CA1055485A - Process for preparing cephalosporins - Google Patents
Process for preparing cephalosporinsInfo
- Publication number
- CA1055485A CA1055485A CA227,388A CA227388A CA1055485A CA 1055485 A CA1055485 A CA 1055485A CA 227388 A CA227388 A CA 227388A CA 1055485 A CA1055485 A CA 1055485A
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- CA
- Canada
- Prior art keywords
- methyl
- compound
- inorganic
- group
- mononuclear
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
- C07D205/095—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Document Processing Apparatus (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A process is disclosed for preparing cephalosporins of structure:
III
where R is selected from the class consisting of hydrogen, alkyl having from 1 to 4 carbon atoms, cyano-methyl-, thienyl-methyl, furyl-methyl-, naphthyl-methyl, phenyl-methyl-, phenoxy-methyl-, phenyl-isopropyl-, phenoxy-isopropyl-, pyridyl-4-thiomethyl-, and tetrazolyl-1-methyl;
R1 is selected from the class consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, trichloroethoxy-, benzyloxy-, p-methoxy-benzyloxy-, p-nitrobenzyloxy-, benzhydryloxy-, benzyloxy-, phenylmethoxy-, phenacyloxy-, and p-halophen acyloxy;
Z is selected from the class consisting of hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl, -Br, -I, -N3, -NH2, -O-CO-CH3, -O-CO-nH2 and an -S-mononuclear nitrogen heterocyclic ring;
wherein a compound of structure:
(I') Abstract of the Disclosure continued:
is reacted in a suitable solvent at a temperature between -20°C
and +80°C, in the presence of an aqueous organic ox inorganic acid with an azoderivative of the formula: a where R2 and R3 are equal ox different and represent lower alkyl, a mononuclear aryl ring, CN-, a mononuclear heterocyclic ring, or the radicals -COR4, -COOR4, <IMG, -CONHR4, or R2 and R3 together may represent the residues:
where T represents , , and R4 is lower alkyl, a mononuclear aryl ring or a mononuclear heterocyclic, ring to give a compound of structure:
(II') in which R, R1, R2, R3, and Z have the meanings given above, and said intermediate (II') is reacted in a suitable solvent at a temperature between -100° and +120°C with a compound selected from the class consisting of inorganic basic or weakly acid oxides, and inorganic and organic bases, to finally give the desired compound (III) which is isolated and purified in known Abstract of the Disclosure continued:
manner. More particularly, a compound of structure:
(I) is reacted in a suitable solvent at a temperature between -20°C
and +80°C, in the presence of an organic and inorganic aqueous acid, with an azoderivative of the formula:
to give a compound of the formula:
where V may be hydrogen, or an aliphatic, aromatic, arylaliphatic or acylic residue, or the residues:
; where R, R1, R2, R3, and Z have the meanings given above, and M
Abstract of the Disclosure continued:
is hydrogen or an alkyl group with 1 to 4 carbon atoms. Also included are the intermediates, which are 2.beta.-thiohydrazoazetidinones of structure:
where V may be hydrogen, or an aliphatic, aromatic, arylalipha-tic or acyclic residue, and in particular the residues;
; ;
A process is disclosed for preparing cephalosporins of structure:
III
where R is selected from the class consisting of hydrogen, alkyl having from 1 to 4 carbon atoms, cyano-methyl-, thienyl-methyl, furyl-methyl-, naphthyl-methyl, phenyl-methyl-, phenoxy-methyl-, phenyl-isopropyl-, phenoxy-isopropyl-, pyridyl-4-thiomethyl-, and tetrazolyl-1-methyl;
R1 is selected from the class consisting of hydroxyl, alkoxy with 1 to 4 carbon atoms, trichloroethoxy-, benzyloxy-, p-methoxy-benzyloxy-, p-nitrobenzyloxy-, benzhydryloxy-, benzyloxy-, phenylmethoxy-, phenacyloxy-, and p-halophen acyloxy;
Z is selected from the class consisting of hydrogen, hydroxyl, -O-alkyl, -O-CO-alkyl, -Br, -I, -N3, -NH2, -O-CO-CH3, -O-CO-nH2 and an -S-mononuclear nitrogen heterocyclic ring;
wherein a compound of structure:
(I') Abstract of the Disclosure continued:
is reacted in a suitable solvent at a temperature between -20°C
and +80°C, in the presence of an aqueous organic ox inorganic acid with an azoderivative of the formula: a where R2 and R3 are equal ox different and represent lower alkyl, a mononuclear aryl ring, CN-, a mononuclear heterocyclic ring, or the radicals -COR4, -COOR4, <IMG, -CONHR4, or R2 and R3 together may represent the residues:
where T represents , , and R4 is lower alkyl, a mononuclear aryl ring or a mononuclear heterocyclic, ring to give a compound of structure:
(II') in which R, R1, R2, R3, and Z have the meanings given above, and said intermediate (II') is reacted in a suitable solvent at a temperature between -100° and +120°C with a compound selected from the class consisting of inorganic basic or weakly acid oxides, and inorganic and organic bases, to finally give the desired compound (III) which is isolated and purified in known Abstract of the Disclosure continued:
manner. More particularly, a compound of structure:
(I) is reacted in a suitable solvent at a temperature between -20°C
and +80°C, in the presence of an organic and inorganic aqueous acid, with an azoderivative of the formula:
to give a compound of the formula:
where V may be hydrogen, or an aliphatic, aromatic, arylaliphatic or acylic residue, or the residues:
; where R, R1, R2, R3, and Z have the meanings given above, and M
Abstract of the Disclosure continued:
is hydrogen or an alkyl group with 1 to 4 carbon atoms. Also included are the intermediates, which are 2.beta.-thiohydrazoazetidinones of structure:
where V may be hydrogen, or an aliphatic, aromatic, arylalipha-tic or acyclic residue, and in particular the residues;
; ;
Description
~55~
The object of the present invention is a neW process for preparing cephalosporins starting from suitably subskituted thiazoline~azetidinones.
The conversion step from the penicillanic framework ko the cephalosporanic framework has been achieved chemically for the first kime by treaking sulphoxides of penicillins with acetic anhydride ~R.R.Chauve~te, J.Org. Chem. 36; 1971, p. 1259) or with acid catalysks (Belgian Pakenk No. 747,119). More recently the kransformation of the sulphoxide of penicillins into cephalosporins, in the presence of azodicarboxylate, has been reported (S.Terao, Chem. Corp. 1304,1972), wikh low yields and in mixture with other products.
The object of the present invention is ko obtain cephalosporins by a completely original process as indicaked diagrammakically hereinafter.
- S~nthesis Diagram a) Opening of khe khiazoline ring with an azoderivakive:
R ~ :
N S
H..... ~ ~ ........ H ~
'. ' : :
O V
(I) -N ~2 Il 3 H
N - R
~ / ~.
NH _ R2 M - ~3 H H S
R-CONH
N
(II) .
~ :. ~ ., , . . :
:
.. ' ' : : ' . ; . :
, . . . ,: .
SS~85 1 where, a~art fromthe other substituents, V may be hydrogen, or an aliphatic, aromatic, arylaliphatic or acyl residue, and in particular the residues:
3 ~ CH3 COR COR
b) closure of the intermediate 2~-thiohydrazoazetidinone with inorganic oxides or bases:
R2 :~
N ~ R3 H H S
;, i / :
:R-CON~ ~'T ~Z ~
~I . COR' (II') : Xnorganic oxides or bases ~ -\ ~ .
H H
: R-CONH i ' ~ S ~ . :
~ N ~ Z ~ : .
; ~ ' "
COR' (XII) where R is taken from the group consisting of hydrogen, alkyl having from 1 to 4 carbon atoms and from the following groups:
cyano-, methyl-, thienyl- methyl-, furyl-methyl-, naphthyl-methyl-, phenyl-methyl phenoxy-methyl-, phenyl-isopropyl-, phenoxy~isopropyl-,
The object of the present invention is a neW process for preparing cephalosporins starting from suitably subskituted thiazoline~azetidinones.
The conversion step from the penicillanic framework ko the cephalosporanic framework has been achieved chemically for the first kime by treaking sulphoxides of penicillins with acetic anhydride ~R.R.Chauve~te, J.Org. Chem. 36; 1971, p. 1259) or with acid catalysks (Belgian Pakenk No. 747,119). More recently the kransformation of the sulphoxide of penicillins into cephalosporins, in the presence of azodicarboxylate, has been reported (S.Terao, Chem. Corp. 1304,1972), wikh low yields and in mixture with other products.
The object of the present invention is ko obtain cephalosporins by a completely original process as indicaked diagrammakically hereinafter.
- S~nthesis Diagram a) Opening of khe khiazoline ring with an azoderivakive:
R ~ :
N S
H..... ~ ~ ........ H ~
'. ' : :
O V
(I) -N ~2 Il 3 H
N - R
~ / ~.
NH _ R2 M - ~3 H H S
R-CONH
N
(II) .
~ :. ~ ., , . . :
:
.. ' ' : : ' . ; . :
, . . . ,: .
SS~85 1 where, a~art fromthe other substituents, V may be hydrogen, or an aliphatic, aromatic, arylaliphatic or acyl residue, and in particular the residues:
3 ~ CH3 COR COR
b) closure of the intermediate 2~-thiohydrazoazetidinone with inorganic oxides or bases:
R2 :~
N ~ R3 H H S
;, i / :
:R-CON~ ~'T ~Z ~
~I . COR' (II') : Xnorganic oxides or bases ~ -\ ~ .
H H
: R-CONH i ' ~ S ~ . :
~ N ~ Z ~ : .
; ~ ' "
COR' (XII) where R is taken from the group consisting of hydrogen, alkyl having from 1 to 4 carbon atoms and from the following groups:
cyano-, methyl-, thienyl- methyl-, furyl-methyl-, naphthyl-methyl-, phenyl-methyl phenoxy-methyl-, phenyl-isopropyl-, phenoxy~isopropyl-,
- 2 - :
, ~
,' ' ~ .
, , , . , . : : , . :
: . , - . . . ... .
' ': ' '. :,', ; '. ~ ' '' ' ' ~55~35 . 1 p~ridyl-4-thiomethyl-, tetrazolyl-l~methyl-, and where Rl is taken from the CJroup consisting of: hydroxyl, alkoxyl, with l $o 4 carbon atoms, trichloro-ethoxy-, benzyloxy, p-methoxy-benzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenyl-methoxy, phenacyloxy, p-halophenacyloxy.
Z is taken from the group consisting of hydrogen, hydroxyl, -O-Alkyl,-O-CO-Alkyl, and from the residue -Br, -I, -N3, -NH2, -O-CO-CH3, O-CO-NH2, and -S-mononuclear nitrogen hetero- ..
cycllc ring. . ..
The product (I~ may be obtained by heating the sulphoxyde of-penicillin in the presence of trialkylphosphite (Neth.Patent 70/08271). The process of the present invention consists ~ . .
essentially of reacting the compound I in a suitable solvent at a temperature between -20C and ~80C in the presence of an organic and inorganic aqueous acid with an azoderivative of the ~ ~.
type: ..
N ~ 3 N- R ..
where the groups R2 and R3 are equal or different and represent .
20~ a lower alkyl, a mononuclear aryl, CN-group, and a mononuclear heterocyclic ring or the radicals -CoR4, CooR4, - P -(OR )2~ -CONHR , '~ or O
~ R2 and R3 together may represent the residues:
1~ ~
~: C \ \ \ T
Iî CH2 where T represents ~ CH2, ~ N - R4, and .
R4 ici a lower alkyl, a mononuclear aryl and a mononuclear _ , ~
' :.
.. . . . . . .
- . .
.- ,~ ~ ' , , , ', :
1C~55~
1 heterocyclic ring or the like. The i.ntermediate compound (II) is reacted in a suitable solvent and at a temperature between -100C
and ~120C with inorganic oxides such as A1~03, Fe203, Cr203, SiO2, or with inorganic and organic bases such as KOH, Na2C03, NH40H, alkali metal alcoholates, aliphatic, aromatic and heterocyclic amines, alkylammonium bases and basic resins. In this manner the cephalosporin derivative (III) is obtained, which is isolated and purified in known manner.
The following examples serve to illustrate the invention 10 without however limiting it.
. . .
Methyl-2~-thiohydrazodicarboxymethyl-a-iso~ropen~1-4-oxo-3~-phenoxyacetamldo-l-aze_idino acetate H H S
, ~
,' ' ~ .
, , , . , . : : , . :
: . , - . . . ... .
' ': ' '. :,', ; '. ~ ' '' ' ' ~55~35 . 1 p~ridyl-4-thiomethyl-, tetrazolyl-l~methyl-, and where Rl is taken from the CJroup consisting of: hydroxyl, alkoxyl, with l $o 4 carbon atoms, trichloro-ethoxy-, benzyloxy, p-methoxy-benzyloxy, p-nitrobenzyloxy, benzhydryloxy, triphenyl-methoxy, phenacyloxy, p-halophenacyloxy.
Z is taken from the group consisting of hydrogen, hydroxyl, -O-Alkyl,-O-CO-Alkyl, and from the residue -Br, -I, -N3, -NH2, -O-CO-CH3, O-CO-NH2, and -S-mononuclear nitrogen hetero- ..
cycllc ring. . ..
The product (I~ may be obtained by heating the sulphoxyde of-penicillin in the presence of trialkylphosphite (Neth.Patent 70/08271). The process of the present invention consists ~ . .
essentially of reacting the compound I in a suitable solvent at a temperature between -20C and ~80C in the presence of an organic and inorganic aqueous acid with an azoderivative of the ~ ~.
type: ..
N ~ 3 N- R ..
where the groups R2 and R3 are equal or different and represent .
20~ a lower alkyl, a mononuclear aryl, CN-group, and a mononuclear heterocyclic ring or the radicals -CoR4, CooR4, - P -(OR )2~ -CONHR , '~ or O
~ R2 and R3 together may represent the residues:
1~ ~
~: C \ \ \ T
Iî CH2 where T represents ~ CH2, ~ N - R4, and .
R4 ici a lower alkyl, a mononuclear aryl and a mononuclear _ , ~
' :.
.. . . . . . .
- . .
.- ,~ ~ ' , , , ', :
1C~55~
1 heterocyclic ring or the like. The i.ntermediate compound (II) is reacted in a suitable solvent and at a temperature between -100C
and ~120C with inorganic oxides such as A1~03, Fe203, Cr203, SiO2, or with inorganic and organic bases such as KOH, Na2C03, NH40H, alkali metal alcoholates, aliphatic, aromatic and heterocyclic amines, alkylammonium bases and basic resins. In this manner the cephalosporin derivative (III) is obtained, which is isolated and purified in known manner.
The following examples serve to illustrate the invention 10 without however limiting it.
. . .
Methyl-2~-thiohydrazodicarboxymethyl-a-iso~ropen~1-4-oxo-3~-phenoxyacetamldo-l-aze_idino acetate H H S
3 CH2C~
20 H.... ¦ - .. H O
COOC~3 N ~
solution of 5.0 g of methyl-a-isopropen~1-3-phenoxy-methyl~la, 5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 200 ml of acetone containing 5ml of methyl azodicarboxylate, ~.5 g of p-toluenesulphonic acid monohydrate and 2.5 ml of water, is left at room temperature for 6 8 hours. It is then cooled to 0C, neutralized with a saturated solution of NaHC03.
The sodium salt of the p-toluenesulphonic acid which precipitates is filtered off and after evaporation of the acetone ~ 4 ,: . :
.
.,~ ;, . . . ~ . : . .
,. , , , , : . , .
~q:)S5~85 1 at room temperature, the residue is dissolved in methylene chloride and washed with salt water. The organic layer is dried over anhydrous Na2SO~ and evaporated. The residue is chromatographed over silica, eluting with 15~ benzene-ethyl acetate. In this way 6.2 g of methyl-2~-thiohydrazodicarboxymethyl--isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate are obtained; m.p. 133-I.R. (CHC13) : 3410 (N-H), 1775 (C = O ~-lactam) 1735 (C=O ester and carbamates) 1685 cm 1 ~C = O amide) N.M.R. (CDC13):1.94 (singlet, 3H, CH3-~=) 3.68, 3.73 and 3.81 (singlets, 9H, three COOCH3),
20 H.... ¦ - .. H O
COOC~3 N ~
solution of 5.0 g of methyl-a-isopropen~1-3-phenoxy-methyl~la, 5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 200 ml of acetone containing 5ml of methyl azodicarboxylate, ~.5 g of p-toluenesulphonic acid monohydrate and 2.5 ml of water, is left at room temperature for 6 8 hours. It is then cooled to 0C, neutralized with a saturated solution of NaHC03.
The sodium salt of the p-toluenesulphonic acid which precipitates is filtered off and after evaporation of the acetone ~ 4 ,: . :
.
.,~ ;, . . . ~ . : . .
,. , , , , : . , .
~q:)S5~85 1 at room temperature, the residue is dissolved in methylene chloride and washed with salt water. The organic layer is dried over anhydrous Na2SO~ and evaporated. The residue is chromatographed over silica, eluting with 15~ benzene-ethyl acetate. In this way 6.2 g of methyl-2~-thiohydrazodicarboxymethyl--isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate are obtained; m.p. 133-I.R. (CHC13) : 3410 (N-H), 1775 (C = O ~-lactam) 1735 (C=O ester and carbamates) 1685 cm 1 ~C = O amide) N.M.R. (CDC13):1.94 (singlet, 3H, CH3-~=) 3.68, 3.73 and 3.81 (singlets, 9H, three COOCH3),
4.56 (singlet, 2H, OCH2CO), 4.90 ~singlet, lH, N-C~H-COOCH3), 5.07 and 5.16 (widened singlets, 2H,=CH2), 5.3 -5.7 (multiplet, 2H, CH ~ lactam) and 6.9-8.0 ~ (multiplet, 7H, aromatic H and NH).
Mass spectrum: m/e 510 (M ) and 363 a;m.u. [ NH-COOCH3 , 2l,2l,2'-trichloroethyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-l~azetidinP aceta-te ,~ .
NH~COOCH3 I H H
N ~ ~ -OC~l2COW
H.. ~- ~ ....... H CoocH
~ N
COOCH2CCl3 ;
' -w 5 _ ~
.~ , . . . .
,~ , , ' , .
~OSS4~3S
1 0.15 ml of water, 0.25 ml of methyl azodicarboxylate and 125 mg of p-toluenesulphonic acid monohydrate are added to a solution of 300 mg of 2',2',2'-trichloroethyl-a-isopropenyl-3-phenoxymethyl-la,5a-thia-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7~
one in 10 ml o~ acetone. It is left for a total of 6 hours at room temperature. It is neutralized with a saturated solution of Na HCO3, methylene chloride is added and it is shaken with salt water. The or~anic layer is collected over anhydrous Na2SO4 and evaporated. The residue is chromatographed over 10 silica eluting with 85/15 v/v benzene-ethyl acetate. In this way 320 mg of 2', 2', 2'-trichloroethyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate are obtained, as amorphous solid.
I.R. (CHC13) : 3400 (N-H), 1770 (C = O ~-lactam), 1740 ~C = O ester and carbamates) and 1690 cm 1 (C = O amide).
Methyl-2~-thioh~drazodicarboxyethyl-a-isopropylidene-4-oxo-3~-phenoxyacetamido-1-azetidine acetate ........ .... ..... ... ..... .. ~ ' ' , , ' .
NHCOOC2H5 '~: ' . CH2 NCOOC2H5 N ~ S ~ ~ OCH2CON~
H~
N ~ COOCH3 O
COOCH ;
Mass spectrum: m/e 510 (M ) and 363 a;m.u. [ NH-COOCH3 , 2l,2l,2'-trichloroethyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-l~azetidinP aceta-te ,~ .
NH~COOCH3 I H H
N ~ ~ -OC~l2COW
H.. ~- ~ ....... H CoocH
~ N
COOCH2CCl3 ;
' -w 5 _ ~
.~ , . . . .
,~ , , ' , .
~OSS4~3S
1 0.15 ml of water, 0.25 ml of methyl azodicarboxylate and 125 mg of p-toluenesulphonic acid monohydrate are added to a solution of 300 mg of 2',2',2'-trichloroethyl-a-isopropenyl-3-phenoxymethyl-la,5a-thia-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7~
one in 10 ml o~ acetone. It is left for a total of 6 hours at room temperature. It is neutralized with a saturated solution of Na HCO3, methylene chloride is added and it is shaken with salt water. The or~anic layer is collected over anhydrous Na2SO4 and evaporated. The residue is chromatographed over 10 silica eluting with 85/15 v/v benzene-ethyl acetate. In this way 320 mg of 2', 2', 2'-trichloroethyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate are obtained, as amorphous solid.
I.R. (CHC13) : 3400 (N-H), 1770 (C = O ~-lactam), 1740 ~C = O ester and carbamates) and 1690 cm 1 (C = O amide).
Methyl-2~-thioh~drazodicarboxyethyl-a-isopropylidene-4-oxo-3~-phenoxyacetamido-1-azetidine acetate ........ .... ..... ... ..... .. ~ ' ' , , ' .
NHCOOC2H5 '~: ' . CH2 NCOOC2H5 N ~ S ~ ~ OCH2CON~
H~
N ~ COOCH3 O
COOCH ;
5 ml of Water, 10 ml of ethyl azodicarboxylate and 10 g of p-toluenesulphonic acid monohydrate are added to a solution o~ 10 g ` 30 of methyl-a-isopropylidene-3-phenoxy-methyl-la,Sa-4-thia-2,6-
- 6 -', , ', ' ' ~
;: , ,: , ,'; ', ' '. "'' ', ' ' ' ' ' ' ' ' ' ' ' '', : .
; .. . .
~554i3S
1 diaza-[3,2,0]~2-heptene-6-acetate~7-one in 300 ml of acetone.
It is left at room temperature for one night, it is neutralized with a saturated solution of NaHCO3. The insoluble sodium salt of p-toluene-sulphonic acid which precipitates is filtered off. Then salt water and methylene chloride are added and it is shaken.
The dried organic layer is chromatographed over si]ica, eluting firstly with benzene to eliminate the unreacted azodicarboxylate and then with benzene-ethyl acetate (80:20) v/v.
In this way 10.8 g of a white solid are obtained, resulting 13 from adding petroleum ether to a small-volume solution of the product in benzene.
N.M.R. (CDC13) : 1.21 (triplet, 6H, 2CH3, C(H2)), 2.12 and 2.28 (two s, 6H, (CH3)2C=), 3.77 (s, 3H, COOCH3), 4-13 (q, 4H, 2CH2-C(H3)), 4.56 (s, 2H, O-CH2-CO), S.14 (dd, lH, C(3) H), 5.86 (d, lH, C~4)H) and 6.8-7.8 ~ (m, 7H, C6H5 and amide 2NH~.
I.R. tcHcl3) : 3410 (N - H) 1765 (C = O ~-lactam) 1730 tC = O ester and carbamates) 1690 cm 1 tC= O amide) 2'j2', 2'-trichloroethyl-2~-thiohydrazodicarboxyethyl-a~isopr lidene-4-oxo-3~-phenoxyacetamido~l-azetidine_acetate : ~
~0 ' ' '~ ' ' , - ' . . ; . ', . : :
: ' ', '. ' , , ' ''~ :
. . ; . ~ I .
" ., ~
55~5 , .
~f 1 OCH2COI N~
N ~ COOCH2CC13 COOC~2CC13 A solution of 4.63 g of 2',2',2'-trichloroethyl-a-isopropylidene-3-phenoxymethyl-la,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7~one in 200 ml of acetone containing 3 ml of ethyl azodicarboxylate, 3 ml of water and 1.91 g of p-toluene-sulphonic acid monohydrate is left at room temperature for 24 hours. It is neutralized with NaHC03, CH2C12 and salt water are added and the organic layer is separated. It is chromatographed over silica eluting with benzene~ethyl acetate (95:5) v/v and the combined fractions give 6.0 g of the required product.
; N-M-R- (CDC13~ : 1.22 and 1.27 (two t~ 6H, 2CH3-C(H2)), 2.22 and 2.37 (two s, 6H, (CH3)2C=), 3.9-4.5 (m, 4H, 2 CH3 C(H3)), 4.58 (s, 2H, 0-CH2-C0), 4.79 (dd! 2H, -0-CH2-CC13), 5.10 (s, lH, C(3)H), 5.98 ` ~ (d, lH,C(4)H), 6.64(s,2H,2NH) and 6.8-7.5 ~ (m, SH, C6H5).
- (CHCl3) : 341C (N-H) 1760 (C - 0 ~-lactam) 1730 (C = 0 ester and carbamate) and 1680 cm 1 (C = 0 amide~ -. . .
.. : , , ' ~3559L~35 EXP~IPLE 5 Methvl~2~-thioh drazodicarboxymeth~l~y-l'-methoxyethylidene ~henoxy~
~ . _ ~ AY
acetamido-l-azetidine acetate . _ . . . _ IH NHCOOCH
1 NCOOCH~
N ~ ~ S H H I J
H.. \ ~ OCH3 ~ ~ OCH2CON ~ 1 3 -~
_N ~\ \~
~ solution of 0.500 g of methyl-a~ methoxyethylidene-3-phenoxymethyl-1~,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-
;: , ,: , ,'; ', ' '. "'' ', ' ' ' ' ' ' ' ' ' ' ' '', : .
; .. . .
~554i3S
1 diaza-[3,2,0]~2-heptene-6-acetate~7-one in 300 ml of acetone.
It is left at room temperature for one night, it is neutralized with a saturated solution of NaHCO3. The insoluble sodium salt of p-toluene-sulphonic acid which precipitates is filtered off. Then salt water and methylene chloride are added and it is shaken.
The dried organic layer is chromatographed over si]ica, eluting firstly with benzene to eliminate the unreacted azodicarboxylate and then with benzene-ethyl acetate (80:20) v/v.
In this way 10.8 g of a white solid are obtained, resulting 13 from adding petroleum ether to a small-volume solution of the product in benzene.
N.M.R. (CDC13) : 1.21 (triplet, 6H, 2CH3, C(H2)), 2.12 and 2.28 (two s, 6H, (CH3)2C=), 3.77 (s, 3H, COOCH3), 4-13 (q, 4H, 2CH2-C(H3)), 4.56 (s, 2H, O-CH2-CO), S.14 (dd, lH, C(3) H), 5.86 (d, lH, C~4)H) and 6.8-7.8 ~ (m, 7H, C6H5 and amide 2NH~.
I.R. tcHcl3) : 3410 (N - H) 1765 (C = O ~-lactam) 1730 tC = O ester and carbamates) 1690 cm 1 tC= O amide) 2'j2', 2'-trichloroethyl-2~-thiohydrazodicarboxyethyl-a~isopr lidene-4-oxo-3~-phenoxyacetamido~l-azetidine_acetate : ~
~0 ' ' '~ ' ' , - ' . . ; . ', . : :
: ' ', '. ' , , ' ''~ :
. . ; . ~ I .
" ., ~
55~5 , .
~f 1 OCH2COI N~
N ~ COOCH2CC13 COOC~2CC13 A solution of 4.63 g of 2',2',2'-trichloroethyl-a-isopropylidene-3-phenoxymethyl-la,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7~one in 200 ml of acetone containing 3 ml of ethyl azodicarboxylate, 3 ml of water and 1.91 g of p-toluene-sulphonic acid monohydrate is left at room temperature for 24 hours. It is neutralized with NaHC03, CH2C12 and salt water are added and the organic layer is separated. It is chromatographed over silica eluting with benzene~ethyl acetate (95:5) v/v and the combined fractions give 6.0 g of the required product.
; N-M-R- (CDC13~ : 1.22 and 1.27 (two t~ 6H, 2CH3-C(H2)), 2.22 and 2.37 (two s, 6H, (CH3)2C=), 3.9-4.5 (m, 4H, 2 CH3 C(H3)), 4.58 (s, 2H, 0-CH2-C0), 4.79 (dd! 2H, -0-CH2-CC13), 5.10 (s, lH, C(3)H), 5.98 ` ~ (d, lH,C(4)H), 6.64(s,2H,2NH) and 6.8-7.5 ~ (m, SH, C6H5).
- (CHCl3) : 341C (N-H) 1760 (C - 0 ~-lactam) 1730 (C = 0 ester and carbamate) and 1680 cm 1 (C = 0 amide~ -. . .
.. : , , ' ~3559L~35 EXP~IPLE 5 Methvl~2~-thioh drazodicarboxymeth~l~y-l'-methoxyethylidene ~henoxy~
~ . _ ~ AY
acetamido-l-azetidine acetate . _ . . . _ IH NHCOOCH
1 NCOOCH~
N ~ ~ S H H I J
H.. \ ~ OCH3 ~ ~ OCH2CON ~ 1 3 -~
_N ~\ \~
~ solution of 0.500 g of methyl-a~ methoxyethylidene-3-phenoxymethyl-1~,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-
7-one in 50 ml of acetone containing 0.5 ml of methyl azodicarboxyl-ate, 3 ml of water and 50 ml of p-toluenesulphonic acid mono~
hydrate is left at room ~emperature for 12 hours. It is neutra-lized with the equivalent quantity of NaHCO3 and is extracted with methylene chloride, The residue is chromatographed over silica, eluting with benzene-ethyl acetate (85:15) v/v. In this wa~ 320 mg o~ the required product are obtained.
IR ~CHC13) : 3420 (N - H) 1770 tC = O ~-lactam) 1730 ( C -- O ester and carbamates) 1680 (C = O amide) Mass : m/e 378 M -. ~ NH~COOCH3 fNN-CO~C~I
m-e 148 ~NH-COOCH
_ g _ .:,.
~ . , '~ ', ' - . ' . :
1~55~8S
1 EX~MPLE 6 Meth~1-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate N-COOCH H H
CONH ~ ~ ~ C~COWH
O H COOCH3 COOCH3 ;
. .
A solution of 1.0 g of methyl 8 ~-thiohydrazodicarboxymethyl~
a-isoproponyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate in 40 ml of benzene is put on a magnetic stirrer with an excess of A12O3 ~ ~
at room temperature. After 60 minutes a complete conversion ~ -occurs to the derivative methyl-7 phenoxyacetamido-3-methyl-3-cephem~4-carboxylate.
The A12O3 is filtered off and the residue is crystallised from ethyl ether or chromatographed over silica, eluting with 90/10 v.v. benzene-ethyl acetate, to obtain 0.580 g of methyl-7-;phenoxyacetamido-3-methyl-3-cephem-4-carboxylate; m.p. 140-141C
(crystallised from ethyl ether).
~ . . - .
I.R., N.M.R. in accordance with the literature (R.B.Morin:
J.Am. Chem. Soc. 91, 1401 (1969)).
EXAMPL~ 7 . . . _ .
Methyl-7-phenoxyacetamido-3-methyl~3-c_phem-4-carbo~ylate ;~ ' ' , ' ' ',~'.' ". ' ~ 30 ~ ' ... .
, . : . : . ", , . :
, . , . . . . . . , . , ... :, : .
.... . . . .. . .
.. . . . .. .
1~5~ 5 H H ~~COOCH3 H H
CH2CoN~
A solution of 400 mg of methyl-2~-thiohydrazodicarboxy-methyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidino-1~ acetate,in 30 ml of ethyl acetate, is put on a magnetic stirrerin the presence of an excess of SiO2 and heated under reflux for 48 hours. It ls filtered from the silica, it is evaporated and the residue is crystallized or chromatographed over silica.
In this way 180 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate are obtained; m.p. 141 - 142C.
I.R. and N.M.R. in accordance with data given in the literature~
(R.B. Morin, J.Am. Chem. Soc. 91, 1969, p. 1401).
. . .
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxy~late ~-COOCH
H H ~-COOCH3 H
~3--0CH2CON ~ ~ ~ ~OCH2coN~
0.8 ml of a 30% aqueous solution o KOH are added under magnetic stirring and at room temperature to a solution oE
510 mg o~ methyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-30 oxo 3~-phénoxyacetamido-1-azetidine acetate in 20 ml of benzene. It is left under stir~ing ~or 30 minutes then the organic layers is .. . .
,' . ,~ ' ' ' , ' , , ~0554t35 1 separated, washed with acidified water, then with wat~r and finally dried. The residue is crystallized from ethyl ether giving 310 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate;
m.p. 141 - 142C. I.R. and N.M.R. in accordance with data reported in the literature, [R.B. Morin, J. Am. Chem. Soc. 91, 1401 (1~69)).
2'_,2',2'-trichloroethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate ~H-COOCH3 OCN2CON ~ ~ ~ 0C 2 H OOCH OCl .-., A solution of 250 mg of 2',2'~,2'-trichloroethyl-2~- -thiohydrazo-dicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxy-acetamido-l-azetidine-acetate in 15 ml of benzene is put under magnetic stirring at room temperature in the presence of an excess o~ A1203. It is left for 60 minutes, then filtered and chromatographed over silica, eluting with 93/7 v.v. benzene-ethyl acetate. In this way 150 mg of 2',2',2'-trichloroethyl-7-pheno~yacetamido-3-methyl-3-cephem-4-carhoxylate are obtained;
m.p. 11~ - 117C. I.R. and N.M.R. in accordance with data reported in theliterature, ~R.R. Chauvette, J. Org. Chem. 36, n. 9, 1259 (1971)).
~ 12 -- , . ... ., ,: .
- ~LOS541~S
Methyl-7-phenoxyacetamido-3-methyl~3-cephem-4-carboxylate O ..
H H
-> ~ OCH2CON~
In this example the process is described for passing -from ~I) to (III) without isolating (II).
A solution of S00 mg of methyl-a-isopropenyl-3- -phenoxymethyl-la,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 25 ml of acetone with 0.5 ml of methyl azo-dicarboxylate, 250 mg of p-toluene-sulphonic acid monohydrate and 0.25 ml of water is left at room témperature for 6 hours.
It is cooled to OC, the acid neutralised with a saturated solution of NaHCO3~ and it is extracted by shaking with benzene and salt water. The organic layer is dried over anhydrous Na2SO4, A12O3 is added and it is left for 60 minutes at room temperature under magnetic stirring. Ik is filtered, the benzene is evaporated and the residue is crystallised from ethyl ether to give 350 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-~-; carboxylate; m.p. 140 - 141C. I.R. and N.M.R. in accordance with data reported in the likerature, (R.B. Morin J. Am. Chem.
Soc. 91, 1401 (1969)).
: , .
':
.,. -. - , :
.
. . ' , .' , :,.
~L~SS~S
.
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carbox~late H J _ ~ ~ ~ CH2c ' A solution of 750 mg of methyl-a-isopropenyl-3-phenoxy~ --methyl-la,5a-4-thio-2,~-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 35 ml of acetone, with 0.75 ml of methyl azodicarboxylate, 375 mg of p-toluenesulphonic acid monohydrate and 0.375 ml of water is left at room temperature for 6 hours. After cooling to ~ ~-0C it is neutralised with a saturated solution of Na~IC03, water ~ -is added and it is extracted with benzene. The organic layer is dried, and 1.2 ml of a 30% solution of KOH are added under magnetic stirring at room temperature. It is left for 30 minutes, ...... .... . .
the organic layer is separated, washed with acidified water, with water, and then dried over anhydrous Na2S04. After eva-poration, the residue is crystallised from ethyl ether giving S40 mg of methyl-7-phenoxyacetamido-3-methyl-3~cephem-4-carboxylate; m.p. 141 - 142C. I.R. and N.M.R. in accordance with data given in the literature, ~R.B. Morin, J. Am. Chem. Soc.
91, 1401 ~969)).
p-nitrobenzyl-7-[N-benzyloxycarbonyl~D-a-phenylglycinamido]-3 methyl-3-cephem-4-carboxylate ',"~ ,".
.,, . . ~ ~, .,, , . , . : ~
,. . ~ ,,. ,, . . ~ .
.. . . . . . . . . . . . .
~1355~85 CH-N-Cbzo ~ H
N S H H
H. ~ ....... H ~ ~ ~H-CONH ~ ~`
~ Cbzo ~
H COOCH2 ~ 2 COOCH2 ~ 2 A solution of 600 mg of p-nitrobenzyl-a-isopropenyl-3 ~N-benzyloxycarbonyl-benzylamido] -la, 5a-2, 6-diaza-[3,2,0]-2-heptene-6-acetate-7-one, melting at 141 - 143C, in 20 ml of acetone containing Q.60 ml of methyl azodicarboxylate, 200 mg of p-toluenesulphonic and monohydrate and 0.2 ml o~ water is le~t at room temperature for 20 hours. It is neutralised at OC with NaHCO3, water is added and it is extracted with benzene. It is dried over anhydrous Na2SO4 and the solution is put under magnetic stirring at room temperature with 0. 2 ml of a 30~ KOH
solution and left for 60 minutes. Finally the organic layer is separated, washed with acidified water, then with water, and dried over anhydrous Na2S04 giving a residue which upon crys~
tallization from ether g.ives 230 mg of p-nitrobenzyl-7-[N-benzyloxy-carbonyl-D-a-phenylglycinamido]-3-cephem-4-carboxylate;
m.p. 198 - 202C. I.R. and N.M.R. in accordance with data obtained from a sample prepared by another method.
NMR (CDC13): 1.80 ~(widened s, 3H, CH3-~= ), 4.89 ~(s, lH, N-CH-COO-), 5.08 and 5.25 ~ (two s, 4H, COO-C~12-( ~ ), 5.10 ~ (m, lH, =C~ ), 5.35 ~ (d, J=6 H2, lH, CH-N(H)), 5.70-6.05 d ~m, 3H, 2CH
of the ~-lactam c = C~EI ), 6.06 ~ (d, J=6 H2, lE~, NH-C~II)), 7.2-7.7 and 8.1-8.35 (m, 14EI, ~romatic 1l).
~' ' ." ', ' ' '' . , ,, ., ,, ,, ,: , , ", , :,. . . . . .
" . , .: :
~3S5~8S
The following compounds were obtained in a manner analogous to that illustrated heretofore:
2',2',2'-trichloroethylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 163C.
p-methoxybenzylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 151 - 152C.
p-chlorophenacylester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 176Ca Phenacylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 190 - 191C.
p-bromophenacylester of 7-phenylacetamido-3-methyl 3-cephem-4-carboxylic acid; mOp. l9G- 198C.
t~-butylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 122C.
p-nitrobenzylester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 191 - 193C.
Methylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 188 - 190C.
p-nitrobenzylester of 7-(thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid; m.p. 217C~
p~methoxybenzylester of 7-~thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid; m.p. 160C.
Methyl-7-phe _ ~acetamido 3-methyl-3-cephem-~-carboxylate (See Example ~) ~
A solution o 1.0 g o~ methyl-2~-th:;ohydrazodicarboxy- `
ethyl-~isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate ` ~`
in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 16 ~
~ .
. .
:, :
, ., - .
:~, . . . . .
' ' ~L~55~35 5 e~uivalents of lithium methoxide in 30 rnl of anhydrous tetrahydrofuran at -40C and the resulting mix-ture is stirred for 1 hour. After neutralization with acetic acid, the solution is warmed up to room temperature, neutralized with an aqueous solution of sodium bicarbonate and extracted with ethylacetate.
The organic layer is washed with water, dried over anhydrous sodium sulphate and the solvent evaporated in vacuo to give methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate which is then crystallized from diethyl ether. I.R. and N.M.R.
in accordance with data reported in--the literature (R.B.Morin, J.Am.Chem. Soc. 91, 1401 (1369)).
SUPPLEMENTARY DISCLOSURE
:
E ~MPLE 15 ..... .. .... _ Methyl-2~-thiohydrazodicarboxyethyl-~-[3l-acetoxy-ll-isopropen~l]
4-oxo-3~-acetamido-1-azetidino acetate CH3 ~ H-N-COOC2H5 _COOc2H5 N f CH3CONH ~ S
` J ~o~c A solution of 0.8 g of methyl-a-[3'-acetoxy-1'-isopropenyl3 3-methyl-la,5a-4-thia-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one (a mixture o~ two epimers in 30 ml of acetone containiny 0.8 ml of ethyl azodicarboxylate, 0.3 ml of water and 0.5 g of p.toluenesulfonic acid monohydrate is kept at room tempera-ture for 2 hours. It is neutralized with NaHC03 and the product is extractedwith ethyl acetate. The organic layer is dried over anhydrous Na2SO~ and the solvent evaporated in vacuo.
~ 17 -~ . .
~ .
. . . , ", . . . . . . . .
~0~541!35i 1 The residue is chromatographed over si]ica eluted with benzene/
ethylacetate 60:40 v/v to give ~.6 g of the title compound as a mixture of two epimers.
N.M.R. (CDC13) : 2.06 and 2.09 (two s, CH3COO- and CH3CONH~
3.80 and 3.82 (two s, CH30), 4.75 and 4.95 (two m, = CH2~
5.29 - 5.60 (two broad d, ~-lactam protons). ~ ' .... _ . ... .
Methyl-2~-thiohydrazodicarboxyethyl-a-I3''~acetoxy~ isopropenyl]-4-oxo-3~-trimethylacetamldo-1-azetidino-a'cetate __ :.
CEI
1 3 H-~N-COOC2H5 N ~ ~ CH ~I_CONH ~ -COOC2H5 ~ ~c ~ H
H OOCH
COOCH3 3 , A solution o 0.750 g of methyl-a-[3~-acetoxy~ isopropenyl]-3-tert.butyl-1,5a-4-thia-2,6-diaza-13,2,03~2~heptene-6-acetate-; 7-one ~a mixture of two epimers) in 10 ml of acetone containing 0.750 ml of ethyl azodicarboxylate, 0.2 ml of water and 0.390 g of p.toluenesulfonic acid monohydrate is kept at room temperature ' ' for 24 hours. After neutralization with NaHCO3, the product is extracted with ethyl acetate and the organic layer dried ' over anhydrous Na2SO4, The solvent is evaporated in vacuo and the residue is chromatographed over silica eluted with ; benzenetethyl acetate 70:30 v/v to give 0.5 g of the title compound as a mixture of two epimers.
~, ". . ~ " ~, ,",.,.,.,.. ,.. , , , . , . ,~ , . .
: ,,;: .
. : . :, . , :
. ~ , . , .. . .
~(3554~5 Methyl-7-acetamido-3-acetoxymethyl-3-cephem-4-carboxylate H-l-COOC2H5 CH3CONH~ CH3CON3~ ~OP.C
J\/OAc ~
1~ A solution of 0.5 g of methyl-2~-thiohydrazodicarboxy-ethyl-a-[3'-acetoxy-1'-isopropenyl~ 4-oxo-3~-acetamido-1-aze-tidino-acetate in 15 ml of dimethylformamide and 5 ml of tetrahydro-furan is cooled to -78C and treated with 1.1 g of potassium tert.butoxide. After stirring for 20 minutes, the reaction mixture is quenched with acetic acid, diluted with water and extracted with ethyl acetate. The solvent is evaporated in ~ vacuo and the residue chroma-tographed on silica eluted with ;~ benzene/ethylacetate 70:30 v/v to give 0.180 g of methyl-7 acetamido-3-acetoxymethyl-cephem-4-carboxylate as a mixture of :~
20 ~ and ~3 isomers. ~ :
D.O. SPRY, J.A.C.S. 92, 5006 ~1970) -Methyl-7-trimethylacetamido-3-acetoxymethyl-3-cephem-4-carboxylake. ~
:
H-~l-COOC 2H
~CH3 H H ~-COOC2H5 CH3- I CONH~ ~S
CH3 ~' ~ C 3~" J~,,OA--3 o H COOCH3 . .
, '.' ', ~:: ' ,, :., :. ,, . , :
~: . : .
... . . , :
: - , '. : : :
. , : . . .
' ,: ' . :
~10 5S~35 1 A solution of 0.850 g of methyl-23-thiohydrazodicarboxyethyl- :
a~[3'-acetoxy-l'-isopropenyl]-4-oxo-3~-trimethylacetamido-l-azetidino acetate in 15 ml of dimethylformamide and 3 ml of tetrahydrofuran is cooled to -70C and treated with 1.2 g of potassium tert.butoxide. After stlrring for 15 minutes, the reaction mixture is quenched with acetic acid, diluted with water and extracted with ethyl acetate. The solvent is evaporated in vacuo and the residue chromatographed on silica eluting with benzene/ethyl acetate 80:20 v/v to give 0.190 g of methyl-7-trimethylacetamido-3-acetoxymethyl-cephem-4-carboxylate as a mixture of a 2 and ~3 isomers.
N.M.R. (CDC13) : 2.08~ ~s, CH3CO), 3.51~ ~dd, C~2)H2), 3.83 and 3.90~ (two s, CH30), 4.69 (s, C~4)H), 4.87 and 5.30~ ~two d, C~6)H), 5.62 and 5.82 (two dd, C(7)H), and 6.50~ (broad s, =C (2) H). .
':
. ' :
- 20 ~
- ., .
:
.:, .
. . .
.. . .
hydrate is left at room ~emperature for 12 hours. It is neutra-lized with the equivalent quantity of NaHCO3 and is extracted with methylene chloride, The residue is chromatographed over silica, eluting with benzene-ethyl acetate (85:15) v/v. In this wa~ 320 mg o~ the required product are obtained.
IR ~CHC13) : 3420 (N - H) 1770 tC = O ~-lactam) 1730 ( C -- O ester and carbamates) 1680 (C = O amide) Mass : m/e 378 M -. ~ NH~COOCH3 fNN-CO~C~I
m-e 148 ~NH-COOCH
_ g _ .:,.
~ . , '~ ', ' - . ' . :
1~55~8S
1 EX~MPLE 6 Meth~1-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate N-COOCH H H
CONH ~ ~ ~ C~COWH
O H COOCH3 COOCH3 ;
. .
A solution of 1.0 g of methyl 8 ~-thiohydrazodicarboxymethyl~
a-isoproponyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate in 40 ml of benzene is put on a magnetic stirrer with an excess of A12O3 ~ ~
at room temperature. After 60 minutes a complete conversion ~ -occurs to the derivative methyl-7 phenoxyacetamido-3-methyl-3-cephem~4-carboxylate.
The A12O3 is filtered off and the residue is crystallised from ethyl ether or chromatographed over silica, eluting with 90/10 v.v. benzene-ethyl acetate, to obtain 0.580 g of methyl-7-;phenoxyacetamido-3-methyl-3-cephem-4-carboxylate; m.p. 140-141C
(crystallised from ethyl ether).
~ . . - .
I.R., N.M.R. in accordance with the literature (R.B.Morin:
J.Am. Chem. Soc. 91, 1401 (1969)).
EXAMPL~ 7 . . . _ .
Methyl-7-phenoxyacetamido-3-methyl~3-c_phem-4-carbo~ylate ;~ ' ' , ' ' ',~'.' ". ' ~ 30 ~ ' ... .
, . : . : . ", , . :
, . , . . . . . . , . , ... :, : .
.... . . . .. . .
.. . . . .. .
1~5~ 5 H H ~~COOCH3 H H
CH2CoN~
A solution of 400 mg of methyl-2~-thiohydrazodicarboxy-methyl-a-isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidino-1~ acetate,in 30 ml of ethyl acetate, is put on a magnetic stirrerin the presence of an excess of SiO2 and heated under reflux for 48 hours. It ls filtered from the silica, it is evaporated and the residue is crystallized or chromatographed over silica.
In this way 180 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate are obtained; m.p. 141 - 142C.
I.R. and N.M.R. in accordance with data given in the literature~
(R.B. Morin, J.Am. Chem. Soc. 91, 1969, p. 1401).
. . .
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxy~late ~-COOCH
H H ~-COOCH3 H
~3--0CH2CON ~ ~ ~ ~OCH2coN~
0.8 ml of a 30% aqueous solution o KOH are added under magnetic stirring and at room temperature to a solution oE
510 mg o~ methyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-4-30 oxo 3~-phénoxyacetamido-1-azetidine acetate in 20 ml of benzene. It is left under stir~ing ~or 30 minutes then the organic layers is .. . .
,' . ,~ ' ' ' , ' , , ~0554t35 1 separated, washed with acidified water, then with wat~r and finally dried. The residue is crystallized from ethyl ether giving 310 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate;
m.p. 141 - 142C. I.R. and N.M.R. in accordance with data reported in the literature, [R.B. Morin, J. Am. Chem. Soc. 91, 1401 (1~69)).
2'_,2',2'-trichloroethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate ~H-COOCH3 OCN2CON ~ ~ ~ 0C 2 H OOCH OCl .-., A solution of 250 mg of 2',2'~,2'-trichloroethyl-2~- -thiohydrazo-dicarboxymethyl-a-isopropenyl-4-oxo-3~-phenoxy-acetamido-l-azetidine-acetate in 15 ml of benzene is put under magnetic stirring at room temperature in the presence of an excess o~ A1203. It is left for 60 minutes, then filtered and chromatographed over silica, eluting with 93/7 v.v. benzene-ethyl acetate. In this way 150 mg of 2',2',2'-trichloroethyl-7-pheno~yacetamido-3-methyl-3-cephem-4-carhoxylate are obtained;
m.p. 11~ - 117C. I.R. and N.M.R. in accordance with data reported in theliterature, ~R.R. Chauvette, J. Org. Chem. 36, n. 9, 1259 (1971)).
~ 12 -- , . ... ., ,: .
- ~LOS541~S
Methyl-7-phenoxyacetamido-3-methyl~3-cephem-4-carboxylate O ..
H H
-> ~ OCH2CON~
In this example the process is described for passing -from ~I) to (III) without isolating (II).
A solution of S00 mg of methyl-a-isopropenyl-3- -phenoxymethyl-la,5a-4-thio-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 25 ml of acetone with 0.5 ml of methyl azo-dicarboxylate, 250 mg of p-toluene-sulphonic acid monohydrate and 0.25 ml of water is left at room témperature for 6 hours.
It is cooled to OC, the acid neutralised with a saturated solution of NaHCO3~ and it is extracted by shaking with benzene and salt water. The organic layer is dried over anhydrous Na2SO4, A12O3 is added and it is left for 60 minutes at room temperature under magnetic stirring. Ik is filtered, the benzene is evaporated and the residue is crystallised from ethyl ether to give 350 mg of methyl-7-phenoxyacetamido-3-methyl-3-cephem-~-; carboxylate; m.p. 140 - 141C. I.R. and N.M.R. in accordance with data reported in the likerature, (R.B. Morin J. Am. Chem.
Soc. 91, 1401 (1969)).
: , .
':
.,. -. - , :
.
. . ' , .' , :,.
~L~SS~S
.
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carbox~late H J _ ~ ~ ~ CH2c ' A solution of 750 mg of methyl-a-isopropenyl-3-phenoxy~ --methyl-la,5a-4-thio-2,~-diaza-[3,2,0]-2-heptene-6-acetate-7-one in 35 ml of acetone, with 0.75 ml of methyl azodicarboxylate, 375 mg of p-toluenesulphonic acid monohydrate and 0.375 ml of water is left at room temperature for 6 hours. After cooling to ~ ~-0C it is neutralised with a saturated solution of Na~IC03, water ~ -is added and it is extracted with benzene. The organic layer is dried, and 1.2 ml of a 30% solution of KOH are added under magnetic stirring at room temperature. It is left for 30 minutes, ...... .... . .
the organic layer is separated, washed with acidified water, with water, and then dried over anhydrous Na2S04. After eva-poration, the residue is crystallised from ethyl ether giving S40 mg of methyl-7-phenoxyacetamido-3-methyl-3~cephem-4-carboxylate; m.p. 141 - 142C. I.R. and N.M.R. in accordance with data given in the literature, ~R.B. Morin, J. Am. Chem. Soc.
91, 1401 ~969)).
p-nitrobenzyl-7-[N-benzyloxycarbonyl~D-a-phenylglycinamido]-3 methyl-3-cephem-4-carboxylate ',"~ ,".
.,, . . ~ ~, .,, , . , . : ~
,. . ~ ,,. ,, . . ~ .
.. . . . . . . . . . . . .
~1355~85 CH-N-Cbzo ~ H
N S H H
H. ~ ....... H ~ ~ ~H-CONH ~ ~`
~ Cbzo ~
H COOCH2 ~ 2 COOCH2 ~ 2 A solution of 600 mg of p-nitrobenzyl-a-isopropenyl-3 ~N-benzyloxycarbonyl-benzylamido] -la, 5a-2, 6-diaza-[3,2,0]-2-heptene-6-acetate-7-one, melting at 141 - 143C, in 20 ml of acetone containing Q.60 ml of methyl azodicarboxylate, 200 mg of p-toluenesulphonic and monohydrate and 0.2 ml o~ water is le~t at room temperature for 20 hours. It is neutralised at OC with NaHCO3, water is added and it is extracted with benzene. It is dried over anhydrous Na2SO4 and the solution is put under magnetic stirring at room temperature with 0. 2 ml of a 30~ KOH
solution and left for 60 minutes. Finally the organic layer is separated, washed with acidified water, then with water, and dried over anhydrous Na2S04 giving a residue which upon crys~
tallization from ether g.ives 230 mg of p-nitrobenzyl-7-[N-benzyloxy-carbonyl-D-a-phenylglycinamido]-3-cephem-4-carboxylate;
m.p. 198 - 202C. I.R. and N.M.R. in accordance with data obtained from a sample prepared by another method.
NMR (CDC13): 1.80 ~(widened s, 3H, CH3-~= ), 4.89 ~(s, lH, N-CH-COO-), 5.08 and 5.25 ~ (two s, 4H, COO-C~12-( ~ ), 5.10 ~ (m, lH, =C~ ), 5.35 ~ (d, J=6 H2, lH, CH-N(H)), 5.70-6.05 d ~m, 3H, 2CH
of the ~-lactam c = C~EI ), 6.06 ~ (d, J=6 H2, lE~, NH-C~II)), 7.2-7.7 and 8.1-8.35 (m, 14EI, ~romatic 1l).
~' ' ." ', ' ' '' . , ,, ., ,, ,, ,: , , ", , :,. . . . . .
" . , .: :
~3S5~8S
The following compounds were obtained in a manner analogous to that illustrated heretofore:
2',2',2'-trichloroethylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 163C.
p-methoxybenzylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 151 - 152C.
p-chlorophenacylester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 176Ca Phenacylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 190 - 191C.
p-bromophenacylester of 7-phenylacetamido-3-methyl 3-cephem-4-carboxylic acid; mOp. l9G- 198C.
t~-butylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 122C.
p-nitrobenzylester of 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 191 - 193C.
Methylester of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid; m.p. 188 - 190C.
p-nitrobenzylester of 7-(thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid; m.p. 217C~
p~methoxybenzylester of 7-~thiophene-2-acetamido)-3-methyl-3-cephem-4-carboxylic acid; m.p. 160C.
Methyl-7-phe _ ~acetamido 3-methyl-3-cephem-~-carboxylate (See Example ~) ~
A solution o 1.0 g o~ methyl-2~-th:;ohydrazodicarboxy- `
ethyl-~isopropenyl-4-oxo-3~-phenoxyacetamido-1-azetidine acetate ` ~`
in 10 ml of anhydrous tetrahydrofuran is added to a suspension of 16 ~
~ .
. .
:, :
, ., - .
:~, . . . . .
' ' ~L~55~35 5 e~uivalents of lithium methoxide in 30 rnl of anhydrous tetrahydrofuran at -40C and the resulting mix-ture is stirred for 1 hour. After neutralization with acetic acid, the solution is warmed up to room temperature, neutralized with an aqueous solution of sodium bicarbonate and extracted with ethylacetate.
The organic layer is washed with water, dried over anhydrous sodium sulphate and the solvent evaporated in vacuo to give methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate which is then crystallized from diethyl ether. I.R. and N.M.R.
in accordance with data reported in--the literature (R.B.Morin, J.Am.Chem. Soc. 91, 1401 (1369)).
SUPPLEMENTARY DISCLOSURE
:
E ~MPLE 15 ..... .. .... _ Methyl-2~-thiohydrazodicarboxyethyl-~-[3l-acetoxy-ll-isopropen~l]
4-oxo-3~-acetamido-1-azetidino acetate CH3 ~ H-N-COOC2H5 _COOc2H5 N f CH3CONH ~ S
` J ~o~c A solution of 0.8 g of methyl-a-[3'-acetoxy-1'-isopropenyl3 3-methyl-la,5a-4-thia-2,6-diaza-[3,2,0]-2-heptene-6-acetate-7-one (a mixture o~ two epimers in 30 ml of acetone containiny 0.8 ml of ethyl azodicarboxylate, 0.3 ml of water and 0.5 g of p.toluenesulfonic acid monohydrate is kept at room tempera-ture for 2 hours. It is neutralized with NaHC03 and the product is extractedwith ethyl acetate. The organic layer is dried over anhydrous Na2SO~ and the solvent evaporated in vacuo.
~ 17 -~ . .
~ .
. . . , ", . . . . . . . .
~0~541!35i 1 The residue is chromatographed over si]ica eluted with benzene/
ethylacetate 60:40 v/v to give ~.6 g of the title compound as a mixture of two epimers.
N.M.R. (CDC13) : 2.06 and 2.09 (two s, CH3COO- and CH3CONH~
3.80 and 3.82 (two s, CH30), 4.75 and 4.95 (two m, = CH2~
5.29 - 5.60 (two broad d, ~-lactam protons). ~ ' .... _ . ... .
Methyl-2~-thiohydrazodicarboxyethyl-a-I3''~acetoxy~ isopropenyl]-4-oxo-3~-trimethylacetamldo-1-azetidino-a'cetate __ :.
CEI
1 3 H-~N-COOC2H5 N ~ ~ CH ~I_CONH ~ -COOC2H5 ~ ~c ~ H
H OOCH
COOCH3 3 , A solution o 0.750 g of methyl-a-[3~-acetoxy~ isopropenyl]-3-tert.butyl-1,5a-4-thia-2,6-diaza-13,2,03~2~heptene-6-acetate-; 7-one ~a mixture of two epimers) in 10 ml of acetone containing 0.750 ml of ethyl azodicarboxylate, 0.2 ml of water and 0.390 g of p.toluenesulfonic acid monohydrate is kept at room temperature ' ' for 24 hours. After neutralization with NaHCO3, the product is extracted with ethyl acetate and the organic layer dried ' over anhydrous Na2SO4, The solvent is evaporated in vacuo and the residue is chromatographed over silica eluted with ; benzenetethyl acetate 70:30 v/v to give 0.5 g of the title compound as a mixture of two epimers.
~, ". . ~ " ~, ,",.,.,.,.. ,.. , , , . , . ,~ , . .
: ,,;: .
. : . :, . , :
. ~ , . , .. . .
~(3554~5 Methyl-7-acetamido-3-acetoxymethyl-3-cephem-4-carboxylate H-l-COOC2H5 CH3CONH~ CH3CON3~ ~OP.C
J\/OAc ~
1~ A solution of 0.5 g of methyl-2~-thiohydrazodicarboxy-ethyl-a-[3'-acetoxy-1'-isopropenyl~ 4-oxo-3~-acetamido-1-aze-tidino-acetate in 15 ml of dimethylformamide and 5 ml of tetrahydro-furan is cooled to -78C and treated with 1.1 g of potassium tert.butoxide. After stirring for 20 minutes, the reaction mixture is quenched with acetic acid, diluted with water and extracted with ethyl acetate. The solvent is evaporated in ~ vacuo and the residue chroma-tographed on silica eluted with ;~ benzene/ethylacetate 70:30 v/v to give 0.180 g of methyl-7 acetamido-3-acetoxymethyl-cephem-4-carboxylate as a mixture of :~
20 ~ and ~3 isomers. ~ :
D.O. SPRY, J.A.C.S. 92, 5006 ~1970) -Methyl-7-trimethylacetamido-3-acetoxymethyl-3-cephem-4-carboxylake. ~
:
H-~l-COOC 2H
~CH3 H H ~-COOC2H5 CH3- I CONH~ ~S
CH3 ~' ~ C 3~" J~,,OA--3 o H COOCH3 . .
, '.' ', ~:: ' ,, :., :. ,, . , :
~: . : .
... . . , :
: - , '. : : :
. , : . . .
' ,: ' . :
~10 5S~35 1 A solution of 0.850 g of methyl-23-thiohydrazodicarboxyethyl- :
a~[3'-acetoxy-l'-isopropenyl]-4-oxo-3~-trimethylacetamido-l-azetidino acetate in 15 ml of dimethylformamide and 3 ml of tetrahydrofuran is cooled to -70C and treated with 1.2 g of potassium tert.butoxide. After stlrring for 15 minutes, the reaction mixture is quenched with acetic acid, diluted with water and extracted with ethyl acetate. The solvent is evaporated in vacuo and the residue chromatographed on silica eluting with benzene/ethyl acetate 80:20 v/v to give 0.190 g of methyl-7-trimethylacetamido-3-acetoxymethyl-cephem-4-carboxylate as a mixture of a 2 and ~3 isomers.
N.M.R. (CDC13) : 2.08~ ~s, CH3CO), 3.51~ ~dd, C~2)H2), 3.83 and 3.90~ (two s, CH30), 4.69 (s, C~4)H), 4.87 and 5.30~ ~two d, C~6)H), 5.62 and 5.82 (two dd, C(7)H), and 6.50~ (broad s, =C (2) H). .
':
. ' :
- 20 ~
- ., .
:
.:, .
. . .
.. . .
Claims
1. A process for preparing cephalosporins of the formula (III):
III
wherein R is selected from the group consisting of C1-4 alkyl, thienylmethyl, phenylmethyl and phenoxymethyl;
R1 is selected from the group consisting of hydroxyl, C1-4 alkoxy, trichloroethoxy-, benzyloxy, p-methoxybenzoyloxy, p-nitro-benzyloxy, benzhydryloxy, triphenylmethoxy, phenacyloxy, p-halophenacyloxy;
Z is selected from the group consisting of hydrogen and acetoxy;
wherein a compound of the formula:
is reacted in a suitable solvent at a temperature between -20°C
and +80°C in the presence of an organic and inorganic aqueous acid with an azoderivative of the type:
Claim 1 continued ....
where the groups R2 and R3 are equal or different and represent a lower alkyl, a mononuclear aryl, CN-group-, and a mononuclear heterocyclic ring or the radicals -COR4, -COOR4, , -CONHR4, or R2 and R3 together may represent the residues:
where T represents , , and R4 is a lower alkyl, a mononuclear aryl and a mononuclear heterocyclic ring to give a compound of structure:
II' in which R, R1, R2, R3 and Z have the meanings given above, and said intermediate (II) is reacted in a suitable solvent at a temperature between -100°C and +120°C with a compound taken from the group consisting of inorganic basic or weakly acid oxides, of inorganic and organic bases, to finally give the desired compound (III) which is isolated.
2. A process as claimed in claim 1, wherein the inorganic basic or weakly acid oxides used for converting the intermediate II to the desired compound III are selected from the group consisting of aluminium, iron, chrome and silicon oxides, either alone or in mixture with other inorganic compounds.
3. A process as claimed in claim 1, wherein the inorganic bases used for converting the intermediate II to the desired compound III are selected from the group consisting of alkali metals and alkali earth metals hydroxides, ammonium hydroxide, alkali carbonates, and alkali metal alcoholates.
4. A process as claimed in claim 1, wherein the organic bases used for converting the intermediate II to the desired compound III are selected from the group consisting of aliphatic, aromatic and heterocyclic amines and basic exchange resins.
5. A process as claimed in claim 1, wherein a compound of structure:
I
is reacted in a suitable solvent at a temperature between -20°C
and +80°C in the presence of an organic and inorganic aqueous acid with an azoderivative of type:
to give a compound of structure:
Claim 5 continued .....
II
where V is and wherein R, R1, R2, R3 and Z have the meanings given in
claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT23070/74A IT1043958B (en) | 1974-05-22 | 1974-05-22 | PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1055485A true CA1055485A (en) | 1979-05-29 |
Family
ID=11203454
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA227,388A Expired CA1055485A (en) | 1974-05-22 | 1975-05-20 | Process for preparing cephalosporins |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS50160291A (en) |
| AT (1) | AT340047B (en) |
| BE (1) | BE829304A (en) |
| CA (1) | CA1055485A (en) |
| DE (1) | DE2522142A1 (en) |
| DK (1) | DK220375A (en) |
| ES (1) | ES437842A1 (en) |
| FR (1) | FR2279753A1 (en) |
| GB (2) | GB1472865A (en) |
| HU (1) | HU171357B (en) |
| IT (1) | IT1043958B (en) |
| NL (1) | NL170286C (en) |
| NO (1) | NO751781L (en) |
| SE (1) | SE7505751L (en) |
| SU (1) | SU727147A3 (en) |
| ZA (1) | ZA753244B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1472866A (en) * | 1974-06-12 | 1977-05-11 | Farmaceutici Italia | Cephalosporins and intermediates therefor |
| NL7806860A (en) * | 1977-07-05 | 1979-01-09 | Farmaceutici Italia | PROCESS FOR PREPARING NOCARDICIN-RELATED AZETIDINONES. |
| US4482491A (en) * | 1981-05-01 | 1984-11-13 | Otsuka Kagaku Yakuhin Kabushiki Kaisha | Thiazolinoazetidinone derivatives and process for the preparation of the same |
| EP0088488B1 (en) * | 1982-01-22 | 1986-10-01 | Beecham Group Plc | Antibacterial agents, their preparation and use |
-
1974
- 1974-05-22 IT IT23070/74A patent/IT1043958B/en active
-
1975
- 1975-05-16 NL NLAANVRAGE7505800,A patent/NL170286C/en not_active IP Right Cessation
- 1975-05-16 AT AT376875A patent/AT340047B/en not_active IP Right Cessation
- 1975-05-17 DE DE19752522142 patent/DE2522142A1/en not_active Withdrawn
- 1975-05-20 NO NO751781A patent/NO751781L/no unknown
- 1975-05-20 ZA ZA00753244A patent/ZA753244B/en unknown
- 1975-05-20 GB GB2141975A patent/GB1472865A/en not_active Expired
- 1975-05-20 JP JP50059355A patent/JPS50160291A/ja active Pending
- 1975-05-20 HU HU75SO00001145A patent/HU171357B/en unknown
- 1975-05-20 CA CA227,388A patent/CA1055485A/en not_active Expired
- 1975-05-20 FR FR7515596A patent/FR2279753A1/en active Granted
- 1975-05-20 SE SE7505751A patent/SE7505751L/en unknown
- 1975-05-20 GB GB2841076A patent/GB1472870A/en not_active Expired
- 1975-05-20 DK DK220375A patent/DK220375A/en unknown
- 1975-05-21 ES ES437842A patent/ES437842A1/en not_active Expired
- 1975-05-21 BE BE156546A patent/BE829304A/en not_active IP Right Cessation
- 1975-05-21 SU SU752133714A patent/SU727147A3/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FR2279753A1 (en) | 1976-02-20 |
| FR2279753B1 (en) | 1979-03-16 |
| GB1472865A (en) | 1977-05-11 |
| GB1472870A (en) | 1977-05-11 |
| NL7505800A (en) | 1975-11-25 |
| NL170286B (en) | 1982-05-17 |
| SE7505751L (en) | 1975-11-24 |
| NL170286C (en) | 1982-10-18 |
| DK220375A (en) | 1975-11-23 |
| DE2522142A1 (en) | 1975-12-11 |
| IT1043958B (en) | 1980-02-29 |
| SU727147A3 (en) | 1980-04-05 |
| AT340047B (en) | 1977-11-25 |
| AU8131975A (en) | 1976-11-25 |
| ES437842A1 (en) | 1977-01-01 |
| NO751781L (en) | 1975-11-25 |
| ATA376875A (en) | 1977-03-15 |
| JPS50160291A (en) | 1975-12-25 |
| HU171357B (en) | 1977-12-28 |
| ZA753244B (en) | 1976-05-26 |
| BE829304A (en) | 1975-11-21 |
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