DE3101527A1 - PENAMIC CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS THAT CONTAIN THESE COMPOUNDS - Google Patents

Description

J. REITSTÖTTER W. KINZEBACH

PROF. DR. DR. DIPL. ING. DR. PHIL. DIPL. CHEM.

W. BUNTE U958-i97e) K. P. HÖLLER

DR. ING. DR. RER. NAT. DIPL. CHEM. TELKPONi (Ο8Π) TELEXl 62IE2O8 IBAR D BAUEHBTHASBE 22, 80OO MUNICH 40

Munich, January 19, 1981 M / 22 006

BRISTOL-MYERS COMPANY 345, Park Avenue

New York, N.Y. 10022 (U.S.A.)

Penamcarboxylic acid derivatives, processes for their preparation and pharmaceutical agents containing these compounds

contain

POSTAL ADDRESS ι POSTFACH 780, D-BOOO MONCHBN «S

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The present invention relates to 2ß-chloromethyl-2a-methylpenam-3a-carboxylic acid sulfone as well as its pharmaceutically acceptable salts or easily hydrolyzable esters, which are useful as β-lactamase inhibitors.

The assumed connection between the resistance of certain ß-lactam antibiotics to certain bacteria and the ability of these bacteria to produce β-lactamases has led to an intensive search for β-lactamase inhibitors. Clavulanic acid is an example of such a compound which is currently being extensively tested. Another β-lactamase inhibitor in its acid form has the structure shown below

COOH

j and is ' published' in European Patent Application 2927. on July 11, 1979.

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The compound of the formula

-12'-

COOH

is in U.S. Patents 4,036,847; 4,009,159; 3,993,646; I. 3,989,685 and 3,954,732. j

US Patent 4,155,912 describes 2-penem-3-carboxylic acid compounds the formula

COOH

as well as their esters and salts, see also Farmdoc Abstracts j 82090A, 10336B and 44337B.

The compound (under the number CP-45899) of the formula

H ₃ CH.

COOH

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is an irreversible ß-lactamase inhibitor with excellent stability in solution. She has a weak antibacterial effect and increases the producing in vitro and in. Vivo potencies of Ampicillen against beta-lactamase ¹ strains [AR English et al .. Antimicrobial \ Agents and Chemotherapy, J_4, 414-419 (1978), et al Aswapokee ., j J. Antibiotics 31 (12) , 1238-1244 (Dec. 1978) and Derwent's \ Farmdoc Abstracts 89627A and 73866B].

In".". B. Baltzer et al., Mutual Pro-Drugs of ß-Lactam Antibiotics and ß-Lactamase Inhibitors, J. Antibiotics, 33 (10) , 1183-1192 (1980) discloses that ^the principle, ß-lactam

\ Antibiotics with a ß-lactamase inhibitor all in one

\ Molecule to join, which is then called a "pro-drug" for the two

j active ingredients acts through the-linked esters

! and Fig. 4 is illustrated wherein ampicillin and mecillinam, respectively

* with the ß-lactamase inhibitor penicillanic acid sulfone

■ j are combined. It is shown that in humans this

\ Ester is excellently absorbed from the gastrointestinal tract

\ and after absorption with simultaneous release of the

j active ingredients are hydrolyzed. As a result

i one reaches high blood and tissue levels of the antibiotic

'and the ß-lactamase inhibitor in a balanced relationship

I ratio. The advantages of "mutual pro-durgs"

> discussed versus simple combinations.

The esters 3 and 4 identified above have the following structures:

. / \ —CH-CO-NHV.

^ 2 Y N

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- rf-

N-CH = N

ο ο

/ - ^H

CO

CO-O

In GB 2044255, published on October 15, 1980, it is stated that that the invention hitherto unknown compounds of the general formula 1:

₁ —CH — CO— NH 1 I

relates where R .. is phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or a 3-thienyl group; R "a primary Represents an amino or a carboxy group; R, for a hydrogen atom or a lower alkyl, aryl or aralkyl radical and A stands for the residue of a β-lactamase inhibitor which has both a β-lactam ring and a carboxy group contains, where A is bound via the carboxy group. '

130067/0503

The new compounds are useful in treating bacterial infections and are particularly extreme effective against ß-lactamase-producing bacteria. See also Farmdoc Abstracts 60773C and 60776C.

The present invention thus provides the acid of the formula

and pharmaceutically acceptable salts or easily hydrolyzable esters of this acid.

These pharmaceutically acceptable salts include non-toxic metal salts such as sodium, potassium, calcium and magnesium

salts, the ammonium salt and substituted ammonium salts, j

e.g. salts of non-toxic amines, such as trialkylamines \

(e.g. triethylamine), procaine, dibenzylamine, N-benzyl-ß- j

phenethylamine, 1-ephenamine, Ν, Ν'-dibenzyl-ethylenediamine, \

Dehydroabietylamine, N, N'-bis (dehydroabietyl) ethylenediamine, j

N- (lower) alkyl-piperidine (e.g. N-ethylpiperidine) and others j

Amines, which are used for the production of pharmaceutically acceptable |

Salts of penicillins and cephalosporins were used. ;

The most preferred salts are the alkali metal salts, namely ι the sodium and potassium salts and the ammonium salt.

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The term "physiologically hydrolyzable ester" used in describing the present invention refers to those pharmaceutically acceptable esters known in the art that they hydrolyze to the free acid form in vivo. Examples of suitable physiologically hydrolyzable esters are phenacyl, acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, phthalidyl (3-phthalidyl), Indanyl (5-indanyl), methoxymethyl, benzoyloxymethyl, a-ethylbutyryloxymethyl, propionyloxymethyl, Valeryloxymethyl, isobutyryloxymethyl, 6 - [(R) -2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl- and 6- [(R) ^ -amino ^ -p-hydroxyphenylacetamido] -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl ester. Preferred are the acetoxymethyl, pivaloyloxymethyl, methoxymethyl, phthalidyl, 5-indanyl, 6 - [(R) -2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo [3.2.0] · heptane-2-carbonyloxymethyl- and 6 - [(R) -2-amino-2-p-hydroxyphenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] -heptan 2-carbonyloxymethyl ester.

The present invention also relates to a process for the preparation of an acid of the formula:

0 O

or a pharmaceutically acceptable salt of this acid, where:

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an ester of formula A:

X CH-Cl

ß ^ J ²

O"

} where R is benzyl or substituted benzyl,

j for example with a noble metal catalyst such as palladium,

j catalytically hydrogenated and then

j bji the hydrogenated product is oxidized to the desired acid j or the salt thereof and, if desired, subsequently-I

; cj this acid or its salt esterifies to one easily to obtain hydrolyzable ester of this acid.

The present invention also provides a process for the preparation of an acid of the general formula:

COOH

or a pharmaceutically acceptable salt thereof, wherein ^:

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a) an ester of the formula

Br,

CH ₂ Cl i "'* CI

VOCH ₂ CCl ₃ 0

oxidized for example with KMnO., H ₃ O ₃ or a similar peroxide or a peracid, an ester of the formula

C-OCH ₀ CCl, 0

receives, and then

b) this ester sulfoxide with a metal in an acid, for example reacted with zinc in glacial acetic acid so that the desired acid or salt is obtained, and then if necessary

c) esterifies this acid or its salt in order to obtain an easily hydrolyzable ester of this acid-

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A large number of oxidants known from the prior art can be used for the oxidation of the sulfides to sulfones will. However, alkali metal permanganates, e.g. potassium permanganate, and organic peracids are particularly suitable, e.g. 3-chloroperbenzoic acid.

As protecting groups for R are the benzyl group and substituted

4-nitrobenzyl.

ated benzyl groups, particularly / suitable. Benzyl and substituted benzyl groups can easily be removed by catalytic hydrogenation. A solution of the compound of the formula A, in which R is benzyl or substituted benzyl, is stirred or shaken in an inert solvent under a hydrogen atmosphere, or hydrogen mixed with an inert diluent, such as nitrogen or argon, in the presence of a catalytic amount of a hydrogenation catalyst. Suitable solvents for this hydrogenation are lower alkanols such as methanol; ethers such as tetrahydrofuran and dioxane; Low molecular weight esters such as ethyl acetate and butyl acetate; Water; and mixtures of these solvents. However, it is common. To choose conditions under which the starting material is soluble. The hydrogenation is generally carried out at temperatures in the range from about 0 C to about 60 ⁰ C and at a pressure in the range from 1 to

2
about 100 kg / cm. This hydrogenation reaction is used for this type of conversion

common catalysts are used, typical examples thereof are the precious metals like nickel, palladium, platinum and rhodium. The catalyst is generally used in an amount from about 0.01 to about 2.5% by weight, preferably from about 0.1 to about 1.0% by weight, based on the compound of Formula A, used. It is often convenient to suspend the catalyst in an inert support; particularly suitable is palladium suspended in an inert carrier such as carbon. It is also common to use the reaction mixture buffer to operate at a pH of 4 to 9, and preferably 6 to 8. Generally one uses

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Borate and phosphate buffers. The reaction usually takes about an hour.

The invention also relates to esters of the formula:

R -— CH — CO -NH,

/ 7

Jl

ο ο

C = O

ι— t *

created in what

R for

C-

Il

or

• O.

stands,

1

where R is hydrogen or hydroxy and R is hydrogen, hydroxy, methyl, methoxy or chlorine,

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preferably the ester of the formula

CH-CO-NH

IiH,

0 0

CILCl

C-

Il

C = O

CH,

and the ester of the formula

The invention also includes the method of manufacture such an ester, after which one is a compound of the formula

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R-CH

CO-NH

^) N

C-

Il

C = O

CH,

where R is

·. O. O. σ-

stands.

wherein R is hydrogen or hydroxy and R ^{5 is} hydrogen, hydroxy, methyl, methoxy or chlorine

mean, and

R ^{1 represents} alkyl, aralkyl or aryl,

ο
R is hydrogen, alkyl, aralkyl or aryl

and

R for alkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy

or -N

stands,

wherein R and R are each hydrogen, alkyl, aralkyl or

Mean aryl, or, together with the 130067/0509

Μ / 22 006

Nitrogen atom to which they are attached, piperidino or morpholino mean,

with an acid, preferably in an organic solvent such as acetone or chloroform, or in aqueous or partially aqueous solution, and preferably at a pH between pH 1 and pH 5, treated at room temperature.

According to a further preferred embodiment are in

1 2

the amino group R for methyl, R for hydrogen and

R for methoxy, ethoxy or methyl; in this reaction is the use of methyl acetoacetate, fithylacetoacetate or Acetylacetone required.

It is preferred to use to remove the α, -amino protecting group a strong inorganic acid such as hydrochloric acid or formic acid.

The invention also provides an intermediate product of the formula:

wherein R is benzyl or substituted benzyl, and is preferably p-nitrobenzyl, and the process to its preparation, after which a compound of the formula

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wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, in an inert, anhydrous organic solvents, preferably dioxane, in the presence a large, and preferably equimolar, amount of a weak tertiary amine, preferably quinoline, and of an acid chloride, preferably benzoyl chloride, heated, preferably at reflux temperature, until the reaction is practically complete.

The present invention also provides, as an intermediate, a new ester of the formula:

-OR

wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, and the process for it Preparation, after which in an inert solvent, preferably methylene chloride, a compound of the formula:

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wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, at about room temperature below Use of a peracid, preferably m-chloroperoxybenzoic acid, oxidized.

The invention also provides, as an intermediate, a new ester of the formula:

C-OCH ₀ CCl, 0

and the process for its preparation, after which a solution of a compound of the formula:

CH ₂ Cl

C-OCH ₂ CCl
0

in an inert solvent, preferably methylene chloride at about room temperature using an oxidizing agent, like KMnO., H-Op or similar peroxides, or preferably a peracid, preferably m-chlorophenoxybenzoic acid, oxidized.

"Skellysolve B" is a petroleum ether fraction with a boiling point of 60 68 ° C, which consists essentially of η-hexane ("Skellysolve" is a trade name of Skelly Oil Co.).

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- ZfT-

The following examples are only intended to illustrate the preparation of representative compounds of the invention and in no way limiting.

example 1

Production of 2ß-chloromethyl-2a-methylpenam-3a-potassium carboxylate-sulfone (BL-P2013)

-N-

"CO ₂ H

-N

CH ₂ Cl CH,

CO ₂ H

KMnO,

CJ ^ ^CO 2 ^K

(BL-P2013)

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ßa-Srompenicillanic acid-S-sulfoxide (1)

1) Dissolve 30 g (37.5 mol) of Sa-bromopenicillanic acid-Ν, Ν ¹ -dibenzylethylenediamine salt [G. Cignarella et al., J. Org. Former. 22, 2668 (1962) and E. Evrard, Nature 201, 1124! 1964}] in 330 ml of methylene chloride, stirred and cooled to 0 ⁰ C

2} 13 ml (156 mmol) of conc. Hydrochloric acid • into the methylene chloride solution. The precipitation of the difaenzylethylenediamine HCl salt (DBED'HCl) takes place within one minute. The slurry is then stirred at 0-5 ^° C. for 10 minutes.

3) It is filtered to remove the DBED-HCl precipitate through a pretreated diatomaceous earth ("Dicalite") filter, then the filter cake is washed with 150 ml of methylene chloride. The filtering process should be done as quickly as possible. You should avoid letting the acidic methylene chloride solution stand for a long time. Since the precipitate is very fine, filtration problems can arise and the addition of filter aid to the slurry can be useful.

4} The combined methylene chloride filtrates and washing liquids are washed with 60 ml of cold water, stirred for 5 minutes and the aqueous phase is discarded. The pH of the washing liquids is 2.0 to 2.3.

5 ,, Γ 1 * 2 A'efhylenchloridlösung which the öa-Brompenicillan-.? Contains äXxZft is at reduced pressure to a volume '■., Cn' evaporated .'5-2C XNL. Then the solution is cooled

^v '"J w ~' ivii stirs. i

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6) While stirring vigorously, 13 ml (86.9 mmol) of 40% peracetic acid are carefully added over the course of 30 minutes. The reaction is exothermic. The temperature is maintained by cooling in an ice bath at 15-18 ⁰ C. After 10 ml of peracetic acid was added, the sulfoxide begins to crystallize. The slurry is cooled and stirred for two hours at 0 to 5 ^° C.

7) The mixture is filtered and washed the snow white filter cake successively as follows: 10 ml of water at 5 C, then 10 ml of methylene chloride at 0-5 ⁰ C and finally with 15 ml heptane.

8) The cake is dried ^{to constant weight in a 45 °} C. air oven, for about 6-10 hours should be sufficient. If you heat it for a longer period of time, it can turn a slight pinkish-red color. The weight of compound λ_ is about 16.25 g, which corresponds to a yield of 73.24%.

9) The reaction mixture and the final product can be analyzed by thin layer chromatography using 15 parts toluene / 4 parts acetone / 1 part acetic acid (HAC) or 8 parts acetone / 8 parts methanol / 3 parts toluene / 1 part HAC solvent systems. That Final product should be monitored by NMR and IR.

p-nitrobenzyl-6a-bromopenicillanate-S-sulfoxide (2)

To a solution of 12 g (0.04 mol) of 6a-bromopenicillanic acid-S-sulfoxide 7.5 g (0.041 mol) of potassium 2-ethylhexanoate are added to 100 ml of acetone. The salt is made by filtering collected, washed with cold acetone and air dried to give a total of 10 g. You solve that crystalline potassium salt in 75 ml of dimethylacetamide and gives

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C. 98 H Ό5 N , 52 41, OO 3, 48 6th , 98 42, 3, 6th

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7.8 g (0.04 mol) of p-nitrobenzyl bromide. The solution is then stirred for 24 hours at 23 ° C. The mixture is diluted with 500 ml of water and extracted with ethyl acetate, the ethyl acetate layer is washed four times with water and dried over anhydrous magnesium sulfate. The solvent becomes a at 35 ° C. (15 mm) evaporated oil, which crystallized. The slightly brownish crystals of compound 2 is slurried with ether and collected by filtration to j 9 g (70%) is obtained; mp. 124-125 ⁰ C (dec.).

Analysis C ", .H. _r BrN "O, S:

calculated: found:

IR (KBr): 1800 (s), 1740 (s), 1610 (w), 1520 (s), 1450 (m),

j 1350 (s), 1060 (m), 740 (m) cm " ¹ .

H-NMR (60 mHz, DMSO): δ 1.22 (s, 3H), 1.6 (s, 3H), 4.67 (S, 1H),

5.2fd, J- / 1.5 Hz, 1H), 5.45 (s, 2H),

5.68 (d, J ~ 1.5 Hz, 1H), 7.5-8.5 (m, 4H).

p-Nitrobenzyl ^ ß-chloromethyl ^ a-methyl-e-bromopenam-Sa, carboxylate (3)

A solution of 5 g (0.012 mol) of p-nitrobenzyl-öa-bromopenicillanate-S-sulfoxide (2) in 120 ml of anhydrous dioxane is refluxed for 4 hours with 1.5 g (0.012 mol) of quinoline and 1.6 g under a nitrogen atmosphere (0.012 mole) benzoyl chloride. The solution is diluted with 600 ml of water and extracted with ethyl acetate. The ethyl acetate extract is washed with 5% sodium bicarbonate solution, 5% phosphoric acid solution and finally with water, the organic layer is dried over anhydrous magnesium sulphate and evaporated at 35 ° (D. (15 mm) to give an oil. The oil crystallizes and becomes collected, with ether and finally with cold toluene

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washing to obtain 3.5 g (65%) of compound _3, j

Mp. 130-135 ⁰ C (dec.). |

Analysis CH ClBrN ₃ O ₅ S:;

CHN j calculated: 40.06 3.14 6.23%

'found: 40.19 3.12 6.75%

^! IR (KBr): 1792 (s), 1740 (s), 1610 (w), 1520 (s), 1353 (s),

; 1280 (m), 1025 (w), 990 (w), 750 (w) cm " ^{1 .:}

j NMR (60 mHz, DMSO): δ 1.45 (s, 3H), 3.5-4.3 (m, 2H), 5.05 (s, 1H) ,:

5.42 (s, 2H), 5.5 (d J-1.5 Hz, 1H),

5.62 (d, J ~ 1.5 Hz, 1H), 7.5-8.5 (m, 4H).

p-Nitrobenzyl- 2 ß -chlorine thy 1- 2a-me thy lpenam-oa-carboxylate sulfoxide (_4)

A solution of 1 g (0.0022 mol) of p-nitrobenzyl-2β-chloromethyl-2a-methyl-6a-bromopenam-3a-carboxylate (^) dissolved in 50 ml of methylene chloride is stirred with 473 mg (0.0022 mol) of m -Chloroperoxybenzoic acid. The solution is stirred at 23 ° C. for 3 hours. The methylene chloride is concentrated to 20 ml at 15 mm (19.998 mbar) and 33 ° C. and the concentrated solution is diluted with 50 ml of heptane ("Skellysolve B"). The solvent is decanted off and the residue is suspended with ether, which rapidly connects (£) crystallized, 250 mg, 24%, mp. 136-137 ⁰ C (dec.).

Analysis C H .BrCIN.OgS:

calculates '..:' ". · ._ UH den:

C. 68 H , 02 N , 02 38, 14th 3 , 13 6th , 96 39 3 5

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IR (KBr): 1800 (s), 1760 (s), 1520 (s), 1350 (s), 1200 (s), 1050 (m), 830 (w), 740 (w) cm " ¹ .

H-NMR (60 mHz, DMSO): δ 1.32 (s, 3H), 3.8-4.5 (m, 2H),

4.97 (s, 1H), 5.25 (d, JM, 5 Hz, 1H), 5.45 (s, 2H), 5.6 (d, J- ^ 1.5 Hz, 1H), 7.8-8.5 (m, 4H).

Potassium ^ ß-chloromethyl ^ a-methylpenam-Sa-carboxylate sulfone (5) (B1-P2013)

A suspension of 4 g of 30% palladium is added to a solution of 7 g (0.015 mol) of p-nitrobenzyl-2β-chloromethyl-2a-methyl-6a-bromopenam-3a-carboxylate sulfoxide (£) in 150 ml of ethyl acetate Diatomaceous earth ("Celite") and 2.8 g of matriculate bicarbonate in 150 ml of water. The mixture is hydrogenated at 3.445 bar (50 psi) for 3 hours. The catalyst is removed by filtration, the aqueous layer is separated off and treated with 1.5 g of potassium permanganate in 50 ml of water. The mixture is then stirred for 1 hour and 250 mg of sodium bisulfite are added, the mixture is filtered and the filtrate is concentrated. Hydrochloric acid to pH 2. The solution is lyophilized to give a white, amorphous powder. The solid is extracted with ethyl acetate, concentrated to a volume of 20 ml and diluted with 100 ml of heptane ("Skellysolve B"). White, hygroscopic, solid 2 ß-chlorine thy 1-2amethylpenam-3a-carboxylic acid sulfone is obtained. Dissolve the acid in acetone and treated with solid potassium 2-ethyl hexanoate, wherein a crystalline white salt precipitates, one of which after completion 'filter 170 mg of compound 5_ obtained, mp.> 140 ⁰ C (dec.). ■

Analysis C ₃ H ₇ ClKNO ₅ S * 2H 2 ^0: C. 27 H 24 N ,1" 28, 27 3, 69 4th , 84 calculated: 28, 3, 3 found:

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IR (KBr): 1790 (s), 1770 (m), 1620 (S), 146O (m), 1370 (s), 1310 (s), j 1200 (s), 1140 (s), 955 (m) , 740 (m) cm " ^1. J

H-NMR (100 mHz,

: δ 1.68 (s, 3H), 3.2-3.9 (m, J ~ 2 Hz, J ~ 4Hz, J-v6 Hz, 2H), 4.0-4.4 (m, 2H) , 4.3 (p
5.02 (dd, J ^ 4 Hz, J-2 Hz, 1H).

example

Pivaloyloxymethyl ^ ß-chloromethyl ^ a-methylpenam-Saca rboxylate sulfone

2ß-chloromethyl-2a-mefchylpenam-3a-carboxylic acid sulfone in Dimethylformamide is treated with one equivalent of triethylamine and stirred until solution occurs. Then you give Bromomethyl pivalate (1 equivalent) in dimethylformamide is added and the resulting solution is stirred at room temperature. Afterward the mixture is clarified by filtration and the filtrate is poured into ice water. The separated solid is recovered by filtration, washed with water and dried to give the ester named in the title.

The corresponding acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters of the same acid are prepared by using in the above procedure Bromomethyl pivalate by an equimolar amount by weight of chloromethyl acetate, chloromethyl methyl ether, chloroacetone or Replaced phenacyl bromide.

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Example 3

Pivaloyloxymethyl-2ß-chlo: methyl-2a-methylpenam-3acarboxylate-sulfone, BL-P2024

ο ο

LJ-J

Λ ¹ N- £

O + NaI + H ₂ O + ClCH ₂ -OCC (CH ₃ J ₃ acetone. ^

o ⁽³⁰⁶⁾ CO ₂ -K- (BL-P2013)

0 O

CO ₂ CH ₂ -OCC (CH ₃ }

(BL-P2024)

To a stirred suspension of 14.6 g (0.0487 mol) of compound BL-P2013 (5)) in 200 ml of acetone is added 4 ml of a 10 % strength aqueous sodium iodide solution and the mixture is refluxed on a steam bath. To this mixture, kept at reflux, add 1? ^ § ^m ml (0.1 mol)

ο again distilled chloromethyl pivalate (bp 34 C at

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7 mm Hg (9.3325 mbar)). The mixture is stirred for three hours at reflux temperature and then cooled to room temperature (22 ⁰ C). The crystalline solids are collected by filtration, washed with 3 × 30 ml of acetone and the combined filtrates are concentrated in an oil in vacuo at < 22 ° C. The oil is then taken up in 500 ml of ethyl acetate and once with water (200 ml) and once with saturated Na “SO. washed while stirring with 2 g of decolorizing charcoal while cooling (ice bath). After 20 minutes, the mixture is filtered through a diatoms (Dicalite) bed with suction and the filter bed is washed 4 with 100 ml of ethyl acetate. The combined filtrates are concentrated to an oil at 22 ° C. in vacuo. The oil is then at 22 C and <T1 mm Hg

Most of the (1.3332 mbar) concentrated further in order to remove the / remaining chlorine methyl pivalate. The remaining oil is then triturated twice with 50 ml portions of n-pentane and then left to stand over the weekend in a cold room (about 10 ° C.) under n-pentane. The solid crystalline mass is then broken up into a solid powder under 40 ml of a 4: 1 mixture of ether-n-pentane. The product is then recovered by filtration, washed with 1: 1 ether-pentane and then with pentane and air-dried. After 4 hours in a vacuum over P ₇ O ₁ . has dried to obtain 13.37 g of pivaloyloxymethyl 2ß-chloromethyl-2amethylpenam-3a-carboxylate sulfone (yield about 75%), mp 93 ° to 95 ⁰ C.

Analysis C ₁

calculated: found:

C. , 03 H , 27 N , 67 44 , 11 5 , 08 3 , 85 44 5 3

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Example 4

Recrystallization from potassium 2β-chloromethyl-2a-methylpenam-3a-carboxylate sulfone (BL-P2013)

1 ml of water is added all at once to a mixture of 20 ml of n-butanol and 1 g of compound BL-P2013 (5) , while shaking in a separating funnel until a pale yellow solution is obtained. The clear solution is passed through a folded filter and the flask and the filter paper are washed with about 10 ml of a 9: 1 n-butanol-H_0 mixture. The combined filtrates are diluted with a further 20 ml of n-butanol. The solution obtained is placed in a round bottom flask on a rotary evaporator and concentrated to about half the initial volume under reduced pressure. The snow-white, crystalline product is obtained by filtration, washed with 6 × 10 ml of acetone and air-dried. The yield is 810 mg. After drying for 6 hours in vacuo over P ₂ Q ₁ - kei <1 mm Hg (1.3332 mbar), 800 mg are obtained, melting point 215 ° C. (decomp.) (Yield 80%).

Analysis C ₈ H ₉ ClNO ₅ SK 1H ₃ O:

calculated: 29.67 found: 29.23

With this recrystallization process one obtains a crystalline monohydrate which differs from the essentially anhydrous starting material.

H 39 N 63 Cl 94 H ₂ O K .F. 3, 38 4, 49 . 10, 74 5, 56 α 3, 4, 10, 5, 74

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Example 5

If

CH ₃₅ OC-Cl

Cl ₂

ClCH ₂

-O-C-Cl

light

+ ClSO-H

ClCH ₂ -OS-Cl

1

See Chemical Abstracts 27, 2427 and 22_, 382; and

GB 299064.

(6)

ν »

Well. acetone

0 \ l

, S.

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CH-CO-NH

isr

OCK,

ί 9 (U.S. Patent 3,316,247)

CO

i- ^N - ⁴ Vo

10

H'

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-yr-

CH CO NH

ο ο

ί Ί ^ η,

CH,

Il

a) A solution of 0.115 mol of chloromethylchlorosulfate in 40 ml of dichloromethane is added dropwise, keeping the reaction temperature below 30 ° C., to a solution of 0.1 mol of compound 5_, 0.3 mol of potassium bicarbonate and 0.01 mol of tetrabutylammonium hydrogen sulfate in 200 ml dichloromethane-water (1: 1). When the addition is complete, the mixture is stirred for 30 minutes at room temperature, the organic phase is separated off and the aqueous phase is extracted with 50 ml of dichloromethane. The combined organic phases are dried (Na SO.) And concentrated in vacuo, giving a residue which is dissolved in 150 ml of ether. Insoluble material is filtered off after adding diatomaceous earth and the filtrate is concentrated in vacuo to give compound 7_ .

b) 1.6 g of bis-chloromethyl sulfate are added to a suspension of compound 5 ^ (1.5 g) in dimethylformamide (12 ml) and the mixture is stirred for 45 minutes at room temperature. After dilution with 50 ml of stylacetate, the mixture is washed with water and then with aqueous sodium bicarbonate, dried and concentrated in vacuo, giving compound ] _ in the form

130067/0509

of an oil.

c) 0.007 mol of triethylamine and 0.030 mol of chloroiodomethane are added to a solution of 0.005 mol of compound 5_ in 7.5 ml of dimethylformamide, and the mixture is stirred for four hours at room temperature. After diluting with 30 ml of ethyl acetate, the mixture is washed with 3 × 10 ml of water and then with 5 ml of saturated aqueous sodium chloride, dried and concentrated in vacuo to give compound 1_ as an oil.

d) To a mixture of 0.15 mol of compound 5_, 0.15 mol Silver nitrate and 7.5 g of silver oxide in 750 ml of acetonitrate are added to 1.5 mol of chloroiodomethane. After getting 48 hours has stirred at room temperature, the silver salts are filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in 200 ml of ethyl acetate, the solution is washed with saturated aqueous sodium chloride, filtered, dried and concentrated in vacuo, compound 2

receives.

The compound 7 as well as other intermediates and the j end products according to the invention are, if desired, purified by means of column chromatography, for example on j "Sephadex" LH20 using 65:35 chloroform; Hexane as an eluent or through silica gel; Chromatography, e.g. B. using Mallinckrodt ^CC-7 and hexane-ethyl acetate, 3: 2, or ethyl acetate-petroleum _ether; 8: 2, or 7: 3, or 1: 9 or 15:85, or ethyl acetate-hexane, 4: 6 or 3: 1, hexane-ethyl acetate, 3: 1 or 1: 1 j or 1: 4 or cyclohexane Ethyl acetate, 1: 1.

Thin layer chromatography can also be used. "Sephadex" is cross-linked dextran-2- (diethylamino) -ethyl-2 - [[2- (diethylamino) -ethyl] -diethylammonio] -ethyl-ether chloride-hydrochloride-epichlorohydrin (see Merck Index,

130067/0509

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- «tr-

9th edition, No. 7337).

A solution of 0.2 mol of compound T_ and 0.3 mol of sodium iodide in 150 ml of acetone is stirred for 18 hours at room temperature. Cool the suspension to about 0 ⁰ C and the pH is adjusted by addition of saturated aqueous sodium bicarbonate with stirring to about pH 7.2 ein.Nach decolorizing by titration with 0.5 M aqueous sodium thiosulfate, 150 ml of water are added dropwise to the stirred mixture to precipitate compound JJ as a solid, which is obtained by filtration, washed with 2 × 20 ml 1: 1 acetone-water, 2 × 20 ml isopropanol and 2 × 20 ml ether and dried.

Ampicillin is converted to compound £ using methyl acetoacetate by the procedures of US Pat. No. 3,316,247. Are then added to a stirred solution of 0.57 mol of compound j) to "1 liter of dimethylformamide at 5 ° C for 0.5 mol of compound 8. After stirring for 15 minutes at 5 ⁰ C, the reaction mixture is poured into an ice cold mixture of ethyl acetate (4 liters) and saturated aqueous calcium chloride (2 liters) with stirring, separating the organic layer, washing with saturated aqueous calcium chloride (2 × 500 ml), filtering and concentrating in vacuo to about 1 liter , a concentrated solution of the compound J_0 being obtained. To this concentrate are then added 500 ml of water and 500 ml of n-butanol and then, dropwise, 4N hydrochloric acid, with stirring until the amino-protecting group is removed and one solution of compound V ^ is obtained. When the addition of the acid is complete, adding 1 liter of ether and 500 ml of water to the stirred mixture, the aqueous phase is separated off and the organic phase extracted with 800 ml of water. the combined aqueous extracts with 1 Liters of ether, then 640 g of sodium chloride and 2 liters of dichloromethane are added and the mixture is stirred for 15 minutes. The organic phase is separated off

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the aqueous phase is extracted with 1 liter of dichloromethane and the combined extracts are dried over MgSO 4. and tightens reduced pressure to about 600 ml to obtain a concentrated solution of compound 1_1_. If you set 200 ml of 2-butanone are added to the concentrate and then cooled, solid 6 - [(R) - ^ - Amino - ^ - phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2 .0] heptane-2-carbonyloxvmethyl ^ ß-chloromethyl ^ -cx-methylpenam-Sa-carboxylate sulfone (11) which is recovered by filtration.

example

6 - [(R) -2-amino-2-p-hydroxypheny / acetamido] -3,3-dimethyl- ■ 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl- ; 2ß-chloromethyl-2-a-methylpenam-3a-carboxylate sulfone der; Formula:

CH,

JZ

-N k

* C

Il

is obtained if amoxicillin is used instead of the ampicillin used in Example 5.

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JA / 22 006

- jar-

Example 7

a)

⁺ N-bromo-succinimide

α-azo-isobutyronitrile CCl

As described in US Pat. No. 3,860,579, recrystallized phthalide (50 g, 0.375 mol) and recrystallized N-bromo-succinimide (0.375 mol) are heated in the presence of about 100 mg of α-azobutyronitrile in one liter of CCl. 4.5 hours at reflux. The mixture is cooled to about 15 ° C. and filtered to remove the succinimide, which in turn is washed with about 100 ml of CCl and filtered. The combined CCl phases are concentrated in vacuo to about 150 ml, solid 3-bromophthalide being obtained, which is obtained by filtration, with about 50 ml CCl. washed and air-dried to obtain 54 g, which weigh g after recrystallization from boiling cyclohexane 50, mp. 84-86 ⁰ C.

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31P1527

DMP
22 ⁰ C.

BL-P2O36
* dl

To a stirred partial solution and partial suspension of compound 5 (BL-P2013; 2.3 g, 0.0075 mol) in 20 ml of dimethylformamide (DMF; dried over 3 Å molecular sieves for at least 3 weeks), 1.7 g (0.008 mol) of 3-bromophthalide (Vl) and the mixture stirred for 4 hours at 22 ⁰ C. the resulting mixture is poured into a mixture of 200 ml of ice-cold water and 200 ml of ice-cold ethyl acetate (wherein rinsing the flask with a small amount of ethyl acetate), then you shake the mixture. The organic phase is then separated off and washed with seven portions of ice-cold water (100 ml). The ethyl acetate phase is washed once with

13006 7/050 9

saturated, aqueous Na SO., dried in the cold over Na_SO., filtered and evaporated to dryness in vacuo, an oil being obtained as residue which was treated twice with methylcyclohexane (25 ml), twice with "Skellysolve B" (bp. 60-68 ⁰ C, essentially n-hexane) (25 ml) and four times with 25 ml

2.5 g
η-hexane is triturated, compound J ^ 3_ being obtained as an almost white solid after drying in air. The product is ₂ ⁰ C then dried at less than 1 mm Hg (1.3332 mbar) over P, wherein 2.5 g of compound J_3 obtained, mp. 104 ⁰ C (dec.). Its estimated purity is 85-95%.

Analysis C ₁ ^ H ₁

calculated:

found:

H ₃ O KF 0.27%

Example 8

Pivaloyloxymethyl ^ ß-chloromethyl ^ a-methylpenam-sacarboxylate sulfone

A mixture of 1 g (0.0031 mol) K.alium-2ß-chloromethyl-2amethylpenam-3a-carboxylate sulfone-hydrate and 1 g of 3A molecular sieves is stirred for 2 hours at 23 ⁰ C in 15 ml of dimethylacetamide. : 470 mg (0.0031 mol) of pivaloyloxymethyl chloride are added to this mixture and the mixture is stirred for a further 18 hours. The molecular sieves are removed, the filtrate is diluted with 100 ml of water and extracted with ethyl acetate. The ethyl acetate is washed nine times with \ water and dried over anhydrous magnesium sulfate. The solvent is removed at 30 ° (15 mm (19.9983 mbar)), leaving an oil which is chromatographed on silica gel using Silicar CC-7 (methylene chloride8, ethyl acetate2) and shows a spot Rf 0.5. The residue obtained is recrystallized from heptane

C. 61 H 79 N / 77 Cl 53% 51, 59 3, 67 3 , 21 9, 73% 52, 4, 3 7,

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("Skellysolve B") 100 mg (melting point 94 ° -95 °) pivaloyloxymethyl-2β-chloromethyl-2a-methylpenam-3a-carboxylate sulfone.

Analysis: calculated: found:

The NMR and IR spectra are consistent with the structure

Example 9

C. 03 H 27 N 67 44, 20th 5, 24 3, 63 44, 5, 3,

Sodium 2β-chloromethyl-2a-methylpenam-3a-carboxylate sulfone

CgH _g ClNO_SNa (306) (289.67)

j To a stirred solution of 500 mg of compound BL-P2013 J (potassium salt) in 5 ml of H ₂ O and 10 ml of ethyl acetate are added 2 N! HCl until a pH 1 is reached (one works in an ice bath with vigorous stirring). The mixture is then saturated with Na ₃ SO ₄ , the aqueous layer is separated off, the organic layer is briefly dried in ice over Na ₃ SO ₄ , filtered and treated dropwise with 50% NaEH (sodium 2-ethylhexanoate) in anhydrous n-butanol until neutrality is achieved with moist pH paper. After scratching the product does not crystallize and is concentrated in vacuo to an oil, which is dissolved in 5 ml of acetone, after scratching no crystals result, ether is added up to the cloud point, there are still no crystals. It is concentrated in vacuo on a rotary evaporator to an oil, which is dissolved in ethyl acetate, one is given

1300B7 / OB09

-fr

M / 22 006

Drops of H-O close, scratches, and does not yet receive any crystals. The residue is then concentrated in vacuo and triturated with 5 ml n-butanol. 200 mg of amorphous white powder are obtained

in the air

washed with ether / and _{dried in vacuo for Ρ 2} ° ς ^ 4 hours. The final yield of sodium 2β-chloromethyl-2a-methylpenam-3a-carboxylate sulfone is 180 mg, decomp. J point> 100 ° not defined.

Analysis C ₀ H ₀ ClNO ₁ -SNa:

calculated: found:

C. 10 H 13th N , 89 ί H H 4th 2 33, 20th 3, 69 4th , 44 33, 3, 4th .04%

example

Potassium 2β-chloromethyl 1-2-methylpenam-3-carboxylate sulfone (BL-P2013)

To 10 L of water, 130 g (1.25 mol) of sodium hydrogen carbonate and 200 g of 10% Pd on BaSO ₄ are added 272 g (0.565 mol) of p-nitrobenzyl-6α-bromo-2β-chloromethyl-2-methylpenam-3-carboxylate sulfone, dissolved in 5 liters of ethyl acetate. The mixture is hydrogenated at 40 ^° C. and 1 kg of pressure. After 5 hours, the uptake of hydrogen becomes very slow and 200 g of 10% Pd on BaSO are added and the mixture is hydrogenated until no more noticeable hydrogen absorption can be detected.

The slurry is filtered through a diatomaceous earth ("Celite") pad, the pad is washed with water and the aqueous phase is washed with 3 liters of ethyl acetate. To the aqueous solution is added 3 liters of ethyl acetate and the pH of the mixture with 150 ml 12 N HCl at 10 ⁰ C on a 1.5. The organic phase is separated off, the aqueous solution is saturated with Na ₂ SO ₄ MO H ₃ O and extracted with 2 χ 1 liters of ethyl acetate. The combined extracts are dried with magnesium sulfate. You remove that

130Q67 / 0B09

M / 22 006

Desiccant and gives at 0 C 260 ml of 2N potassium-2-ethylhexanecarboxylic acid in butanol too.

After stirring for 2 hours at 0 C, the potassium 2ß-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) obtained and dried under vacuum at room temperature. Yield: 134.8 g (about 70%).

example

p-Nitrobenzyl-Ga-bromopenicillanate sulfoxide

(296)

TEA + (101)

BrCH ₂

(216)

CO ₂ CH ₂ -

Procedure:

44 g (0.148 mol) of ect-bromopenicillanic acid sulfoxide and then 20.5 ml (0.148 mol) of triethylamine and 38.2 g (0.177 mol) of p-nitrobenzyl bromide are added to 200 ml of Ν, Ν-dimethylacetamide. The mixture is stirred at 22 ^° C. for 20 hours.

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The reaction mixture is poured into 1 liter of H 2 O and extracted in 3 300 ml of methylene chloride. The combined methylene chloride extracts are washed with 200 ml of 5% aqueous:. 'Sodium bicarbonate solution and dry at 5 half an hour over sodium sulfate. The solution is filtered and concentrated
in vacuo to a residue. Diluted the residue

if ether is used, the solid is recovered by filtration, with a yield of 54 g of p-nitrobenzyl-6a-bromopenicillanate sulfoxide after drying receives. Yield: 85%.

The NMR is consistent with the structure.

The yield in this stage corresponds to that in
K-SaIz is achieved by esterification. The advantage is that it was not necessary to prepare the K salt (a stage which gives 85 to 90% yield).

Example 12;

Production of p-nitrobenzyl-öa-bromopenicillanate sulfoxide

To 4.375 liters of N, N-dimethylacetamide are added 873.0 g (2.95 mol)
6a-bromopenicillanic acid (S) sulfoxide and then with stirring,
keeping the internal temperature below 35 ^° C., 293 g (2.95 mol). Triethylamine followed by 764 g (3.54 moles) of p-nitrobenzyl bromide.
Then the mixture is stirred for 5 hours at room temperature and
lets stand overnight.

The reaction mixture is poured into 20 liters of water and
extracted with 3x7 liters of methylene chloride. The combined organic extracts are mixed with 5 × 7 liters of water and then with 7 liters of 5% strength aqueous sodium bicarbonate solution
washed and dried over anhydrous magnesium sulfate.

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The magnesium sulfate is filtered off and the solution is then concentrated to a crystalline residue; 4 liters of diethyl ether are added and then the crystals are removed, after drying at room temperature 1171 g (92%) of p-nitrobenzyl-6abromopenicillanate sulfoxide receives.

Br 18.48% (calculated 18.53%),
a _D (0.25% MeOH) + 162 °.

Example 13

Preparation of p-nitrobenzyl-6a-bromo-2ß-chloromethyl-2-j methylpenam-3-carboxylate sulfone

364.6 g (0.812 mol) of p-nitrobenzyl-6a-bromo-2ß-chloromethyl-2-methylpenam-3-carboxylate are added to 16 liters of acetic acid. A solution of 282 g is added dropwise over 3 hours to the solution thus obtained, which is stirred at room temperature (1.78 moles) KMnO. in 26 liters of water. The mixture is then stirred for 1 hour at room temperature and HO " (37%) until a colorless solution is obtained. Then 30 liters of water are added, the mixture is stirred for 1 hour at room temperature, collects the crystalline precipitate, washes with 3x5 liters of water and 2x2 liters of ethanol and dries in vacuo at room temperature.

Yield: 297 g (76 %)

a _D (0.5% CH ₂ Cl ₂ ) + 75.9 °.

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Example 14

Production of BL-P2013 free acid

CÖi "E ₁ PO,

H-

800 mg (0.00261 mol) of compound BL-P2013 in the form of the potassium salt are added to a mixture of 25 ml of ethyl acetate and 10 ml of water. After all of the solid has dissolved, the mixture is treated dropwise with 50% aqueous phosphoric acid, shaking vigorously until no more material precipitates from the aqueous layer. The ethyl acetate layer is separated off, then washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent is removed by filtration and washed with 10 ml of ethyl acetate. (The washing liquid is combined with the original filtrate). Then "Skellysolve B" is added to the ethyl acetate up to the cloud point (approx. 10 ml). The mixture is treated with 500 mg of activated charcoal ("Darko KB") and filtered. The filtrate is diluted with 15 ml of "Skellysolve B" and then inoculated with crystals of the free acid from BL-P2013. After about 3 hours at room temperature, the crystalline precipitate of the free acid is collected and dried (15 min) in vacuo over P ₉ O, 323 mg (46%) being obtained.

ο Fp. slow decomposition over 100.

Analysis C ₀ H _1n ClNO-S:

calculated:
found:

This product was found to be unstable after 7 days of storage at 23 ° C.

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C. 89 H , 77 N , 23 Cl , 25 35, 88 3 , 91 5 , 41 13th , 52 35, 3 5 13th

M / 22 006

- Type -

example

6a-Brompenici uric acid sulfoxide

MG 800-64

MG 296.14

300 g (0.75 mol) of öa-Brc ·; - penielllansäure-NjN'-dibenzyl-ethylenediamine salt and cools them Suspension on 5. Then you add for 15 minutes vigorous stirring dropwise 130 ml conc. HCl too. Afterward The slurry is stirred for 2 hours at 5 °, then filtered over a ("Gelite") cushion of diatomaceous earth and washes the filter cake with 3 × 250 ml of methylene chloride.

The combined methylene chloride solutions are washed with 2 × 500 ml of H 2 O and dried over sodium sulfate for 15 minutes. The sodium sulfate is removed by filtration. The filtrate concentrated to about 750 ml under reduced pressure.

This solution is cooled to 5 and, while stirring vigorously, 130 KiI of 40% peracetic acid are added dropwise so that the | Temperature is maintained at 5 to 12 °. The addition is exothermic. After the addition is complete, stir the slurry! 2 hours at 5 ° and the product is removed by filtration, washing with 100 ml of cold H-O (5 °) and 100 ml of cold methylene chloride {5 °). 126 g (57%) of Ga-bromopenicillanic acid sulfoxide are obtained, Mp 129 °.

The IR and NMR spectra are consistent with the one desired Product.

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Analysis of CqH ₁

calculated: found:

Potassium öa-bromopenicillanate sulfoxide

C. , 44 H 40 N 73 \ H ₂ O I. 2, 32 , 30 3, 35 4, 71 32 3, 4,

<f

MG 334.2 *

126 g (0.43 mol) of ea-bromopenicillanic acid sulfoxide and 162 ml of 50% strength by weight potassium 2-ethylhexanecarboxylic acid in n-butanol are added to 3 liters of acetone. After stirring for 1 hour at 22, the product is recovered by filtration,
washed with 2 × 250 ml of acetone and dried. 127 g (90%) of potassium δa-bromo-penicillanate sulfoxide are obtained, melting point 185

The IR and NMR spectra are consistent with the desired structure.

Analysis of CgH ₉ BrKNO ₄ S:

calculated: found:

C. 7-5 H 71 N 19th 28, 03 2, 78 4, 04 29 2, 4,

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p-nitrobenzyl-öa-bromopenicillanate sulfoxide

CCU C

MG 43I.28

To 1 liter of Ν, Ν-dimethylacetamide are added 145 g (0.43 mol) Potassium ea-brompenicillanate sulfoxide and then sets Stirring at 22 ° 115 g (0.53 mol) of p-nitrobenzyl bromide. The mixture is stirred at 22 ° for 20 hours.

The reaction mixture is poured into 3 liters of HO and extracted with 3 × 1500 ml of ethyl acetate, the combined ethyl acetate extracts were washed with 2 × 500 ml of 5% aqueous sodium bicarbonate solution and dry over sodium sulfate for 1/2 hour. The sodium sulfate is filtered off and the filtrate is concentrated at ver-j reduced pressure to a residue to which 1 liter of diethyl ether is added so that the product crystallizes. The crystals are obtained by filtration, washed with 2 × 100 ml of diethyl ether and dried, 162 g (87%) p-Nitrobenzyl-ea-bromopenicillanate sulfoxide is obtained, m.p. 111

The IR and NMR spectra are consistent with the desired structure.

Analysis C.

calculated: found:

C. 78 H 51 N 50 1 H ₃ O 41, 66 3, 45 6, 85 41, 3, 6, 0.6

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p-Nitrobenzyl-öa-bromo ^ ß-chloromethyl ^ -methylpenam-3-carboxylate

Mg ^ 9-71

To 1 liter of p-dioxane are added 70 g (0.16 mol) of p-nitrobenzyl-6a-bromopenicillanate sulfoxide, followed by 21.2 ml (0.10 mol) of benzoyl chloride and 21.8 ml (0.19 mol) Quinoline. The reaction mixture is refluxed for 4 hours, then cooled to 22 °, poured into 2500 ml of HO and extracted with 3 × 800 ml of ethyl acetate. The combined ethyl acetate extracts are washed with 300 ml of 5% aqueous sodium bicarbonate solution, 300 ml of 5% aqueous phosphoric acid and 300 ml of H ₂ O. The ethyl acetate solution is dried over sodium sulfate for 1/2 hour and the sodium sulfate is removed by filtration. The filtrate is evaporated under reduced pressure to a residue which is redissolved in 1 liter of ethyl acetate and concentrated again under reduced pressure to a residue. 1 liter of diethyl ether is then added and the product is recovered by filtration, 41 g (57%) of p-nitrobenzyl-6a-bromo-2ß-chloromethyl-2-methylpenam-3-carboxylate being obtained, melting point 132.

The IR and NMR spectra are consistent with the desired structure.

Analysis C. calculated: found:

C. 06 H 14th N 23 40, 62 3, 11 6, 13th 40, 3, 6,

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I p-Nitrobenzyl-öa-bromo ^ ß-chlorinethyl - ^ - methylpenam-S-i carboxylate sulfoxide

Zn "J2G0 ml of methylene chloride is one 51 g (0.11 mol) of p-iiItxobenzyl-6a-bromo-2ß-chloro-2-methyl-3-jnethylpenam earJboxylat and then 23 g (0.12 mol) of m-chloroperoxybenzoic acid. The mixture is stirred the solution obtained for 2 hours at 22 ° and concentrated under reduced pressure to a wet residue. This then stirred for 1 hour with 4 liters of diethyl ether and then allowed for 20 hours at 10 ⁰ C are. the product crystallizes out, 'vxrd by filtration, Washed with 2 × 200 ml of diethyl ether and dried, 39 g of p-nitrobenzyl-6a ~ broiK ~ 2ß-chloromethyl-2-raethylpenam-3-carboxylate sulfoxide (75%) being obtained, melting point 132 °.

The IR and NMR spectra are consistent with the desired one Structure.

Analysis C ₁ , - H ₁₄ BrClN ₃ O ₆ S: C. 69 H 03 N 07% H ₂ O 38, 98 3, 04 6, 84% calculated: 38, 3, 5, 0.35% found:

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-JfS -

Potassium 2β-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013)

BL-P2O13 MG 305-77

8 g of 30% Pd on "Celite" and 16 g (0.19 mol) of sodium bicarbonate are added to 600 ml of HaO. 32 g (0.69 mol) of p-nitrobenzyl-ea-bromo-β-chloromethyl-methylpenam-carboxylate sulfoxide are then dissolved in 400 ml of ethyl acetate and added to the aqueous slurry. The mixture is hydrogenated on a Parr hydrogenator for 4 hours at 22 ° and 3.445 bar (50 psi). The slurry is filtered through a thin "Celite" pad on a sintered glass funnel, the pad is washed with 2 × 50 ml of H ₃ O and separates the aqueous layer of the combined filtrates and washing liquids. The aqueous layer is washed with 200 ml of diethyl ether, then cooled to 5 ° and a solution of 12 g (0.076 mol) of KMnO is added dropwise with stirring. in 200 ml of H ₃ O for half an hour, the pH being kept between 7.5 and 8.0 _{by adding 40% H 3} PO _4. If the pink color persists for 5 minutes, do not add any more KMnO ^ solution. One stir; the reaction mixture with a small amount (about 50 mg) of sodium bisulfite for half an hour and then filtered the slurry through a "Celite" pad. This is washed with 2 × 50 ml H_O. The combined filtrates and washing liquids are coated with 500 ml of ethyl acetate and the pH is adjusted to 1.5 with stirring by adding 2N HCl. Separate the layers and saturate the aqueous layer with sodium sulfate. It is then extracted again with 2 × 400 ml

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Ethyl acetate and dry the combined ethyl acetate extracts for half an hour at 5 ° over sodium sulfate. Man removed the sodium sulfate by filtering off and the filtrate is concentrated

to a residue under reduced pressure. This is dissolved in 160 ml of acetone and 160 ml of diethyl ether and 50% by weight Add potassium 2-ethylhexanoate in n-butanol until the solution is at moist pH paper remains neutral. The potassium salt of the compound BL-P2013 crystallizes out and is filtered off collected, washed with diethyl ether and dried. The yield is 16 g of potassium 2β-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) (76%), m.p. 202 °.

The IR and NMR spectra are consistent with the desired structure.

Analysis of CgH ClKNO ₅ S:

calculated: found:

Example 16

Pivaloyloxymethyl ^ ß-chloromethyl ^ -methylpenam-S-carboxylate sulfone (B1-P2024)

C. 42 H 97 N 58% H 2 ° 31, 18th 2, 98 4, 51 31, 2, 4, O , 93%.

j
ι L. O C αΟΠλΟΙ 0 0 '' r, H ₂ Cl
CH ₃ ί U CO ₂ CH ₂ OCOC (CH-) ^J BL-P2O24
MG 38I.83

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4 ml of 10% strength are added to a stirred suspension of 14.6 g (0.0487 mol) of potassium j 2β-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) j in 200 ml of acetone aqueous | Natriumjodidlosung and the mixture is heated on a steam \ bad reflux. To this refluxed suspension
14.8 ml (0.1 mol) of redistilled chloromethyl pivalate (boiling point 34 ° C. at 7 mm Hg) are added, all at once.
The mixture is stirred under reflux for three hours and then cooled
to room temperature (22 ⁰ C). The crystalline solids ^: are collected by filtration, washed with 3 × 30 ml of acetone and the combined filtrates are reduced with reduced ^! Pressure concentrated to an oil at <22 ° C. Then you take that. oil in 500 ml of ethyl acetate, washed once with water (200 ml) and once with saturated Na_SO solution (200 ml). One dries
then briefly pour the solution over Na SO., while cooling with! Stir 2 g of decolorizing charcoal (ice bath). After 20 minutes filtered: the mixture is filtered through a "Celite" pillow and the pillow is then washed with 4 × 100 ml of ethyl acetate. The United ; Filtrates are concentrated to an oil at reduced pressure at 22 ^{° C.} This oil is then concentrated further at about 22 ° C. and <1 mm Hg i (1.3332 mbar) in order to remove most of the remaining chloromethyl pivalate. The remaining oil is then triturated twice with 50 ml portions of n-pentane and then left in at about 10 ^° C. over the weekend
n-pentane. The resulting solid crystalline mass

is then with 40 ml of a 4: 1 mixture of diethyl ether and

to a powder,,,

n-petan / broken. The product is then filtered

collected, washed with diethyl ether / n-pentane (1: 1) and on
air dried. After 4 hours in a high vacuum
has dried over P ₂ O 5 is then obtained 13.37 g of pivaloyloxymethyl 2ß-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-p2024), about (75%), mp 93-95 ⁰ C..

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Cleaning the BL-P2024 connection

About 3 g of crude compound BL-P2024, which was obtained as described above, is dissolved in 5 ml of ethyl acetate, placed on a 4.5 × 40 cm silica gel column (Mallinckrodt CC-7) and eluted with 4: 1 vol / vol CH ^ Cl ^ ethyl acetate. The fractions which had a single spot at R _f 0.84 (TLC on silica gel plates with 4: 1 CH C ^ ethyl acetate, detection) are combined and concentrated under reduced pressure to give 1.38 g of a crystalline solid. Part of this material (900 mg) is dissolved in 5 ml of ethyl acetate; the resulting solution is filtered, diluted almost to the cloud point with petroleum ether ("Skeliysolve B") and then stored for 3 days at room temperature. The crystals that formed were filtered off, washed with petroleum ether and dried to give 560 mg, pp. 100-101 °, of purified compound BL-P2024.

Analysis C ₁ -H ₀

calculated:
found:

ι ο

! All temperatures in this application: are given in C.

C. 03 H 27 N , 67 44, 11 5, 08 3 , 85 44, 5, 3

Example 17 Preparation of the ammonium salt of the compound BL-P2013

1) The free acid of the compound BL-P2013 (250 mg) dissolved in 20 ml of acetone / methanol (1: 1 by volume) is filtered in order to obtain a clear solution.

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2) Prepare an anhydrous ammonium solution by

1 ml of ammonium hydroxide (30%, pa quality) is added to 10 ml of acetone / methanol (1: 1 vol) solvent and then 1 g of anhydrous magnesium sulfate is added to the solution with gentle stirring. The mixture is then filtered through a filter paper; the filtrate is referred to as "anhydrous ammonium solution ¹¹ ".

3) The filtrate from stage 1 is gradually added about

2 ml of "anhydrous ammonium solution" and mix well.

4) 100 ml of diethyl ether are mixed with the mixture from step whereby the ammonium salt of the compound BL-P2013 precipitates.

5) The white ammonium salt is isolated from the solvent • and washed with 2 50 ml portions of diethyl ether.

6) The isolated powder is dried overnight at 35 ^° C. in a vacuum oven.

7) the analysis values are as follows:

Calculated:
found:

Microscopic examination: crystalline substance.

C. 7th H 6th N 8th % dry 33, 66 4, 63 9, 12; after theatrical version 33, 4, 10,

130067/0509

Example 18

Preparation of the non-hygroscopic sodium salt of the compound BL-P2013

j 1) 50 mg of the free acid of the compound BL-P2013 are dissolved in 4

(ml of an acetone-methanol mixture (1: 1 vol. I, filtered

and get a clear solution.

2) A sodium 2-ethylhexanoate solution is prepared, by placing 40 mg of sodium 2-ethylhexanoate in a 10 ml Acetone-methanol mixture (1: 1, vol.) Dissolves.

3) Add the '! 0 ml solution from j

ί Level 2 and stir thoroughly.

4) Mix 10 ml of diethyl ether with the mixture from stage 3, whereby the sodium salt of the compound BL-P2013 precipitates.

j 5) The white salt is left covered by the diethyl ether j for 1 to 2 hours, then isolated from the solvent and ! washed with three portions of 5 ml of diethyl ether each.

6) The isolated powder is ^{dried at 30 °} C. in a vacuum oven overnight.

130067 / OS09

M / 22 006

Example 19

Recrystallization of compound BL-P2013

JN \,

CH ₂ Cl recryst. OH,

'CO ₂ KH ₂ O

A minimum amount of 400 mg of compound BL-P2013 is dissolved Acetone -H_O (1: 1, VolI), diluted with 10 ml acetone, filtered, then diluted again with acetone to about 25 ml, scratched, and got the crystalline hydrate through after 30 minutes Filter off, wash thoroughly with acetone, dry on the air and then in a vacuum at <1.3332 mbar (<1 mm Hg) over night.

The yield is about 280 mg.

Analysis C ₀ H ₀ ClNOSK-H ₀ O:

calculated: found:

C. , 67 H 39 N , 63 Cl , 94 H 2 ° 29 , 32 3, 32 4th , 44 10 , 31 5 , 55 29 3, 4th 11 5 , 90

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M / 22 006

Example 20

N, N ¹ -dibenzylethylenediamine salt of compound BL-P2013

BL-P2013 + 1/2 Ν, Ν'-dibenzylethylenediamine diacetate

Omkrist.

Acetone ether

306 mg (0.001 mol) of compound BI.-P2013 are dissolved in 7 ml of HO and added to a solution of 180 mg (0.0005 mol) of N, N ¹ -dibenzylethylenediamine diacetate in 7 ml of HO. The mixture is stirred, the salt crystallizes, and after stirring for about 10 to 15 minutes, the salt is filtered off and air-dried to give 300 mg of the N, N'-dibenzylethylenediamine salt of the compound BL-P2013. The material is recrystallized by dissolving it in about 10 ml of boiling acetone and diluting with ether to the cloud point. 260 mg of air- and vacuum-dried material are obtained.

Analysis: C. 69 H 42 N 53 Cl 55% H ₂ O (KF) 51, 39 5, 49 7, 05 9, 96% calculated ί. 49, 5, 7, 8th, 1 , 23% found:

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M / 22 006 - ^ T- 01010-7

Example 21

Chloromethyl ester of the compound BL-P2013

+ ClCH ₂ -O-SO ₂ Cl

+ 3 KHCO ₃

To a vigorously stirred mixture of 15.25 g (0.05 mol): compound BL-P2013 (5), 15 g (0.15 mol) KHCO and 1.7 gj (0.005 mol) tetrabutylammonium hydrogen sulfate (Aldrich Chem. Co. )! in a mixture of 50 ml of water and 50 ml of CH ₂ Cl ₂ are added; dropwise a solution of 9.5 g (0.0575 mol) ClCH ₂ -O-SO ₂ Cl in 40 ml CH ₂ Cl ₂ - The temperature rises to 26 ⁰ C and after the addition (which takes about 15 minutes) the mixture is stirred the mixture for another 30 minutes. Since the product crystallizes out, more CH ₂ Cl ₂ (approx. 400 ml) is added in order to obtain a solution. The separated CH ₂ C1 ₂ layer and 50 ml of CH ₂ Cl ₂ washing liquid are combined, with stirring over MgSO ₄

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dried and 2g decolorizing carbon ("Darko KB") are added. After about 30 minutes, the mixture is filtered off, concentrated to about 50 ml and 150 ml of isopropyl alcohol are added to- The remaining CH-Cl is then removed under reduced pressure. The crystalline precipitate obtained is through Filtration recovered, washed well with isopropyl alcohol, and air dried. After vacuum drying at less than 1.3332 mbar (1 mm Hg), 8.5 g of chloromethyl-2β-chloromethyl-2-methylpenam-3-carboxylate sulfone are obtained (7 ^) M.p. 116 ° (dec

Analysis C ₉ H ₁₁ Cl

calculated: found:

approx above 8th H 100 C. N dark) • , 43 H % 0 2 ° (Theatrical Version) C. 6th 3, 4th Cl , 46 34 ,1 3, 51 4th , 43 22nd , 33 % 34 ,1 45 , 47 22nd

Estimated purity in the range of 90 to 95%.

Iodomethyl ester of the compound BL-P2013

CH ₂ Cl

C-OCH ₂ Cl

Well

To a stirred mixture of 5 g (0.0159 mol) of the chloromethyl ester of BL-P2013 (2) in 25 ml of acetone is added 3 g (0.02 mol) of sodium iodide. The resulting slurry is stirred for 17 hours and then cooled to about 0.degree. Two drops of saturated aqueous KHCO ₃ are added and the mixture is slowly diluted dropwise over 10 minutes with water until 50 ml have been added. The slurry is subject to one

130067 / OB09

M / 22 006

- yr-

rapid color change from yellow to gray to purple to black, that's why! the crystals are immediately filtered off and washed with cold j acetone-water (1: 2) and then with isopropyl alcohol (3 χ 10 ml), j then with diethyl ether and finally with n-pentane
and air dried, giving 5.55 g (91% yield)
of the iodomethyl ester of the compound BL-P2013 {8) .
Mp. 118-119 ⁰ C, dec.

Estimated purity about 90%.

6 - [(R) -2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-; thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl-2ß-chloromethyl-2a-methylpenam-3a-carboxylate-sulfone (11)

CH-CO-NH »

T T

N L

CH,

'"CH,

COOK

(A Dane salt of amnicillin; see U.S. Patent 3,316,2 ^ 7)

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C-C

Il

CH CO -

, N

OCH,

10

O

CH CO -NH

NH,

11 O O

Γ ³ I.

Il

130067/0509

M / 22 006 & f

To a stirred mixture, which is cooled in an ice bath, of 5.46 g (0.01 mol) of the indicated Dane salt of the ampicillin compound JJ (which is solvated with 1 molecule of isopropyl alcohol) in 60 μl of acetone is added 4.08 g (0.01 mol) of the methyl iodide ester of the compound BL-P2013 (8) and stir the almost clear solution obtained for five hours, the ice bath being removed after 30 minutes. Most of the acetone is removed in vacuo on a rotary evaporator and the concentrated solution obtained is then dissolved in 200 ml of cold ethyl acetate, which is then washed with 2 50 ml of ice-cold water and 2 100 ml of saturated aqueous Na ₃ SO ₄ . The ethyl acetate solution obtained is then dried over Na ₃ SO ₄ , filtered and most of the ethyl acetate is removed in vacuo on a rotary evaporator. The residue is triturated with 2 × 200 ml of dry diethyl ether and the solids obtained are filtered off, 5.5 g of compound JjO being obtained in the form of a slightly pink powder. This powder is then stirred in a mixture of 50 ml of water, 50 ml of n-butanol and 20 ml of ethyl acetate, 6N HCl being added dropwise to pH 2.5. One or two drops of HCl are then occasionally added to maintain the pH at 2.2-2.5 for 45 minutes. When the pH no longer increases, 100 ml of diethyl ether are added to this mixture, while stirring vigorously. The aqueous phase is separated off and combined with a second 25 ml H ₂ O extract from the organic layer. The aqueous solution is extracted once with 50 ml of diethyl ether and the ether is discarded.

The aqueous layer is then vigorously stirred under a 100 ml layer of 2-butanone (methyl ethyl ketone) while Na ₃ SO _{4 is} added to saturate the aqueous solution.

The 2-butanone layer is separated off, dried over Na ₃ SO _{4 for} 30 minutes in an ice bath, filtered and concentrated to almost dryness in vacuo. The skid oil is denoted with n [

> vl! / df / Jj ft J ^ * j

n-Butanol triturated to a solid, thoroughly with ether

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and then washed with n-pentane, _{dried in air and then in vacuo over P 2} ⁰ S ^ ^{ei a} pressure <1.3332 mbar (<1 mm Hg), 1.6 g of 6 - [(R) - 2-Amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicylco [3.2.0] heptane-2-carbonylmethyl ^ ß-chloromethyl ^ a-methylpenarii-Sa-carboxylate sulfone QjO in raw form.

The IR and NMR spectra are consistent with the structure of the compound _1_1_, but not in high purity. It will believed that this solid contained at least 40% and perhaps up to 80% 6 - [(R) -2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2. 0] -heptane-2-carbonyloxymethyl-2β-chloromethyl-2-α-methyl-penam-3a-carboxylate-sulfone contains.

example

22nd

Improved synthesis of BL-P2013

This process simplifies the production of the compound BL-P2013, since the previous catalytic reduction is no longer necessary.

step 1

COOH

+ CH ₂ CCl, + dicyclohexylcarbodiimld OH

Pyridln
CH ₂ Cl ₂

C-OCH ₂ CCl ₅

130067 / ^) 501

M / 22 006

(see page 633 "Cephalosporins and Penicillins" by Edwin H. Flynn, Academic Press, New York, 1972)

30 g (0.1 mol) of δ-bromopenicillanic acid sulfoxide (I) are dissolved in 1 liter of dry CH-Cl- and then 16.2 ml (0.2 mol) of pyridine and 29.8 g (0.2 mol ) Trichloroethanol too. Then was added 20 g (0.1 mol) of dicyclohexylcarbodiimide is added and the mixture stirred for 16 hours at 22 ⁰ C. dicyclohexylurea begins to precipitate and is ahfiltriert after completion of the reaction. The filtrate is washed with 200 ml of 5% aqueous sodium bicarbonate, 200 ml of 10% phosphoric acid and 100 ml of saturated aqueous sodium sulfate. The organic phase is dried for 30 minutes at 5 ^° C. over sodium sulfate, filtered and concentrated to an oil. Diethyl ether is added and, after scratching, the product 2 crystallizes out (27 g, 63% yield).

Level 2

Quinoline

O CH ₂ Cl

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Jl

26.5 g (0.062 mol) of compound 2 are dissolved in 500 ml of p-dioxane and 8.5 ml (0.078 mol) of benzoyl chloride and 8.75 ml (0.078 mol) of quinoline are added. The mixture is refluxed for four hours, then poured into 1100 ml of water and the product 3 is extracted into 2 × 400 ml of ethyl acetate. Combine the ethyl acetate extracts washed successively with 200 ml of 5% aqueous sodium bicarbonate, 200 ml of 5% phosphoric acid and 200 ml of saturated aqueous sodium sulfate, dried for 30 minutes at 5 ⁰ C over sodium sulfate and concentrated to an oil ( _3_), which is used in this form for the next implementation.

level 3

in glacial acetic acid

O O

C-OCH ₂ CCl ₅

The obtained compound 2 in the previous stage ^{to öst} l in 1 liter of glacial acetic acid and added, with stirring at 22 ⁰ C was added dropwise a saturated aqueous solution of KMnO. until a pink color persists (i.e. a drop on a piece of filter paper gives a pink color)

130087 / OBO »

30% Η_Ο ₂ dropwise with cooling; some white precipitate appears. The solution is poured into 2.5 l of water and the product is extracted in 3 × 500 ml of ethyl acetate. The ethyl acetate is washed with 5% aqueous sodium bicarbonate until neutral (ie no more bubbling occurs with further addition), dried over sodium sulfate and concentrated to give compound 4_ as the residue. It is measured at 10 ⁰ C for one day was allowed to stand and then treated with "Skellysolve B" to give 9.1 g of solid compound £ obtained. The yield is 28% of theory for stages 2 and 3 together.

Level 4

⁺ © Zn In glacial acetic acid
+ @KEH

£ (BL-P2O13) \

COOK

(see below patent 4,164,497)

3.75 g of zinc dust are suspended in 5 ml of glacial acetic acid and cooled to 5 ° C. A solution of 3 g (0.0057 mol) of compound 4 in 15 ml of dimethylformamide and stir the resulting slurry at 5 ° C. for 2.5 hours.

130087/0501

"/ 32 006 ^ T ₃₁₀

The zinc is then filtered off and the pale yellow solution is poured into 80 ml of 5% aqueous hydrochloric acid. This mixture is extracted with 3 × 25 ml of ethyl acetate. The combined ethyl acetate extracts are mixed with 3 × 20 ml 5% aqueous sodium bicarbonate extracted, the ethyl acetate phase being kept after separation.

The bicarbonate extracts are combined and coated with Ethyl acetate, adjusts the pH to 1.5 by adding 2N HCl and saturates with sodium sulfate. You separate that Ethyl acetate and extracted the aqueous phase with 2 × 30 ml of ethyl acetate.

All the ethyl acetate phases are combined, dried over sodium sulfate and concentrated to give an oil (which is the free acid of the compound BL-P2013), which in turn is dissolved in 20 ml of acetone, to which 20 ml of diethyl ether are added. Then 50% potassium ethyl hexanoate (KEH) in dry n-butanol is added until neutral. Compound f> (BL-P2013) crystallizes out. After stirring at 22 for 0.5 hours, it is collected by filtration to give 650 mg of compound 5 (37% yield).

A 50 mg sample of compound 5 is dissolved in 0.5 ml of water and 20 mg of N, N ¹ -dibenzylethylenediamine (DBED) diacetate are added. The DBED-Saiz of compound 5_ crystallizes out, is filtered off, washed with water and dried in vacuo over P ₂ ⁰ S dried to give N'-dibenzylethylenediamine-2ß-chloromethyl-2-methylpenam-3-carboxylate sulfone receives N, ( DBED salt of free acid 5).

Another sample of 450 mg of compound 5 is dissolved in 3 ml of water, to which a solution of 270 mg of DBED diacetate in 2 ml of H ₂ O is added. After scratching, the DBED salt of compound 5 crystallizes out (430 mg). Recrystallization from about 5 ml of boiling acetone gives 270 mg.

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IS

Example 23

6- [(R) ^ -amino - ^ - p-hydroxypheny! .Acetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl-2ß- chloromethyl-2-a-methylpenam-3a-carboxylate sulfone

the formula:

CH CO NH

N.

^{: H} 3

C = O

ο ο

is prepared by using the corresponding Dane salt of amoxicillin in the process of Example 21 instead of ampicillin used.

130067/0509

j NAOHOewaOHT M / 22 006 - JtT-

Biological values

The product from Example 1, compound 5 ^ of the formula

hereinafter referred to as BL-P2013.

Although this compound alone is a very weak antibacterial agent at best, BL-P2013 inhibits ß-lactamases and protects ceforanide and amoxicillin in vitro and in vivo against destruction by ß-lactamase-producing Bacteria when given in combination with these two other compounds.

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Table 1

Antibacterial effectiveness of the new sulfone

organism

MIC (. Y / ml)

BL-P2013

Ampicillin. S. pneumoniae

A-9585

16

0.004

5. Pyogenes

A-9604

63

0.004

aureus

A-9537

> 125

0.16

. aureus + 50% serum

A-9537

> 125

0.06

. aureus Penkies A-9606

> 125

> 12S

S. aureus meth-

Eles A15097

> 125

125

S. faecalis

A20688

> 125

0.13

coli

A15119

> 125

coli

A20341-J.

> 125

> 125

K. pneumoniae

Al5130

> 125

125

tia «

A20468

> 125

> 125

P. «irabilie

A-9900

> 125

0.13

vulgaris

A21559

> 125

125

rganii

Al5153

> 125

> 125

rettgeri

A21203

> 125

wurcescens

A20019

> 125

E. cloacae

A-9659

> 125

E. cloacae

A-9656

> 125

> 125

aeruginosa A-9843A

> 125

> 125

aeruginosa A21213

> 125

> 125

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T a b ~ e 1 "1 e 2

Antibacterial efficacy of ceforanide and amoxicillin alone and in combination with BL-P2013

Organism

Beta-lactamase

MIC t γ / ml)

Cefo- Ceforanxd __ _ Amoxicillin Amoxiranid + BL-P2013 frT, + BL-P2013 cillij (1: 1) ^ ⁰¹³ (1: 1)

B. fragilis

A21916

A22053

A22021

A2187!

A22534

A22697

A22693

A22694

A22695

A22696

A22533

A2253 £

A22792

A22793

A2279 ^

Α2279Ϊ

A22797

A2279

JB. thetaiotaomic- ron A2227

A2227

63 2_ > 125 2_ 8th 32 £ 63 2_ 8th 32 32 -? - 4th 32 £ 63 2_ 8th > 125 32. 125 16 > 125 63 63 2_ 8th 63 £ 63 2_ 16 125 16_ 63 2_ 16 > 125 YES 32 £ 125 > 125 _3JL 63 £ > 125 > 125 -3JL 32 32 > 125 > 125 32 125 ³ JL > 125 > 125 32 £ 125 32 £ 32 2_ 8th 32 £ 32 2 8th 63 £ 32 £ 16 63 £ 63 2_ 16 32 4th 63 2. 8th

125 125

63 63

2_ 4

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Table 2 - (continued)

Antibacterial efficacy of ceforanide and amoxicillin alone and in combination with BL-P2013

MIC I.

Organism

Beta lact amasi

Cefo-Ceforanide ranide + BL-P2013 dsl)

Amoxicillin Amoxi- + BL-P2013 cillin (lsi)

Bacteroides species

A2093

A2195 A2092! A2195 <A2093: A2093 ( A2093] A20927-] Α2093Ϊ

32 £ 32 63 £ 32 63 £ 32 63 16. 63 63 £ 1 63 125 125 63 £ 32 0.5 1 63 2 2 125

2 ^ 8th 2_ 16 2_ 16 2 ^ 16 4_ 8th £ 32 2_ 16 0.13 0.1 0.13 0.1

good synergism

little synergism

* MIC concentration determined using the agar dilution method. using 50-fold dilution of 24 hour cultures as inocula, dispensed with the Steer-Inoculator. The test medium consists of Brucella Agar plus 5% "laked" Sheep blood and 10 γ / ml vitamin K.

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so

Tabel

Therapeutic efficacy of amoxicillin in combination with BL-P2013 in mice experimentally with a B-lactamase strain are infected by Staphylococcus aureus

organism

Challenge

(Number of organisms)

Amoxicillin (A] IM PO

Treatment (mg / kg)

BL-P2013 (B) IN PO

A + B (1: 1) IM PO

S. aureus A-9606

5 χ 10 '5 χ 7 χ 10 ^l

> 800> 800> 800> 800> 800

>50> 200
>50> 200
> 50

6.3 19 9.6

Treatment plan: drug administered 0 and 2 hours after

the infection.

130067/0509

ο
ο »
ο

Table 4

Blood level of BL-P2013 and its pivaloyloxymethyl ester
(BL-P2024) after oral administration to mice

link dose
(rag / kg) Blood level (Hg / W
15 30 60 90 120 150
Minutes after administration Half
worth
Time
(min) Test-
organism BL-P2013 100
100
200 4.5 5.1 3.9 2.3 1.5 0.8
4.6 4.1 3 <2.6 <2.6 <2.6
7.4 9.8 7.1 4.1 2.8 <2.6 Ul ul
0 1 0 E. coil
A-9675
S. aureus
A-9606
S. aureus
A-9606 BL-P2024 100
100
200 12.8 12.9 9.7 7.2 5.5 4.2
13.1 12 8 5.7 3.8 <2.5
14.7 14.4 9.8 8.7 5.1 <2.5 70
60
60 E. coil
A-9675
S. aureue
A-9606
S. aureua
A-9606

The values are average values from 2 to 4 attempts.

CD-CD

Table 5

Blood levels and half-lives of BL-P2024 after oral administration different doses to mice

link dose
(mg / kg) 15th Blood levels
30 60
Minutes after 3. (Μg / ml)
90 120
administration 1.9 1. 3 150 .7 t 1/2
(min.) 25th 5. 9 6.2 6th 6th 4.7 3. 5 0 .3 40 BL-P2024 50 7th 7 9.5 9. 3 7.2 5. , 7 2 .6 60
I. 100 12th 3 12.2 9. 4th 8.7 5 ,1 4th , 5 85 200 14th 7 14.4 8th <2 60

BL-P2024 was suspended in Tween-CMC water.

The values are average values for 2 experiments at 25 and 50 mg / kg doses, 5 to Try for the 100 mg / kg dose and 2 to 3 attempts for the 200 mg / kg dose.

Test organisms: E. coli A9675 at all doses with the exception of the 200 mg / kg BL-P2024

(S. aureus A9606).

IT to

O O

CO CD

cn K)

;?O

Tabel

Therapeutic efficacy of amoxicillin in combination with BL-P2013 in the mice are experimentally infected with ß-lactamase producing strains of S. aureus and E. coli. g

organism Challenge ■ ·
(Sahl the
Organisms) 10 ⁸ PD ,. g / treatment (mg / kg) Amoxicillin: BL-P2Q13
4: 1 2: 1 ItI 44:22 33:33 5 1: 2 1: 4 BL-P
2013 S. aureus 7 χ 10 ⁹ Amoxicillin > 200:> 50 33:17 14:14 38:76 25: 100 > 200 A9606 2 χ 10 ⁸ > 200 78:39 44:44 10:20 > 200 S. aureus 4 χ 10 ⁸ > 800 132: 66 114: 57 100: 100 > 200 A15091 5 χ 10 ⁸ > 200 44:22 25:25 66: 132 > 200 S. aureua 6 χ 10 ⁸ > 800 174: 44 50:25 43:43 22:44 19:76 174 A20379 5 χ 10 ⁵ > 200 11: 5. 5 11:11 35:70 > 200 E. coli 5 χ 10 ⁵ > 200 25: 6.3 8: 4 6: 6 > 200 A20649 6 χ 10 ⁵ > 200 20: 5 6: 3 5: 5 10:20 63:25 > 200 E. coli 7 χ 10 ⁵ > 200 6: 1.5 6s3 6: 6 > 200 A21223 6 χ 10 ⁵ > 200 8: 2 7: 3. 4: 8 3.5: 14 ■ > 200 7 χ > 200 > 200 > 200

Tabel

(Port setting)

Challenge
(Number of .
Organisms) PD ₅₀ / treatment (if.gAg) 8: 2 6: 3 3: 3
10: 2.5 6: 3 7: 7
13: 3.3 6: 3 5: 5 1: 2 1: 4. BL-P
2013 Organ
mus 8 χ ΙΟ ⁵
7 st 10 ⁵
6 χ 10 ⁵ Amoxicillins BL-P2013
Amoxicillin 4: 1 2: 1 IiI 4: 8
2.5: 5
5:10 4:16 > 200
> 100
> 200 E. coil
A9675 "200
> 100
> 400

Treatment plan: The drugs were given orally 0 and 2 hours after infection administered.

The drugs were suspended in TCMC.

Cd »O O

Tabel

Therapeutic efficacy of ancodcillin In various combinations with the PivaloylOBcymethyl-Eater (BD-P2024) van BLr-P2013 in mice that were experimentally! are not infected β-tactamsaa-producing strains of S. aureus and E. coil.

I. organism Challenge
(Count e'er.
Organisms) Medicament PD ₅₀ / treatment (mg / kg) ^a AmoxT-
cillin Amoxicillint BL-P2024
4il 2: 1 lsi BL-P
2024 S S. aureua 5 χ 10 ⁸ medium- b
carrier > 800 66:33 57157 > 200 j Al5091 TCMC S. aureus 5 χ 10 ⁸ > 800 12: 6 9: 9 200 A20379
I.
I.
E. coil
A9675 9 χ 10 ⁵ TCMC > 100 12:12 6: 3 3: 3 > 25 E. coil
AJ675 7 χ 10 ⁵ 50%
DMSO > 100 10: 2.5 7: 3.5 4: 4 > 25 E. coil 7 χ 10 ⁵ 50%
DMSO > 100 8: 2 6: 3 5: 5 > 25 A9675 TCMC E. coil 6 χ 10 ⁵ > 400 9.2: 2.4 7: 3.5 7: 7 > 200 A9675 TCMC

^a Mice were treated orally at 0 and 2 hours after infection.

^b Amoxicillin: BL-P2024 combinations are soluble in 50% DMSO. Amoxicillin was soluble (aqueous Tween carboxymethyl cellulose), while BL-P2024 was administered as a suspension in vehicle.

ο ο σι

in TCMC this

cn
ο
«Ο

Table 8
Oral blood levels in the mouse of BL-P2036 and BL-2013 or BL-2024

dose
(mgAg) 15th Versuct 0.9
(0.6-1 <0.6 Ό 120 .5) <0 L50 .0) link 25th 1.7
(1.3-2.5) 1 1 , ² · ⁵
(1.2-5 (0.7-2. 7) <0.6 •1) <0 .6 BL-P2O36 50 2.8
(1.6-4.8) Blood levels
50 60
Minutes after 5.2
(2.4-4 2
(1.5-2. 0.8
(0.5-1 (0 .6 • 5) BL-P2O36 100 5.6
(2.6-4.9) 2.5
(2-2.6) 1.0
(0.8-1 <0.6 1) , ^{1> 5}
(1.1-2 Λ) <0 0.8
.7-1 • 2) BL-P2O36 25th IO
(1.1-1.6) 5.5
(2-5.5) 1.9
(1.4-2 1.5
(1.1-2. <0.6 .5) (0 .6 BL-P2013 50 2.2
(1.8-2.7) (2.9-5.I) 5.9
(5.4-4 5.6
(2.5-5) 1.1
(0.8-1 (1 0.8
.5-1 BL-P2013 100 5.4
(2.1-5Λ) 1.4
(1.2-1.6) 2.7
(1.7-4 2.1
.4-5 BL-P2013 2.6
(2.1-5.2) 4.5
(5.6-5.7) (Ύ / ml)
90
Verification • 5) • 5) - ² O • 2) .6) .6)

Connections made in Tween-CMC-H-O Values in brackets: 95% confidence limit of test organism: E. coli A9675 (pH = 6.6, 0.1% inoculum)

cn NJ

Attempt 2

link dose 15th Blood level
30 60
Minutes after Vera] 2.5
(0.9-5.8) γ / ml)
90
Poultice 120 150 BL-P2024 25th (2.6-5.5) 4.3
(3-6.2) 4.9
(2.4-9.8) 0.8
(0.4-1.8) <0.6 > 0.6 BL-P2024 50 5
(O.8-55.5) 4.5
(1.5-13.4) 7.8
(4.2-14.5) 3.6
(3.1-4.1) 2.6
(1.5-4.5) 1.7
(O.9-3.I) BL-P2024 100 8.5
(5.5-12.6) 9.5
(5.2-17.5) 2.1
(1.6-2.8) 4.8
(3.4-6.7) (2.2-6.8) 5.7
(2.8-5) BL-P2O56 25th 5.6
(2.2-5.9) 3.5
(2.2-4.7) 2.2
(1.4-5.7) 1.4
(0.7-2.8) 0.8
(0.4-1.7) <0.6 BL-P2O56 • 50 4.0
(3-5.3) 5.6
(1.4-9) 4.5
(3.4-5.9) 2.1
(I.3-3.6) 1.5
(Ο.6-5.6) 1.0
(0.5-2.4) BL-P2O56 100 4.9
(3.7-6.5) 6.5
(5.7-II.5) 2.8
(2.2-5.6) 1.9
(1-3.7) 1.5
(0.4-4)

Compounds made in 5% propylene glycol and Tween-CMC-HjO Values in brackets: 95% confidence limit Test organism: E.coil A9675 (pH = 6.6, =, 1% inoculum)

attachment dose
(mg / kg) 15 ·· Attempt 3 1.4
(0.9-2.1) I.
1.2
(0.6-2.3) 120 150 2 006 BL-P2O13 25th 1.4 '
(l.1-1.9) 3.6
(2-6.4) 3.1
(1.7-5.7) f
<1.2 <1.2 BL-P2O13 50 4.6
(3-6.9) Blood level (γΑ ¹ ^)
30 6o 90
Minutes after administration 6.4
(3.2-12.8) 4.2
(2.1-8.6) (0.8-5) 1.1
(0.8-1.5) BL-P2O13 100 6.8
(4.8-9.6) 2.0
(1.5-2.6) 3-5
(1.7-7.2) 2.5
(1.3-4.8) 3.3
(1.4-7.6) 2.5
(0.7-8.9) ft. m 900 BL-P2036 25th 4.3
(2.9-6.5) 5.5
(3-10.1) 3.5
(1.8-7) 2.2
(1.2-4) 2.2
(1-4.9) 2.0
(1-3.7) ^ tr * BL-P2036 50 4.6
(2.3-9.2) 11.5 _Λ
(7.3-18) 5-8
(3.9-8.5) 4.3
(3-6) 1.9
(1.2-3) 1.8
(0.3-4.6) ^ 5 BL-P2O36 100 7.1
(3.I-I6.2) 4.5
(2.2-9.2) Compounds are made in 5% propylene glycol and '
Values in brackets: 95% confidence limit
Test organism: E. coli A9675
(pH = 6.6, 0.1% inoculum). rween-CMC-l 4th
(2.8-5.6) 2.7
(1.8-4) 4.8
(3-3-7.1) I ₂ O. CJ
O
cn
ro
- • j 6.7
(3.6-12.3)

M / 22 006

When administered orally and parenterally, the compounds according to the invention are therefore valuable for improving the effectiveness of ß-lactam antibiotics against ß-lactamase-producing bacteria. Based on the weight, the dose is one fifth to five times, preferably it is the same, the amount of d _e s B-lactam antibiotic. For example, the compounds according to the invention, when administered in a ratio of 1: 1, markedly improve the activity of ceforanide and amoxicillin against β-lactamase-producing strains of anaerobic bacteroids such as B. fragilis, B. thetaiotaomicron and other species of this type, as well as to resistant Staphylococcus aureus. The compounds according to the invention are administered either as a mixture or simultaneously with the β-lactam antibiotic in a dose within the specified and customary dosage range of the antibiotic.

The property of the compounds according to the invention, the effectiveness of a ß-lactam antibiotic against certain Improving ß-lactamase-producing bacteria therefore makes them valuable when concomitantly with certain ß-lactam antibiotics in the treatment of bacterial infections in mammals, especially humans. For the treatment of bacterial infections, an inventive Compound with the ß-lactam antibiotic and the two active ingredients can thus be mixed at the same time administered. Alternatively, a compound according to the invention can also be used as an independent agent during the Treatment with a ß-lactam antibiotic may be administered.

13006770609

M / 22 006

If a compound according to the invention or one is used of their salts to improve the antibacterial effectiveness of a ß-lactam antibiotic, they can alone, or, preferably, formulated with conventional pharmaceutical carriers and diluents. One compound according to the invention, which is in the form of the acid or as a pharmaceutically acceptable salt thereof, can be administered orally or parenterally; an inventive Compound that is in the form of an ester readily hydrolyzable in vivo is best administered orally. Parenteral administrations are intramuscular, subcutaneous, intraperitoneal and intravenous administration.

If a compound according to the invention is used in the presence of a carrier or diluent, the Carrier or diluent selected depending on the intended mode of administration. For oral administration can the compound in the form of tablets, capsules, lozenges, troches, powders, as a syrup, elixir, aqueous solution or Suspension and the like can be used, as is common in pharmaceutical practice.

The proportional ratio of the active ingredients to the carrier depends of course on the chemical nature, solubility, The stability and effectiveness of the active ingredients as well as the intended dosage. This pharmaceutical However, agents typically contain from about 5% to about 80% carrier. When tablets are for oral use lactose, sodium citrate and salts of phosphoric acid are usually used as carriers. Various disintegrants, such as starch, and lubricants such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral use in capsule form are suitable diluents are lactose and high molecular weight polyethylene glycols. Are for oral use If aqueous suspensions are required, the active ingredients are combined with emulsifying and suspending agents. if desired

130067 ₄ / 050Ö

'Certain sweeteners and / or flavorings can be added. For parenteral administration, including intramuscular, Intraperitoneal, subcutaneous, and intravenous administration will usually be sterile solutions the active ingredients are produced and the pH value or the solutions are suitably adjusted and buffered. For intravenous Administration, the total concentration of the solute should be adjusted so that the preparation is isotonic.

While the prescribing physician will ultimately determine the dose to be used in humans, those are daily doses of a compound of the invention or one of its salts and the β-lactam antibiotic normally in the range of about 1: 5 to 5: 1, and preferably about 1: 1. Additionally is the daily oral dose each compound usually in the range of about 10 to about 200 mg. per kg of body weight and the daily parenteral The dose of each compound will normally be from about 10 to about 100 mg per kg of body weight. These numbers serve for explanation only and in some cases it may be necessary to use dosages outside this range.

The present invention can be used industrially.

130065 / ÖSO «

Claims (29)

Claims and the pharmaceutically acceptable salts or physiologicallyj hydrolyzable esters of this acid. j 2. The phenacyl, acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, 3-phthalidyl, 5-indanyl, methoxymethyl, benzoyloxymethyl, a-ethylbutyryloxymethyl-, propionyloxymethyl-, Valeryloxymethyl-, isobutyryloxymethyl-, 6 - [(R) -2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo ~ 4-thia-1-azabicyclo- [3.2.0] -heptane-2- carbonyloxy-methyl- or 6 - [(R) -2-amino-2-p-hydroxyphenylacetamido1-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethy 1- ^ Bster of the acid according to claim 1. 130067/0509 M / 22 006 3. 6- [(R) - ^ - Amino ^ -phenylacetamido] -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonyloxymethyl. 4. 6- [(R) ^ -amino - ^ - p-hydroxyphenylacetamido] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carbonylmethyl. 5. Esters of the formula: R-CH-CO-NH stands, wherein R ^{1 is} hydrogen or hydroxy and R ^{2 represents} hydrogen, hydroxy, methyl, methoxy or chlorine. 130067/0609 6. Process for the preparation of the compounds according to Claims 1 to 4, characterized in that one a) an ester of the formula X CH_C1 \ 1 CO ₂ R ¹ wherein R is benzyl or substituted benzyl, and then catalytically hydrogenated b) oxidizing the hydrogenated product to the desired acid or salt thereof, and if desired c) esterifying the acid or a salt thereof in order to obtain an easily hydrolyzable ester of the acid. 7. The method according to claim 6, characterized in that the hydrogenation is carried out with a palladium catalyst will. 8. The method according to claim 6, characterized in that the oxidation reaction with an alkali metal permanganate or an organic peracid. 9. Process for the preparation of the compounds of claims 1 to 4, characterized in that one 1300B7 / 0509 a) an ester of the formula oxidized with KMnO, ^H o ° 2 ^oc ^ ^er- like peroxides or peracids, an ester sulfoxide of the
Formula: C-OCH ₀ CCL 0 receives and then b) the ester sulfoxide with a metal in acid, such as | ι, for example, zinc in glacial acetic acid, where one | receives the desired acid or salt and j then if desired c) this acid or its salt esterified to a
easily hydrolyzable ester of this acid to be obtained. 130067/0509 M / 22 006 10. A process for the preparation of the compounds according to claim 5, i characterized in that a solution of a compound of the general formula: j R-CH R ³ ^ -C ₂ H RC 'C where R is or CO-NIL 0 '' 'CH, C- Il stands, C = O wherein 4th
R is hydrogen or hydroxy and R stands for hydrogen, hydroxy, methyl, methoxy or
Chlorine stands, and in what 130067/0508 ί Μ / 22 006 - 6 - R represents alkyl, aralkyl or aryl, R is hydrogen, alkyl, aralkyl or aryl R is alkyl, aralkyl, aryl, alkoxy, aralkoxy or aryloxy and rl, aralkyl, .R ⁴
or -N,. means, wherein 4 5
R and R are each hydrogen, alkyl, aralkyl or Mean aryl, or, together with the nitrogen atom to which they are attached, Mean piperidino or morpholino, with an acid in an organic solvent or in aqueous or partially aqueous solution at room temperature treated. 11. The method according to claim 10, characterized in that R ^{1 is} methyl, R ² Wa
Mean methyl. 12 3 R methyl, R hydrogen and R methoxy, ethoxy or 12. The method according to claim 10, characterized in that the reaction is carried out in acetone or chloroform. 13. The method according to claims 10 to 12, characterized in that that the reaction occurs at a pH between 1 and 5 is carried out. 14. Pharmaceutical agents to improve the effectiveness of ß-lactam antibiotics against ß-lactamase producing Bacteria containing the free acid or a pharmaceutically acceptable salt of a compound according to claim 1 in a conventional carrier or diluent. 130067/0509 M / 22 006 15. Antibacterial agent which acts as an active ingredient an ester according to any one of claims 2 to 5 contains. 16. Antibacterial agent which acts as an active ingredient the ß-lactamase-inhibiting free acid or a pharmaceutically acceptable salt of the acid according to claim 1 contains in a mixture with a ß-lactam antibiotic in the presence of a conventional carrier or diluent. 17. Means according to claim 16, characterized in that the ß-lactam antibiotic is ceforanide, ampicillin or amoxicillin. 18. Means according to claims 16 and 17, characterized in that that the ratio of the active ingredients is from about 1: 5 to 5: 1. 19. Means according to claims 16 and 17, characterized in that that the ratio of the active ingredients is about 1: 1. 20. Use of the free acid according to claim 1 or one of its pharmaceutically acceptable salts for improvement the effectiveness of ß-lactam antibiotics against ß-lactamase producing bacteria. 21. Use of an ester according to claims 2 to 5 to fight infectious diseases. 22. Use of the free acid according to claim 1 or one of its pharmaceutically acceptable salts in combination with a ß-lactam antibiotic to fight infectious diseases. 130067/0509 M / 22 006 23. Esters of the formula: , Cl "'CH -OR where R is benzyl or p-nitrobenzyl. 24. Esters of the formula: where R is benzyl, p-nitrobenzyl or ß, ß, ß-trichloroethyl stands. I. 25. Ester according to claim 24, wherein R is ß, β, β-trichloroethyl stands. 26. Esters of the formula: 130067/0509 M / 22 006 27. Process for the preparation of the compounds according to claim 23, characterized in that a compound of the general formula: wherein R represents benzyl or substituted benzyl, in an inert, anhydrous, organic solvent, in the presence of large, equimolar amounts of a weak tertiary amine and an acid chloride heated until the reaction is practically complete. 28. Process for the preparation of the compounds according to claims 24 and 25, characterized in that a solution of a compound of the general formula: Η egg wherein R is benzyl or substituted benzyl, in an inert solvent at about room temperature oxidized by using a peracid. 130087/0509 M / 22 006 29. A method for the preparation of the compounds according to claim 26, characterized in that a solution of a Compound of formula 3: CH ₂ Cl C-OCH ₂ CCiL in an inert solvent at about room temperature with the aid of an oxidizing agent such as KMnO., H2O ₂ or similar peroxides or a peracid. 130067/0509