Note: Descriptions are shown in the official language in which they were submitted.
This inven-tion relates to an in-termediate in a pro-
cess for producing a 2-(2-aminothiazol-4-yl)glyoxylic acid
derivative or a salt thereoF,
and a process for producing the intermed-iate.
This application is a divisional application of co-
pending application No. 430,079 filed June 9, 1983.
2-(2-Aminothiazol-4-yl)glyoxylic acid deriva-tive
represented by the general formula or salts thereof:
N C - C - OH (I)
R ~ ~ O O
wherein pl is an amino group which may be pro-tected, are use-
ful starting materials for producing various cephalosporin
antibiotics, and as processes for producing said starting
compounds, there have heretofore been known (1) a process by
which an ester of 2-[2-(protected or unprotected)amino-thiazol-
4-yl] acetic acid is oxidized with selenium dioxide or potas-
sium permanganate (Japanese Patent Application Kokai (Laid-
Open) No. 125,190/77 or 5,193/78) and (2) a process by which
an ester of acetylglyoxylic acid is halogenated, the result-
ing halogenation product is reacted with thiourea, and thenthe reaction product is hyrolyzed (Japanene Patent ApplicationS
Kokai (Laid-Open) Nos. 112,895/78 and 154,785/79).
Under such circumstances, in order to find a novel
process for producing a compound represented by the general
formula (I) or a salt thereof, the present inventors have
conducted extensive research. As a result, they have found
a novel production process, which is described hereinafter,
and moreover a novel intermediate used in said production
process and a process for producing the same. ;~
,,. .
~ .~
- 1 - ~.
31~
In copending app1ication No. 430,079 there is pro-
vided a novel process For producing a 2-(2-amino-thiazol-~-yl)-
glyoxylic acid derivative represented by -the general formula
(I) or a salt thereof.
The invention is to provide a novel intermediate
for use in said production process (a compound represented
by the general formula (VI) or a salt thereo-f, which are
hereinafter described.
The present inven-tion also provides a process for
producing the intermediate.
This invention will be explained below in detail.
The invention of the copending application relates
to a novel process for producing 2-(2-aminothiazol-4-yl)
glyoxylic acid derivative represented by the general formula
(I) or a salt thereof through the following production route:
. ~
-- 2
.
3;~
Dialkyl sulEoxide
or diaralkyl
1 sulfoxide 2
N - CCH2X N - -C - C - SR
R~ s~l o Oxidation ~ Rl~ S'
(II) (III)
or a salt thereof or a salt thereof
~ ~Iydrolysis
N C - C - OH
R ~ S~ O O
(I)
or a salt thereof
1 wherein Rl is as defined above; Xl is a halogen atom; and
R is an alkyl group or an aralkyl group.
Protecting groups for the amino group of R
include all groups which can usually be used as amino-
protecting groups, and there may be specifically used,for example, easily removable acyl groups such as
trichloroe~hoxycarbonyl, tribromoethoxycarbonyl, benzyl-
oxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl,
o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chloroacetyl,
trifluoroacetyl, formyl, tert.-amyloxycarbonyl, tert.-
butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-methoxy-
benzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,
4-(4-methoxyphenylazo)benzyloxycarbonyl, (pyridine-
l-oxide-2-yl~methoxycarbonyl, 2-furyloxycarbonyl,
3~
diphenylmetlloxycarbonyl, 1,l-dime~hylpropoxycarbonyl,
isopropoxycarbonyl, l-cyclopropylethoxycarbonyl,
phthaloyl, succinyl, l-adamantyloxycarbonyl, 8-
quinolylo~ycarbonyl and the like. Further, there may be
used other easily removable groups such as trityl, o-nitro-
phenylsulfenyl, 2,4-dinitrophenylsulfenyl, 2-hydroxy-
benzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-
naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-
methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-
propylidene, 3-ethoxycarbonyl-2-butylidene, 1-ace-tyl-2-
propylidene, l-benzoyl-2-propylidene, 1-[N-(2-methoxy-
phenyl)carbamoyl~-2-propylidene, 1-[N-(4-methoxyphenyl)-
carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclo-
hexylidene, 2-ethoxycarbonylcyclopentylidene, 2-
acetylcyclohexylidene, 3,3-dimethyl-5-oxocyclo-
hexylidene, (di-, tri-)alkylsilyl groups and the
like.
As the halogen atom for Xl, there may be
used, for example, a fluorine atoml a chlorine atom,
a bromine atom, an iodine atom and the like.
As the alkyl group for R2, there may be used,
for example, lower alkyl groups such as methyl, ethyl,
n-propyl and the like, and as the aralkyl group for R ,
there may be used, for example, ar-lower-alkyl groups
such as a benzyl group and the like.
The salt of the compound represented by the
general formula (I) includes salts at the amino group or
3;~
1 salts at the carboxyl group. ~s the salts at the amino
group, there may be used, for example, sal-ts with a
mineral acid such as hydrochloric acid, hydrobromlc
acid, hydroEluoric acid, sulfuric acid or the li]ce;
salts with an organic carboxylic acid such as oxalic acid,
formic acid, trichloroacetic acid, trifluoroacetic acid
or the like; or salts with a sulfonic acid such as
methanesulfonic acid, p-toluenesulfonic acid, 1- or 2-
naphthalenesulfonic acid or the like. As the sal-ts
at the carboxyl group, there may be used, ~or example,
salts with an alkali metal atom such as sodium, potas-
sium or the like or salts with an alkaline earth metal
atom such as calcium, magnesium or the like.
The -term "salt of the compound represented by
the general formulas (II) or (III)" means a salt at the
amino group in the formula (II) or ~III), and includes
syeciEically -the same salts as -those mentioned as the
salts at the amino group of the compound represented by
the general formula (I).
The reaction for obtaining a compound
represented by the general formula 1III) or a salt
thereof from a compound represented by the general
formula (II) or a salt thereof is effected by reacting
the compound represented by the general formula (II) or
the salt thereof with a dialkyl sulfoxide such as dimethyl
sulfoxide, diethyl sulfoxide, di-n-propyl sulfoxide or the
like or with a diaralkyl sulfoxide such as dibenzyl sulf-
1;~3Lt~3~
1 oxide or tlle llke in a solve~-t inert to the reaction, ~or
e~ample, an alcohol such as meti-anol, ethanol, isopropanol
or the like, an ether such as tetrahydrofuran, dio~ane or
the like, an amide such as N,N-dimethylformamide, N,N-
dimethylacetamide, hexamethyl phosphoramide or the like, ora mixed solvent thereof. The dialkyl sulfoxide or the
diaralkyl sulfoxide is pre~erably used in an amou~t of 2.0
moles or more, more preferably 3.0 to 4.0 moles, per mole
oE the compound represented by the general formula (II) or
the salt thereof, and, if necessary, it may be used as a
solvent. When using a compound represented by the general
formula (II) in which Xl is a chlorine atom, or a salt
thereof, it is preferable to effect the reac-tion in the
presence of a bromide such as hydrogen bromide, potassium
bromide, ammonium bromide, triethylammonium bromide or the
like, and the amount of the bromide used in this reaction
is preferably 0.5 mole or more, more preferably 0.5 to l.0
mole, per mole of the compound represented by the general
formula (II) or the salt thereof. The reaction is completed
usually in 5 minutes to 20 hours at a reaction temperature
of 10 to 80C. The reaction is accelerated by adding a
dialkyl sul~ide such as dimethyl sulide, diethyl sulfide
or the like, a dialkyl disulfide such as dimethyl disul~ide,
diethyl disulfide or the like, a diaralkyl sulfide such
as dibenzyl sulfide or the like, a diaralkyl disul~ide
such as dibenzyl disulfide or the like, an alkyl
mercaptan such as methyl mercaptan, ethyl mercaptan
or tha like, or an aralkyl mercap-tan such as benzyl
-- 6 --
, . .
.a~ 3~
1 mercaptan or -the like in an amount of 1.0 mole or more
per mole of the compound representecl by the general
formula (II) or the salt thereoE.
By subjecting to usual hydrolysis the thus
obtained compound represented by the general formula (III)
or a salt -thereof, it can be converted into a compound
represen-ted by the general formula (I) or a salt -thereof
which are useful in producing a cephalosporin compound.
The hydrolysis in -this case is effected in water or an
alcohol such as methanol, ethanol or the like, preferably
in the presence of a base. As the bases, there may be
used, for example, inorganic bases such as sodium hydroxide,
potassium hydroxide, barium hydroxide, calcium hydroxide,
sodium carbonate, potassium carbonate and -the like, or
organic bases such as triethylamine, pyridine and -the
like. These bases are used in an amoun-t of 2.0 moles
or more per mole of the compound represented by the
general formula (III) or the salt thereof.
The compounds represented by the general formuias
(I), ~II) and (III) or salts thereof form adduc-ts with
.various solvents, and all -the adducts are included in
this invention.
A compound represented by the general formula
(II) or a salt thereof can be produced in the following
manner:
3~i~
~ Elalogena~ Halogena- ll
CH3CCcH3 ~ XlCH2CCCT13 _iO~X C112CCC112X a
(IV) ~V) ~VIa)
Ring
closure
R CSNH2
(VII)
R ~ CCH2X
- ~ (II)
or a sal-t -thereof
1 wherein Xl and X2a, which may be the same or different, are
halogen atoms, and Rl is as defined above.
X in the general formula (VIa) represen-ts
a halogen atom such as a fluorine atom, a chlorine atom,
a bromine atom, an iodine atom or the like.
The halogenation for obtaining a l-halogeno-
butane-2,3-dione represented by the general formula
(V) from butane-2,3-dione represented by the
formula (IV) and the halogenation for obtaining a
1,4-dihalogenobutane-2,3-dione represented by the
general formula (VIa) from a l-halogenobutane-2,3-
dione represented by the general formula (V) are effected
under the same condi-tions. For example, they are effected
in the absence of a solvent or in the presence of a solvent
.a~ti3~
1 lnert to the reac-tions, e.g., an aromatic hydrocarbon
such as berlzene, toluene, xylene or the lilce, an ether such
as diethyl ether, diisopropyl ether, tetrahydrofuran,
dioxane or the like, a halogenated hydrocarbon such as
methylene chloride, chloroform, carbon te-trachloride,
dichloroethane or the like, a carboxylic acid such as
acetic acid or the like, or a mixed solvent thereof.
As -the halogenating agen-t, there may be used a
halogenating agen-t which is usually employed for
halogenating a paraffin. For e~ample, as chlorinating
agents, there may be used chlorine, sulfuryl chloride,
N-chlorosuccinimide, N-chlorophthalimide and the like,
and as brominating agents, there may be used bromine,
sulfuryl bromide, N-bromosuccinimide, N-bromophthalimide
and -the like. The amount of the halogenating agent
used is preferably about equimolar -to the compound
represented by the formula (IV) or the general formula
(V). Although the reaction conditions may vary depending
on the kinds oE halogenating agents to be used and
the like, reaction is usually effected at a temperature of
10C to the reflux temperature of the solvent for a period
of 30 ~inutes to 10 hours.
When a compound of the general formula (VIa)
in which Xl and X2a are the same halogen atoms is
produced, dihalogena-tion may be effected in one step
by directly reacting a halogenating agent with a
compound represented by the ~ormula (IV), in
an amount of about 2 moles per mole of said compound.
1 The reaction conditions in this case are tile same as
mentioned above.
Preferable h~logena-tions are reac-tions in which
-the compound represented by -the formula (IV) is first
chlorinated with sulEuryl chloride to obtain a compound
represen-ted by the general formula (V) wherein ~l is a
chlorine a-tom, which is -then brominated wi-th bromine
to obtain a compound represented by the general
formula (VIa) wherein X2a is a bromine atom.
Subsequen-tly, in order to obtain a compound~repre-
sen-ted by the general formula (II) or a salt thereof by
reacting a 1,9-dihalogenobutane-2,3-dione, for instance,
l-bromo-4-chlorobutane-2,3-dione with a thiourea represent-
ed by the general formula (VII), the reaction is effected
in the presence of a solvent iner-t to the reac-tion, for
example, an alcohol such as methanol, ethanol, isopropanol
or the like, an ether such as te-trahydrofuran, dio~ane
or the like, an amide such as M,N-dimethylformamide, N,N-
dimethylacetamide, hexamethyl phosphoramide or the like,
or a mixed solvent thereof or a mixed solvent of one or
more of them and water. The amount of the thiourea of
the general formula (VII) used may be 0.90 mole or more
per mole of the compound of the general formula (VIa),
and is particularly preferably 0.95 to l.00 mole per
mole of said compound. This ring closure reaction is
completed usually in 5 minutes to 20 hours at a reaction
temperature of -50 to 10C.
The present invention relates to
-- 10 _
~Zl~i3~
1 a compound representecl by -the general forl1lula (Vl) shown bel~w and co-
pending applica-tion No.47S,3~.~ filed on even date herewith provides
a compound represented by the general formula (VIII) or a salt of the
compound of the general formula (VIII), said compollnd or salt beiny a
novel and useful in-termediate, and to a process for producing the same:
a 1,~-dihalogenobutane-2,3-dione represented by the general formula
00
X CH2CCCH2X (VI)
wherein Xl and x2 represent different halogen atoms,
a 2-aminothiazole derivative represented by the general
formula or a salt thereof:
N C - R3
Rl~ (VIII)
wherein Rl is as defined above and R3 i9 a mono-
halogenomethyl, an alkylthiocarbonyl or an aralkylthio-
carbonyl group.
The compounds represented by the general formulas
(VI) and (VIII) and salts of the compounds of the general
formula (VIII) are obtained by the process described above.
The compound represented by the general
formula (VIII) or the salt thereof includes the
above-mentioned compounds represented by the general
formulas (II) and (III) or salts thereof.
As the monohalogenomethyl group in R3,
there may be used, for example, a chloromethyi group,
-- 11 --
3~
1 a bromomethyl group, an iodomethyl yroup and the llke;
as the alkylthiocarbonyl yroup, there may be used,
for example, a methylthiocarbonyl group, an ethylthio-
carbonyl group, a n-propyl-thiocarbonyl group and the
like; and as the aralkylthiocarbonyl group, there may
be used, for example, a benzylthiocarbonyl group and
the like.
Among the compounds of the general formula
(VIII), par-ticularly preferable are compounds in which
R is an amino group or a formylamino group and R is a
chloromethyi group or a methylthiocarbonyl group.
With respect to the N Irgroup in each of
RlJ~S~
the above-mentioned general formulas, tautomers exist
as shown in the following equilibrium formulas and the
tautomers also are included in this invention:
R ~ Rla ~ ~
wherein Rla is an imino group which may be protected,
and Rl is as defined above.
As the protecting group for the imino group
in Rla, there may be used the monovalent aminoprotecting
groups explained in the case of Rl~
. The present invention is explained below
3~L~
1 reEerring to Examples, which are not by way of llmita-
tion bu-t by way of illustration.
Example l
(1) To a mixed solution of 172 g of butane-2,3-
dione and 172 ml of benzene was added dropwise 163 mlof sulfuryl chloride with stirring at 60C over a period
of 3 hours. After completion of the addition, the thus
obtained reac-tion mixture was stirred a-t said tempera-
ture for 1 hour and then under reflux ~or 1 hour, ancl
thereafter rectified under reduced pressure to obtain
124 g (51.5-~ yield) of 1-chlorobutane-2,3-dione having
a boiling point of 53.5 to 55.0C/14 mmHg.
IR (neat) cm : Vc O 1720
NMR (CDC13) ~ values:
2.45 (3H, s, -fCH3),
o
4.71 (2H, s, ClCH2C-~
o
(2) To a mixed solution of 120.5 g of l-chloro-
butane-2,3-dione and 120 ml of dichloroethane was
added dropwise 160 g of bromine with stirring under
reflux over a period o~ 2 hours. ~Eter completion of
the addition, the thus obtained reaction mixture was
further stirred under reflux for 30 minutes, and then
cooled to 20C. The deposited crystals were collected by
filtration, washed with dichloroethane, and then dried
to obtain 109 g (54.6~ yield) of 1-bromo-4-chiorobutane-
- 13 -
3:~
1 2,3-dio~e having a melting point of 120 to 121.5C.
IR (RBr) cm : Vc O 1760, 1735
NMR (CD30D) ~ values:
3.70 (lH, 5), 3.83 (lH, s), 4.63 (lH, s),
4.81 (lH, s)
(3) A ~uspension consisting of 20.0 g of l-bromo-
4-chlorobutane-2,3-dione and 140 ml of ethanol was cooled
-to -35C, and 7.3 g of thiourea was added with stirring.
The resulting reaction solution was stirred at said tem~
perature for 4 hours, and the temperature of the solution
was raised to -20C over a period oE 30 minutes, after which
the solution was further stirred at said tempera-ture for
2 hours. Thereaf-ter, the temperature of the reac-tion
solution was raised to 10C over a period of 1 hour and
30 minutes to deposit white crystals. The crystals were
collected by filtration, washed with ethanol, and then
dried to obtain 24.9 g (81.8~ yield~ of 1:1 solvate of
ethanol and the hydrobromide salt of 2-amino-4-chloro-
acetylthiazole having a melting point of 191C (decomp.).
IR ~KBr) cm : vC=O 1695
NMR (d6-DMSO) ~ values:
1.09 (3H, t, J=7.5Hz, CH3CH2OH),
3.54 (2H, q, J=7.5Hz, CH3CH2OH),
5.17 (2H, s, -CCH2Cl),
8.40 (4H, bst N 11
~ ~ S ~ H
--;~3 ' ~
Br
- 14 -
3~
1 Example 2
A mixed solution of 30.4 g of 1:1 ~olvate of
ethanol and hydrobromide salt of 2-amino-4-chloroacetyl-
thiazole, 91 ml oE dimethyl sulfoxide and 11.9 g oE
potassium bromide was heated to 30C, and 8.9 ml of dimethyl
disulfide was added. .The resulting reaction mixture
was stirred at 30 to 35C for 2 hours, and then
poured into 300 Ml of ice water.
Subsequently, the resulting mixture was
adjusted to pH 5.5 with sodium hydrogencarbonate. The
deposited solld was collected by filtration and dis-
solved in 80 ml of 1 N hydrochloric acid, and a small
amount of the insoluble material was removed therefrom
by filtration, after which the filtrate was adjusted to
pH 5.5 with sodium hydrogencarbonate. The deposited
crystals were collected by filtration, washed with
water, and then dried to obtain 11.7 g (61.4~ yield) of
2-(2-aminothiazol-4-yl)thioglyoxylic S-acid methyl ester
having a melting point of 130C (decomp.).
IR (KBr) CM 1: Vc_o 1675, 1650
NMR (dG-DMSO) ~ values:
2.45 (3H, s, -CSCH3),
. O
7.60 (2H, bs, H2N-~,
8.24 (lH, s, N 11 - )
S ~ H
- 15 -
3~Li3
1 Example 3
lo 10.1 g of 2-(2-aminothiazol-4-yl)tllio~lyoxylic
S-acid methyl ester and 80 ml oE water was added 10.6 g
of sodium carbona-te with ice-cooling, and the resulting
mixture w~s stirred at the same temperature.for 1 hour.
Subsequently, tlle thus obtained reaction mixture was
adjusted to pH 2.5 wi-th 6 N hydrochloric acid at -the
same temperature. The deposi-ted crystals were collected
by Eiltration, washed with water, and then dried to
obtain 6.2 g (~7.8~ yield) of 2-(2-aminothiazol-4-yl)-
glyoxylic acid having a melting poin-t of above 200C.
IR (KBr) cm : Vc O 1660
NMR (d6-DMSO) ~ values:
8.11 (lH, s, N
~ S ~ H N
7.50 - 8.30 (21l, bs, H2N ~ ~ )
Example 4
A mixture of 40.8 g of ace-tic anhydride and
18.4 g o~ formic acid was stirred at 40 to 45C for
1 hour. To the resulting mixture was added 20.2 g of
2-(2-aminothiazol-4-yl)thioglyo.yylic S-acid metyl
ester, with water-cooling, after whi~ch the resul-ting
mixture was stirred at 25C for 1 hour. Subsequently,
160 ml of water was added dropwise to the thus obtained
reac-tion mixture with ice-cooling, after which the
resulting mixture was stirred ~ith water-cooling for
30 minutes, and the deposited crystals were collected by
- 16 -
~L2~ D
Eiltration. The crystals were washed successively with
water and acetolle and then dried to obtain 21.9 g
(94.4~. yield) o~ 2-(2-Eormylaminothiazol-4-yl) thioylyoxylic
S-acid methyl ester having a melting point oE above 230C.
IR (KBr) cm : VC O 1690, 1670, 1650
E~cample 5
In 50 ml o~ water was suspended 7.8 g oE 1:1
solvate of ethanol and hydrobromide salt of 2-amino-4-
chloroacetylthiazole, and -to the suspension was gradually
10 added 2.3 g of sodium hydrogencarbonate at 20C with
stirring over a period of 15 minutes. The deposited
crystals were collected by filtration, washed with
10 ml of water, and then dried to obtain 4.5 g 198.8%
yield) of 2-amino-4-chloroacetylthiazole having a
15 melting point of 147C (decomp.).
IR (KBr) cm : v C=O 1675, 1600
NMR (d6-DMSO¦ ~ values:
5.0Q (2H, s, -CCH2Cl),
7.47 (2H, bs, H2N--I,
7.80 (lH, s,
- 17 --
~2.~L~3~
.
1 Example 6
(1) In 200 ml oE water is suspended 23 g of 2-(2-
formylamlnothiazol-4-yl)thioglyoxylic S-acid methyl
ester, and 125 ml of a 2 N aqueous sodium hydroxide
solution was added thereto dropwise with water-cooling
over a period of 30 minutes, after which the resulting
mixture was stirred at room temperature for 1 hour.
After completion of the reaction, the thus o~tained
reaction mixture was adjusted to pH 2.5 with 6 N hydro-
chloric acid. The deposited crystals were collectedby filtration, washed successively wi-th water and
acetone, and then dried to obtain 16.2 g (81.6~ yield)
of 2-(2-formylaminothiazol-4-yl)glyoxylic acid having a
melting point of above 210C.
IR (KBr) cm : Vc O 1660
NMR (d6-DMS0~ ~ values:
8.31 (lH, s),
8.60 (lH, s),
12.8 (lH, bs)
(2) 2-(2-Formylaminothiazol-4-yl)glyoxylic acid
was hydrolyzed according to a conventional method to
obtain 2-(2-amino-thiazol-4-yl)glyoxylic acid.
The physical properties of this compound were
identical with those of the compound obtained in Example 3.
- 18 -
