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Transformation of penicillin sulfoxide ester into 2-halogen-substituted penicillin ester, intermediate to cepham system
T&,r&adron
NO. 38,
Letters
TRANSFORMATION
OF
pp 3303
Tanida,*
3306,
PENICILLIN
PENICILLIN
Hiroshi
-
Tadahiko
Tsuji,
Research
Laboratory,
m Jtqmn 25 July
(Received
ESTER INTO
INTERMEDIATE
Toshisada Yano, Shionogi
Pergomon
SULFOXIDE
ESTER,
Teruji
1975.
TO
Tsushima,
Shionogi
1975;
received
One of the most important approaches to the conversion structure
is due to Morin
anhydride (Eq.
affords two principal
1).
cedure
and coworkers’
Although leading
several
entirely
into a 3-sutetituted
products,
modified
of a penicillin
nucleus
(3
1975)
into a cephalosporin ester (I_) with acetic
and a 3-acetoxycepham
we wish to present
(3
here a simple pro-
It is also found that this penam can be transformed
penam.
cepham or a deacetoxycephem
553 Japan
12 August
penicillin
methods have been reported,2-4
to a 2-halogen-substituted
Osaka,
of a penam sulfoxide
a 2-acetoxy-substituted
Britr&.
Tori
publication
who found that treatment
great
Tadashi Irie,
Fukushima-ku,
in UR for
in
SYSTEM
Ishitobi,
and Karuo
Ltd.,
& Co.,
printed
P-HALOGEN-SUBSTITUTED
CEPHAM
Hiroyuki
Hiromu Matsumura
Praaa.
derivative.
(Eq. 1) CO,R
CO,R
1
When
a toluene
amide side chain fluxed
ester, 3.62 30-7m i
2
solution
at C-6)
of a penicillin
G (S)-sulfoxide
and one equivalent
of each of acyl
for 1-2 hrs, it was found that a sort of 8-lactam
established
as the 28-chlorcmethyl
m.p.
116-117”:
(CH,Ph),
4.95
depending
was obtained
CO,R
vz!:13 (3-H),
-5.6
upon the C-6
frcm 13C and ‘H
penam
w
1788,
1745,
(5-
and 6-H,
(Eq. 2),
NMR6
as well
ester (1) (or an analogue halide
derivative =,
and 1680 cm”:
amide chain
?
(or aroyl halide) was formed,
SB-chloro
’H
NMR
and the acyl halide
8(CDC13)
ernpl~yed.~
as other spectroscopic
methods.
a secondary
and pyridine
the structure
derivative
(CHPb) .
and NH) , and 6.93
bearing
of which
of penicillin I .25 (CH,),
The yield Evidence
was re-
varied
was
G benzhydryl 3.25
(CH&f),
in a range of
for the structure
of
Nb. 38
AcCl 2
-
(Eq. 2)
Pyridine d02R tL
(Eq. 3) CO,CH,
CO&H,
2
COz~3
,6
22
Z
z.CH,
0 C02R &
When mixture cally
the reaction
was carried
of two p-lactam
established
[cz]~~*~D 205 f 2.5O methylpenam
out with phthalimidopenicillin
derivatives
by 13C and ‘H (c 0.996
derivative
Q,
was obtained
in CH,CN): m .p.
107-l
It appeared
obtained
from the reported
reaction
structure
of a 3P-chlorocepham
‘H
NMR
In fact,
(the Table),6
dimethylsulfoxide Preparation a satisfactory sulfoxide
was realized
of 67%;
NMR
(Table),
[o]23*5D
08”:
253.7
from the physical thionyl
*3.1”
of s
m.p.
on heating
194-196O:
7 in a solvent
derivative
m.p.
is identical
125.3
(9,
163-165”:
and as the 2p-chloro-
in Cl-l&N):
‘H
NMR
(Table),
with the major product
and triethylamine,
[a]24D
a 53 :47
were unequivo-
(c 0.996
However,
ester (3,
their structures
for the major product
data that2
chloride
methyl
although
a different
this was recently
corrected
i5.Y
in CH&N):
of a high dielectric
(c 0.304 constant,
to
for example,
in
was achieved
in
for 1 hr.
directly
in the presence
yield
(8J has been proposed for that. ’
of a corresponding
yield
‘H
of zwith
the formation
at 100”
in a total
(R)-sulfoxide
NMR studies6 as the Sa-chloromethylpenam
for the minor one (Eq. 3).
structure_7.sr9
li.
cephem derivative
from a penam chloride
of a weak
base, *,
(9J by eliminating
or -via a cepham
urea.
hydrogen
chloride
chloride
by warming
at 130”
in dimethyl-
No.
3305
38
TABLE
Solvent
Compound Methyl
3B-H
CDClsb
phthalimido-
6
a
CO&H,
5.61
5.69
1 .52
1.83
3.80
5.42
1.29
1.69
3.29
CDCI,
4.78
5.62
5.67
3.80
3.87
1 .93
3.81
C6D6
4.77
5.26
5.34
3.48
3.67
1 .79
3.31
5.13 5.22
5.73
5.73
1.60
3.72
4.50
5.53
5.39
1.42
3.65
4.65
3.83 3.28
C02CH3
C6D6
4B-H
6o-H
7a-H
2a-H
2B-H
3-CH,
CDCI,
4.96
5.39
5.61
3.42
3.09
1.78
3.83
C6D6
5.04
4.95
5.24
2.91
2.?’
1.35
3.15
‘H NMR spectra
Identical
28-CH2X
2a-CHZX
5.35
’
CDCIB
b
6o-H
6a
4.72
Z
&
50-H
Shifts,
4.68
C,D,
penicillanate
‘H Chemical
were taken with a Varian
with the reported
values.tO
’
A-60A
spectrometer
Considerably
differ
at 38’;
precisions
from the reported
of 6H are iO.02.
values.iO
REFERENCES (1)
R. B. Morin,
(2)
R. D.
(3)
D.
J. Amer. G.
E. H. H.
B. G. Chem.
Cooper Flynn,
Jackson, Sot.
85,
1869
and D. 0.
Spry,
Chapter
Chem.
g,
(4)
T. Kamiya,
J. Synthetic
Experimental
Procedure
tracted
(6)
dried
over Na,SO,,
ethyl
acetate).
acetate.
3-H
and S.
L. Andrew,
Chemistry
and Biology,”
Ed.
(1972).
Sot.
Bm, --
Tanida,
The mixture
The extract
345 (1971);
D. H.
R. Barton,
Pure
24 (1975). methyl
ester (3.
A solution
in 20 ml of toluene
of 380 mg of the
was refluxed
was poured into a 3% aq NaHCO,
solution
was washed with water,
The residue was purified
dilute
solution HCI,
by TLC (Merk-silica
for 80 min and ex-
and water, gel,
benzene-
of 4_ was 180 mg.
assignmenk
See,
the following the structure
of a penicillin
33,
and 79 mg of pyridin
NMR spectroscopy
method for diagnosing follows:
B. Scanlon
(1969).
York
Roy.
W.
and Penicillins.
V (S)-sulfoxide
and evaporated.
of structural
and H.
Press, New Proc.
chloride,
not simply be distinguished. Tsuji,
1401
Chem . Japan
Org.
The yield
using 13C and ‘H
9i,
“Cephalccporins
for Penicillin
to room temperature.
with ethyl
Some details
(1963);
Sammes,
140 mg of benzoyl
and cooled
E. R. Lavagnino,
1 (1973).
(5)
ester,
Mueller,
5, Academic
R. Barton and P. G.
Appl.
R. A.
of isomeric
2-halogenomethylpenams
are presented K.
Tori,
in the following
T. Tsushima,
paper.
After
as above
by about +O.l
communication,
Tamura,
completing
of such a chloride
ester is deshielded
Y.
and 3-halogenocephams
H.
the assignment, by ‘H and +0.5
since they could
Shigemoto,
NMR
H.
however,
could
Ishitobi,
T.
a simple
ba derived
ppm by ik respective
as change
No.
into a 2a*J value (7)
S. Kukolja
(8)
S. Kukolja,
(9)
X-ray of z
(10)
and 2P-chloro-substituted
for gerninal
and S. R. Lammert, 5.
analyses
R. Lammert, by Dr.
H.
M.
Cooper,
P. V.
J. Amer.
14.5
(see the Table); Hz (2J for W&l
Chem.
R. Gleissner
Koyama
and 8_, for which we thank
R. D. G.
derivative
CH, should be ca.
Sot.
g,
if it is a cepham derivative, should be ca.
7169
of this laboratory
97,
3192
(1975).
unequivocally
proved
the structures
them.
Darnarco
and D. 0.
Spry,
J. Amer.
the
12 Hz).*
(1972).
and A. I. Ellis, --Ibid.
and coworkers
3tt
Chern.
Soc.&
1528
(1969).
NO. 38,
Letters
TRANSFORMATION
OF
pp 3303
Tanida,*
3306,
PENICILLIN
PENICILLIN
Hiroshi
-
Tadahiko
Tsuji,
Research
Laboratory,
m Jtqmn 25 July
(Received
ESTER INTO
INTERMEDIATE
Toshisada Yano, Shionogi
Pergomon
SULFOXIDE
ESTER,
Teruji
1975.
TO
Tsushima,
Shionogi
1975;
received
One of the most important approaches to the conversion structure
is due to Morin
anhydride (Eq.
affords two principal
1).
cedure
and coworkers’
Although leading
several
entirely
into a 3-sutetituted
products,
modified
of a penicillin
nucleus
(3
1975)
into a cephalosporin ester (I_) with acetic
and a 3-acetoxycepham
we wish to present
(3
here a simple pro-
It is also found that this penam can be transformed
penam.
cepham or a deacetoxycephem
553 Japan
12 August
penicillin
methods have been reported,2-4
to a 2-halogen-substituted
Osaka,
of a penam sulfoxide
a 2-acetoxy-substituted
Britr&.
Tori
publication
who found that treatment
great
Tadashi Irie,
Fukushima-ku,
in UR for
in
SYSTEM
Ishitobi,
and Karuo
Ltd.,
& Co.,
printed
P-HALOGEN-SUBSTITUTED
CEPHAM
Hiroyuki
Hiromu Matsumura
Praaa.
derivative.
(Eq. 1) CO,R
CO,R
1
When
a toluene
amide side chain fluxed
ester, 3.62 30-7m i
2
solution
at C-6)
of a penicillin
G (S)-sulfoxide
and one equivalent
of each of acyl
for 1-2 hrs, it was found that a sort of 8-lactam
established
as the 28-chlorcmethyl
m.p.
116-117”:
(CH,Ph),
4.95
depending
was obtained
CO,R
vz!:13 (3-H),
-5.6
upon the C-6
frcm 13C and ‘H
penam
w
1788,
1745,
(5-
and 6-H,
(Eq. 2),
NMR6
as well
ester (1) (or an analogue halide
derivative =,
and 1680 cm”:
amide chain
?
(or aroyl halide) was formed,
SB-chloro
’H
NMR
and the acyl halide
8(CDC13)
ernpl~yed.~
as other spectroscopic
methods.
a secondary
and pyridine
the structure
derivative
(CHPb) .
and NH) , and 6.93
bearing
of which
of penicillin I .25 (CH,),
The yield Evidence
was re-
varied
was
G benzhydryl 3.25
(CH&f),
in a range of
for the structure
of
Nb. 38
AcCl 2
-
(Eq. 2)
Pyridine d02R tL
(Eq. 3) CO,CH,
CO&H,
2
COz~3
,6
22
Z
z.CH,
0 C02R &
When mixture cally
the reaction
was carried
of two p-lactam
established
[cz]~~*~D 205 f 2.5O methylpenam
out with phthalimidopenicillin
derivatives
by 13C and ‘H (c 0.996
derivative
Q,
was obtained
in CH,CN): m .p.
107-l
It appeared
obtained
from the reported
reaction
structure
of a 3P-chlorocepham
‘H
NMR
In fact,
(the Table),6
dimethylsulfoxide Preparation a satisfactory sulfoxide
was realized
of 67%;
NMR
(Table),
[o]23*5D
08”:
253.7
from the physical thionyl
*3.1”
of s
m.p.
on heating
194-196O:
7 in a solvent
derivative
m.p.
is identical
125.3
(9,
163-165”:
and as the 2p-chloro-
in Cl-l&N):
‘H
NMR
(Table),
with the major product
and triethylamine,
[a]24D
a 53 :47
were unequivo-
(c 0.996
However,
ester (3,
their structures
for the major product
data that2
chloride
methyl
although
a different
this was recently
corrected
i5.Y
in CH&N):
of a high dielectric
(c 0.304 constant,
to
for example,
in
was achieved
in
for 1 hr.
directly
in the presence
yield
(8J has been proposed for that. ’
of a corresponding
yield
‘H
of zwith
the formation
at 100”
in a total
(R)-sulfoxide
NMR studies6 as the Sa-chloromethylpenam
for the minor one (Eq. 3).
structure_7.sr9
li.
cephem derivative
from a penam chloride
of a weak
base, *,
(9J by eliminating
or -via a cepham
urea.
hydrogen
chloride
chloride
by warming
at 130”
in dimethyl-
No.
3305
38
TABLE
Solvent
Compound Methyl
3B-H
CDClsb
phthalimido-
6
a
CO&H,
5.61
5.69
1 .52
1.83
3.80
5.42
1.29
1.69
3.29
CDCI,
4.78
5.62
5.67
3.80
3.87
1 .93
3.81
C6D6
4.77
5.26
5.34
3.48
3.67
1 .79
3.31
5.13 5.22
5.73
5.73
1.60
3.72
4.50
5.53
5.39
1.42
3.65
4.65
3.83 3.28
C02CH3
C6D6
4B-H
6o-H
7a-H
2a-H
2B-H
3-CH,
CDCI,
4.96
5.39
5.61
3.42
3.09
1.78
3.83
C6D6
5.04
4.95
5.24
2.91
2.?’
1.35
3.15
‘H NMR spectra
Identical
28-CH2X
2a-CHZX
5.35
’
CDCIB
b
6o-H
6a
4.72
Z
&
50-H
Shifts,
4.68
C,D,
penicillanate
‘H Chemical
were taken with a Varian
with the reported
values.tO
’
A-60A
spectrometer
Considerably
differ
at 38’;
precisions
from the reported
of 6H are iO.02.
values.iO
REFERENCES (1)
R. B. Morin,
(2)
R. D.
(3)
D.
J. Amer. G.
E. H. H.
B. G. Chem.
Cooper Flynn,
Jackson, Sot.
85,
1869
and D. 0.
Spry,
Chapter
Chem.
g,
(4)
T. Kamiya,
J. Synthetic
Experimental
Procedure
tracted
(6)
dried
over Na,SO,,
ethyl
acetate).
acetate.
3-H
and S.
L. Andrew,
Chemistry
and Biology,”
Ed.
(1972).
Sot.
Bm, --
Tanida,
The mixture
The extract
345 (1971);
D. H.
R. Barton,
Pure
24 (1975). methyl
ester (3.
A solution
in 20 ml of toluene
of 380 mg of the
was refluxed
was poured into a 3% aq NaHCO,
solution
was washed with water,
The residue was purified
dilute
solution HCI,
by TLC (Merk-silica
for 80 min and ex-
and water, gel,
benzene-
of 4_ was 180 mg.
assignmenk
See,
the following the structure
of a penicillin
33,
and 79 mg of pyridin
NMR spectroscopy
method for diagnosing follows:
B. Scanlon
(1969).
York
Roy.
W.
and Penicillins.
V (S)-sulfoxide
and evaporated.
of structural
and H.
Press, New Proc.
chloride,
not simply be distinguished. Tsuji,
1401
Chem . Japan
Org.
The yield
using 13C and ‘H
9i,
“Cephalccporins
for Penicillin
to room temperature.
with ethyl
Some details
(1963);
Sammes,
140 mg of benzoyl
and cooled
E. R. Lavagnino,
1 (1973).
(5)
ester,
Mueller,
5, Academic
R. Barton and P. G.
Appl.
R. A.
of isomeric
2-halogenomethylpenams
are presented K.
Tori,
in the following
T. Tsushima,
paper.
After
as above
by about +O.l
communication,
Tamura,
completing
of such a chloride
ester is deshielded
Y.
and 3-halogenocephams
H.
the assignment, by ‘H and +0.5
since they could
Shigemoto,
NMR
H.
however,
could
Ishitobi,
T.
a simple
ba derived
ppm by ik respective
as change
No.
into a 2a*J value (7)
S. Kukolja
(8)
S. Kukolja,
(9)
X-ray of z
(10)
and 2P-chloro-substituted
for gerninal
and S. R. Lammert, 5.
analyses
R. Lammert, by Dr.
H.
M.
Cooper,
P. V.
J. Amer.
14.5
(see the Table); Hz (2J for W&l
Chem.
R. Gleissner
Koyama
and 8_, for which we thank
R. D. G.
derivative
CH, should be ca.
Sot.
g,
if it is a cepham derivative, should be ca.
7169
of this laboratory
97,
3192
(1975).
unequivocally
proved
the structures
them.
Darnarco
and D. 0.
Spry,
J. Amer.
the
12 Hz).*
(1972).
and A. I. Ellis, --Ibid.
and coworkers
3tt
Chern.
Soc.&
1528
(1969).