stability of the solid and its Solutions, e.g. B, the above-mentioned solvents and in water / water at pH = 7, depends to a considerable extent on the degree of purity and the 3 color of the product. Pest colorless 6-isothiocyanatopenicillanic acid retains its good quality when stored at room temperature for several positions and the same also applies to solutions made from the colorless! solid became.

Isomerization (Cg epimerization) of ö-isothiocyanatopenicil- acid in an alkaline medium,

Solutions of δ-isothiocyanato-Ccis-Sfej-penioillanic acid in water with a pH of about 5 and 7 ₉ 5 are relatively stable. The addition of dilute sodium hydroxide solution causes a relatively rapid partial isomerization to 6-isothiocyanato- (trans-5,6) -penicillanic acid (Cg epimerization).

The conversion can also be brought about by adding small amounts of the irimethylsilyleate of β-lbothiocyanatopenicillanic acid to _{an aqueous, alkaline solution, the pH value being adjusted to a pH value of 9.0 to 9 f} in the course of the experiment by adding a dilute sodium hydroxide solution 5 holds. In about 60 minutes at ^{0 0} O and a pH of 9 "to 9.5

109126/1944 *

reached equilibrium. An extension of the reaction time has no effect. According to the thin-layer chromatography, no further sulfur-containing reaction products were formed; the starting product has been epimerized to a degree of about 45 ° ß> in the trans isomer, which has a slightly larger Rf value. Acidification to pH 4.5 and extraction with diethyl ether gives a semi-solid oil which, according to thin-layer chromatography, still has the same composition. The IR spectrum shows the values given above for the cis isomer.

A study carried out at a pH of 10 to 10.5 resulted in a mixture containing relatively larger amounts of the trans isomer - apart from sulfur-containing compounds and sulfur-free breakdown products - contained. A series of extractions resulted in the isolation of an oil from which Thin layer chromatography could show that it was free from other sulfur-containing compounds. An IiMR spectrum showed the presence of small amounts of one or two byproducts that may not have an S atom in the ring. Disregarding the by-products, the NMR spectrum of a solution of the mixture in CDCl ,, can be analyzed as follows (recorded at 60 Mc; <5 values in ppm; internal Standard: tetramethylsilane):

CH ₃ C ₂ -H Cc-H and C ₆ -H AB quartets Ois-5.6 (45 50
trans-5.6
(55 #) 1.60 1.72
1.57 1.60 4.60
4.60 5.11 5.18 5.54 5.61 (J = 4.0 + 0.2
cps)
4.85 4.88 5.37 5.40 (J = 1.8 + 0.2
cps)

109826/1944

Example 4

Dieyclohexylojninsalz of G-isothiocyanatopenicillanic acid,

Essentially in accordance with the procedure described in Example 3, 1.86 g of the solid trimethylsilyl ester of 6-isothiocyanatopenicillanic acid, dissolved in about 10 ml of ethyl acetate, are quantitatively converted into G-isothiocyanatopenicillanic acid. At -5 ⁰ G, a pre-cooled solution of 1.029 g (1 in excess) of dicyclohexylamine in 15 ml of ethyl acetate and 5 ml of acetone is quickly added with stirring. Thin-layer chromatography showed that no decomposition of the isothiocyanato compound occurs and that it is furthermore very unlikely that the amine will react with the isothiocyanato group.

The pale yellow solution thus obtained is concentrated under reduced pressure until the solution becomes cloudy. The mixture is kept for 15 minutes at room temperature and then left to stand over Uacht at · -18 ^0C. The crystalline precipitate is ^{filtered off at -20 0} C and washed successively with Äthvla ^ stat and diethyl ether. After drying, 1.70 g of the colorless dicyclohexylamine salt of δ-isothiocyanatopenicillic acid, which is a new compound, are obtained. Yield? 66 ^ ₀

Properties of the dicyclohexylamine salt of 6-isothiocyanatopenicillanic acid.

The compound does not show a sharp melting point; between 120 ° and 125 ⁰ C, the product begins to turn brown au; liquefaction and decomposition occur between about 175 and 185 ^° C.

Thin-layer chromatography (silicon dioxide; diethyl ether / formic acid = 98/2) shows a component with the same Rf value (0.48) like δ-isothiocyanatopenicillanic acid.

20 °
[a] _D = + 137.1 ° in dichloromethane (c = 1).

109826/1944 ■ »« «» «.

Analysis: ^ 21 ** 33 ^ 3 ^ 3 ^ 2

Calculated: O 57.39 # H $ 7.57 N 9.56 % S 14.59 5 ^

O 10.89 f °
Found: C 57.19 1 ° H 7.58 56 N 9.36 # S 14.30 j5

O 11.57 1 »

The NMR spectra of solutions of the compound in CDOL and CD ₃ -OO-OD ₅ and the IR spectra of the solid (KBr pellet) and a solution in chloroform confirmed that the compound obtained was indeed the dicyclohexylamine salt of the '6 -Isothic- k is cyanatopenicillanic acid.

Stability.

The solid salt is relatively stable. In aprotic solvents that are not too polar, the salt is present for at least one time Relatively stable for hours at room temperature. However, it occurs when the salt is dissolved in dimethyl sulfoxide or dimethylformamide immediately a rearrangement along with a decomposition occurs. Solutions of the salt in water or in aqueous buffer solutions are also unstable at room temperature.

The new N-ethylpiperidine and Cyclohexylamine salts of o-isothiocyanatopenicillanic acid by one solutions of ö-isothiocyanatopenicillanic acid and N-Äthylpiperidih or cyclohexylamine brings together. The structure and the Purity of these salts is determined using the IiMR and IR spectra or thin-layer chromatography.

Example 5

sssss— »ί» mn'in »jsssssB

Preparation of G-isothiocyanatopencillanic acid methyl ester, starting of δ-isothlocyanatopenicillanic acid.

0.5 ml of water is added to a solution of 1.88 g of tri-methylsilyl 6-isoth.iocyanatopenicillanate in 15 ml of diethyl ether, which has been ^{cooled to 0} ° C., in order to effect the hydrolysis of the ester and then the solution becomes 30 Minutes stirred. A diazomethane solution is then added ^{at 0} ° C. over the course of 15 minutes

1 09826/1044

(prepared from 2.14 g of li-methyl-U-nitroso-p-tolylsulfonamide in "about 15 ml of diethyl ether). The evolution of a gas is observed. The reaction mixture is then ^{stirred at 0} ° C. for 1 hour and then overnight at -18 ⁰ G allowed to stand, after which it is in 80 ml of ice water, which was brought to a pH value of 4 before poured. Under stirring, "the pH value is raised to 7 and the layers formed separately. After drying over magnesium sulphate, the ether layer is evaporated to dryness, resulting in a solid which, according to thin layer chromatography, is almost pure. Yield; 1.50 g.

To prepare a colorless crystalline sample, which is suitable for analysis purposes, the product is recrystallized twice from a mixture of equal parts diethyl ether and petroleum ether and 600 mg of the pure 6-isothio- »cyanatopenicillanic acid methyl ester, which is a new product, is obtained. Melting point: 86 to 87 ⁰ C.

or, ⁰ _Λ
[α] £ ^υ = + 178 ', 5 in dichloromethane (c = 1).'

Molecular weight according to the mass spectrum: 272 (calculated 272).

Analysis:
Calculated;

Found:

0 44.10 fo H 4.44 ° i.d.

0 $ 17.62

0 44.18 % H 4.47

0 17.67 fo

N $ 10.29> S 25.55 1? 10.16 fo S 25.52

Analysis of the NMR spectra of 6-isothiocyanatopenicillanic acid. methy! esters (recorded at 60 Mcj £ values in ppm; internal, standard; (detramethylsilane) concentration; about 200 mg / ml.

solvent CH ₅ OCH ₅ C ₂ -H Cc-H and Cg-H AB quartet
Y as 4.0 + 0.2 cps % K 4 3D ₅ COCD ₅
ODCl,
I Jt 1.51 1.70
1.51 1.71 3.85
5.81 4.70
4.58 5.57 5.65 5.76 5.85
5.13 5.20 5.58 5.65 I uv IXiI

Partial analysis of the IR spectrum of the 6-isothiocyanatopenicillanic acid methyl ester (absorbed in chloroform; concentration about ..1O mg / ml; V / erte in cm):

N = O = S G = O (ß-lactam) G = O (ester) 2055 1790 1745

The new benzyl 6-isotiocyanatopeiiicillanate is obtained in an analogous manner by reacting the 6-isothiocyanatopenicillanic acid (prepared in situ from the trimethylsilyl ester) with phenydiazomethane. The mixture, which is isolated directly from the reaction mixture, melts at 122 "to 127 ° C and is according to the Thin-layer chromatogram and the NMR spectrum almost pure.

Example 6

Production of the phenacyl o-isothiocyanatopenicillanate.

1.7 g of trimethylsilyl e-isothiocyanatopenicillanate are added at _5 ° C. to a mixture of 30 ml of acetone and 1 ml of water. After stirring for 10 minutes, the solvent is separated off by evaporation under reduced pressure at ⁰ ° C. and the remaining oil is dissolved in 10 ml of acetone. At ⁰ ° C., a solution of 0.43 g of sodium bicarbonate in 20 ml of water is added with stirring. After the end of the coal! Oxy dent v / i cklung, a solution of 1.04 g of phenacyl bromide in 10 ml of acetone is added over the course of 15 minutes at ^{0 ° C.} The mixture is stirred for 23 hours at room temperature, a precipitate gradually forming. The mixture is concentrated under reduced pressure and the precipitate is filtered off, triturated with water, filtered and washed with a little cold diethyl ether. After drying under reduced pressure, 1.4 g of the product are obtained. According to thin layer chromatography and IR and NMR spectra, the product is 90 to 95 # pure. The Umkristallisatlon of di- i ethyl ether yields the pure crystalline 6-Isothiocyanatopeni- cillansäurephenacylester, which is a novel compound.

Melting point: 110 to 111 ⁰ C; [a] | ° = + 153 ° in dichloromethane ^{(C = 1) #} . 109826/1944

Analysis of the IR spectrum (recorded in chloroform, concentration: about 10 mg / mg, values in cm).

N = C = SC = O (ß-lactam) C = O (ester) C = O (phenacyl) 2058 1798 1758 1709

C = C aromatic C-O-C ester 1599 1580 1170

Analysis of the NMR spectrum of a solution in COCl, (recorded at 60 Mc; 6 values in ppm using tetramethylsilane as internal standard):

CH ₃ C ₂ -H C ₅ -H and Cg-H AB quartet
j "= 4.0 + 0.2 cps CH ₂ (in ester
..... groups) ° 6 ^H 5 ..; 1.72
1.79 4.71 5.11 5.18 5.58 5.65 5.47 5.50 7.4 * 8.2

The outer lines of the AB quartet it with gsr ^ inger intensity, those assigned to the CH-p-G group were not observed,

Analysis: ° 17 H _{1 β} Έ ₂ Ο _έ l · 2 H 4, 29 Calculated: C. 54.23 O 17.00 H 4, 33 Found: C. 54.41 O 16.83 * Example 7

7.44

7.45

S 17.04

S 16.98

Preparation of the 6- (N ^f -Cyclohe2cyl-thioureido) -penieillansäuremethy! Ester.

110 mg of 6-isothiocyanatopenicillanic acid methyl ester are dissolved in 0.5 ml of CD ₅ -CO-CD ₅ in a glass tube which is normally used to record the NMR spectrum. At ⁰ ° C., the HMR spectrum of this solution is first recorded. Their properties are given in Example 5. Then about 50 mg

109826/1944

Cyclohexylamine (20 ft excess) is added, after which a further spectrum is recorded directly - again at ⁰ ° C. It seems that the 6-isothiocyanato (cis-5,6) -penicillanic acid methyl ester is already converted into the new 6- (N »-cyclohexylthioureido) - (cis-5,6) -penicillanic acid methyl ester (about $ 85 and a by-product ( was converted about 15 f ') the by-product is the new 6- (N'-cyclohexyl-thioureido) -. (trans-5,6) -penicillansäuremethyiester.

The reaction mixture is ^{kept at 0} ° C. for several hours in order to give the less stable tran3 isomer the opportunity to gradually convert into other compounds, possibly including the cis isomer. The slightly discolored solution is then concentrated to a small volume, whereby a solid precipitate separates out. (Cis-5,6) has -penicillansäuremethylester> obtained with a purity of about 95 ° / in good yield - by IR and NMR spectra and their interpretation that the b- (N ^l -Cyclohexylthioureido) was determined.

Partial analysis of the NMR spectrum of the δ-tN'-cyclohexylthioureido) - (cis-5,6) -penicillanic acid methyl ester at O ⁰ C in GD ₃ -CO-CD ₅ (recorded at 60 Mc; 6- fourth in ppm, internal standard: Tetramethylsilane):

CH ₅ OCH ₅ C ₂ -H C ₅ H doublet
J = 4.3 + 0.2 cps Cg-H quartet
J = 4.3, Jt = 7.7+ o, 2
cps " 1.48 1.63 3.83 4.46 5.67 5.74 6.10 6.17 6.23 6.30

NH (2 protons: 2 overlapping doublets J ¹ ^ J "= 7.7 cps) 7.40 + 7.63

109826 / 19U

Example 8

Preparation of the cyelohexylamine salt of ö - ^ - Cyclohexylthioureido) ~ (cis-5-, 6) -penicillanic acid.

140 mg of cyclohexylamine are added at ⁰ ° C. to a solution of 500 mg of δ-isothiocyanatopenic ulanic acid (in the form of its cyolohexylamine salt) in 5 ml of anhydrous and purified acetone. The solution is stirred for 3 hours at room temperature and then evaporated to dryness . the solid residue weighs 635 mg the product obtained is due to the IR and HMR spectra, the cyclohexylamine salt of the new 6- (N ^t -CyclohexyltMoureido.) - (cis-5,6) -penicillansäure liat and a purity of about 90 fo .

Example 9

Preparation of the crystalline H-ethylpiperidine salt of 6-ihioureido- (cis-5,6) -penicillanic acids.

In a manner analogous to the procedure “described” in Example 8, six amines given below were treated with the ΪΓ-ethylpiperidine salt the G-isothiocyanatopenicillanic acid implemented what the IT-ethylpiperidine salts of 6-shioureido- (cis-5,6) -penicillanic acids quickly in good yields in crystalline form resulted in:

Reagent product

N-Ethiopiperidine salt of:

1) 2-kethoxyaniline 6- [N '- (2-methoxy) ~ phenyl-thioureido] peni-

cillanic acid

2) Benzylamine 6- (N ¹ -Benzylthioureido) ~ penicillanic acid.

3) Butylamine 6- (IT ^t -n-butylthioureido) -penicillanic acid

4) Gyclohexylamine 6- (N ¹ -CycloliGxylthioureidoJ-penicillanic acid '5) Allylamine 6- (N'-allylthioureido) -penicillanic acid

6) 2.2 ~ diethoxyethyl

amine 6- [li '- (2,2-diethoxy) ethylthioureido] peni-

cillanic acid
Yield of the II-ethylpiperidine salt in %

1) 60 fa 2) 75 0; 3) 75 0; 4) 65 fc 5) 84 i \ 6) 49 ^ _QmmmL

109826/1944

NH D. 3400 2) 3400 3280

The o-thioureidopeiiicillin products given above are at least 90 % pure with the main impurities being a residual amount of the solvent and some N-ethylpiperidine.

The penicillins produced under 1), 2), 4) and 6) and their salts are new compounds.

The IR spectra were recorded in chloroform, the concentration of the compounds etv / a being 10 mg / ml. Partial analysis of the IR spectra gives the following results (in, cm):

C = O (ß-lactam) C = 0 (carboxylate, on) 1775 1595

1770 1610

The KMR spectra were recorded at 60 Mc in CDCl ^.

Part analysis of these spectra gives the following results (<i values in ppm using Tetramcthylsilan as inter ner Standard):

CH ₅ 1) 1.57 and 1.60 (6 protons) 2) 1.58 (6 protons)

C ₂ -H, 1) 4.33 2) 4.29

C ₅ -H 1) (doublet; J = 4.0 + 0.2 cps): 5.69 and 5.76 2) (doublet; J = 4.0 + 0.2 cps): 5.62 and 5 , 69

C ₆ -H 1) (multiplet): 6.07
2) (Multiplott): 6.0

0-CH ₃ 1) 3.87

C ₆ -IL 1) (and NH) (multiplet; 6 protons): 6.85- ^ 8.35 2) 7.36

CH ₂ 2) (doublet): 4.71 and 4.80

N-CH ₂ 1) (multiplet, 6 protons): 2.80> 3.30

109826 / 19U

- · 27 ~
2) (multiplet, 6 protons): 2.65 - * 3.25

OH, (ethyl group) 1) 1.30 (triplet)

2) 1.25 (triplet)
Example 10

Production of methyl e-methoxythiocarbonamido-penicillanate.

CH, -O -'C-NH-CH-CH C (CH _Z ) _O

⁵ Ϊ ■ Il \ ^{} Z} ■

O = C- K --—- CH - COO - CH,

1 g of the trimethylsilyl ester of δ-isothiocyanatopenicillanic acid is dissolved in 15 ml of pure distilled methanol under a nitrogen atmosphere. About 15 mg of aluminum chloride are then added and the reaction mixture is heated to reflux. After about 1 1/2 hours, a further amount of about 15 mg aluminum chloride is added. After 2 1/2 hours the reaction mixture is concentrated and a "crystalline" precipitate is formed. The precipitate is filtered off, washed with methanol and dried. The piltrate is evaporated to dryness. The residue is treated with anhydrous diethyl ether. The precipitate is filtered off with diethyl ether gewasohen "and dried The yield of the combined precipitates is 375 mg;. Melting point = 128-134 ⁰ C. According to the IR and NMR spectra formed of the above-mentioned Methylester.

Mass spectrum analysis shows a molecular weight of 304 (calculated 304). Analysis of the NMR spectra of the end product, dissolved in CDOl ₅ and (CD ₅ J ₂ SO, (60 Mc; cf values in ppm, internal standard: tetramethylsilane):

CDCl ₅ (CD _{5 I 2} SO

C ₅ - CH ₅ 1.52 and 1.63 1.45 and 1.55

0 - CH ₅ (2 x) 3.83 and 3.87 3.77 and 3.79

C ₆ -H 4.60, 4.66 (d, J ₁ = 3.5) 4.73, 4.76, 4.78, 4, BC

109826 / 19U ^{(q> J} 1 ^{= 2} ' ⁷ ' ^J 2 = ¹ ' ^{3 0}

W-H

CDCl,

° 2 - H 5, 24 6, 06 (d, ^C 5 - H 6, 00, 3, 5)

by 7.7

(CD ₅ ) ₂ SUN

5.12

5.82, 5.87 (d, J ₁ = 2.7 cps)

by 10.0 (broadened singlet)

Partial analysis of the IR spectrum of the end product, dissolved in chloroform (Concentration about 10 mg / ml, values in cm ""):

3346 NH 1755 CO ß-lactam 1734 CO ester 1495 probably MH Def Example 11

Production of ö-Benzyloxythiocarbonaniido-penicillanic acid.

CH

O - C - NH - CH - CiI

»II

^s O = C- Ii

CH - COOK

A mixture of 2 g of the 6-Trimethylsilylesterg Isotliiocyanatopenicillansäure, 15 ml of freshly distilled benzyl-lkohols and about 15 mg of aluminum chloride was heated for 5 minutes at 65 ⁰ C. The compound formed is separated off and is obtained in a yield of 150 mg in the form of a solidified oil. The IR and UMR spectra showed that the free acid of the formula mentioned above was formed.

Analysis of the NjMR spectrum of the end product, dissolved in CDCl (60 Mc; 6 values in ppm, internal standard: tetramethylsilane):

- H

- H

around 1.65 (6 protons) 4.60, 4.66 (d, J = 3.6 cps, 1 proton)

5.22 (1 proton)

5.26 (1 proton)

5.97, 6.03 (d, J = 3.6 cps, 1 proton)

109826 / 19U

CgH, - around 7.4 (5 protons)

N-H ■ around 8.0 (broadened singlet, about 0.8

Protons)
COOH (+ H ₂ O) at 9.1

Partial analysis of the IR spectrum of the end product, dissolved in chloroform (Concentration about 10 mg / ml, values in cm ""):

around 3450 NH 0 ß-lactam 1750 C = 0 carboxyl 1728

Example 12

Production of ö-n-butoxythiocarbonamido-penicillanic acid.

JS

C ₄ H ₉ -CH ₂ - O - C - NH -CH- CH C (CH ₃ J ₂

SO = C-N CH-COOH

A mixture of 1 g of 6-trimethylsilyl IsotMocyanato- "penicillanic acid, 15 ml of freshly distilled n-butanol IMD about 15 mg of aluminum chloride is heated for 20 minutes at 65 ⁰ C. The reaction mixture is filtered off, the piltrate is evaporated to dryness and the residue is dissolved in sodium bicarbonate solution. The solution is washed with diethyl ether, acidified and extracted with diethyl ether. The ether extract is used to obtain the end product. The IR and NMR spectra showed that the free acid of the formula mentioned above was formed.

Analysis of the MR spectrum of the end product, dissolved in ODCl ^ (6Ö Mc, 6 values in ppm, internal standard: tetramethylsilane):

CH ₂ CH ₂ 0.8- * 2,

5 ~ CH ₃

θΛθΗ «1.65) (13 protons)

0)

O -CH ₂ 4.27 (center of a triplet; J =

6.5 cps, 2 protons) O ₆ -II 4.59, 4.65 (d, J = 3.6 ops, 1 proton)

"109826 / 1.044

- $ Ό -

C ₂ - H 5.21

C ₅ -H 5.94, 6.00 (d, J "- 3.6 ep: - :, 1 proton)

N-II 8.03 (broadened singlet; etv / a 0.0

Protons)
COOH (+ 1I ₂ O) at 10.2

Example 13

Preparation of the 6-Cyclohe: £ yloxythiocarbon & mxdo - peniciilanoi: iurecyclohexyl ester.

^ t; --υ - υ - mi - υπ - CIi C (CII ₂ )

O - C - HH - CH

N CII - COO

In a similar manner, 1 g of trimethylsilyloist of 6-methylthiocyanatopenicillanic acid was obtained and 15 ml of cyclohexanol in the presence - unit of about 15 mg of aluminum chloride lei at a temperature of 45 C implemented. After about 1 hour, the reaction is essentially complete and the product formed is separated off. !The Yield is about 500 mg of an oil per year, which according to the IR and NMR spectra of the cyclohexyl esters of the above .Vormel int.

Analysis of the NMR spectrum of the end product, dissolved in Cl) Cl ₇
(60 Mc, 6 values in ppm, internal standard: tetraraethylsilane):

< ^CH 2> 5 0.9-2.3) _{(26 protonon)}

1.63)

0 - CH (ester) around 3.7 (unresolved multiple fet,

1 proton)

C ₆ -H around 4.55, 4.61 (d ,. J = 3.6 cpa, 1 proton)

S = C-O-ClI by 4.9 (unresolved multiplet,

1 proton)

C ₂ -H 5.19 (1 proton)

C ₅ - II 5.95, 6.01 (d, J = 3.6 cps, Λ proton)

N-H 8.00 (about 0.8 protons)

109826 / 19U BATHROOM

Example 14

Production of 6-tert-butoxythiocarbonaraido-penicillanic acid.

(CH ₇ ) ^ C - O - C - NH - CH - CH C (CH ₇ ) _P

5 5 κ ij \ ^J

^S O KCH CO

j \

O β C - K - CH - COOH

■ ι

1 g of the Trimothylsilylesters ö-Isothiocyanatopenicillansäure and 15 ml of freshly distilled tert-butanol were reacted in the presence of about 265 mg Aluminiumclilorid at 60 ⁰ G. ITh about. The product formed is separated off in crystalline form in a yield of about 150 rag for 5 minutes. The end product of the above formula is the free acid according to the IR and M-IR spectra.

Analysis of the Hiffi spectrum of the end product, dissolved in CDCl ,, (60 Mc, S values in ppm, internal standard: letramethylsilane) -:

1.50 (0 protons)

1.64 (6 protons)

4.48, 4.54 (d, J = 4.0, 1 proton) 5.19 (1 proton)

5.93, 5.99 (d, J = 4.0, 1 proton) around 6.1 (1 proton)

around 6.7 (about 1 proton).

Example 15

Production of 6- (Hethoxymethy! Mercapto) -methylideniminopenicillanic acid methyl ester.

O - C ₃ Cg C ₂ C ₅ IT - -.C (CH ₃ ) - GH »
3 - II - H - H - II coon

C = N-CH-CH C (CH,) _O

cn -s ^ III? ²

^ O = C - K - CH - COO - CH ₃

One gives
/ a solution of diazomethane (hergeste3.lt from 1 g IT-Hitroso-II-methyl-p-tolylsulfonamide) in diethyl ether to an ice-cold solution clay 62 mg of the methyl ester of e-methorythiocarbonainido penicillanic acid in a mixture of 3 ml diethyl ether and

109826 / 19U BADORiQfNAU

0.6 ml of dimethyl sulfoxide. After stirring the reaction mixture for 10 minutes at ⁰ ° C., the reaction mixture is kept at room temperature overnight. A thin-layer oinatogram shows an almost complete conversion of the 6-methoxythiocarbonamidopenicillanic acid ester. The diethyl ether is completely evaporated and the resulting oil is subjected to column chromatography over silica using diethyl ether as the eluent. The fractions containing the new compound of the above formula are collected and evaporated in vacuo. A pale colored oil is obtained with a yield of 45 mg. An IR spectrum of the final product, dissolved in chloroform, shows the absence of a N! I bond and the presence of two intense, almost coincident absorptions at about 1750 cm "originating from carbonyl bonds, and an intense absorption at 1570 cm" caused by the C = N bond.

Analysis of the NMR spectrum of the final product, dissolved in CDCl-, (60 Mc, <5 * values in ppm, internal standard: tetramethylsilane):

1.47, 1.56 (6 protons)

2.57 (3 protons)

3.80 (superimposed absorptions, 6 protons)

4.51 (1 proton)

4.86, 4.92 (d, J = 3.5 cps, 1 proton)

5.87, 5.93 (d, J = 3.5 cps, 1 proton)

° 3
S - - CH ₃ O - CH ₃ ° 2
° 6 - H.
- H or ° 5
^C 5
^C 6 - H:
- H or
- H

109826/1944 ^

Claims (38)

Patent claims C N-UH-COOLD wherein E is hydrogen or a separable ester group or Amine, an ammonium, alkali or alkaline earth metal means. 2. Ester according to claim 1, characterized in that the easily separable group is a silyl, phenyl, benzyl or benzhydryl group is. 3. Trimethylsilyl δ-isotiocyanatopenicillanate. 4. Phenacyl ester of δ-isothioeyanatopenicillanic acid. 5. Benzyl ester of G-isothiocyanatopenicillanic acid. 6. Benzhydryl ester of G-isothiocyancitopenicillanic acid. 7. O-isothiocyanatopenicillanoic acid. 8. Dicyclohexylamine salt of δ-isothiocyanatopenicillanic acid. 9. Process for the preparation of 6 ~ isothiocyanatopenicillanic acid or a derivative thereof according to claim 1, characterized in that that an ö-aminopenicillanoic acid derivative of the formula: W - NH - CH CH- J-Ui " ¹ OH ₃ CH - COOR ^! wherein E ^{1 is} an easily separable group, as indicated above, and W is a hydrogen atom or a group dor has the same meaning as E ^f , is reacted with thiophosgene and then, if necessary, converting the product obtained into the free acid, an ester 10 9826/19 A4 _BAD or a salt transferred. , 10. The method according to claim 9, characterized in that the Reaction is carried out in an inert organic medium. 11. The method according to claim 10, characterized in that the inert organic medium dichlorinethane, optionally in a mixture with toluene, is. 12. The method according to claim 10, characterized in that the inert organic medium is toluene, which is optionally mixed with di- P chloromethane is mixed. 13. The method according to claim 9, characterized in that a organic base is added before or after the introduction of thiophosgene to bind the hydrogen chloride formed. 14. The method according to claim 9, characterized in that the reaction temperature is so low that the penicillan core is not is attacked. 15. Thiopenicillin of the formula: NH H CH ^X C ^ li IN O = C NH CH - Q-C-NH-CH-CH Uli IN ™ CH COOH or 1 / \ / 3 QC = N-CH-CH ^X C ^. _B. III ^CH 3 2 I I Q-S O = C JIH CH - COOH wherein Q in formula A N or O substituted by alkenyl or ο denotes heterocyclic groups, and Q in formula B is an alkyl, Aryl or aralkyl group and Q is a substituted O atom means or a salt or an ester of these compounds. that Q is a group: 16. Thiopenicillins according to claim 15 »characterized in that 109826/1944 R ₁ -E denotes wherein R _{1 is} a lower alkenyl group, an alieyeIisehe group, a heterocyclic group which is bonded via carbon to the nitrogen atom indicated, denotes a substituted amino group, and each of these groups may be substituted by other groups, and R ″ denotes hydrogen or , a lower alkyl group, - R. and R ₂ together with the The nitrogen atom to which they are attached is a mononuclear heterocyclic Group, preferably with 6 or 5 atoms in the ring. 17. Ihiopenicillins according to claim 16, characterized in that R _{1 is} a 1-phenethyl, phenylpropyl, 2-piperidyl, 1-isochino-IyI, 2-pyridyl, 4-pyri ^ yi, 3-morpholyl , 1-piperidyl, 3-aminoquinolyl, 1-aminoisoquinolyl, adenyl, 4-aminomorpholyl, S-aminopenicillanyl ester, phenylamino, acetylamino or benzenesulfonylamino group and Rp denotes hydrogen or a lower alkyl group or R ₁ and R " together with "the nitrogen atom to which they are attached, form a piperidino or morpholino group. 18. Thiopenicillins according to claim 15, characterized in that Q ₁ / denotes the group χ - O-, wherein Y denotes an optionally substituted hydrocarbon radical, such as a lower alkyl, aralkyl or alicyclic group. 19. Thiopenicillins according to claim 18, characterized in that that Y is a methyl, n- or tert-butyl, benzyl or cyclohexyl group means. 20. Thiopenicillins according to claim 15, characterized in that Q ₁ / denotes an EySrlzyl-, hydrazidyl- or a sulfonylhydrazidyl group. 21. Thiopenicillins of the general formula: 109826 / 19U * > C «N - C - CIT C (CfI) 2 ^R ₄ - ^s II -U ^ C - N G ν ^ COO-R ₅ where R ~, R, and Rj-, which can be the same or different, each mean a medrigalkyl or aralky group. 22. 6- [N ^f - (2,2-diethoxy) ethylthioureido] penicillanic acid and its salts or esters. ,. . - 23. K-ethylpiperidine salt der'penicillanic acid according to claim 22. 24. ö-EMethoxythiocarbonamido-penicillanic acid and its salts and esters. 25. ö-rBenzyloxythiocarbonamidojpenicillanic acid and its esters and salts. 26. 6- [n ~ Butoxythioearbonamido] penicillanic acid and its salts and esters. 27. ö-rOyclohexyloxythiocarbonamidolpenicillanic acid and its Salts and esters. .28. o-itert.-Butoxythiocarbonamidojpenicillanäure and their Salts and esters. 29. 6 - [(Methoxymethylmercapto) methylidenimino] penicillanic acid and their salts and esters. 30. A method for the preparation of thiopenicillins according to a of Claims 15 to 21, characterized in that the isothiocyanato group of an δ-isothiocyanatopenicillanic acid ester is used by processes that do not affect the rest of the molecule, converted into a substituted amino group and, if necessary 1 09826 / 19U BADORiGlNAL - 37 -
■ converting the disfiguring acid into a salt or an ester. 31. A process for the preparation of thiopenicillins according to claim 30, characterized in that a 6-isothiocyanatopenicillanic acid ester is reacted with an amine of the formula R ^ R ₂ UH, in which IL and Rp have the meanings given above and, if desired, the resulting thioureidopenicillin ester into the corresponding one Acid or a salt thereof or another ester. - 32. A method for the production of ehiopenicillins according to claim 20, characterized in that a 6-isothiocyanatopenicillanic acid ester with hydrazines, hydrazides and sulfonyl hydrazides. 33. A process for the production of hiopenicillins according to claim 18, characterized in that 6-isothiocyanato- · penicillanic acid or its ester with an alcohol, if appropriate in the presence of a small amount of a catalyst. 34. Thiopenicillins made according to the method of claim 30. 35. Chiopenicillins prepared according to the method of claim 30, the general 3? Formula: U h CH ₃ ^ 0OH or ι ¹ - C β N - CH - CH C ^ _CH Z i h - 1 CH wherein Qu in formula AN or 0 denotes which is substituted by an optionally substituted alkyl, aryl, alkenyl, cycloalkyl, aralkyl or heterocyclic group and in formula BQ ^ a substituted O atom and Q ₀ a optionally substituted alkyl, alkenyl, aryl or arole mean kylgruppe, as well as their salts and esters. 36. TMopenicillins according to claim 35, characterized in that that in formula A CL the group: R ₁ - IT ¹ I. means in which R ^ means a medrigalkyl group, a lower alkenyl group, an ary! group, an alicyclic group, an aralkyl group, a heterocyclic group which is bonded to the indicated nitrogen atom via the carbon atom, a substituted amino group, and each of these groups can be substituted by others Groups are substituted and Rp denotes hydrogen or a Medrigalkylgruppe, or iL · and Rp denote agree with the nitrogen atom to which they are attached, a mononuclear heterocyclic group, preferably with 6 or 5 atoms in the ring. 37. Thiopenicillins according to claim 35, characterized in that Ε * an optionally substituted methyl, ethyl, propyl, n- or isobutyl, pentyl, hexyl, allyl, phenyl, capthyl, cyclopentyl, cyclohexyl -, cycloheptyl, benzyl, phenethyl, 1-phenylethyl, phenylpropyl, 2-piperidyl, 1-isoquinolyl, 2-pyridyl, 4-pyridyl, 3-morpholyl, 1-piperidyl, 3 -Aminoquinolyl, I-aminoisoquinolyl, adenyl, 4-aminomorpho-IyI-, OTAminopenicillanyl ester, phenylamino, acetylamino or ben ^ blsolfonylamino group and R ₂ means V / water or a lower alkyl group, or R ₁ and R ₂ together with the nitrogen atom to which they are attached form a piperidino or morpholino group. , nnonc # io ## lUiJoZo / iiJ *% 38. Process for the production of thiopenicillins according to claim 21, characterized in that one. a 6-isothiocyanatopenicillanic acid or a salt or an ester is reacted with an alcohol, the compound thus obtained on the free sulfur atom alkylated or aralkylated and optionally the formed Ester converted into a free acid or a salt. 39 Pharmaceutical compositions, characterized in that that they as active ingredient at least one compound according to one of claims 15 "to 29 and 34- to 37 together with one contain conventional pharmaceutical carriers or binders.