Note: Descriptions are shown in the official language in which they were submitted.
~9BO
1 The present invention relates to a process for pro-
ducing 7~-methoxycephalosporin derivatives. More particularly,
it pertains to an improved process for producing a 7~-methoxy-
cephalosporin of the formula:
OCH3
~S~
R1SCH2C~H ~ 1 (I)
N
OOH
wherein Rl is an organic moiety and A is a hydrogen atom, a
halogen atom, an alkyl group, a hydroxy group, an alkoxy group,
an acetoxymethyl group or a heterocyclic ring-substituted thio-
methyl group, and its derivatives.
The 7-methoxycephalosporin of the formula (I) as
above and its carboxyl group-substituted derivatives such as
salts, esters and amides are known to be useful as an anti-
microbial agent. In particular, 7-methoxy-7~-cyanomethylthio-
acetamido-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
20 carboxylic acid, and 7~-methoxy-7~-(1,3,4-thiodiazol-2-thio-
acetamido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-
carboxylic acid are known to possess a potent antimicrobial
activity against a wide variety of bacteria lJapanese Patent
Publication (Kokai) No. 51-59890; J. Antibiotics, Vol. 29
(No. 9), 969 (1976)].
So far, several methods for the production of said
~: 7~-methoxycephalosporin derivatives have been known, but these
methods are unsatisfactory for the commercial production-of
said compounds. For example, it is reported in The Journal
` 30 of Antibiotics, Vol. 29 (No. 9), 969 (1976) that said 7~-methoxy-
7~-cyanomethylacetamido-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-
-- 1 -- ~
- l~S~3~
1 3-cephem-4-carboxylic acid is prepared in the following procedures:
N~
COOH _ +
COO M
(1) (2)
EIO~H=~ ~ ~21~`CE2R
oo M COO M
(3) (4j
OCH
> Ncc~2scH2coN~ ~
N ~ CH2R
COOH
However, the intermediate of the for~ula (4) was found
~: to be unstable and hence difficult to handle in our own experiment
As the xesult of a study.on the production of 7~-methoxy-
cephalosporin derivative, it has now been found that a compound
of the formula:
R2so3cH2coN ~ S ~ (III)
.,
-
OOH
- 2 -
~ ~ . . . .
l~SZ980
1 which characteristically has a unique substituent, R2S03CH2CO-
on the amino group at the 7-position, can advantageously be
converted into the corresponding 7a-methoxycephalosporin compound
and the resulting 7~-methoxycephalosporin compound can advantage-
ously be employed for the production of the 7a-methoxycephalo-
sporin derivatives of the formula (I) as above without removing
the protective group at the 7-position.
Thus, the present invention provides a process for
producing a compound of the formula:
10OCH3
c~
2 3C 2C ~ ~
o ~ N ~ (II)
COOH
wherein R2 is a hydrocarbon moiety and A is as defined above, or
its carboxyl group substituted derivative, which comprises re-
acting a compound of the formula:
S
R2SO3cH2cONHT~ ~
200 ~ N ~ A (III)
COOH
wherein R2 and A are defined above, or its carboxyl group-
substituted derivative, with a halogenating agent in the
presence of methanol and an alkali metal salt of methanol.
`~ The present invention also provides a process for
producing a compound of the formula:
QCH3 S
RlSCH2cONH~
30. ~ N ~ (I)
COOH
~ ~ - -
~15~0
1 wherein Rl and A are as defined above, and its carboxyl group
substituted derivative, which comprises reacting a Gompound of
the formula:
R2SO3CH2CONH ~ S ~ (III)
O N ~ A
COOH
wherein R2 is a hydrocarbon moiety and A is as defined above,
or.its carboxyl group-substituted derivative with a halogenating
agent in the presence of methanol and an alkali metal salt of
methanol to give a compound of the formula:
- 3 .
2 3 2 ~ S ~ (II)
N
COOH
wherein R2 and A are as. defined above, or its carboxyl group-
substituted derivative, and then reacting the compound of the
formula (II) or its carboxyl group derivative with a thiol of
the formula:
Rl-SH (IV)
wherein Rl is as defined above or its salt.
As used hexein, the term "organic moiety" for Rl means
any organic moiety which is inert to the reactions involved in
: ~ the process of the present invention. Examples of such organic
moieties are an aralkyl group (e.g. benzyl), an aryl group (e.g.
phenyl, naphthyl, etc.) ur a heterocyclic ring containing one
ll:~o ~
1 or more nitrogen, sulfur or oxygen atoms (e.g. pyridyl, thia-
diazolyl, tetrahydrofuryl, etc.), each of which may be substituted
with a lower alkyl group such as methyl, ethyl or propyl, a
halogen atom such as chlorine, a cyano group, a nitro group,
a hydroxy group or a lower alkoxy group such as methoxy or
ethoxy. The organic moiety can also be a lower alkyl group
(e.g. methyl, ethyl,propyl, etc.) which may further be
substituted with a halogen atom (e.g. chlorine, fluorine), a
cyano group or a nitro group. The symbol A of the formulae (I),
! 10 (II) and (III) represents a hydrogen atom, a halogen atom
(e.g. chlorine), a lower alkyl group (e.g. methyl, ethyl or
propyl), a hydroxy group, a lower alkoxy group (e.g. methoxy,
ethoxy or propoxy~, an acetoxymethyl group or a heterocyclic
ring substituted thiomethyl group such as tetrazolthiomethyl,
thiadiazolylthiomethyl, thiazoylthiomethyl, isothiazoylthiomethyl,
oxadiazolylthiomethyl, triazolylthiomethyl, oxazolylthiomethyl
or imidazolylthlomethyl. These heterocyclic rings can be
substituted with a lower alkyl group (e.g. methyl, ethyl, etc.)
which can also be substituted with a carboxyl, a sulfonyl or
~20 an amino. The term "hydrocarbon moiety" for R2 means any
hydrocarbon moiety which is inert to the reaction involved in
the process of the present invention. Examples of such hydro-
carbon moiety are an aralkyl group (e.g. benzyl) or an aryl
group (e.g. phenyl, naphthyl, etc.), each of which may be
substituted with a lower alkyl (e.g. methyl, ethyl or propyl),
a halogen atom (e.g. chlorine), a cyano group, a nitro group,
a hydroxy group or an alkoxy group (e.g. methoxy, ethoxy,
propoxy, etc.). Another example of the hydrocarbon moiety
for R2 are lawer alkyl groups (methyl, ethyl, propyl) which may
30 be substituted with a halogen atom, a cyano or a nitro. T~e
hydrocarbon moiety for R2 may also comprise a vinyl group
or an allyl group. The
- 5 -
''
,
--- llS;~8~3
1 term "carboxyl group-substituted derivative" means salts, esters
and amides of the compounds concerned. Examples of such salts
are an alkali metal salt such as lithium salt, sodium salt,
potassium salt, etc., an amine salt such as triethylamine
salt, N,N-dimethylbenzylamine salt, N,N-diethylbenzylamine,
N,~-dimethylcyclohexylamine salt, N,N-diethylcyclohexylamine
salt, cyclohexylamine salt or quinoline salt. Examples of
said esters are lower alkyl esters (methyl, ethyl, propyl,
isopropyl, butyl, isobutyl or t-butyl esters), trimethylsilyl
ester, 2-methyl ester, trichloromethyl trichloroethyl ester,
4-methoxybenzyl ester, benzyl ester, 4-nitrobenzyl ester,
phenacyl ester, diphenylmethyl ester, bis-(methoxyphenyl)methyl
ester or 3,4-dimethoxybenzyl ester.
In the present invention, the compound of the formula
(II) and its carboxyl group-substituted derivative can be prepared
by reacting the compound of the formula (III) or its carboxyl
group-substituted derivative with an alkali metal salt of
methanol in the presence of methanol at a temperature of -95
to -10C in an inert solvent, and then adding a halogenating
agent at the same temperature as above. The reaction usually
finishes in such a short period of time as 5 minutes to 2 hours.
Thereafter, a carboxylic acid such as formic acid or acetic acid
is added to the reaction mixture to decompose excess of the
alkali metal salt of methanol. When the reaction mixture contains
unreacted halogenating agent, a reducing agent such as trimethyl
phosphite, triphenyl phosphine or sodium thiosulfate is added
to the reaction mixture after or before the addition of the
carboxylic acid, thereby decomposing the unreacted halogenating
agent. When either the starting material or the product is
unstable and likely to decompose with an alkali metal salt of
-- 6 --
~15~98D
1 methanol or a halogenating agent, the addition of the alkali
metal salt of methanol and the halogenating agent is
preferably carried out in two or more times so that the
decomposition may be avoided.
As an alkali metal salt of methanol, lithium methoxide,
potassium methoxide or sodium methoxide, etc. is used in this
process, and, among them, lithium methoxide is preferable~
These alkali metal salts are prepared in a conventional
manner, for example, by adding an alkali metal into methanol
or an inert solvent containing an excess amount of methanol,
ana the reaction mixture may be used without isolating the alkali
metal salt of methanol in the process of the present invention.
In the process of the present invention, approximately
2 to 10 equimolar amounts of the alkali metal salt of methanol
is reacted with one equimolar amount of the compound of the
formula (III) or its derivatives in the presence of at least
one equimolar amount, preferably a large excess of methanol.
As the solvent to be used in this process, there may be
exemplified dimethylformamide, dimethylacetamide, hexamethyl-
phosphortriamide, ethyl acetate, toluene, tetrahydrofuran,dichloroethylene, acetonitrile, acetone, chloroform or a
mixture thereof.
As the halogena*ing agent, there may be exemplified
chlorine, bromine, N-haloamides such as N-chloroacetamide or
N-bromoacetamide, N-haloimide such as N-chlorosuccinimide or
~; N-bromosuccinimidè; N-halosulfonamide such as N-chlorobenzene-
sulfonamide and an alkyl hypohalite such as t-butyl hypochlorite_
; Among them, t-butyl hypochlorite is particularly preferred.
The 7~-methoxycephalosporin of the formula tI) and its
carboxyl group-substituted derivative can be prepared by reacting
-- 7 --
'`"'` l~S29~
1 the compound of the formula (II) or its carboxyl group-
substituted derivative with the thiol of the formula (IV) or
its salt Generally, the process is conducted in the presence
of a base in an inert solvent, but when the starting compound
of the formula (II) or the thiol is used in the form of salt,
the reaction can be carried out without adding any base. The
reaction temperature is not particularly limited, but it is
preferable to conduct the xeaction at a room temperature or
below.
As the solvent used in this process, there may be
exemplified usual solvents such as dimethylformamide, dimethyl-
acetamide, water, acetone, dioxane, methanol, ethanol aceto-
nitrile, methylene chloride, chloroform, tetrahydrofuran,
dichloroethane, benzene, toluene, pyridine, ethyl acetate or
a mixture thereof.
For the production of the compound (I) or its carboxyl
group-substituted derivative, the reaction mixture of the
aforesaid process may be used without isolating the product.
In this case, the thiol or its salt is directly added to the
reaction mixture when the reaction of the compound of the
formula (II) with a halogenating agent in the presence of
methanol and an alkali metal salt of methanol has finished,
and for the commercial production of the compound of the
formula (I), this way is quite advantageous.
~ ~ As the salt of the thiol, alkali metal salts (e.g.
,.~
~1 lithium, sodium or potassium salt), amine salts (e.g. triethyl-
- amine salt, N,N-dimethylbenzylamine, N,N-dimethylcyclohexylamine
salt, N,N-dimethylcyclohexylamine salt or dicyclohexylamine
salt) and quinoline salt are preferably used in the present
invention.
-- 8 --
1152~
1 Generally, the compounds of the formulae (II) and
(III) and their derivatives are very soluble in said solvents
and hence very conveniently used in the process of the present
invention, but some salts thereof such as dicyclohexylamine
salt are relatively low in solubility. In such a case, the salt
is subjected to a further reaction after dissolving in a solvent
by adding an equimolar amount of an acid such as p-toluene-
sulfonic acid.
The compound of the formula (III) and its carboxyl
group-substituted derivative can be prepared by reacting a
compound of the formula:
H2N ~ S~ (V)
o N~A
COOH
wherein A is as defined above, or its derivative with a compound
of the formula:
RlSO3CH2COOH (VI)
wherein R is as defined above, or its reactive derivative.
The derivative of the compound of the formula (V)
includes the derivatives of the compound (V) of which amino or
carboxyl group is substituted. Examples of such amino-substituted
derivative are salts such as hydrochloride, acetate or toluene-
sulfonate or the raction product of the compound (V) with a
silyl compound such as bistrimethylacetamide. Exam~les of said
carboxyl group substituted derivative of the compound (VI) are
an acid anhydride, an acid halide, an acid azide or an active
ester. Among them, a halide thereof ~e.g. chloride) is preferred.
1~ 80
1 The reaction is usually carried out in an inert
solvent such as water,acetone, dioxane, dimethylformamide,
aeetonitrile, methylene chloride, tetrahydrofuran, chloroform,
diehloroethane, pyridine and the like at a room temperature or
below (e.g. iee-cooling), but it is not particularly limited
thereto. In this process, when the compound of the formula (VI)
is used in the form of a free aeid or salt, it is preferable
to earry out the reaetion in the presence of a condensing agent
sueh as phosphorus triehloride, or eyclohexylearbodiimide.
Moreover, the reaction may preferably be carried out in the
presence of a base such as alkali metal hydrogen earbonate,
trialkylamine, dialkylaniline, pyridine, or dieyelohexylamine~
An alternative method for the production of the
compound ~II) as above is as follows:
OCH3
2 ~ S ~ + RlSO3CH2COOH >
~J~ ~,~
O ' ~ A or its reaetive derivative
COOH
OCH3
RlS03CH2CONH~S~ .
N ~ A
COOH
~ .
This-proeess ean be earried out in substantially the same manner
as that of the produetion of the eompound of the formula (III)
- from the eompound of the formula ~V) as explained above.
The eompound of the formula ~II) can advantageously
be used for the produetion of the compound of the formula (I),
and they are also useful as an antimierobial agent with a good
antimierobial speetrum.
-- 10 --
.
~`` llSZ9~0 (
1 The following examples are given to illustrate the
present invention more precisely, but the present invention is
not limited thereto.
Example 1
Production of tosyl~lycolic acid
Glycolic acid (38 g, 0.5 mole) was dissolved in water
(150 g), and sodium hydroxide (20 g, 0.5 mole) was then
gradually added and dissolved. This solution was cooled to
0 to 10C with ice, and to the solution were added a solution
of p-toluenesulfonyl chloride (143 g, 0.75 mole) in e~her
(500 ml) and a 20 wt% aqueous sodiumhydroxide solution (100 g~
at the same time over 30 minutes with vigorous stirring. After
stirring for further 3 hours at 0 to 10C, the solution wàs
separated into aqueous and organic layers. The aqueous layer
was acidified to a pH of 1 with conc. hydrochloric acid to
precipitate a white needle-like crystal.
The crystal was filtered with Nutsche filter, washed
with water (500 ml) and dried under reduced pressure at 60C
to 80C to obtain 92 g of tosylgl~colic acid.
Melting point : 135 to 137C (known value 137C)
Infrared spectrum ~nujol~ : 1710 cm
Synthesis of 7~-[2-(p-toluenesulfonyloxy)acetamido]cephalo-
sporanic acid and its salt
p-Toluenesulfonyloxyacetic acid (2.3 g, 0.01 mole) was
suspended in a mixture of methylene chloride (4.6 g) and dimethyl-
formamide (0.02 g~, and after adding thionyl chloride (1.19 g,
0.01 mole), the suspension was heated under reflux for 3 to 5
hours with stirring.
~t the time when the suspension became an almost
homogeneous solution, the solution was cooled to obtain a
*Trade Mark - 11 -
Al,
~iSZ980
1 solution of p-toluenesulfonyloxyacetic acid chloride in methylene
chloride.
Using a separate reactor, 90%-purity 7-aminocephalo-
sporanic acid (2.72 g) was suspended in dimethylformamide (10 g),
and triethylamine (1.515 g, 0.015 mole) was dissolved therein
with stirring. This solution ~las cooled to -10C to 0~C in an
ice/sodium chloride bath, and to the solution was added dropwise
the above methylene chloride, solution over 30 to 60 minutes
with vigorous stirring. Thereafter, stirring was continued
for further 60 minutes. Produced triethylamine hydrochloride
was filtered and washed with dimethylformamide (2 g), and the
filtrates were combined.
After adding acetone ~50 g) to the combined filtrate,
dicyclohexylamine ~1.81 g, 0.01 mole) was added thereto with
stirring, and thencrystals precipitated immediately. After
stirring for further 1 to 2 hours, the crystals were filtered!
washed with acetone and dried under reduced pressure to obtain
4.8 g of the dicyclohexylamine salt of the objective compound
~yield : 80% based on 7-aminocephalosporanic acid).
Melting point : 173 - 175C (decomp.)
NMR (CF3COOH) : ~
1 - 2.5 (20H), 2.3 (3H), 2.5 (3H), 3.4 (2H),
3.7 (2H), 4.8 (2H), 5.2 - 5.5 (3H), 5.9 (lH),
7.7 (7H), 8.2 (lH)
Synthesis of 7a-methoxy---7~ [2-(p-toluenesulfonylox~)acetamido]
cephalosporanic acid and its salt
The dicyclohexylamine salt of 7a-[2-(p-toluenesulfonyl-
oxy)acetamido]cephalosporanic acid (10.7g) was added to a
mixture of dimethylformamide (40 ml), tetrahydrofuran (16 ml)
and ethyl acetate (40 ml) and p-toluenesulfonic acid (2.75 g) was
1~5~98t)
1 added thereto with stirring. This solution was cooled to -60C,
and to the solution was added dropwise a lithium methoxide solution
prepared from lithium (0.48 g) and methanol (26 ml) over 20 minutes.
ThereaEter, stirring was continued at -60C for further 30 minutesr
and then a mixture of tert-butyl hypochlorite (3.75 g) and ethyl
acetate (26 ml, diluent) was added dropwise thereto over 25
minutes. After stirring at -60C for further 10 minutes, the
reaction was stopped by adding a solution of triphenyl phosphine
(13 g) in ethyl acetate (60 ml) and acetic acid (2.1 ml).
The reaction solution was warmed to 5C in 40 minutes, and
insolubles were filtered and washed with acetone (50 ml). The
filtrates were combined, and ethyl acetate (600 ml) was added
thereto. The precipitates were collected by filtration,
washed with ethyl acetate and dried under reduced pressure to
obtain the lithium salt of the objective compound.
IR (nujol) :~C=O 1780 cm 1 (~-lactam)
NMR (CH3COOH) : ~ -
2.30 (3H,s), 2.55 (3H,s), 3.60 (2H, broad s),
3.73 (3H,s), 4.86 (2H,s), 5.3 - 5.5 (3H,m),
~0 7.40 - 8.10 (4H,q), 8.50 (lH,s)
mp : 179C (decomp.)
Example 2
Synthesis of 7~-[2-(p-toluenesulfonyloxy)acetamido]-3-(1-methyl-
lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and
its salt
p-Toluenesulfonyloxyacetic acid (23 g) was suspended
in a mixture of methylene chloride (75 g) and dimethylformamide
(0.2 g), and after adding thionyl chloride (11.9 g), the suspension
was heated under reflux for 3 to 5 hours with stirrin~.
3~ At the time when the suspension became an almost homo-
geneous solution, the solution was cooled ta give a solution of
p-toluenesulfonyloxyacetic acid chloride in methylene chloride.
- 13 -
115; :~8~
. . "
1 Using a separate reactor, 7-amino-3-tl-methyl-lH-
tetrazole-5-yl-thiomethyl)-3-cephem-4-carboxylic acid (32.8 g~
was suspended in dimethylformamide ~95 g), and after cooling
the suspension to -10C, bistrimethylsilylacetamide (44.7 g) was
gradually added dropwise thereto~ Thereafter, the suspension
was warmed to room temperature and stirred until the suspended
acid was completely dissolved. After cooling the solution
to -30~ to -40~C, diethylaniline (14.9 g) was added, and then
the above prepared methylene chloride solution was added drop-
wise over 30 to 60 minutes, followed by stirring for 1 hour.
This reaction solution was poured into a mixture of ethyl
acetate (200 ml) and distilled water (500 ml), and after con-
fîrming that the pH of the aqueous layer was 2.0 to 2.5, the
organic layer was separated. The aqueous layer was extracted
with 100 ml of ethyl acetate for three times. The extracts
and the above ethyl acetate layer were combined, washed with
a sodium chloride-saturated water(60 ml), dried over anhydrous
magnesium sulfate and concentrated under reduced pressure
until the volume became 170 ml. Dicyclohexylamine (18.1 g) was
added to the concentrated liquor, and then crystals precipitated.
After stirring for 1 hour, the crystals were collected by
filtration washed with ethyl aoetate and dried under reduced
pressure to give 67 g of the dicyclohexylamine salt o the
objective compound.
NMR ~CF3COOHl : ~
1.0 - 1.3 (20H, m), 2.51 (3H, s), 3.1 - 3.7 ~2H, m),
3.83 ~2H, broad sl, 4.16 (3H, s), 4.3 - 4.9 (4H, m),
5.32 (lH, d), 5.92 (lH, q), 7.4 - 8.0 (4H, q),
8.12 ~lH, d)
_ 14 -
llS~g8~
1 Synthesis of 7~-methoxy-7~-[2-(p-toluenesulfonyloxy)acetamido]-
3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic
acid and its salt
The dicyclohexylamine salt of 7~-~2-(p-toluenesul~onyl-
oxy)acetamido]-3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-
cephem-4-carboxylic acid (23.1 g) and p-toluenesulfonic acid
(5.5 g) were dissolved in a mixture of dimethylformamide (96 ml)
and ethyl acetate (96 ml). After cooling this solution to
-60C, a lithium methoxide solution prepared from lithium
10 (0.672 g) and methanol (49 ml) was added dropwise thereto over
35 minutes. Thereafter, the solution was stirred at -60C for
minutes, and a mixture of tert-butyl hypochlorite (6.95 g)
and ethyl acetate (48 ml, diluent) was added dropwise thereto
over 45 minutes. After stirring at -60C for further 20 minutes,
a lithium methoxide solution prepared from metallic lithium
(0.224 g) and methanol (16.5 ml) was added dropwise over 20
minutes. After stirring at the same temperature for further 20
minutes, a mixture of tert-butyl hypochlorite ~1.74 g) and
~ ethyl acetate (12 ml, diluent) was added dropwise over 15
minutes. Thereafter, the reaction solution was stirred for
further 15 minutes, and a solution of triphenyl phosphine (13 g)
in ethyl acetate (60 ml) and acetic acid (4.5 ml) were added
dropwise thereto. The reaction solution was then poured into
a mixture of distilled water (800 ml~ and ethyl acetate (600 ml),
and after adjusting the pH of the aqueous layer to 2.5 with
lN hydrochloric acid, the ethyl acetate layer was separated
from the aqueous layer. The aqueous layer was extracted
twice w~th 200 ml of ethyl acetate. All the ethyl acetate
layers were com~ined, washed with a sodium chloride-saturated
water, dried over anhydrous magnesium sulfate and concentrated
- 15 ~
~15Z980
1 under reduced pressure until the liquor volume became 260 ml.
After adcling dicyclohexylamine (5.9 g) to the concentrated
liquor, c:arbon tetrachloride ~630 ml) was added thereto. The
precipitates were collected by filtration, washed with carbon
tetrachloride and dried under reduced pressure to obtain 19.2 g
of the dicyclohexylamine salt of the objective compound.
IR (nujol) : 1778 cm 1
NMR (CF3COOH) : ~
1.0 - 2.3 (2nH, m), 2.49 (3H, s), 3.1 - 3.6 (2H, m),
3.60 (2H, broad s), 3.67 (3H, s), 4.10 (3H, s),
4.58 (2H, broad s), 4.76 (2H, broad s), 5.23 (lH, s),
7.35 - 7.93 (4H, q), 8.23 (lH, s)
m.p. : 150C (decomp.
Example 3
Synthesis of 7a-methoxy-7~-[2-(4-pyridylthio)acetamido]-3-(1-
methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid
The dicyclohexylamine salt (1.81 g) obtained in
Example 2 and 4-mercaptopyridine (0.233 g) were dissolved in
a mixture of methylene chloride (30 ml) and dimethyl sulfoxide
(0~2 ml), followed by stirring for 24 hours. The precipitates
were collected by filtration, washed with methylene chloride
and dried under reduced pressure to obtain the objective
compound of high purity.
NMR (CF3COOH~ : ~
3.69 (5H, s), 4.15 (3H, s), 4.30 t2H, broad s),
4.3 - 4.9 (2H, q), 5.30 (lH, s), 7.8 - 8.7 (4H, q),
8.5 (lH, broad s)
m.p. : 135C (decomp.)
Example 4
Synthesis of 7~-methoxy-7~-cyanometh~lthioacetamido-3-1-methyl-
lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its
sodium salt
- 16 -
~ 1529~3
1 A mixture of cyanomethylisothiourea hydrochloride
(3.03 g) and dimethylformamide (15 ml) was cooled to -50C with
stirring, and a lithium methoxide solution prepared from
metallic lithium (0.280 g) and methanol (21 ml) was added
dropwise thereto over 10 minutes. Thereafter, the solution
was stirred at -30C for further 10 minutes and poured, at
-30C with stirring, into dimethylformamide (20 ml) containing
the dicyclohexylamine salt (7.51 g) obtained in Example 2.
Thereafter, reaction was carried out at -20C for 1 hour, and
acetic acid (2.4 ml) was added thereto. This reaction solution
was then poured into a mixture of distilled water (100 ml) and
ethyl acetate (100 ml), and the pH of the aqueous layer was
adjusted to 2 with 2N hydrochloric acid. The ethyl acetate
layer was separated from the aqueous layer, and the aqueous
layer was extracted twice with 40 ml of ethyl acetate. All
the ethyl acetate layers were combined, washed twice with 40 ml
of a sodium chloride-saturated water, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure
until the liquor volume became 80 ml. A solution of sodium
20 2-ethyl-hexanoate (2.01 g) in ethyl acetate (20 ml) was then
gradually added dropwise thereto. The precipitates were collected
by filtration and dried under reduced pressure to obtain the
sodium salt of the objective compound of high purity.
IR (nujol) : 1775 cm 1
NMR (CF3CO2H) : ~
-2.27 (3H, s), 3.55 - 3.85 (6H, not clear because
of the overlapping of the peaks~,
3.72 (3H, s), 5.12 - 5.56 (2H, q), 5.31 (lH, s),
8.45 (lH, s)
liS;~9E~
1 Example 5
Synthesis of 7~-methoxy-7~-[(4-carboxy-3-hydroxyisothiazole-5-yl)-
thioacetamido]cephalosporanic acid
7-~ethoxy-7~-[2-(p-toluenesulfonyloxy)acetamido]cephalo-
sporanic acid (9.7 g) was dissolved in methanol (90 ml), and the
solution was cooled to 5C. To the solution was gradually added
dropwise a solution of sodium salt trihydrate of 4-carboxy-3-
hydroxy-5-mercaptoisothiazole (5.94 g) in distilled water (20 ml)
with ice-cooling. Thereafter, the solution was stirred at 0C to
5C for 2 hours. Methanol was then re~moved under reduced pressurer
and the solution was acidified to a pH of 1.5 with 2N hydro-
chloric acid, and extracted three times with ethyi acetate.
All the ethyl acetate layers were combined, washed twice with
a sodium chloride-saturated water and dried over anhydrous
magnesium sulfate. Ethyl acetate was then removed under reduced
pressure to obtain the objective compound of powdery form.
Example 6
Synthesis of 7~-methoxy-7~-2-(1,3,4-thiadiazolyl)thioacetamido-
3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic
acid and its sodium salt
A mixture of 2-mercapto-1,3,4-thiadiazole (0.36 g~ and
dimethylformamide (2.5 ml) was cooled to -30C with stirring,
and a lithium methoxide solution prepared from lithium (0.021 g)
and methanol (1.5 ml) was added dropwise thereto. This solution
was added at -3QC to a solution of sodium 7-methoxy-7~-~2-(p-
tolucnesulfonyloxy)acetamido]-3-(1-methy~-lH-tetrazole-5-yl-thio-
methylj-3-cephem-4-carboxylate (1.78 g) in dimethylformamide
(12 ml). Reaction was carried out at -30C for 1 hour and then at
-10C for further 3.5 hours. After adding acetic acid (0.2 ml),
the reaction solution was poured into a mixture of distilled
water (150 ml) and ethyl acetate (100 ml), and the pH of the
- 18 -
115Z~
1 aqueous layer was adjusted to 2.5 with 2N hydrochloric acid.
The organic layer was separated from the aqueous layer, and the
aqueous layer was extracted twice with 100 ml of ethyl acetate.
All the organic layers were combined, washed twice with a
sodlum chloride-saturated water and dried over anhydrous
magnesium sulfate. After concentration, the residue was
crystallized from isopropyl alcohol using sodium 2~ethyl-
hexanoate. The crystal was collected by filtration and dried
under reduced pressure to obtain the sodium salt of the objective
compound.
IR (nujol) : 1775 cm 1
NMR (d6-DMSO) : ~
3.1 - 3.8 (2H, q), 3.41 (3H, s), 3.93 (3H, s), 4.15 -
4.40 (4H, m), 4.93 (lH, s), 9.48 (lH, s), 9.57 (lH,s)
Example 7
Synthesis of 7~-methoxy-7~-cyanomethylthioacetamido-3-(1-methyl-
lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid and its
sodium salt
7~-[2-(p-Toluenesulfonyloxy)acetamido]-3-(1-methyl-lH-
tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.16 g) was
dissolved in dimethylformamide (24 ml) with stirring. This
solution was~cooled to -50C, and to the solution was gradually
added dropwise a lithium methoxide solution prepared from metallic
lithium (0.056 g) and methanol (4 ml). After stirring for
30 minutes, tert-butyl hypochlorite (0.434 g) was added dropwise.
After stirring for 20 minutes, a lithium methoxide solution
prepared from metallic lithium (0.028 g) and methanol (2 ml)
was gradually added dropwise. After stirring for 30 minutes,
tert-butyl hypoclllorite (0.434 g) was added dropwise. After
20 minutes, an ~lCCH2SLi solution, which was obtained by adding
-- 19 --
li5;~
1 lithium methoxide [prepared from metallic lithium tO.17 g) and
methanol (12 ml), at -30C with stirring, to a mixture of
cyanomethylisothiourea hydrochloride (1.82 g) and dimethyl-
formamide (9 ml)],was added to the rea~tion solution. The
reaction solution was stirred at -30~C for 1.5 hours and then
at -10C for further 20 minutes. After adding acetic acid
(2 ml), the reaction solution was poured into a mixture of
distilled water (200 ml) and ethyl acetate (100 ml), and the
pH of the aqueous layer was adjusted to 2.5 with 2N hydrochloric
acid. After separating the organic layer, the aqueous layer
was extracted twice with 50 ml of ethyl acetate. All the
organic layers were combined, washed twice with sodium chloride-
saturated water, dried over anhydrous magnesium sulfate and
treated with activated carbon. After concentration under
reduced pressure, the residue was crystallized as sodium salt
from isopropyl alcohol using sodium 2-ethylhexanoate. The
crystal was collected by filtration and dried under reduced
pressure to obtain sodium 7~-methoxy-7~-cyanomethylthioacetamido-
3-(1-methyl-lH-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate.
The IR spectrum and NMR spectrum of this compound agreed
completely with those of the compound obtained in Example 4.
Compounds represented by the formula, RSO3CH2COOH,
could be synthesized in the same manner as in Example 1 or
Acta. Chem. Scand. 22, 2043 (1968). The starting compounds
shown below were obtained in the same manner as in Examples 1 and
2, and the objective compounds shown below were prepared from the
starting compounds in the same manner as in Example 1 or 2.
- 20 -
0
OCH3
RS03CH2cONH T l ~ ~ > RS03CH2CNH ~ S ~
Starting Objective ¦ l l
compound O ~ N ~ A compound ~ N ~ A
COOW COOW'
R A Starting compound Objective compound
_ _
(W= ~ N ~ ) (~ a)
NMR(CF3COOH):~ IR(nujol): ~C=O
C 3 ~ CH3- 1.0-2.4(20H,m), 1768 cm 1
2.37(3H,s), 2.52 NMR(CF3COOH):
(3H,s), 3.2-3.7 2.41(3H,s), 2.50
(2H,m), 3.53(2H, (3H,s), 3.2-3.5
broad s), 4.70 (2H,m), 3.63(3H,s),
(2~,s), 5.23(1H,d), 4.78(2H, broad s),
5.71(1H,q), 7.4- 5.23(1H,s), 7.4-7.9
8.0(4H,q), 8.10 (4H,q), 8.35(1H,s)
(lH,d) m.p.: 175-180C(decomp~
(W= ~ N ~ ) ~ H
~ NMR(CF3COOH):~ IR(nujol): ~C=O
-CH2- 1.0-2.3(20H,m), 1780 cm
OCOCH 2.30(3H,s), 3.0-3.6 NMR(CF3COOH):
(2H,m),3.4-3.8 1.0-2.4(20H,m),
(2H,q), 4.74 2.30(3H,s), 3.1-3.6
(2H,s), 5.07-5.47 (2H,m), 3.3-3.8
(3H,m), 5.85(lH,q), (2H,not clear because
7.5-8.7(8H,m) of overlapping)
3.60(3H,s), 4.82(2H,
broad s), 5.19(lH,s),
5.12-5.55(2H,q), 7.5-
8.7(8H,m)
m.p.: 170-180C(decomp.)
_ ,
- 21 -
11 ~298~
R A Startlng compound Objectiv~ compound
~ H ~ (W' = Na)
N - N NMR(CF3COOH): ~ IR(nujol): ~C=0 1772 cm
1.0-2.3(20H,m), NMR(CF3COOH): 3.52
-CH2S ~ N 3.1-3.6(2H,m), 3.78 (3H,s), 3.5-3.6(2H,
CH3 (2H,broad s) 4.13 not clear because of
(3H,s), 4.2-4.8(4H, overlapping), 4.08(3H,s) r
m), 5.19(lH,d), 5.82 4.52~2H, broad s), 4.70
(lH,q),7.5~8.7(8H,m) (2H, broad s), 5.13
(lH,s), 7.5-8.7(8H,m)
m.p.: 185C (decomp.
(W= -C(CH3)3) (W= -C(CH3)3)
NMR(CDC13):~ IR(nujol): UC=0 1785 cm
1.55(9H,s), 2.07 NMR(CDC13): 1.55(9H,s),
CH3- (3H,s), 2.45(3H,s), 2.06(3H,s), 2.44(3H,s),
-CH2OCOCH3 3.2-3.7(2H,q), 4.52 3.1-3.7(2H, not clear
(2H, broad s), 4.7- because of overlapping),
5.2(3H,m), 5.77(1H,q) 3.50(3H,s), 4.53(2H,
7.28-7.85[5H:(4H,q) broad s), 4.7-5.1(2H,q),
+lH] 5.00(lH,s), 7.29-7.86[5H:
(4H,q)+lH]
m.p.: 150C (decomp.)
(W= ~ N ~ ) (W'= ~ N ~ )
NMR(CF3COOH):~ IR(nujol): VC=0 1780 cm 1
N- N 1.0-2.3(20H,m), ¦NMR(CF3COOH):
CH3- CH2S ~ / 3.1-3.6(2H,m), 1.0-2.3(20H,m),
CH3 3.27(3H,s), 3.1-3.5(2H,m),
3.70(2H,broad s) 3.28(3H, s),3.63(2H,
.
- 22 -
llSZ980
.. .. . .
R A Starting compound Objective compound
.__
4.12(3H,s), 4.2-4.8 broad s), 3.69t3H,s),
(2H,q), 5.00(2H,s), 4.10(3H,s), 4.57
5.26(1H,d), 5.89 (2H, broad s), 5.00
(lH, q), 8.03(1H,d) (2H, s), 5~25(1H,s),
8.24(lH, s)
m.p.: 170C (decomp.)
__ ......... . .
(W= ~ N ~ ) (W'=(CH3)2~H CH
IR(nujol):vC=0 1780cm
NMR(CF3COOH): ~ NMR(CF3COOH): ~
1.0-2.3(20H,m), 2.24(3H,s), 2.93
2.25(3H,s),3.0-3.6 ~6H,d), 3.29(3H,s),
CH3- -CH2OCOCH3 (2H,m), 3.28(3H, s), 3.3-3.7(2H, not clear 3.44-3.89(2H,q), because of overlapping~,
4.8-5.5(5H,m),5.93 3.68(3H,s), 4.32(2H,
(lH,q), 8.03(1H,d) d), 5.01(2H, broad s),
5.26(lH, s), 5.0-5.5
(2H,not clear because
of overlapping 7~3-7.6
(5H,m),8.29(1H, broad s)
m.p.: 165C (decomp.)
. _ _ . . ............ . .
¦ ~ ¦ ( <~11~> ¦
IR: ~C=0 1760 cm IR: uC=0 1770 cm
~ - N MMR(CF3COOH): ~ NMR(CF3COOH): ~
2H5- -CH2S ~ / 1.43(3H,t), 1.0- 1.43(3H,t), 1.0-2.4
CH3 2.4(20H,m),3.1- (20H,m), 3.0-3.6
3.6(2H,m),3.40(2H,q), (2H,m), 3.42(2H,q),
- 23 -
~52980
R A Starting compound Objectlve compound ¦
_
3.80(2H, broad s), 4.13 3.6(2H, not clear
(3H, s), 4.1-4.8(4H, m), because of overlapping),
4.97(2H, broad s), 5.23 3.67(3H,s), 4.12(3H,s),
(lH, d), 5.90(lH,q), 4.55(2H, broad s),
8.00(1H,d) 4.97(2H, broad s),
5.23(1H,s~,6.0-6.9
(2H, broad s), 8.23
(lH,s)
(W = H) (W'= ~ N ~ )
NMR(CF3COOH): ~ NMR(CF3COOH): ~
3.80(2H,s),4.10 1.0-2.3(20H,m), 3.0-
N- N
CH2- -CH2S~ N (3H,s), 4.57(2H,s), 3.6(2H,m), 3.5-3.7
N 4.65(2H,s), 4.67 (5H, not clear because
CH3 (2H,s), 5.23(lH,d), of overlapping)
5.86(lH,q), 7.46 4.06(3H, s)~ 4.55
(5H,s), 7.93(lH,d) (2H,s), 4.61(2H,s), -
4.67(2H,s), 5.18(1H,s~ r
7.43(5H,s~, 8.03(1H,s)
(W= ~ N ~ ) (W~- ~ N ~ )
NMR(CF3COOH): ~ NMR(CF3COOH): ~
N -INl 1.0-2.3(20H,m), 1.0-2.3(20H,m), 3.1-
H2=CH- CH2S ~ ~ 3.0-3.6(2H, broad s), 3.6(2H, broad s),
CH3 3.70(2H,s), 4.13 3.65(2H,s), 3.72(2H,s) r
(3H,s), 4.33-4.76 4.13(3H,s), 4.61(2H,s),
(2H,q), 4~87(2H,s~, 4.90(2H,s), 5.27(1H,s),
5.24(1H,d), 5.90(1H, 6.31-6.94(3H,m), 8.28
q), 6.3-6.7(3H,m) (lH,s)
_ 8.13(lH,d) _
- 24 -
liS2980
Starting compound Objection compouna
(W = ~ N ~ ) (W'= ~ N ~ )
NMR(CF3COOH): ~ NMR(CF3cOOH):
-1.0-2.3(20H,m), 1.0-2.3(20H,m),
3.1-3.6(2H, broad 3.1-3.6(2H, broad s),
CH2=CHCH2- -CH2S ~ ~ s), 3.77(2H,s), 3.65(2H,s), 3.72
CH 4.0-4.2(5H,m),4.3- (3H,s), 4.13(3H,s),
3 4.7(2H,q), 4.97 4.15(2H,d), 4.62(2H,s),
(2H,s), 5.20(1H,d), 5.03(2H,s), 5.27(1H,s),
5.43-6.17(4H,m), 5.47-6.17(3H,m), 8~22
7.99(lH,d) (lH,s)
Compounds obtained in the same manner as in Examples 1
and 2 and thiols were treated in the same manner as in Examples
3 to 6 to obtain the compounds described below.
.
- 25 -
llS2~80
_ ._ ... . ..
s~ a
a) ~ ~ c
a) ~ ~ Z=
~o ~ ~ I Z-c~
o ~: o 8 z~
o m N m
~ o ~ a) ~) O C' S: ~ O
8~ ~ o~ /~o, u~
~ ~ ~ x~ ~ m~ m~ ~1
~s~ o"".. ~ o.~ ~b
o ,1 o ~ 8~ 8N ~
~ a) ~ o ~q m c>
.G~ m~ mN ~
X-~ Z Z mN
. ._ .
o ' ~
~ ~ mN I .
. . . _
~ . ,
j~ U ~UZ ~ ~
~ ~ N m
$ ~ o~ u~
L 1~
-- 26 --
115Z980
~ _
a) ~
3~ ~ U Z=Zj ~7
U 0~1 a) I z--o
a) ~ z--~ ~ ~ z~
~ .~ x ~ \ m r u~
a) o o z~
~ R Cl ~ ~ ~ 0 3
E~ ~ ~
0~ U ~ ~ 0~ 0
4~ ~ ~ I o c~ m \\ o
~o ~ ~ / ( ~ o
~o, o ~ ~ '~' \~'' 6 \~
o ~ ~ 3 m r~ m~ \~z m
o ~ ~u u ~.~ ~o ~
z m N
r~ u~ l z m
O ~ Q ~1 0 ~ ~ O C,
~1 $ a~ U mN ~ \
~ o C) ~ `'
R ~ ~\
c) ~ ~ u~ z~ \Z m ~
R X ~l to U C)
o a) ~ ~ ~ 0 m =z ~ ~
. ~
m
z z m
o~z \=/
E~ ~:
.
z u ~ ~ m
~ ~ æ
~r1 U ~ N
~ i~ U~ UO~
L 1~ ~
-- 27 --
``` 115Z~B~
_ ~
~ ra
~ O) O ~ O ~
a) rQ X O ~ ) _
~w~ ~m ~N ~_~
r~ ,~, r~ ~ ~r~l o~
Jr~ O r l ~r^¦ ~ O ~ O ~ )
r~ r-l ~1 0 ~
n ~ cn
, = ~ r ~1 ~ Z
aD s-, O ~ ra ra ,~ ~ i~ I
r ¦ ~r l
Q X ~r l U~ ~ t) ~ .
O ~ Id ~ ~ ~
. . .. _. _
:C ~tC
o ~ 3 N
. . ._: ._ ___ . .. _ _
~r ~ ~ N :C
ul ;~_ ~ 'g ~o
r~ ~ ~tq~-)
O 0~ ~
o~ lu ~ z
~q ~ ~ ~
. ~ ~ ~
S~
.. _ ~ , ... ,.__~ . ~ . .
-- 28 --
