PROCESS FOR PREPARING CEPHALOSPORINS

PROCEDE DE PREPARATION DE LA CEPHALOSPORINE

English Abstract

ABSTRACT OF THE DISCLOSURE
A process is disclosed for preparing cephalosporins
of structure:

Image 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:

Image (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

Image
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:

Image Image


where T represents Image, Image, and
R4 is lower alkyl, a mononuclear aryl ring or a
mononuclear heterocyclic, ring to give a compound of structure:

Image (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:


Image (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:

Image

to give a compound of the formula:

Image
where V may be hydrogen, or an aliphatic, aromatic, arylaliphatic
or acylic residue, or the residues:
Image ; Image Image
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:

Image

where V may be hydrogen, or an aliphatic, aromatic, arylalipha-
tic or acyclic residue, and in particular the residues;
Image ; Image ; Image
and where R, R1, R2, R3, M and Z have the meanings given above.

Claims

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:

1. A process for preparing cephalosporins of the formula
(III):

Image 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:


Image

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:


21

Claim 1 continued ....

Image

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, Image ,
-CONHR4, or R2 and R3 together may represent the residues:


Image Image


where T represents Image , Image , and R4 is a lower alkyl, a
mononuclear aryl and a mononuclear heterocyclic ring to give a
compound of structure:

Image 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.


22

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:

Image 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:

Image

to give a compound of structure:

23

Claim 5 continued .....

Image II
where V is

Image
and wherein R, R1, R2, R3 and Z have the meanings given in
claim 1.

24

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)

-- 1 --

.

~ :. ~ ., , . . :
:
.. ' ' : : '
. ; . :
,
. . . ,: .

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.
EXAMPLE 1
. . .
Methyl-2~-thiohydrazodicarboxymethyl-a-iso~ropen~1-4-oxo-3~-

phenoxyacetamldo-l-aze_idino acetate


NH-COOCH3

N-COOCH3

H H S

3 CH2C~
20 H.... ¦ - .. H O
COOC~3
N ~

COOCH3
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-
135C
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

N-COOCH3

EXAMPLE 2
,
2l,2l,2'-trichloroethyl-2~-thiohydrazodicarboxymethyl-a-isopropenyl-

4-oxo-3~-phenoxyacetamido-l~azetidinP aceta-te

,~ .
NH~COOCH3

O N -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).
EXAMPLE 3
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)
EXAMPLE 4
2'j2', 2'-trichloroethyl-2~-thiohydrazodicarboxyethyl-a~isopr
lidene-4-oxo-3~-phenoxyacetamido~l-azetidine_acetate
: ~




~0 ' '




'~ ' ' , - ' . . ; . ', . : :
: ' ', '. ' , , ' ''~ :
. . ; . ~ I .
" ., ~

55~5
, .



CH NHCOOC21I5
1 2 INCOOC2H5

~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~ -




- 8



. . .

.. : , , '

~3559L~35
EXP~IPLE 5

Methvl~2~-thioh drazodicarboxymeth~l~y-l'-methoxyethylidene ~henoxy~
~ . _ ~ AY
acetamido-l-azetidine acetate
. _ . . . _



IH NHCOOCH
C 2
1 NCOOCH~
N ~ ~ S H H I J
H.. \ ~ OCH3 ~ ~ OCH2CON ~ 1 3 -~
_N ~\ \~

COOCH3




~ 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)

NH-COOCH3
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




NH-COOCH3

N-COOCH H H
H H 1 3

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


IH-COOCH3
H H ~~COOCH3 H H
CH2CoN~

COOCH3


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).

EXAMPLE 8
. . .
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carboxy~late


~-COOCH
H H ~-COOCH3 H
~3--0CH2CON ~ ~ ~ ~OCH2coN~

OOCH3 COOCH3



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)).

EXAMPLE 9

2'_,2',2'-trichloroethyl-7-phenoxyacetamido-3-methyl-3-cephem-4-
carboxylate




~H-COOCH3


OCN2CON ~ ~ ~ 0C 2



H OOCH OCl
2 3 COOCH20C13
.-.,
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
1 EXAMPLE 10


Methyl-7-phenoxyacetamido-3-methyl~3-cephem-4-carboxylate



O ..

H H
-> ~ OCH2CON~

COOCH3
H COOCH3


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)).




- 13 -
: , .
':
.,. -. - , :

.
. . ' , .' , :,.

~L~SS~S
1 EXAMPLE 11
.
Methyl-7-phenoxyacetamido-3-methyl-3-cephem-4-carbox~late




H J _ ~ ~ ~ CH2c




COOCH3 COOCH3
'
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)).

EXAMPLE 12

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).


- 15 -




~' ' ." ', ' ' '' . ,
,,
., ,, ,, ,: , , ",
, :,. . . . . .
" . , .: :

~3S5~8S

1 EXAMPLE 13

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.

EXAMPLE 14

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

H COOOEI3
COOCH3
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). ~ '

EXAMPLE 16
.... _ . ... .
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
1 EXAMPLE 17

Methyl-7-acetamido-3-acetoxymethyl-3-cephem-4-carboxylate


H-l-COOC2H5
N-COOC2H

CH3CONH~ CH3CON3~ ~OP.C
J\/OAc ~

COOCH3 COOCH3

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 . .
,

19



'.' ', ~:: ' ,, :., :. ,, . , :
~: . : .
... . . , :
: - , '. : : :
. , : . . .
' ,: ' . :

~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 ~




- ., .
:
.:, .
. . .
.. . .