Note: Descriptions are shown in the official language in which they were submitted.
Novel cephalosporin compounds and preparation thereof
This application has been divided out of Canadian
Patent Application Serial No. 433,824 filed August 3, 1983
entitled "Novel Cephalosporin Compounds and Preparation
Thereof".
This invention relates to novel thiazolylacetic acid
derivatives of the formula:
R~-~TH~ 2
- N~ (II)
O~
C'l
( C ~ )
O~
1 1
wherein R is hydrogen or lower alkyl, R is a protecting
group and n is an integer of 2 or 3, and processes for
preparing the same.
The compounds of formula (II) of the present inven-
tion are novel and are useful as an intermediate in the
preparation of cephalosporins.
Among the compounds of the present invention, pre-
ferred compounds include those of the formula (II) in
which Rl is hydrogen or lower alkyl such as methyl,
ethyl or propyl; R is lower alkanoyl such as formyl,
acetyl and pivaloyl, mono-, di- or trihalogeno-lower
alkanoyl such as chloroacetyl and trifluoroacetyl, lower
~.
alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl
and tert.-butoxycarbonyl, substituted or unsubstituted
benzyloxycarbonyl such as benzyloxycarbonyl and p-
methoxybenzyloxycarbonyl, substituted or unsubstituted
phenyl-lower alkyl such as p-methoxybenzyl, benzyl and
3,4-dimethoxybenzyl, or di- or triphenyl lower alkyl
such as benzhydryl and trityl; and n is an integer of
2 or 3. More preferred compounds include those of the
formula (II) in which Rl is hydrogen or methyl, R4 is
trityl and n is an integer of 2 or 3. A most preferred
compound is the compound of the formula (II) in which
is hydrogen, R4 is trityl and n is the integer 2. In
addition, the structural formula (II) shown above is
intended to show that the isomeric configuration of
the oxyimino group is the Z (i.e., syn)-configuration.
Although the ~ (i.e., syn)-isomers of the invention are
preferred, they may coexist with the E(i.e., anti)-isomers
due to isomerization during the chemical preparation.
Moreover, while the compound of formula (II) can exist
in the form of two optical isomers due to an asymmetric
carbon involved in the group of the formula:
~ (CH2)n
-C*H N-R
CO
(wherein the asterisk denotes an asymmetric carbon atom),
either optical isomer of the compound of formula (II) or a
racemic modification thereof are included within the scope
of the present invention. ~hroughout the specification
and claims, "levorotatory isomer" of the compound of for-
mula (II) in which Rl is hydrogen and n i9 the integer 2means that the absolute configuration of said compound at
said asymmetric carbon atom is the S-configuration and
"dextrorotatory isomer" means that the absolute config-
uration of said compound at said asymmetric carbon atom
is the R-configuration.
According to the present invention, the compound of
formula (II) can be prepared by reacting a compound of the
formula:
~S 1I N (VI)
- OH
wherein R4 is as defined above, with a compound of the
formula:
/ (CH2)n~
X-CH N-R (IX)
~CO~
wherein X is halogen and Rl and n are as defined above,
to give a compound of the formula:
~/ N 1I C--CO C H (VTI )
O
\C~
( C~,~ 2 )
O =C - N
R
wherein R , R and n are as defined above, and then hydro-
lyzing the compound of formula (VII). Alternatively, the
compound of formula (II) can be prepared by hydrolyzing
the compound of formula (VI) to give a compound of the
formula:
~,4 -N a~ 2
S ~ (VI-~I)
~OH
wherein R is as defined above, and reacting the compound
of formula (VIII) with the compound of formula (IX).
The reaction of the compounds of formulae (VI) and
(IX) or the reaction of the compounds of formulae (VIII)
and (IX) is carried out in the presence of an acid accep-
tor in a solvent. Examples of the acid acceptor include
alkali metal carbonates such as potassium carbonate and
sodium carbonate; alkali metal hydrides such as sodium
hydride; and alkali metal hydroxides such as sodium
~L~
hydroxide and potassium hydroxide. Acetone, tetrahydro-
furan, ethyl acetate, dimethylsulfoxide and dimethylform-
amide are suitable as the solvent. It is preferred to
carry out the reaction at a temperature of 10 to 80C,
especially at 10 to 50C.
The hydrolysis of the compound of formula (VII) or
(VI) is carried out by treating it with an alkali agent
or an acid in a solvent. Examples of the alkali agent
include alkali metal hydroxides such as sodium hydroxide
and potassium hydroxide; an alkali earth metal hydroxide
such as calcium hydroxide and barium hydroxide. Examples
of the acid include hydrochloric acid and hydrobromic
acid. Lower alkanol (e.g., methanol, ethanol), dimethyl-
ormamide and a mixture of said solvent and water are
suitable as the solvent. It is preferred to carry out
the reaction at a temperature of 10 to 80C, especially
at 20 to 60C. As mentioned hereinbefore, the compound
of formula (II) involves two optical isomers due to the
asymmetric carbon involved in the group of the formula:
~(CH2)n\
-C*H N-R
~CO
~wherein the asterisk denotes an asymmetric carbon atom).
If required, however, such optical isomers may be sep-
arated into each optical isomer by optical resolution
thereof. For example, the compound of formula (II) in
which Rl is hydrogen, n is the integer 2 and R~ is trityl
can be readily separated into each optical isomer by
reacting the racemic modification of the compound of
formula (II) with L- or D-phenylalanine methyl ester in
a solvent (e.g., a mixture of methanol and dioxane) to
Eorm the diastereoisomeric salts thereof, and separating
said diastereoisomers into each component thereof by
selective recrystallization. By selective recrystalliza-
tion, the least soluble diastereoisomer is recovered ascrystals Erom the reaction mixture and the more soluble
diastereoisomer remains soluble therein. It is preferred
to carry out the selective recrystallization at a tempera-
ture of 10 to 40C.
The compound of formula (II) of the present invention
is useful as an intermediate in the synthesis of cephalo-
sporin compounds. For example, a cephalosporin compound
of the formula:
//~ ~ C--CON~
~ O ~ 2 ~ (I)
~C~ 00
I (CH~)
O =C - N
11 .
wherein Rl and n are as defined above, is prepared by
condensing the compound of formula (II) with a compound
of the formula: ~ S
o= L N ~ ca2 N
COO
and then removing the protecting group from the resultant
compound. The cephalosporin compound of formula (I) shows
excellent antimicrobial activity upon either gram-positive
or gram-negative bacteria. To illustrate more specifical-
ly, for example, the levorotatory isomer of the compound
of formula ~I) in which R is hydrogen and n is the integer
2, i.e., 7~-{(Z)-2-(2-aminothiazol-4-yl)-2-[(2-pyrrolidon-
3-yl)oxyimino]acetamido}-3-(1-pyridiniomethyl)-3-cepham-4-
carboxylate, exhibits the minimum inhibitory concentration
(M.I.C.) (Agar dilution method, cultured for 20 hours at
37C) o~ 1~.5 ~g/ml against Streptococcus faecalis CN 478,
while the M.I.C. of Cefmenoxime [Chemical name: 7~-[(Z)-
2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(1-
methyl-lH-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic
37~3
-- 6
acid] and Ceftazidime [Chemical name: 7~-[(Z)-2-~2-amino-
thiazol-4-yl)-2-(2-carboxyprop-2-yloxyimino)acetamido]-3-
(l-pyridiniomethyl)-3-cephem~4-carboxylate] against said
microorganism aré more than 100 ~g/ml.
Practical and presently-preferred embodiments of the
present invention are illustratively shown in the follow-
ing Examples. Throughout the specification and claims,
the term "lower alkyl", "lower alkoxy" and "lower alkanoyl"
should be interpreted as referring to alkyl having one to
four carbon atoms, alkoxy having one to four carbon atoms
and alkanoyl having two to five carbon atoms, respectively.
Examp_ _
tl) 15.8 g of ethyl (Z)-2-(2-tritylaminothiazol-
4-yl)-2-hydroxyiminoacetate were dissolved in 70 ml
of dimethylsulfoxide, and 5.8 g of anhydrous potassium
carbonate were added thereto. The mixture was stirred
at room temperature for 20 minutes. 6~6 g of 3-bromo-2-
pyrrolidone were added to said mixture, and the mixture
was stirred at room temperature for 20 hours. The mixture
~0 was poured into 800 ml of water, and crystalline precipi-
tates were collected by filtration and washed with water.
The crystals were dissolved in chloroform, washed with
water and then dried. Then, the chloroform solution was
evaporated under reduced pressure to remove the solvent.
100 ml of ethyl acetate were added to the residue, and
allowed to stand at room temperature. Crystalline preci-
pitates thus obtained were collected by filtration and
dried. 16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-
yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate were obtained.
M.p. 209 - 210C
NMR (CDC13)~: 1.30 (3H, t, J= 7Hz), 2.1 - 2.6 (2H, m)
3.1 - 3.6 (2H, m), 4.34 (2H, q, J= 7Hz)
4.90 (lH, t, J= 7Hz), 6.53 (lH, s)
7.0 - 7.6 (17H, m)
16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-
2-[(2-pyrrolidon-3-yl)oxyimino]acetate were added to a
-- 7
mixture of 160 ml oE methanol and 30 ml oE an aq~leous 2N
sodium hydroxide solution, and the mixture was refluxed
for 30 minutes under heating. After cooling, crystalline
precipitates were collected by filtration and washed with
5 methanol. The crystals were suspended in 30 ml of water.
Then~ the suspension was adjusted to pH 3 with 2N hydro-
chloric acid. Crystalline precipltates were collected
by filtration and dried. 11.4 g of (z)-2- (2-tritylamino-
thiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid
10 were obtained.
M.p. 150 - 153C (decomp.)
NMR (DMSO-d6) ~: 1.8 - 2.4 (2H, m), 2.9 - 3.4 (2H, m)
4.63 (lH, t, J= 7Hz), 6.76 (lH, s)
6.9 - 7.6 (lSH, m), 7.85 (lH, s)
8.70 (lH, broad s)
(2) 30 9 of (Z)-2- (2-tritylaminothiazol-4-yl)-2- [(2-
pyrrolidon-3-yl)oxyimino]acetic acid and 60 ml of methanol
were added to 100 ml of dioxane containing 10.5 g of
methyl L-phenylalaninate, and the mixture was heated at
50C to dissolve said acid therein. 700 ml of dioxane
were added to the solution, and the mixture was stirred
at room temperature for 5 hours. Crystalline precipitates
were collected by filtration (the filtrate is hereinafter
referred to as "Filtrate I"), and 14.3 9 of the crude
product thus obtained were dissolved in 24 ml of methanol.
280 ml of dioxane were added to the methanol solution.
The mixture was stirred at room temperature for 4 hours,
and crystalline precipitates were collected by filtration
(the ~iltrate is hereinafter referred to as "Filtrate
II"). 12.2 9 of (Z)-2- (2-tritylaminothiazol-4-yl)-2- [(2-
pyrrolidon-3-yl)oxyimino]acetic acid (Q-isomer) methyl
L-phenylalaninate salt were obtained.
[a] D ~ 14.0 (C = 1, methanol)
12.2 9 of the above-mentioned salt were dissolved in
120 ml of methanol, and 176 ml of O.lN hydrochloric acid
-- 8
were added thereto. The mixture was stirred for 2 hours
under ice-cooling. Crystalline precipitates were col-
lected by filtration and washed with methanol. 7.5 g of
(Z)-2- (2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)-
5 oxyimino]acetic acid (Q-isomer) were obtained. Another
designation of this levorotatory isomer was shown as
(Z)~2-(2-tritylaminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-
3-yl)oxyimino]acetic acid.
M.p. 142 - 143C (decomp.)
[c~] D ~ 38.8 (C = 1, dimethylformamide)
(3) Filtrate I & II as obtained in the above men-
tioned paragraph (2) were condensed to dryness under
reduced pressure. The residue was dissolved in 250 ml
o~ methanol and then 450 ml o 0.1 N hydrochloric a^id
were added dropwise to the solution. The mixture was
stirred for 2 hours under ice-cooling. The resulting
crystalline precipitates were collected by filtration,
washed with methanol, and dried. 20 g of (Z)-2-(2-tri-
tylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]-
acetic acid (containing excess of the d-isomer) were
obtained. 20.0 g (Z)-2- (2-tritylaminothiazol-4-yl)-2-
[(2-pyrrolidon-3-yl)oxyimino]acetic acid thus recovered
and 40 ml of methanol were added to 70 ml of dioxane
containing 7.0 g of methyl D-phenylalaninate, and the
mixture was heated at 50C to dissolve said acid therein.
450 ml of dioxane were added to said solution. Then, the
mixture was stirred at room temperature for 4 hours, and
crystalline precipitates were collected by filtration.
13.3 g of the crude product thus obtained were dissolved
in 20 ml of methanol, and 260 ml of dioxane were added
thereto. The mixture was stirred at room temperature
for 4 hours. Crystalline precipitates were collected by
~iltration. 12.0 g of (Z)-2- (2-tritylaminothiazol-4-yl~-
2-[(~-pyrrolidon~3-yl)oxyimino]acetic acid (d-isomer)
methyl D-phenylalaninate salt were obtained.
~2~ g
- 9
[~X] D ~ 13.9 (C = 1, methanol)
12.0 g of the above-mentioned salt were dissolved in
120 ml of methanol, and 174 ml of 0.1 N hydrochloric acid
were added thereto. The mixture was stirred for 2 hours
5 under ice-cooling. Crystalline precipitates were col-
lected by filtration and washed with methanol. 7.3 g of
(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)-
oxyimino]acetic acid (d-isomer) were obtained. Another
designation of this dextrorotatory isomer was shown as
(Z)-2- (2-tritylaminothiazol-4-yl)-2- [((3R)-2-pyrrolidon-
3-yl)oxyimino]acetic acid.
M.p. 143 - 144C (decomp.)
[~] T2)5 + 37.4 (C = 1, dimethylformamide)
Example 2
2.7 g of ethyl (Z)-2- (2-tritylaminothiazol-4-yl)-2-
hydroxyiminoacetate were dissolved in 12 ml of dimethyl-
sulfoxide, and 1.0 g of anhydrous potassium carbonate was
added thereto under nitrogen gas atmosphere. The mixture
was stirred at room temperature for 10 minutes. 1.2 g of
20 1-methyl-3-bromo-2-pyrrolidone were added to the mixture,
and the mixture was stirred at room temperature for 5
hours. The reaction mixture was poured into 100 ml of
water, and crystalline precipitates were collected by
filtration. The crystals were dissolved in ethyl acetate,
25 and the solution was washed with water and then dried.
The solution was conce~ntrated under reduced pressure to
remove solvent. Then, the residue was crystallized with
isopropyl ether and collected by filtration. 2.1 g of
ethyl (Z)-2- (2~tritylaminothiazol-4-yl)-2-[(1-methyl-2-
30 pyrrolidon-3-yl)oxyimino~acetate were obtained.
NMR (CDC13) ~: 1.30 (3H, t, J= 7Hz), 2.0 - 2.7 (2H, m)
2.88 (3H, s), 3.0 - 3.6 (2H, m)
4-34 t2H, q, J= 7Hz), 4.92 (lH, t,
J= 7Hz), 6.54 (lH, s), 6.87 (lH, s)
7.0 - 7.5 (15T-T, m)
2.7 g of ethyl (Z)-2~(2-tritylaminothiazol-4-yl)-
2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate were
suspended in 27 ml of methanol, and 4.9 ml of 2N sodium
hydroxide solution were added thereto. The mixture was
refluxed for 20 minutes under heating. After cooling,
the mixture was concentrated under reduced pressure to
remove methanol. The residue was adjusted to pH 3 with
2N hydrochloric acid and extracted with ethyl acetate.
The extract was dried and evaporated under reduced pres-
sure to remove solvent. Then, the residue thus obtainedwas crystallized with ether and collected by filtration.
2.15 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-
~-pyrrolidon-3-yl)oxyimino]acetic acid were obtained.
~5.p. 142 - 145C (decomp.)
NMR (DMSO-d6)~: 2.0 - 2.5 (2H, m), 2.77 (3H, s)
3.1 - 3.4 (2H, m), 4.78 (lH, t, J= 8Hz)
6.87 (lH, s), 6.9 - 7.5 (16H, m)
Example 3
1.3 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxy-
iminoacetic acid were dissolved in 10 ml of dimethylform-
amide, and 0.24 g o~ sodium hydride (60~ oil dispersion)
was added thereto. The mixture was stirred at room tem-
perature for 15 minutes. 0.65 g of 3-bromo-2-piperidone
was added to the mixture, and the mixture was stirred at
room temperature for 1.5 hours. The reaction mixture
was poured into water and washed with a mixture of ethyl
acetate and tetrahydrofuran (1:1). The aqueous layer was
adjusted to pH 3 with 10% hydrochloric acid and extracted
with a mixture of ethyl acetate and tetrahydrofuran (1:1).
The extract was dried and concentrated to dryness under
reduced pressure. Then, ether was added to the residue,
and the resulting powder was collected by filtration. The
powder (1.3 g) was purified by silica gel chromatography
(solvent, methanol: chloroform = 104). 0.85 g of (Z)-2-
tritylaminothiazol-4-yl)-2~[(2-piperidon-3-yl)oxyimino]-
acetic acid were obtained.
M.p. 145 - 150C (decomp.)
Preparation of ComPound (I)
. _
1.~1 g of oxalyl chloride were added at -5 to 0C to
45 ml of chloroform containing 1.15 ml of dimethylform-
amide, and the mixture was stirred at the same temperature~or 15 minutes. A solution of 4.90 g of (Z)-2-(2-trityl-
aminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic
acid (Q-isomer) and 0.97 g of triethylamine in 45 ml of
chloroform was added to said mixture at -30C. The mix-
ture was stirred at the same temperature for 5 minutes.Then, a solution of 7~-amino-3-~1-pyridiniomethyl)-3-
cephem-~-carboxylate in chloroform (said solution was
prepared by suspending 5.8 g of the dihydrochloride of
said cephem compound in 45 ml of chloroform and adding
12.7 ml of N,O-bis(trimethylsilyl)acetamide thereto to
dissolve said salt therein) was added to the said mixture
at -30 to -10C. After the mixture was stirred at the
same temperature for 30 minutes, said mixture was concen-
trated to dryness under reduced pressure. 100 ml of 80
20 aqueous formic acid were added to the residue, and said
aqueous mixture was stirred at room temperature for one
hour. 110 ml of water were added to the mixture, and the
insoluble materials were filtered off. The filtrate was
washed with ethyl acetate and was concentrated to dryness
under reduced pressure. The residue thus obtained was
dissolved in water and chromatographed on a column of
non-ionic polymer resin Diaion HP-20 (registered trade
mark, manufactured by Mitsubishi Chemical Industries Ltd.,
Japan). The column was washed with water, followed by
elution with 20~ aqueous methanol. The fractions con-
taining the cephalosporin compound were collected and
concentrated to dryness under reduced pressure. ~cetone
was added to the residue, and the resulting powder was
collected by filtration. 2.22 g of 7~-{(Z)-2-(2-amino-
thiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetamido}-
3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (Q-isomer)
~2~7~
- 12 -
were obtained. Another designation of this levorotatory
isomer was shown as 7~-{(Z)-2-(2-aminothiazol-4-yl)-2-
[((3s)-2-pyrrolidon-3-yl)oxyimino]acetamido~-3-(l-pyri
diniomethyl)-3-cephem-4-carboxylate.
NMR (D20)~: 2.2 - 2.7 (2H, m), 3.1 - 3.8 (4H, m)
5.05 (lH, t, J= 7Hz), 5.28 (lH, d, J= 5Hz),
5.36 (lH, d, J=14Hz), 5.63 (lH, d, J=14Hz),
5.87 (lH, d, J= 5Hz), 6.98 (lH, s),
8.10 (2H, t, J=7.5Hz), 8.57 (lH, t, J=705Hz)
8.98 (lH, d, J= 7.5Hz)
[~] D - 38.0 (C = 1, H20)
