FI63414C - REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC PRODUCT 7-CYLAMIDO-3-ACETOXIMETHYL-2- (ELLER 3 -) - CEFEM-4-CARBOXYL SYRA DEIVAT - Google Patents

Description

ΓβΙ ^ ANNOUNCEMENT cxa «λ J0Tä LBJ (11) utläggnincsskript 6341 4 • ^ 35 t * 5) Patent pushed 10 06 1983

Patent (sedcelat ”(51) Kv.lk.3 / lnt.CL3 e 07 D 501/08 (88) Kv.liak · - Int sitsgtr ·» FINLAND —FINLAND (21) Pstonttlh.k.mu.-Prtsnts.- ftknln, 810593 • (22) HtkemlspUv »- Ansöknlnpdsg 25.02.8l '* (13) Start Date — GlMghetsdsf qj q2 (H1) Become Public - Blivlt affentllg 05 no gl

Patent and Registration Board .... 5 * '\. (44) Date of publication and other publication. -

Petent- och regiaterstyrelaen AmMcm utisgd och utUkriftm pubiturto 28.02.83 (32) (33) (31) Requested privilege —ftefärd prloritet 08.02.74

United Kingdom-Storbritannien (GB) 05811/74 Proven-Styrkt (71) Gist-Brocades nv, Wateringseweg 1, Delft, United Kingdom-Nederlandema (NL) (72) Jan Verveij, Leiden, Hong Sheng Tan, Bleiswijk, Netherlands-Nederlän -derna (NL) (74) Berggren Oy Ab (54) Process for the preparation of therapeutically useful 7-acylamido-3-acetoxymethyl-2- (or 3 ~) -cephem-4-carboxylic acid derivatives - Förfarande för framställning av therapeutiskt användbara 7- -acylamido-3-acetoxymethyl-2- (or 3 -) - cephem-4-carboxylic acid derivatives (62) Separated from application 750346 - Avdelad frän trap 750a46 (5T) Abstract j) This invention relates to · a new process for the preparation of cephalosporan / derivatives » with common kaa-, ____ '8 "H., R2 emt -" 1 * "-“ l

* t - CH-CH 2 CH 2 C - N

II f / Xch-2 ^ K \ H ~ 0152 - o - C - CHj VIA C ^ ° CH2Br 0 5 ^ 0 ° 'OR3 wherein R1 and R3 are as defined above and R2O3 is one of the groups of general formulas j * »cl, Γη 1 I \ 1 R. R, 1 R. OR,? * and SII! · I 1 • ‘-f — r>. -roj! '? *! * tc 1 IL ^ Jn1 H. / 1 «5 I rs> - ^ ^ c-ch2-oc-ch3 vxb'O HA XIB HC 110 ^ is 3 _ in which formulas R4, Rs and Rfi are the same or different in different formulas and are each a hydrogen atom or lower alkyl or represent 66-acyl-lower alkenyl of a peniacillanic acid derivative. n is 2 or 3. and in that case, a substituent group and R 3 is lower alkyl, which may be a substituent of the formula HB is a phenyl group, may be substituted in this group by one or two phenyl groups, with 1 to 4 substituents being halogen, lower alkyl may be substituted by nitro, lower alkenyl and phenyl, are reacted with. with an alkali metal, ammonium or tetraalkylammonium acetate in an inert organic medium in the process of the invention at a temperature of general formula I between -20 and + 80 ° C. azetidine derivative 6341 4 (57) Saanadrae

Derived from the basic form of the compound form of the form of the formulation

* 1 - CH-CH CH

I I I

f -V., / J 3 v °

NjRj och ^ S \ R, - CH - CH CH,

II I

/: - V5 '“a _ °' S -“ iv “0 N 0 k ° ^ ORj varl R ^ b« tecnar en 66-acylamidogrupp av ett penlcil-lanayraderlvat, och Rj betecknar ligalkyl, vilken kan vara aubatltuerad mad 1 eller 2 phenyl group, the color of the phenyl group may be substituted by a nitro group.

I fbrfarandet anllgt uppfinnlngen omsittea ett azetldin-derivat med den allinanne formuleln I

Ϊ / C \ x "*" XR2

R 1 - CH-CH C

I I 8 I

, ° - «^ CH2 0 CH - I 0 ^ CH2Br ^ ORj

Varl Rj and R3 are selected from the group consisting of R1 and R3, and R2 is selected from the group consisting of all the formulas I

Γ -i) v I I

R4 l - f 1 Ra R6 I R4 9 Rfi, «I - c c J I4 I6 I I4 I I6 - · C - - I 'J, -C-N - I - C- C- N-

'-i c 1! I

_8sJn I ^ ^ I R5 I R5

I l I

IIA IIB lie IID

varl R4, R5 and R ^ Hr Ilka eller ollka ocardera betecknar vSte, ligalkyl eller ligalkenyl, n har vSr-det 2 eller 3, och 1 dat fall dir formal IIB betecknar phenyl, danna grupp kan innehilla 1-4 aubatituenter, beatienda av halogen, ligalkyl, ligalkenyl and phenyl, mad and alkali metal, ammonium or tetraalkylammonium acetate and inert, organic medium at -20 to + 80 ° C.

6341 4

Process for the preparation of therapeutically useful 7-acylamido-3-acetoxymethyl-2- (or 3 -) - cephem-4-carboxylic acid derivatives

The present invention relates to a new process for the preparation of 7-acylamido-3-acetoxymethyl-2- (or 3 -) - cephem-4-carboxylic acid derivatives, also known as Δ or Δ-cephalosporanic acid derivatives, using as starting materials the azetidine derivatives disclosed in Finnish in Patent Application No. 750346.

Methods are known for the preparation of cephalosporanic acid derivatives in which, for example, penicillin V is first converted to its deacetoxycephalosporin V methyl ester via its methyl ester sulfoxide. This ester is hydrolyzed and co-isomerized to give 2 Δ -deacetoxycephalosporin V, which is converted to its p-methoxybenzyl ester. This compound is converted, after bromination 2 3, to the 3'-acetoxy derivative obtained as a mixture of Δ and Δ compounds. By oxidation / reduction treatment, this mixture is converted into the desired Δ 2 -cephalosporin derivatives (J. Amer. Chem. Soc., 91, 5674 (1969)).

Methods for preparing cephalosporin derivatives in which cephalosporin is produced directly by fermentation are also known. An example of this is Cephalo-sporium sp. cultures to produce cephalosporin C, Merck Index, 9th ed. pp. 248, art. 1937.

The former method of starting synthetically to modify a penicillin compound has the disadvantage that many reaction steps are required to obtain a cephalosporan derivative. Another known method is disadvantageous in the sense that it is usually more economical! r »-j 2 6341 4 uses fermentation to obtain a penicillin compound and then proceeds synthetically to prepare a cephalosporan derivative by direct fermentation.

The object of the invention is to prepare cephalosporanic acid derivatives of the general formula

R 1 --CH -CH CH

I I II

C _ N C - CH, - 0 - C - CH, VIA

// \ H / 2 5 0 \ s °

C

OF

or3 or

Rx - CH-CH CH2

C - N C - CH, - O- C-CH, VIB

</ o 5 1 s

C

or in which R 1 represents an acylamido group and R 1 represents a lower alkyl optionally substituted by one or two phenyl groups, the phenyl groups being optionally substituted by a nitro group, and the invention is characterized in that the azetidine derivative of the general formula I 3 6341 4 o

II

/ C \ -N R0 ^ \ / *

R 1 --CH -CH x C

lii \ ^ CH2 O CH_ | . ° \ '^ xCH9Br or3 wherein R1 and R1 are as defined above and R3 is a group Ha or IIB having the general formulas -ΡΊ

, 4 -C 'C

| Il I -c c R5 ^ c / n _ ~ i

HA IIB

in which R 1 and R 2 are the same or different and are each hydrogen, methyl group or ethyl group, n is 2 or 3, is reacted with alkali metal, ammonium or tetraalkylammonium acetate in an inert, organic medium at a temperature between -20 and + 80 ° C.

Suitable solvents are, for example, acetone and dimethylformamide. In a few cases, it is preferable to add acetic acid to the reaction mixture.

- '? ·· ro 6341 4 2

Usually a mixture of Δ-3 93 and Δ-cephalosporanic acid derivatives of formula VIA 3a VIB is obtained. The Δ and Δ isomers can be obtained separately from the reaction mixture by chromatography on silica gel.

2

If desired, the Δ-cephalosporanic acid derivatives of the formula VIA can be modified by methods known per se.

O

corresponding Δ isomers of formula VIB.

Various cephalosporanic acid derivatives of formula VI, especially the Δ 2 -isomers of formula VIB, are known to have valuable therapeutic properties, especially in the treatment of infections caused by pathogenic bacteria resistant to other abbiotics. The process of the invention now provides a new and rapid way to prepare such a group of therapeutically interesting cephalosporin derivatives from readily available penicillan S (β) or R (a) sulfoxides via azetidine derivatives of formula I.

The following examples illustrate the present invention. Unless otherwise indicated, PMR spectra were determined on a "Varian A 60" using solutions in deuterochloroform containing tetramethylsilane as a reference. <$ values are expressed in parts per million (mo).

Example 1 A. To a solution of 1- (1-methoxycarbonyl-2-bromomethylprop-2-enyl) -3-phenylacetamido-4-marine succinimidothioazetidin-2-one (262 mg and 0.5 mmol) was added. In 1 ml of dimethylformamide, 120 mg (2 mmol) of acetic acid and 250 mg (2.5 mmol) of dry potassium acetate were added. After stirring for 1 hour at 25 ° C under nitrogen, the starting material was converted to a mixture of the two compounds using thin layer chromatography. The reaction mixture was then poured into a mixture of 150 ml of water and 50 ml of ethyl acetate. After separating the layers and extracting the aqueous layer twice with 50 mL portions of ethyl acetate, the combined organic layers were washed and treated with diethyl ether to give 125 mg (64%) of a mixture of methyl esters of Δ3- and A2-Bentylcephalosporanic acids.

PMR: A3 compound: 2.07 (s, 3); 3.25 and 3.61 (ABq, 2; J = 18.5 Hz); 3.65 (s, 2) *, 3.85 (s, 3)? 4.93 (d, 1; J = 4.5 Hz); 4.76 and 5.09 (ABq, 2; J = 13 Hz); 5.79 (dd, 1; J = 4.5 Hz and J = 8.5 Hz); about 6.40 (d, 1; J = 8.5 Hz); 7.32 (s, 5).

Compound A2: 2.07 (s, 3); 3.65 (s, 2); 3.80 (s, 3); 4.62 (s, 2); 4.99 (s, 1); 5.21 (d, 1; J = 4 Hz); 5.62 (dd, 1; J = 4 Hz and J = 8.5 Hz); about 6.40 (s, 2); 7.32 (s, 5).

B. The experiment described in A was repeated using 210 mg of sodium acetate instead of potassium acetate. Received? 3 Mixture of methyl esters of Δ-3a Δ-benzylcephaloporanoic acids.

C. The experiment described in A was repeated using 190 mg of ammonium acetate instead of potassium acetate. A mixture of methyl esters of 2 3 Δ-3a Δ-benzylcephalosporanic acids was obtained.

D. The experiment described in A was repeated using 135 mg of tetramethylammonium acetate instead of potassium acetate. -a ta. A mixture of methyl esters of Δ-Da Δ-benzylcephalosporanic acids was obtained.

6 6341 4

Example 2

To a solution of 1- (1-methoxycarbonyl-2-bromomethylprop-2-enyl) -3-phenylacetamido-4-succinic acid imidothioazetidin-2-one (2 gt 3.8 mmol) in dry acetone (50 mL ) under nitrogen, potassium acetate (2 g »20 mmol) was added and the mixture was boiled for 1 hour. Based on thin layer chromatography, the 3 2 reaction mixture contained a mixture of methyl esters of Δ- and Δ-benzylcephalosporanic acids. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. 8: 1 (v / v) methylene chloride / acetone / · 50 mg of A2-benzylcephalosporanic acid methyl ester were obtained. The structure was confirmed by PMR and IR spectroscopy.

Example 3

A mixture of 172 mg (0.3 mmol) of 1- (1-methoxycarbonyl-2-bromomethylprop-2-enyl) -3-phenylacetamido-4-phthalimidothioazetidin-2-one, 10 ml dimethylformamide, 170 mg (2.8 mmol) of acetic acid and 150 mg (1.5 mmol) of potassium acetate were stirred for 0.5 h under nitrogen at 25 ° C. After the reaction mixture was poured into a mixture of 30 ml of water and 15 ml of ethyl acetate, the layers were separated and the aqueous layer was extracted with additional ethyl acetate. After the combined organic layers were washed with water, dried and treated with charcoal, the ethyl acetate was evaporated and the residue was extracted with a mixture of benzene and ethyl acetate. This extract was chromatographed / silica gel? benzene / ethyl acetate 6: 1 (v / v 2.7) to give 3 20 mg (0.05 mmol? 17%) of Δ-benzylcephaloporine methyl ester and 30 mg (0.074 mmol? 25%) of A2-Bentylcephalosporin methyl ester. The structures were confirmed by PMR and IR spectroscopy.

7 63414

Example 4

To a solution of 150 g (1.5 mmol) of potassium acetate in 150 mg of acetic acid and 12 ml of dimethylformamide was added 1- (1-diphenylmethoxycarbonyl-2-bromomethylprop-2-enyl) -3-phenoxyacetamido-4-phthalic acid. imidothioazetidin-2-one (222 mg; 0.3 mmol). After stirring for 1.5 hours under nitrogen at room temperature, the reaction mixture was poured into a mixture of 100 ml of water and 100 ml of ethyl acetate. Concentration of the organic layer and evaporation of the solvent gave a crude mixture of diphenylmethyl esters of Δ- and Δ-phenoxymethylcephalosporanic acids by TLC. The sample was further separated by preparative TLC (3: 1 toluene / ethyl acetate).

PMR: A3 compound: 2.02 (s, 3); 3.45 (s, br, 2); 4.55 (s, 2}; 4.77 and 5.06 (ABq, 2; J = 12 Hz); 5.01 (d, 1; J = 4.5 Hz); 5.93 (dd, 1 J = 4.5 and 9 Hz), about 6.80-7.47 (m, 6), about 7.35 (s, 10).

PMR: Δ 2 compound: 1.95 (s, 3); 4.55 (s, 2); 4.57 (s, 2); 5.01 (s, 1); 5.25 (d, 1; J = 4 Hz); 5.70 (dd, 1; J = 4 and 9 Hz); 6.42 (s, br. 1); 6.78 - 7.54 (m, 6); 7.35 (s, 10).

Example 5 A. To a solution of 300 mg (3 mmol) of potassium acetate in 300 mg (4.8 mmol) of acetic acid and 25 mL of dimethylformamide was added 1- (1-p-nitrobenzyloxycarbonyl-2-bromomethylprop-2 -enyl) -3-phenoxyacetamido-4-phthalimidothioazetidin-2-one (426 mg; 0.6 mmol). After stirring for 2 hours under nitrogen at room temperature and allowing to stand overnight at 4 ° C, 75 ml of ethyl acetate were added. After filtration of the precipitated phthalimide, the filtrate was washed twice with 0.2 M aqueous sodium acetate solution 8 63414 and acetic acid buffered to pH 4.6, treated with charcoal, dried and concentrated in vacuo.

The residue was chromatographed on silica gel (benzene / acetone 95: 5 (v / v / v / v) to give 35 mg (0.065 mmol) of Δ-phenoxyacetamidocephalosporanic acid p-nitrobenzyl ester.

O

and 40 mg (0.075 mmol) of the corresponding Δ compound.

PMR: Compound A2: 2.03 (s, 3); 4.51 and 4.74 (ABq, 2; J = 13.5 Hz); 4.56 (s, 2); 5.13 (s, 1) ·, 5.28 (d, 1; J = 3.7 Hz); 5.31 (s, 2) ·, 5.56 (dd, 1; J = 3.7 and 9 Hz); 6.46 (s, 1); 6.78 - 7.47 (m, 5); 7.45 (<4.1; J = 9 Hz); 7.51 (d, 2) J = 8.5 Hz); 8.25 (d, 2; J = 8.5 Hz).

PMR: A3 compound: 2.09 (s, 3); 3.34 and 3.69 (ABq, 2; J 19 Hz); 4.58 (s, 2); 4.77 and 5.18 (ABq, 2; J = 13.5 Hz); 5.04 (d, 1; J = 4.8 Hz); 5.37 (s, 2); 5.94 (dd, 1; J = 4.8 Hz and 9.2 Hz); 6.82 - about 7.50 (m, 5); 7.23 (d, 1; J = 9.2 Hz); 7.59 (d, 2; J = 8.8 Hz); 8.24 (d, 2; J = 8.8 Hz).

B. The experiment described in A was repeated using different solvents instead of dimethylformamide. In a few cases, acetic acid was not added to the reaction mixture. In a few cases, the reaction was carried out at a higher temperature than that used in the reaction described in A. The various reaction conditions are shown in the table below.

6341 4

Solvent Acetic acid present Temperature

acetonitrile - 60 ° C

acetone - 60 ° C

dimethoxyethane - 60 ° C

methyl isobutyl-Λο „

ketone "60 C

hexamethylphosphorus + 25 ° C

happotriamidi

dimethyl sulfoxide + 25 ° C

dimethylacetamide + 25 ° C

2 3

In all cases, Δ- and Δ -phenoxyacetamidocephalosporanic acids were obtained from p-nitrobenzyl ester.

Claims (3)

10 6341 4 A process for the preparation of therapeutically useful 7-acylamido-3-acetoxymethyl-2- (or 3 -) - cephem-4-carboxylic acid derivatives of the general formula R, - CH - CH CH II II C - NC - CH , - 0 - C - CH, VIA H \ H / II 3 ° c OR3 or R, - CH-CH CH, II IC -NC - CH. - C - CH, VIB // C ^ 2 II 3 0 i ^ ° 0 C \ OR3 in which R1 represents an acylamido group and R3 represents lower alkyl optionally substituted by one or two phenyl groups, the phenyl groups being optionally substituted by an nitro group, characterized in that the azetidine derivative of the general formula I 6341 4 11 o II / c \ / SN R0 / \ / 2 R, - CH-CH x C II "III o C - N \ h -C ^ ™ 2 I N'Ss CH ~ Br OR3 wherein R 1 and R 2 are as defined above and R 1 is a group IIA or IIB having the general formulas R 1 C 1 I 4 -CC -c- I il i -cc R 5 n IIA IIB wherein R 1 and R 2 are the same or different and are each hydrogen, a methyl group or an ethyl group, n is 2 or 3, is reacted with an alkali metal, ammonium or tetraalkylammonium acetate in an inert organic medium at a temperature between -20 and + 80 ° C. Process according to Claim 1, characterized in that acetic acid is added to the reaction mixture. Process according to Claim 1 or 2, characterized in that the acetate is potassium acetate. 12 6341 4