DE3008257C2 - Process for the preparation of penicillanic acid 1,1-dioxide and its esters - Google Patents

Description

X Y

CH,

(Π)

or a base salt thereof, wherein X and Y are hydrogen, chlorine. Are bromine or iodine with the Provided that 3. if X and Y both have the same meaning, they must both be bromine, rr by means of a catalytic hydrogenolysis in an inert solvent performed dehalogenation and one using a Alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarboxylic acid carried out oxidation, characterized in that the oxidation before the Dehalogenation is carried out.

2. The method according to claim 1, characterized in that that a compound (H) is used in which X is bromine and Y is hydrogen.

3. The method according to claim 1, characterized in that that a compound (H) in which X and Y are both bromine is used.

-}. Method according to one of Claims 1 to 3, characterized in that a compound (II) is used in which R 'is hydrogen.

of a 6-halopenidylanic acid or its in vivo run out of easily hydrolyzable ester and the steps encompasses dehalogenation and oxidation Surprisingly, if the oxidation takes place before the dehalogenation, a better product yield is achieved. Compare BE-PS 8 67 859 and DE-OS 28 24 535 for details of the manufacturing process for penicilic acid-l, l-dioxide and its easily hydrolyzable in vivo esters.

ίο The surprising increase in yield due to the fact that one not first dehalogenation and then oxidation, as in the prior art, but conversely, performing the oxidation first and then the dehalogenation, could be made by comparative experiments be detected.

6-Halogenpenieillanäuren were from Cignarella et al. Journal of Organic Chemistry 27, 2668 (1962), and disclosed in US Pat. No. 3,206,469; the hydrogenolysis of 6-halo penicillanic acid becomes penicillanic acid in GB-PS 10 72 108 disclosed

Harrison et al. Journal of the Chemical Society (London), Perkin I. 1772 (1976). describe a) the oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid to form a mixture of the corresponding Oi- and O-sulfoxides, b) the oxidation of methyl-6,6-dibromopenicillanate with 3-chloroperbenzoic acid to a methyl-6,6-dibromopenicil! ana 't-1,1-dioxide, c) the oxidation of methyl ea-chloropenicillanate with 3-chloroperbenzoic acid to a mixture of the corresponding λ-

JO and ^ -Sulfoxides and d) the oxidation of methyl 6-bromopenicillanate with 3-chloroperbenzoic acid to form a mixture of the corresponding λ and ^ sulfoxides.

Clayton. Journal of the Chemical Society (London), (C). 2123 (1969). describe) a) the production of

Vi 6,6-dibromo- and 6,6-diiodopenicillanic acid, b) the oxidation of 6,6-dibromopenicillic acid with sodium periodate to a mixture of the corresponding sulfoxides, c) the hydrogenolysis of methyl-6,6-dibromopenicillanate to methyl-6 «- brompenicillainate. d) the hydrogenolysis of 6,6-dibromopenicalanic acid and its methyl esters to penicillanic acid and its methyl esters and e) the hydrogenolysis of a mixture of methyl-6,6-dijodpemcillanai and methyl-6a-iodpeniciÜanat to pure ivlethyl-6a-iodpeniciIlanaL

The invention relates to a process for the preparation of a compound of the formula

The invention relates to a new chemical process for the production of penicillanic acid-1,1-dioxide and its esters which are readily hydrolyzable in vivo.

Penicillanic acid 1.1-dioxide and its in vivo easily hydrolyzable esters are known as /? - lactamase inhibitors and useful as agents that enhance the effectiveness of certain / 7-lactam antibiotics, if the latter for the treatment of bacterial infections in mammals, especially in humans, used will. So far, penicillanic acid 1,1-dioxide and its in vivo easily hydrolyzable ester of 6-bromopenicillanic acid or its easily in vivo hydrolyzable esters by debromination to penicillanic acid or their easily hydrolyzable in vivo Esters produced with subsequent oxidation to 1,1-dioxide. Although the method according to the invention

(I)

or a pharmaceutically acceptable salt thereof, in which R ^{1 is} hydrogen, a customary penicillin carboxy protective group or an ester-forming radical which is readily hydrolyzable in vivo, based on a compound of the general formula:

X Y

HS
V

CH ₃

'COOR ¹

(Π)

or a base salt thereof, wherein X and Y Hydrogen. Are chlorine, bromine or iodine, provided that when X and Y are both the same Have meaning, they both have to be bromine, by means of catalytic hydrogenolysis in one inert solvent performed dehalogenation and one using an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarfaonic acid carried out oxidation, characterized in that the oxidation is carried out before the dehalogenation.

In a preferred embodiment of the dehalogenation, the product of the oxidation with hydrogen in an inert solvent at a pressure in the range from about 0.98 to about 98 bar at a temperature in the range from about 0 to about 60 ⁰ C and a pH in the range of about 4 to about 9 and brought into contact in the presence of a hydrogenolysis catalyst. The hydrogenolysis catalyst is usually in an amount of about 0.01 to about 2.5% by weight, preferably about 0.1 to about 1.0% by weight, based on the compound of the formula III

present.

The preferred meaning for X and Y is bromine, and the preferred reagents for carrying out the Oxidation are chewing manganate and 3-chloroperbenzoic acid.

If X and Y are both chlorine, the compound of formula 1 is! difficult to obtain. If X and Y are both iodine, the oxidation is uncomfortably slow.

In the case of derivatives of penicillanic acid, the latter being the formula

CH ₃

(iv)

the interrupted linkage of a substituent to the bicyclic nucleus means that the substituent is below the plane of the nucleus. Such a substituent is called Λ-coniigiirierx !. Conversely, a solid linkage of a substituent to the bicyclic nucleus means that the substituent is above the plane of the nucleus. This latter configuration is referred to as the β configuration. Thus the group X configuration and the group Y configuration in the formula IL

If here R ^{1 is} an ester-forming radical which can be easily hydrolyzed in vivo, it is a group which is imaginedly derived from an alcohol of the formula R ¹ -OH, so that the COOR ¹ radical in such a compound of the formula I is an ester group . Furthermore, R ^{1 is} of such a nature that the COOR ¹ moiety is easily cleaved in vivo to liberate a free carboxyl group (COOH).

That is, R 'is a group such that when a compound of the formula I, in which R ^{1 is} an ester-forming radical which is readily hydrolyzable in vivo, is exposed to mammalian blood or tissue, the compound of the formula I,

-. wherein R ^{1 is} hydrogen easily formed. The groups R ¹ are well known in the penicillin field. In most cases they improve the absorption properties of the penicillin compound. In addition, R 'should be of such a nature that it joins the

m formula I confers pharmaceutically acceptable properties and upon cleavage in vivo releases pharmaceutically acceptable fragments. Groups R ¹ are gi * known and easily identified by those skilled in the penicillin art. B. the

r, DE-OS 25 17 316. Specific examples of such groups R ¹ are 3-phthalidyl, 4-crotonolactonyI, γ-butyrolacton-4-yl and groups of the formula

R ² O

! Il

- C - O - C - R ⁴ (V)

R ³

)-, and

R ² O

I I!

- C —O — C —O — R ⁴

wherein R ² and R ^{3 are} each selected from hydrogen and alkyl of 1 to 2 carbon atoms and R ^{4 is} alkyl of 1 to 5 carbon atoms. Preferred groups R ¹ , however, are alkanoyloxymethyl with 3 to 7 carbon atoms, 1- (alkanoyloxy) ethyl with 4 to 8 carbon atoms, 1-methyl-1- (slkanoj,! Oxy) ethyl with 5 to 9 carbon atoms, Alkox> carbonyloxymethyl with 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) -ethyl with 4 to 7 carbon atoms, -Methyl- 1-aikoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, 5-thaiidyi. 4-crotonoiactonyi and γ-butyroiacton-4-yl.

3-phthalidyl, 4-crotonolactonyl and γ-butyrolacton-4-yI refer to structures VII, VIII and IX. The wavy lines should be either one of the two Denote epimers or their mixture.

(VD)

(VHI)

(IX)

Step a) of the process according to the invention comprises the oxidation of the sulfide grouping in a compound of the formula H to form a siphon group. what to a compound of formula III leads. Oxidizing agents are alkali metal permanganates, such as sodium and Potassium permanganate, alkaline earth metal pennan £, anate, such as Calcium and barium permanganate. and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid.

When a compound of the formula JI. in which X. Y and R ^{1 are} defined as previously: "The corresponding compound of the formula III is oxidized by the process of converting a metal ferranganate. The reaction is usually carried out by treating the bond of the Formula II with about 0.5 to eiwa! " .- Ί equivalents. preferably about 1 to 4 molar equivalents of permanganate in a _solvent system which is inert to the reaction. A suitable reaction inert solvent system is one that does not adversely interact with any of the starting materials or the product, and water is ordinarily used. If desired, a coiolvens can be used. which is miscible with water but does not interact with the permanganate, like tetrahydrofuran. can be added. The reaction may be carried out at a temperature ranging from about -30 to about 5O ⁰ C, preferably it is carried out at about -10 to about 10 ⁰ C. At about 0 'C, the reaction is usually within a short time. z. B. within 1 h. practically finished. Although the reaction can take place under neutral, basic or acidic conditions, a pH in the range from about 4 to 9, preferably 6 to 8, is used. It is important, however. To choose conditions that avoid decomposition of the ß-lactam ring system of the compound of the formulas II or III. Indeed, it is often advantageous to buffer the pH of the reaction medium around the neutral point. The product is obtained using conventional techniques. Any excess permanganate is usually decomposed using sodium bisulfite and then when the product is no longer in solution it becomes. obtained by filtration. It is separated from the manganese dioxide by extraction into an organic solvent and obtained by evaporating the solvent. On the other hand, if the product is still in solution at the end of the reaction, it is isolated according to the usual procedure in the solvent reaction.

Weiin a compound of the formula II. Wherein X. Y and R 'are as previously defined, to the corresponding compound of formula 11! using a When peroxycarboxylic acid is oxidized, the reaction is purified to those well known in the art will. On the other hand, it can be used directly in stage b) without further purification.

Step b) of the process according to the invention is a dehalogenation reaction. A convenient method of performing this conversion is to stir or shake a solution of a compound of Formula III under an atmosphere of hydrogen or of hydrogen mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenolysis catalyst. Suitable solvents for this hydrogenolysis reaction are those which essentially dissolve the starting compound of the formula III, but which themselves do not undergo any hydrogenation or hydrogenolysis. Examples of such solvents are ethers, such as diethyl ether. Tetrahydrofuran. Dioxane and 1,2-dimethoxyethane. low-molecular esters such as ethyl acetate and butyl acetate, tertiary amides such as NN-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone, water, or mixtures thereof. In addition, it is customary to buffer the reaction mixture in such a way that the pH is in the range from e ^: about 4 to 9, preferably about 6 to 8. Borate and phosphate buffers are commonly used. Hydrogen gas is usually introduced into the reaction medium by carrying out the reaction in a sealed container containing the compound of Formula III, the solvent, the catalyst and the hydrogen. The pressure inside the reaction vessel can vary between about 0.98 and about 98 bar. If the atmosphere in the reaction vessel consists practically of pure hydrogen, the preferred pressure range is about 15 to about 4.9 bar. The hydrogenolysis is generally carried out at a temperature of about 0 to about 6O ⁰ C. preferably about 25 to about 50 ^D C. When applying the preferred temperatures and pressures requires the hydrogenolysis is generally a few hours, eg. B. about 2 to about 20 hours. The catalysts used in this hydrogenolysis are of the type known in the art for the type of conversion. And typical examples are nickel and the noble metal palladium, ι iHtin UHu fViiCuitiiTi. i_ / Cr t ^ ataiySaiOT itCgt gCWOiiniiCii in an amount of about 0.01 to about 2.5, preferably about 0.1 to about 1.0% by weight. based on the compound of the formula III. It is often advisable to distribute the catalyst on an inert support; a particularly suitable catalyst is palladium on a otherwise inert support, such as carbon.

As those skilled in the art will recognize, when a compound of the formula I wherein R ^{1 is} hydrogen is to be prepared, a compound of the formula II. where R ^! Is hydrogen, stages r.) And b) of here

Formula 11 with about 1 to about 6 molar equivalents. preferably about 22 molar equivalents of the oxidizing agent in an organic solvent which is inert to the reaction. Typical solvents are chior ^; er "/ hydrocarbons, such as methylene chloride, chlorine, chlorine, and 1,2-dichloroethane, and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction normally takes place at a temperature of about -30 to about 50.degree. preferably at about 15 to about 30 ° C. At about 25 ° C., reaction times of about 2 to about 16 hours are usually used. The product is usually isolated by removing the solvent in vacuo. The reaction product "j>.? N according to conventional methods, in other words, the process comprises an oxidation and subsequent dehalogenation of a β-halogen or 5,6-dih-, iogen derivative of penicillanic acid with a free carboxyl group in the 3-position. According to a further aspect of the invention, however, each of steps a) and b) can be started with a carboxyl group in the 3-position blocked by a conventional penicillin carboxy protective group. The protective group can be split off during or after stage a) or stage b) with regeneration of the free carboxyl group. In this regard, a variety of protecting groups commonly used in the penicillin art for protecting the 3-carboxyl group can be employed. The main requirements for the protection

group are that they must be attachable to the particular compound of the formula If or Ul and removable from the particular compound of the formula f or III using conditions under which the / J-lactam ring system remains practically intact. Typical examples for stages a) and b) are the tetrahydropyranyl group, the trialkyisilyl groups, the benzyl group, substituted benzyl groups (e.g. 4-nitrobenzyl). the benzydryl group. the 2.2.2-trichloroethyl group. the t-butyl group and the phenacyl group Although all protective groups are not applicable in all situations, this is a particular group that is applicable in a particular situation. easily selected by those skilled in the art. See also IIS PS 30 32 850 and 3197 466. GBPS 1041985. Woodward et al. | ournal of the American Chemical Society 88.852 (1966). Chauveite. Journal of Organic Chemistry ib. 1259 (1971): Sheehan et al. Journal of Organic Chemistry 29, 2006 (1964). and »Cephalosporins and Penicillins. Chemistry and Biology ". by HE Flynn. Academic Press. Inc. 1972. The pericillin carboxy protective group is cleaved off in the conventional manner, with due attention being paid to the lability of the lactamnng system.

The compounds of the formulas I. II and III. where R ' Is hydrogen, are acidic and form salts with bases. These salts can be prepared using standard techniques be e.g. B. by bringing together the acidic and basic components, usually in stoichiometristher.i Ratio in an aqueous, non-aqueous or partially aqueous medium, depending on suitability. she are then carried out by filtering, precipitating with a nonsolvent, and then filtering Evaporation of the solvent or, in the case of an aqueous solution, by lyophilization. depending on suitability, won. Bases which are suitably used for the formation of salts belong to the organic as well as to the inorganic and include ammonia, organic amines. Alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides. as well as alkaline earth hydroxides, carbonates, hydrides and alkoxides. Representative Examples of such bases are primary amines such as n-propylamine. n-butylamine. Aniline, cyclohexylamine, Benzylamine and octylamine. sec-amines. like diet hyiamine. Morpholine, pyrrolidine and piperidine, tert-amines, such as triethylamine, N-ethylpiperidine, N-methylmorpho-jin and 13-diazabicycIo [43.ö] non-5-ene, hydroxides, such as Sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide «. Alkoxides, such as sodium ethylate and potassium ethylate hydrides, such as calcium hydride and Sodium hydride, carbonates such as potassium carbonate and sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate and long-chain alkali metal salts Fatty acids, such as sodium 2-ethylhexanoate, are preferred Salts of the compound of formula I are the sodium, potassium and triethylamine salts.

The compound of the formula I in which R ^{1 is} hydrogen and the salts thereof are effective as antibacterial agents of moderate strength both in vitro and in vivo, and the compounds of the formula I in which R 'is an ester-forming radical which is readily hydrolyzable in vivo are effective as moderate strength antibacterial agents in vivo.

Further, the use and synthesis of compounds Details relating to formula I are disclosed in DE-OS 28 24 535.

The following examples and preparations serve only for further illustration. Infrared (IR) spectra were measured as potassium bromide pellets (KBr pellets), and recognition absorption bands are given in wave numbers (cm- '). Nuclear magnetic (NMR) spectra were recorded at 60 MHz for solutions in deuterochloroform (CDCIj), perdeuteroacetone (CDjCOCDj), perdeuterodimethyl sulfoxide (DMSÖ-de) or deuterium oxide (D2O) measured, and the peak complaints are in parts per million (TjiM) according to tetramethylsilane or sodium 2.2-dimethyl-2-silapentane-5-sulfonate specified. The following abbreviations for peak shapes are used: s for singlet. d for doublet, t for triplet, q for Quadruplet! and m for multiplet

example 1
6- »-Brompenicillan acid 1.1 -dioxide

To a stirred mixture of 560 ml of water. 300 ml of methylene chloride and 56.Og of 6 - «- bromopenicillanic acid were given 4 π sodium hydroxide solution until a stable pH of 72 was reached. This required 55 ml of sodium hydroxide. The mixture was stirred at pH 72 for 10 minutes and then nitrated. The layers were separated and the organic phase discarded. The aqueous phase was then quickly poured, with stirring, into an oxidizing .lemisch, which had been prepared as follows:

632 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid were mixed in a 3 l flask. The mixture was stirred at 20 ° C. for 15 minutes and then cooled to 0 ° C.

After the 6-α-bromopenicillanic acid solution had been added to the oxidation solution. a cooling bath at -15 ° C was kept around the reaction mixture. The internal temperature rose to 15 ° C. and then fell to 5 ° C. over 20 minutes. Then 30.0 g of sodium methabisulfite were added with stirring in 10 minutes at about 10 ° C. After a further 15 minutes, the mixture was filtered and the pH of the filtrate was added reduced from 170 ml of 6 π hydrochloric acid to \ 2 the aqueous phase was extracted with chloroform and then extracted with ethyl acetate Both the chloroform extract and the ethyl acetate extract was dried with anhydrous magnesium sulfate and then concentrated in vacuo the ChloroformJösung afforded 10.0 g (16% yield) the title compound. The ethyl acetate solution provided 57 g of an oil which was triturated under hexane. A white solid appeared. It was filtered off and gave 41 / g (66% yield) of the title compound, m.p. 134 "C (decomp.).

Analysis,%:
calc. for CgH ₁₀ BrNO ₅ S:

C 30.78, H 3.23. Br 25.60, N 4.49, S 10.27;
found:
C31.05. H3.24, Br25.54, N4.66. S 10.21.

Oxidation of 6-α-chlorophenic acid and 6 - «- iodopenic acid with potassium permanganate according to this procedure, e-a-chloropenicilfanic acid 1.l-dioxide is obtained or ö-a-iodopenicflanic acid l.i-dioxide.

Example 2
e-ß-Chlorpenicillanic acid-ll -dioxide

An oxidizing solution was made from 185 mg of potassium permanganate 0.063 ml of 85% phosphoric acid and 5 ml of water were prepared. This oxidizing solution was added to

a solution of 150 mg of sodium 6 - ^ - chlorine penicillanate in 5 ml of Wisser at 0 to 5 ⁰ C until the purple color of the potassium permanganate persisted. About half of the oxidation solution was needed. At this point the potassium ^{permeanate color was removed by the 1} 'addition of solid sodium bisulfite, and then the reaction mixture was filtered. Ethyl acetate was added to the filtrate and the pH was adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated in vacuo to give 118 mg of the title compound. The NMR spectrum (in CDjCOCD) showed absorption at 5.82 (i.e. 1 H). 5.24 (d, 1H) .4.53 (see 1H). 1.62 (see 3 H) and! .50 (see 3 H) tpm.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 with dilute sodium hydroxide solution, the tetrahydrofuran stripped off in vacuo and the remaining aqueous solution freeze-dried. This provided the sodium salt / title compound.

Example 3
6 - ^ - Bromopenicillanic acid 1.1 -dioxide

To a solution of 255 mg of sodium 6 - /? - brompenicillanate in 5 ml of V / water at 0 to 5 ° C was added a solution consisting of 140 mg of potassium pexmanganate 0.11 ml of £ .J% phosphoric acid and 5 ml of V Water was made at 0 to 5 ° C. The pH was between 6.0 and 6.4 during the addition. The reaction mixture was stirred for 15 min at pH 6.3 and then the purple solution was covered with a layer of ethyl acetate. The pH was adjusted to 1.7 and 330 mg of sodium bisulfite were added. After 5 min, the layers were separated and the aqueous layer was further extracted with ethyl acetate were washed with brine, dried (over MgSO4) and concentrated in vacuo. This provided 216 mg of the title compound as white crystals. The NMR spectrum (in D ₂ O) showed absorptions at 5.78 (d, 1 H. J = 4 Hz). 5.25 (i.e. 1H, J = 4 Hz). 4.20 (see 1H). 1.65 (s. 3 H) and 1.46 (s. 3 H) ppm.

Oxidation of 6-ß iodo-penicillanic acid with potassium permanganate according to this procedure yielded 6 - /? - iodo-penicillanic acid-1.1-dioxide.

Example 4
PivaIoyloxymethyl-6-a-bromopenicilanate-II-dioxide

To a solution of 394 mg PivaIoyloxymethyl-6-α-bromopenicilianate 400 mg of 3-chloroperbenzoic acid are added at 0 to 5 ° C. in 10 ml of methylene chloride. The reaction mixture is stirred for 1 hour at 0 to 5 ° C. and then for 24 hours at 25 ° C. The filtered reaction mixture is concentrated to dryness in vacuo to provide the title compound.

The procedure is repeated with the exception that the PivaIoyIoxymethyI-6-j? -BrompenicilIanat replaced is made by:

S-phthalidyl-δ-α-chloropenicillanate

4-Crotonolactonyl-6-ß-Chlorpenicilanate

y-butyrolactone ^ -yl-ö-a-bromopenbillanate

Acetoxymethyl-ö-ß-brompenicillanate,

PivaioyIoxyrnethyI-6 - /? - brompenicilanate

HexanoyIoxymethyI-6 - «- IodpenicilIanat

i- (Acetoxy) ethyl-6-J? -jcdpenic / ilanate ! - (Isobutyryloxyethyl-o-a-chloropenicilianate, 1 -Methyl-1 - (acetoxy) ethyl-6-j? -Chlorpenicillanate,

1 -Methyl-1 - (hexanoyIoxy) ethyl-6-a-bromopenicillanate,

Methoxycarbonyloxymethyl-6-ix-bromopenicillanate,

Propoxycarbonyloxymethyl-ö-jJ-brompeniciilanat, 1- (Äthoxyearbonyfoxy) ethyl-6-Ä-bromopenicillanate,

1 - (ButoxycarbonyIoxy) ethyl 6 - iodo penicillanate, 1 - methyl 1 - (methoxycarbonyloxy) ethyl 6 - /? - iodo per.icillanate respectively.

1 -Methyl-1 - (isopropoxycarbonyloxy) ethylo-a-chloropenicillanate.

This provides:

S-phihalidyl-o-a-chlorpenicillanate-1,1 -dioxide, 4-crotonolactonyl-6-j? -Chlorpenicillanate-

1,1 -dioxide,
γ-Butyrolactone ^ -yl-b-A-bromopenicillanate 1.1-dioxide.

Acetoxymethyl-ö-ß-brompenicillana-1,1-dioxide. Pivaloyloxymethy! -5-l? -Brompenicillanate-

1.1-dioxide.
Hexanoyloxymethyl-6-a-iodopenicilanate 1.1-dioxide.

1- (Acetoxy) ethyI-6 - /? - iodpenicilIanatl.l-d'oxid.

1- (Isobutyryloxy) ethyl-6 - * - chlorine-

penicillanate 1,1 dioxide,
1 -Methyl-1 - (acetoxy) ethyI-6 - /? - chlorine-

peniciIianat-1,1 -dioxid,
j5 1 · methyl-1 (hexanoyloxy) ethyl-6 - «- bromo-

penicillanate 1.1 dioxide.
Methoxycarbonyloxymethyl-ö-Ä-bromopenicilanate-1,1-dioxide,

Propoxycerbonyloxymethyl-ö-ji-bromopenicilianate 1.1-dioxide,

l- (ethoxycarbonyloxy) ethyl-6 - «- bromine-

penicilIanate-1,1-dioxide,
1- {ButoxycarbonyIoxy) älhyI-6-a-iodpeniciIlanat-1,1 -dioxid,
1 -Methyl-1 - (methoxycarbonyloxy) ethyl-6- / il-iodine-

penicillanate 1,1 -dioxide or
1 -Methyl-1 - (isopropoxycarbonyloxy) ethyl-6 - «- chlorpenicil / anate-1,1-dioxide.

so B is ρ ie I 5

Penicillanic acid 1,1 dioxide

9.4 g of 6 - * - bromopenicillanic acid 1,1-dioxide were added to 100 ml of water at 22 ° C, then enough 4 η sodium hydroxide solution to set a stable pH of 73. The resulting solution was coated with 235 g of 5% Pd / C This crosslinked with 65 g of diphalm phosphate trihydrate Mixture was then under a hydrogen atmosphere at a pressure between 3.43 and 1.76 bar shaken After the hydrogen uptake had ceased, the solids were filtered off and the aqueous solution covered with 100 ml of ethyl acetate. The pH was slowly lowered from 5.0 to 1.5 with 6 η hydrochloric acid Layers were separated and the aqueous phase extracted with more allyl acetate. The combined Ethyl acetate layers were washed with brine, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was taken under

Ether triturated and then the solid material was filtered off. This provided 4.5 g (65% yield) of the Title compound.

Analysis,%:
for CbH ι-NO ₅ S:
C4i, 20, H 475, N 6.00, S 13.75;
found:
C4I.16. H 4.81, N 6.11, S 13 51.

The hydrogenolysis of

ö-oe-chlorophenicillanic acid-1.1-dioxide.
6-a- iodnenicillanic acid 1.1 -dioxide,
6 - /? - Chlorppnicilanic acid-l, l -dioxide,
6-ß-bromopenicillanic acid-1.1-dioxide and
6-jS- iodopenicillansäut e-1.1 -dioxid

this procedure also gives penicillanic acid U-dioxide.

Example 6

Pivaloyloxymethylpenicillanate-U dioxide

To a solution of 1.0 g of pivaloy ioxynietnyl-6-α-bromopenicillanate 3 ml of 1M sodium bicarbonate and 200 mg of 10% Pd / C are added to 10 ml of methanol. That Reaction mixture is vigorous under a hydrogen atmosphere at a pressure of about 43 bar shaken until the hydrogen uptake ceases. The mixture is then filtered and most of the The methanol is removed by stripping off in vacuo. Water and ethyl acetate are added to the residue, and the pH is adjusted to 8.5. The layers are separated and the organic layer is washed with water washed, dried (over Na2SO.t) and in vacuo concentrated. This provides the title compound.

Hydrogenolysis of the appropriate 6-halopenicillanic acid ester-1.l-dioxide from Example 4 using this procedure gives the following compounds:

3-Phthalidylpenicilanate M-dioxide.
4-crotonolactonyl penicillanate 1.1 dioxide.
y-ButyroIacton ^ -yl-penicillanat-1,1 -dioxid,
Acetoxymethylpenicillanate 1.1 dioxide,
Pivaloyloxymethyl penicillanate II dioxide,
Hexanoyloxymethylpenicillanate U-dioxide.
1- (Acetoxy) a «hyipenicil! Anat-1,1-dioxide,
1 - (isobutyryloxy ethyl penicillanate 1.1 -dioxide,
1 -Methyl-1 - (acetoxy) ethyl penicillanate-

1,1-dioxide,
1 -Methyl-1 - (hexanoyloxy) äthylpeniriilanat-

1,1-dioxide,
Methoxycarbonyloxymethyl penicillanate

1,! - dioxide,
PropoxycarbonyloxymethylpeniciHanat-

1,1-dioxide,
l-iethoxycarbonyloxy ethyl penicillanate

1,1-dioxide,
! - {Butoxycarbonyljäthylpenicillanai-

1,1-dioxide
1 -Methyl-l - (methoxycarbony! Oxy) ethyl-

penicillanat-l .'.- dioxide or
l-MethyI-l- (i3opropoxycarbonyIoxy) ethyl

penicillanate 1,1 dioxide.

Example 7

Pivaloyloxymethyl-6-Ä-bromophenylariat-1.1-dioxide

By combining 4.25 g of potassium permanganese. ^Ο , 65 g of 5% phosphoric acid and 10 ml of water an oxidizing solution was prepared. The mixture was stirred for 1 h and then slowly at 5 g in 20 min to 10 ⁰ C to emer stirred solution of 5.32 PivaloyIoxymethyl-6-a-bromopenicillanate in 70 ml of acetone and 10 ml of water. The mixture was stirred for 30 min at 5 ⁰ C, and 100 ml of ethyl acetate were added. After a further 30 min, a solution of 3.12 g Natriurnbisulfit in 30 ml water for 15 min was added at about 1O ⁰ C. It was another 30 min at

Stirred at 10 ° C. and then the mixture was filtered. The organic phase was separated off and washed with saturated sodium chloride solution. The dried organic layer was concentrated to give 5.4 g of the title compound as an oil, which slowly crystallized. The NMR spectrum (in CDCI ₁ ) showed absorptions at 5.80 (q, 2 H), 5.15 (i.e. 1 H). 4.75 (i.e. 1H). 4.50 (see 1H). 1.60 (3.3H), 1.40 (s.3H) and 1.20 (i.9H) ppm.

Example 8 Pi'-aloyloxymethylphenicillanate 1.1 dioxide

A solution of 4.4 g of pivaloyloxymethyl 6-a-bromopenicillanate 1.1-dioxide in 60 ml of tetrahydrofuran was added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution was shaken under a hydrogen atmosphere in the presence of 2.0 g of 5% Pd / C at 324 to 332 bar overpressure. The reaction mixture was then nitrated and the residue was washed with 100 ml of ethyl acetate and 25 ml of water. The filtrate and washing liquids were separated after they were combined. The organic layer was washed with saturated sodium chloride solution and dried (over MgSO /; and concentrated to give the title compound as an oil. This oil was dissolved in ethyl acetate (20 ml). The solution was slowly added to hexane (100 ml) and the Precipitate filtered off. Yield 2.4 g. The NMR spectrum (in DMSO-d ₆ ) showed absorptions at 5.75 (q, 2 H), 5.05 (m. 1 H), 4.40 (s, 1 H), 335 -2.95 (m.2H), 1.40 (s.3H), 1.25 (s, 3H), and 1.10 (s.9H) ppm.

Example 9

2.2.2-TrichloräthyI-6-α-bromopenicilIaπat-1,1-dioxide

2,2,2-TrichIoräthyI-6-a-brompeniciIIanat was oxidized with potassium permeanate practically according to the procedure of Example 7 to the title compound in 79% yield. The NMR spectrum of the product (in CDCI ₃ ) showed absorptions at 530 -4.70 (m, 4 H), 4.60 (s, 1 H), 1.70 (s.3 H) and RO (s, 3 H) TPM.

Example 10 Benzyl δ-α-bromopenicillanate 1,1-dioxide

Benzyl-6-a-brompeniciilanat was treated with potassium permanganate substantially according to the procedure of Example 7 to the title compound in 94% yield oxidized The NMR spectrum (in CDCI ₃₎ showed absorptions at 735 (s, 5 H), 5.10 (m, 3 H ), 4.85 (m. 1 H), 4.40 (s, 1 H), IpO (s, 3 H) ur.d 1 25 (s. 3 H) tpm.

Example 11 Penicillanic acid 1.l dioxide

A solution of 4.0 g of Benzyl-6 - * - bronipeniciIIanat-1,1-dioxide in 50 ml of tetrahydrofuran was mixed with a solution of 1.06 g of sodium bicarbonate in 50 ml of water

ί3

combined. To the mixture was added 2.0 g of a 50% suspension of 5% Pd / C in water, then this mixture was pre-prepared under a hydrogen atmosphere at an overpressure. 321 b's i 45 bar shaken for 20 min. The catalyst was then filtered off, and then 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% Pd / C were added. The mixture obtained was shaken under a hydrogen atmosphere at an overpressure of 2.90 to 3.10 bar for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran evaporated. Ethyl acetate was added to the aqueous residue and the pH was adjusted to 7.1, the ethyl acetate layer was removed, and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 13 and the layers were separated. The aqueous phase was extracted further with ethyl acetate, and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (over MgSO2). Concentration in vacuo provided a resin which was triturated under ether. This provided 31 mg of penicillanic acid II-dioxide as a yellow solid. The NMR spectrum (in COClJ DMSO-da) showed absorption at 9.45 (broad, see 1 H). 4.60 (ti H). 4.25U 1 H). 3.40 (d. 2H). 1.65 (see 3H) and U0 (see 3H) tpm.

Example .2
6.6-dibromopenicilanoic acid 1.1-dioxide

To the dichloromethane solution of 6,6-dibromopeniciII-anic acid 300 ml of water from preparation J were added, followed by the dropwise addition of 105 ml 3 η sodium hydroxide over 30 min. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer extracted with (2 × 100 ml) water. To the combined aqueous Solutions became a premix solution at -5 ° C given, made from 59.25 g potassium permanganate, 18 ml concentrated phosphoric acid and 600 ml water, until the pink color of the permanganate stayed. The addition took 50 minutes and 550 ml of oxidant were used At this point, 500 ml of ethyl acetate was added and then the pH was adjusted by adding 105 ml of 6 η hydrochloric acid reduced to 1.23. 250 ml of 1 M Ndtrium bisulfite were then added over 10 to 15 min added at approx.> 0 ° C. During the addition of the sodium bisulfite solution, the pH was adjusted using held at 1.25 to 135 by 6π hydrochloric acid. The aqueous phase was saturated with sodium chloride and the the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2 × 150 m!) and the combined ethyl acetate solutions were washed with brine and dried (over MgS (X)). This provided an ethyl acetate solution of 1,1-6,6-dibromopenicillanic acid -dioxide.

The 6,6-dibromopenicillanic acid-1,1-dioxide can be isolated by stripping off the solvent in vacuo. A sample isolated in this way from an analogous production had a melting point of 20 ° C. (decomp.). The NMR spectrum (CDCij / DMSO-ds) showed absorptions at 935 (s. Ϊ H), 530 (s. 1 H). 4.42 (s. 1 H), i, 63 (s, 3 H) and UO (s. 3 H) tpm. The IR spectrum (KBr pellet) showed absorptions at 3846 to 2500, 1818, 1754, 1342 and 1250-III Ocrr.- ¹ .

Example 13
o-chloro-o-iodopenicillic acid U -dioxide

50 μl of water were added to a solution of 4.9 g of δ-chloro-e-iOdpcnicillanic acid in 50 ml of methylene chloride, and the pH was then increased to T2 with 3 η sodium hydroxide. The layers were separated and the aqueous layer was cooled to 5 ° C. A premix solution was then added to this solution over 20 minutes

ίο dripped, made from 2.61 g potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH was at 6 and the Temperature kept below 10'C. At this point 100 ml of ethyl acetate was added and the pH increased 13 set. 50 ml of 10% sodium bisulfite were then added to this mixture at the temperature below 10 C and the pH was kept at about 1.5 by adding 6 η hydrochloric acid. The pH was up 1.25 and the layers were separated.

The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with brine, (over MgSO Jgetrocknet and concentrated in vacuo to 4.2 g of the title compound. Mp. 143-145 ⁰ C. concentrated.

The NMR spectrum (CDCIi) showed absorptions at 4.86 (see I H). 4.38 (see 1H). 1.60 (s. 3 H) and 1.43 (s. 3 H) TpM. The IRSpekirum (KBr pellet) showed absorptions at 1800.'740 and 1250-1110cm '.

Example J4

o-bromo-o-iodpenicillic acid 1.1 -dioxide

50 ml of water were added to a solution of 6.0 g of δ-bromo-o-judpenicilian acid in 50 ml of methylene chloride. The pH was raised with 3 η sodium hydroxide to 73 and the aqueous layer is removed the organic layer was extracted with 10 ml of water The combined aqueous phases were cooled to 5 ⁰ C and a premixed solution of 284 g Kaüumpermanganat in 2 ml of concentrated phosphoric acid and 5OmI water was added dropwise 5 to 10 ⁰ C. the addition took 20 min. Then, 50 ml of ethyl acetate were added, and the pH of the mixture was decreased with hydrochloric acid to 6 η \ J5. This two-phase system was 50 m! 10% sodium bisulfite was added dropwise, the pH being kept at about 13 by adding 6 η hydrochloric acid. Another 50 ml of ethyl acetate was added, and then the pi. down to 1.23 The layers were separated.

so and the aqueous layer was saturated with sodium chloride. The saturated solution was extracted with ethyl acetate (3 × 50 ml) and the combined ethyl acetate layers were washed with brine, dried (over MgSO +) and concentrated in vacuo , 2 g of the title compound, m.p. 145-147 ° C. The NMR spectrum (CDCI ₃ ) showed absorptions at 4.90 (s. 1 H), 430 (s, 1 H). 1.60 (s. 3 H) and 1.42 (s. 3 H) tpm. The? R spectrum (KBr pellet) showed absorptions at 1800.1 / 40.1330 and 1250-1110 cm- '.

The oxidation of δ-chloro-δ-bromopenicillanic acid with potassium permanganate according to this procedure yielded δ-chloro-δ-bromopenicillanic acid i .Ί -dioxide.
Example! 5

Peniculanic acid 1,1 dioxide

The ethyl acetate solution of 6,6-dibromopenicillansjure-l-dioxide from Example 12 was 705 ml

Saturated sodium bicarbonate solution and 8.8Sg 5% Pd / C catalyst combined. The mixture was shaken under a hydrogen atmosphere at a pressure of about 43 bar for about 1 hour The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with further ethyl acetate (3 × 200 ml). The combined ethyl acetate solutions were dried (over MgSO *) and dried in vacuo to give 333 g (58% yield of 6-aminopenicillanic acid ) Penicillanic acid II dioxide was concentrated. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized with activated charcoal and the solvent was removed in vacuo. The product was washed with hexane. This yielded 31.0 g of retn product

Hydrogenolysis of ö-chloro-ö-iodpenicillanic acid-1.I-dioxide. 6-Bromo-6-iodopenicillanic acid and 6-chloro-6-bromopenicillic acid according to this procedure, penic'IIanic acid 1.l-dioxide was produced in every case

Example 16

Pivaloyioxymethy! -6.6-dibrompenicil! Anat-

il-dioxide ^2j

3.80 g of 3-chloroperbenzoic acid are added at 0 to 5 ° C. to a solution of 4.73 g of pivaloyloxymethyl-6,6-dibrumpenicillanate in 15 ml of methylene chloride. The reaction mixture is stirred for 1 h at 0 to 5 ° C and then 24 h at 25 C ^r. The filtered reaction mixture was concentrated to dryness in vacuo and the residue was partitioned between ethyl acetate and water. The pH of the aqueous phase is adjusted to 73 and the layers are separated. The ethyl acetate phase is dried (over Na ^ SOi) and concentrated in vacuo to give the title compound .

3example 17

PivaIoyloxymethylpenicüIanat-1,1 -dioxid
To a solution of 1.0 g of pivaloyloxymethyl-ö.ö-di-

urOiTipcniCcn2nai-i .l-uiOXiu fil ίΟπΐΐ ivictiiSnCt Iäciucii 3 mi m sodium bicarbonate and 200 mg 10% Pd / C given. The reaction mixture is shaken vigorously under a hydrogen atmosphere at a pressure of about 4.9 bar until the water uptake ceases. The mixture is then filtered and the bulk of the methanol is drawn off in vacuo. Water and ethyl acetate are added to the residue and the pH is raised! 83 set. The layers are separated and the organic layer is washed with water, _{dried (over Na ^ SQ 4} ) and

55

60

65

penicillanate l-dioxide.

Hydrogenolysis of the 6,6-dihalopenicillanic acid ester 1.1-dioxides from Example 16 according to this procedure provides the following connections:

3-Phtha! IdyI-peniciHanat-l, l-dioxide,
4-CrotoπoιacίonyIpenidlIanat-ί, l-dioxide,
y-butyrolactone ^ -yl-penicillanate-U-dioxide,
Acetoxymelhylpenicillanate-lt-dioxide,
Pivaloyloxymethylpenicillanate-l, I-dioxide,
Hexanoyloxymethylpeniculanate-tl-dioxide,
1 - (Acetoxylethylpenicillanat-l, 1 -dioxide,
! ■ (Isobutyryloxy-ethylpene-scillanate-l, I-dioxide,
l-MethyKacetoxyJäthyJpenicillanat-lJ -dioxid,

l-methyl-l- (hexanoyIoxy) ethyIpeniciIIanat-

1.1-dioxide,
Methoxycarbonyloxyrrethyl penicillanate

1,1-dioxide,
Propoxycarbonyloxymethylp'Siicillanate-

y-dioxide,
l- (Athoxycarbonyloxy) ethyIpenicillanate-

1,1-dioxide.
! - {Butoxycarbonyljäthylpenicilanat-

1,1-dioxide,
I -MethyJ-1 - (methoxycarbonyloxy) ethyl-

penicillanate-l, l-dioxide or
1 -Methyl-1 - (isopropoxycafbonyloxyjäthyl-

penicillanate 1.1 dioxide.

Example 18
ö-ö-dibromopenicillanic acid 1.1-dioxide

To a solution of 359 mg of 6,6-dibromopenicilanic acid in 30 ml of methylene chloride are 380 mg of 3-chloroperbenzoic acid given at 0 to 5 ° C. The reaction mixture is 30 min at 0 to 5 "C and then 24 h at 25 ° C stirred The filtered reaction mixture is in Concentrated vacuum to the title compound

Example 19
Penicillanic acid II dioxide

To a solution of 2.0 g of benzyl-ö.fe-dibrompenicil-Ianat-1.1 -dioxide in 50 ml of tetrahydrofuran was a solution of 0.699 g of sodium bicarbonate in 50 ml of water, then added 2.0 g of 5% Pd / C. This mixture was under a hydrogen atmosphere at about 3.45 bar Upper pressure shaken for 70 min. The tetrahydrofuran was evaporated and the residue between The ethyl acetate and water at pH 737 distributed Aqueous layer was removed and fresh ethyl acetate added. The pH was lowered to 1.17 and the Removed ethyl acetate and washed with saturated sodium chloride solution. Evaporation in vacuo provided 423 mg of the title compound.

Example 20

^^ - Trichloroethyl-e.ö-dibrompenicillanate-1.1-dioxide

The titre compound was made from 6,6-dibromopeniculanic acid-II-dioxide and 2.2.2-trichloroethyl chloroformate, essentially according to the method of preparation. manufactured. The product was purified by chromatography on silica gel. The NMR spectrum of the product (in CDCI ₃ ) showed absorptions at 4.85 (m, 2 H). 1.65 (s.3H) and 1.45 (s.3H) ppm.

Production of starting compounds (II)

Manufacturing A
ö-chloro-o-iodopenicillanic acid

To 338 g of iodine monochloride in 30 ml of methylene chloride were added 11.1 ml of 2.5 η sulfuric acid, then 1.92 g of sodium nitrite, with stirring at 0 to 5 ° C. Then 3.00 g of 6-aminopenicillanic acid were added all at once, and stirring was continued for 30 min at 0 to 5 ^° C. 22.8 ml of 1 M sodium sulfite solution were then added in portions to the reaction mixture, and the layers were separated. The aqueous layer was washed with more methylene chloride, and

then all organic phases were washed with saturated sodium chloride solution. The methylene chloride solution was dried (over Na2SO.s) and in vacuo concentrated to 3.48 g of the title compound

The above product was made in 30 ml of tetrahydrofuran dissolved, and then 30 ml of water are added The pH was adjusted to 6.8 with dilute sodium hydroxide solution and the tetrahydrofuran in vacuo deducted. The remaining aqueous phase was freeze-dried and the residue with diethyl ether washed. This provided 3.67 g of the title compound as the sodium salt.

Manufacturing B
e-ß-Chlorpenicillanic acid

A 225 g sample of Namum e-chloro-e-iodpenicillanate was converted to the free acid and then dissolved in 125 ml of benzene under nitrogen. 1.08 ml of triethylamine were added to this solution, and the equipment was cooled to 0 to 5 ° C. 0577 ml of trimethylsilyl chloride were then added to the cooled mixture, and the reaction mixture was stirred for 5 min at 0 to 5 ° C., 60 min at 25 ° C. and 30 min at 50 ° C. The reaction mixture was cooled to 25 ° C. and the triethylamine The hydrochloride was filtered off. The filtrate was admixed with 15 mg of azobisisobutyronitrile and then with 20 ml of tri-n-butyltin hydride. The mixture was then irradiated with UV light for 15 min with cooling to keep at a temperature of about 20 ⁰ C. The solvent was then removed in vacuo and the residue dissolved in a 1: 1 mixture of tetrahydrofuran and water. The pH was adjusted to 7.0 and the tetrahydrofuran removed in vacuo. The aqueous phase was washed with ether and then became an equal volume Ethyl acetate was added, the pH was adjusted to 1.8 and the ethyl acetate layer was removed, the aqueous phase was extracted with more ethyl acetate and then the combined ethyl acetate solutions were dried and concentrated in vacuo.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 and the tetrahydrofuran was stripped off in vacuo. The remaining aqueous phase was freeze-dried to 850 mg To deliver sodium-ö-jS-chlorpenicülanat. The NMR spectrum {D />) showed absorprion at 5.70 (i.e. 1 H, J = 4 Hz), 5.50 (i.e. 1 H. J = 4 Hz). 4.36 (s. 1 H), 1.60 (s. 3 H) and 133 (see 3H) ppm.

Manufacture C
6-0-brofnpenicillanic acid

A mixture of 5.0 g of W-dibromopenicillanic acid. 34 ml of triethylamine and 100 ml of benzene were stirred under nitrogen until solution was obtained. The solution was cooled to 0 to 5 ° C, and 1.78 ml of trimethylsilyl chloride was added The reaction mixture was 2 to 3 min at 0 to 5 ⁰ C and then 35 min stirred at 50 "C. The cooled reaction mixture was filtered and the filtrate was cooled to 0 to 5 ° C. A small amount of azobisisobutyronitrile was added, then 3.68 ml of tri-n-bulyltin hydride. The reaction flask was irradiated with UV light for 15 min, and then the reaction mixture was heated to about 25 ° C 1, The reaction mixture was again irradiated for 15 minutes and

then stirred for a further 23 h. A small amount of azobisisobutyronitrile was then added, then 0.6 ml of tri-n-butyltin hydride (0.6 ml) was added and the mixture was again irradiated for 30 min % sodium bicarbonate solution and diethyl ether added. The two-phase system was shaken vigorously for 10 minutes, and then the pH was adjusted to 2.0. The ether layer was removed, dried and concentrated in vacuo to give 233 g of an oil. The oil was converted into the sodium salt by adding water 1 equivalent of sodium bicarbonate and subsequent freeze-drying of the solution thus obtained were transferred. This gave sodium 6-β-bromopenicilanate, contaminated with a small amount of the α-isomef-n.

The sodium salt was chromatographed on a cross-linked dextran gel (Sephadex LH-20), combined with some other material of the same quality, chromatography and then chromatographed again. The NMR spectrum (D ₂ O) of the product thus obtained showed absorptions at 536 (see 2 H). 4.25 (see 1H). 1.60 (s.3H) and 130 (s.3H) ppm.

Manufacturing D
6- / 3-iodopenicillanic acid

The title compound is obtained by reducing 6,6-Dijodpenicilansäure with tri-n-butyltin hydride the production B procedure

Manufacture E
Pivaloyloxymethyl-6-rtc-brompenicilanate

To a solution of 280 mg of 6-a-bromopenicillic acid in 2 ml of N.N-dimethylformamide are 260 mg Diisopropylethylamine. then 155 mg of chloromethyl pivate and 115 mg of sodium iodide. The reaction mixture is stirred at room temperature for 24 h and then diluted with ethyl acetate and water. The pH is adjusted to 73 and then the ethyl acetate layer is added äbgeirenm and three times with water and once! with washed saturated sodium chloride solution. The ethyl acetate solution is then dried with anhydrous sodium sulfate and in vacuo to give the title compound constricted

Manufacturing F
C.f'-diiodopenicillanic acid

A mixture of 15.23 g iodine, 10 ml 23 η sulfuric acid

ΐΎάίΓίτιϊϊϊΓΐΐτιΐί

was stirred at 5 ° C, and 432 g of 6-aminopenicillanic acid were added over 15 min at 5 to 10 ° C was stirred for a further 45 min after the addition was complete, and then 100 ml of 10% sodium bisulfite solution was added added dropwise. The layers were separated, and the aqueous layer was further washed with methylene chloride extracted. The combined methylene chloride layers were washed with brine, (over MgSCt) dried and concentrated in vacuo. This provided 1.4 g of the title compound contaminated with some 6-iodopenicillanic acid. The product had a melting point of 58 to 64 ° C. The NMR spectrum (CDCIj) showed Absorptions at 5.77 (s, 1 H), 4.60 (s, 1 H), 1.17 (s, 3 H) and 1.54 (s, 3H) ppm.

Manufacturing G
PivaloyIoxymethyl-6-Ä-BromopenicifIanate

To a stirred mixture of 11.2 g of 6- <x-bromopenicillanic acid, 3.7 g sodium bicarbonate and 44 ml NJsI-dimethylformamide 6.16 g of chloromethyl derivative were added dropwise over 5 min at room temperature. It was Stirring was continued for 66 hours and then the reaction mixture became diluted with 100 ml of ethyl acetate and 100 ml of water. The layers were separated, and the Ethyl acetate layer was sequentially washed with water, saturated sodium chloride solution, saturated sodium bicarbonate solution. Washed with water and saturated sodium chloride solution. The decolorized ethyl acetate solution was dried (over MgSOi) and concentrated to dryness in vacuo. This provided 12.8 g (80% yield) the title compound.

Manufacture H
BenzyI-6 - «- brompenici! Ianat

The title compound was prepared by esterifying 6-α-bromopenicillanic acid with benzyl bromide practically according to the procedure of Preparation G (yield 83%). The NMR spectrum (in CDCI ₃ ) showed absorptions at 735 (see 5 H). 535 m. 1H), 5.15 (s. 2H). 4.70 (m. 1H). 4.60 (see 1H). 1.55 (s, 3 H) and U5 (s. 3 H) tpm.

Manufacture I
2,2.2 -Trichloräthylpenicii; _nat

To a stirred solution of 11 ₁ g ^ 6-a-bromopenicillanate in 50 ml of tetrahydrofuran at 0 ⁰ C was added during 1 h 3.48 g of pyridine. 8.47 g of 2,2,2-trichloroethyl chloroformate were added to the cloudy solution thus obtained in the course of 10 minutes, the temperature being kept between 0 and 2 ° C. Stirring was continued for 30 minutes and then the cooling bath was removed. Stirring was continued at room temperature overnight. The reaction mixture was then warmed to 35 ° C. for 5 minutes and then filtered. The filtrate was concentrated and the residue was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was then washed sequentially with saturated sodium bicarbonate solution. Washed with water and saturated sodium chloride solution. The ethyl acetate solution was then decolored and dried and concentrated to a small volume. 100 ml. Hexane was added and the solids filtered v / ere and yielded 10.5 of the title compound, mp. 105-110 ⁰ C. g The NMR spectrum (in CDCI ₃₎ showed absorptions at 5.50 (d, 1 H), 4 .95 (d. 1H), 4.90 (s, 2H),

iif, i, 7v ^ a, 3 Γτ / uiiu

, J rjj

Manufacture J
6,6-dibromopenicillanic acid

To 500 ml of methylene chloride, cooled to 5 ° C., 119.9 g of bromine, 200 ml of 2.5 η sulfuric acid and 34.5 g of sodium nitrite were added. This stirred mixture was then added 54.0 g of 6-aminopenicillanic acid portionwise over 30 min while the temperature was maintained at 4 to 1O ⁰ C. It was further stirred for 30 min at 5 ° C, and then 410 ml of a 1.0 M sodium bisulfite solution were added dropwise over 20 min at ⁰ C 5-1O. The layers were separated and the aqueous layer was extracted twice with 150 ml of methylene chloride. The original methylene chloride layer was combined with the two extracts to form a solution of the 6,6-dibromopenicillic acid. This solution was used directly in Example 12

Manufacturing K
δ-chloro-δ-iodopenicillanic acid

To 100 ml of methylene chloride, were cooled to 3 ° C

ίο 4.87 g iodine chloride, 10 ml 23 η sulfuric acid and 2.76 g Given sodium nitrite. This stirred mixture was then added portionwise with 432 g of 6-aminopenicillanic acid Added over 15 min. Stirring was continued for 20 min at 0 to 5 ° C. and then 100 ml of 10% strength were added Sodium bisulfite solution was added dropwise at about 4 ° C. The mixture was stirred for a further 5 min and then the layers were The aqueous layer was extracted with methylene chloride (2 × 50 ml), and the combined methylene chloride solutions were washed with brine, dried (over MgSO «) and in vacuo to Title compound as a tan solid, m.p. 148-152 ° C. narrowed the NMR spectrum of the product (CDCIj) showed absorptions at 5.40 (s, 1 H), 4.56 (s, 1 H), 1.67 (s, 3 H) and UO (s, 3 H) tpm. That SR spectrum (KBr pellet) showed absorptions at 1780 and 1715 cm '.

Manufacturing L

δ-bromo-δ-iodopenicillanic acid

To 100 ml of methylene chloride, cooled to 5 ° C., 10 ml of 2I sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite were added. 432 g of 6-aminopenicillanic acid were added to this mixture with vigorous stirring at 0 to 5 ° C. in 15 minutes ⁰ C added dropwise. The layers were then separated and the aqueous layer was extracted with (3 × 50 ml) methylene chloride. The combined methylene chloride layers were washed with brine, dried (over MgSO-s) and concentrated in vacuo. The residue 'wümjc under ι iGCuVSKüünr 30 ΐΰΐη gctrOCiCiici üüu provided 6.0 g (72% yield) of the title compound, melting point 144-147 ° C. The NMR spectrum (CDCl ₃ ) showed absorptions at 5.50 (s, 1 H), 433 (s, 1 H), 1.70 (s, 3H) and 133 (s, 3 H) ppm. The IR spectrum (KBr pellet) showed absorptions at 1785 and 1710 cm- '. The mass spectrum showed an outstanding ion at / n / e = 406.

Manufacture M
Pivaloyloxymethyl-o-dibrompenicillanate

To a stirred solution of 3.59 g of 6, t> -Dibrompenicillansäure in 20 ml N ₁ N-dimethylformamide, 130 g of diisopropylethylamine. then 130 g of chloromethyl pivalate at approx. 0 ^° C. are added. The reaction mixture is ^{stirred at about 0} ° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture is then diluted with ethyl acetate and water and the pH of the aqueous phase is adjusted to 73. The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution.

see. The ethyl acetate solution is then anhydrous Dried sodium sulfate and concentrated in vacuo to give the title compound.

Claims (1)

Patent claims: 1. Process for the production of penicillanic acid 1,1-dioxide and its esters of the general formula; (D or a pharmaceutically acceptable salt thereof, in which R ^{1 is} hydrogen, a customary penicillin caiboxy protective group or an ester-forming radical which is readily hydrolyzable in vivo, based on a compound of the general formula: