Note: Descriptions are shown in the official language in which they were submitted.
~3L917Z5~
This invention relates -to intermediates in a process
for produciny d 2-(2-aminothiazol-4-yl)glyoxylic acid deri-
va-tive or a salt thereo-f, ancl a process for producing the
intermediates.
This app1ication is a divisional application of co-
pending application No. 430,079 filed June 9, 1983.
2-(2-Amlnothiazol-4-yl)glyoxylic acid derivative
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 protected, are use-
ful starting materials for producing various cephalosporin
antibiotics, and as processes for producing said starting
compounds, there have hereto-Fore been known (1) a process
by which an es-ter of 2-[2-(protected or unprotected)amino-
thiazol-4-yl] ace-tic acid is oxidized with selenium dioxide
or potassium permanganate (Japanese Patent Applica-tion Kokai
(Laid-Open) No. 125,190/77 or 5,193~78) and (2) a process by
which an ester oF acetyl~lyoxylic acid is halogenated, -the
resulting halogena-tion product is reacted with thiourea,
and then the reac-tion product is hydrolyzed (Japanese Pa-tent
~pplications Kokai (Laid-Open) Nos. 112,895/78and 154,785/79).
Under such circurns-tances, in orcler to ~ind a novel
process for proclucing a compound represen-tecl by the ~eneral
Formula (I) or a salt thereof, the present inventors have
conducted extensive research. ~s a result, they have Found
a novel production process, which is describe(l hereinafter,
and moreover a novel intermediate used in said production
process and a process for proclucing the same.
In copending application No. ~30,079 there is pro-
vided a novel process for producing a 2-(2-aminothiazol-~-yl)-
glyoxylic acid derivative represented by the general Formula
(I) or a salt thereof.
The present invention provides a novel intermediate
for use in saicl procluction process, a compound represented by
the general formula (VIII) or a salt thereoF, which are
hereinaf-ter described.
1~
The present invention provides a process for pro-
ducing the intermediate.
This invention will be explained below in de-tail.
The invention oF the copending applica-tion relates
to a novel process for producing 2-(2~minothia~o~ -yl)
glyoxylic acid derivative represen-ted by the general formula
(I) or a salt thereo-f through the -Following produc-tion route:
z~
Dialkyl sulfoxide
or diaralkyl
sulfoxide 2
N -CCII X N 1 -C - C - SR
2 ~ , , ~
R S O oxidation S O O
(II) (III)
or a sal-t thereof or a sal-t thereof
Hydrolysis
~j
N ---1 C - C - 011
1~ ~J 11 11
R S O O
(.I)
or a salt thereof
1 wherein Rl is as defined above; Xl is a halogen atom; and
R2 is an alkyl group or an aralkyl group.
Protec-ting groups for the amino group of R
include all qroups which can usually be used as amino-
prokecting groups, and -there may be speciEically used,
or exarnple, easily removable acyl groups such as
trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyl-
oxycarbonyl, p-toluenesul~onyl, p-nitrobenzyloxyca.rbonyl,
o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chlo.roacetyl,
trifluoroacetyl, ~ormy:l, tert.-amyloxycarbonyl, -ter-t.-
butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,~-methoxy-
ben~yloxycarbonyl, 4-~phenylazo)benzyloxycarbonyl,
4-~4-metlloxyphellylazo)benzyloxycarbonyl, (pyridine-
l-oxide-2-yl)methoxycarbonyl, 2-furyloxycarbonyl,
-- 3 --
~L1972~
1 di.phenylmethoxycarbonyl, l,l-dime-thylpropoxycarbonyl,
isopropoxycarbonyl, l-cyclopropylethoxycarbonyl,
phthaloyl, succinyl, l-adamantyloxycarbonyl, 8-
quinolyloxycarbonyl 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-
naph-thylme~hylene, 3-hydroxy-4-pyridylmethylene, 1-
methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-
propylidene, 3-e-thoxycarbonyl-2-bu-tylidene, 1-acetyl-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-dime-thyl-5-oxocyclo-
hexylidene, (di-, -tri-)alkylsilyl groups and -the
like.
As the halogen atom for Xl, there may be
used, Eor example, a ~luorine atom, a chlorine atom,
a bromine atom, an iodine atom and the like.
As the alky.L group Eor R2, there may be used,
for e~ample, lower alkyl groups such as methyl, ethyl,
n-propyl and the like, and as the aralkyl group for R ,
-there may be used, Eor example, ar-lower-alkyl groups
such as a benzyl group ancl the l.ike.
The salt of the compound represented by the
general formula (I) includes sal-ts a-t the amino group or
_ L~
s~
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 acld, hyclrobromic
acid, hydrofluoric acid, sulfuric acld or the like;
salts with an oryanic carboxylic acid such as oxalic acid,
formic acid, trichloroacetic acid, trifluoroacetic acid
or the like; or salts with a sul~onic acid suc~ as
methanesulfonic acid, p-toluenesulfonic acid, 1- or 2-
naphthalenesulfonic acid or the like. As the salts
at the carboxyl group, there may be used, for example,
salts with an alkali metal atom such as sodium, po-tas-
sium or the like or salts with an alkaline earth metal
atom such as calcium, magnesium or the like.
The term "sal-t o~ the compound represen-ted by
the general formulas (II) or (III)" means a sal-t at -the
amino group in the formula (II) or (III), and includes
speciEically -the same salts as -those mentioned as the
salts at -the amino group of the compound represen-ted by
the general Eormula (I).
The reac-tion for obtainin~ a compound
represented by the general Eormula (III) or a salt
-thereo:E from a compound represented by the general
Eormula (II) or a salt tllereof is eEEected by reacting
the compound represented by the general Eormula (I:t) or
the salt thereoE with a dialkyl sul.Eoxide such as dimethyl
sulEo~ide, dietllyl sul~Eoxide, di-n-propyl suloxide or -the
li]ce or with a di.aral~cyl sulEoxide such as dibenzyl sulE-
7ZS~
1 oYide or -the like in a solvent iner-t to -the reaction, for
example, an alcohol SUCil as methanol, ethanol, isopropanol
or the like, an ether such as tetrahydrofuran, dio~ane or
the like, an amide such as N,N-dimethyl~ormamide, N,N-
S dimethylacetamide, hexamethyl phosphoramide or the like, ora mixed solvent thereof. The dialkyl sulfoxide or the
diaralkyl sulfoxide is preferably used in an amoun-t of 2.0
moles or more, more preferably 3.0 to 4.0 moles, per mole
o the compound represented by the yeneral formula (II) or
the sal-t thereof, and, if necessary, it may be used as a
solvent. When using a compound represen-ted by the general
formula ~II1 in which Xl is a chlorine atom, or a salt
thereof, it is preferable to eEfect the reaction in the
presence of a bromide such as hydrocJen bromide, po-tassium
bromide, ammonium bromide, triethylammonium bromide or -the
like, and the amo-mt of the bromide used in this reaction
is pre~erably 0.5 mole or more, more preferably 0.5 to 1.0
mole, per mole o~ the compound represented by the general
formula (II) or the salt -thereof. The reac-tion is completed
usually in 5 minutes to 20 hours at a reac-tion temperature
of 10 to 80~C. The reaction is accelerated by adding a
dialkyl sulEide such as d:imethyl sulfide, diethyl sul~ide
or the like, a cliallcyl disul.Eide such as dimetllyl disulEide,
diethyl disulEide or the like, a cliaralkyl sul~.ide such
as dibenzyl sul~ide or the like, a diaralkyl dis~ ide
such as dibenzyl disulEide or -the like, an alkyl
mercaptan such as methyl mercaptan, e-thyl mercaptan
or the like, or an aralkyl mercap-tan such as benzyl
1 mercaptan or the like in an amount of 1.0 mole or more
per mole oE the compound represented by -the general
formula (II) or the salt thereof.
By subjecting to usual hydrolysis the thus
obtained compound represented by the general formula (III)
or a salt thereof, it can be convexted into a compound
represen-ted by the general formula (I) or a sal-t thereof
which are useful in producing a cephalosporin compound.
The hydrolysis in this case is effected in water or an
alcohol such as me-thanol, 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 trie-thylamine, pyridine and the
like. These bases are used in an amount of 2.0 moles
or more per mole of the compound represented by the
general formula (III) or the salt thereof.
The compoundsrrepresented by the general Eormulas
(I), (II) and (I:~I) or salts thereoE ~orm adducts with
varlous solvents.
~ compound represented by -the ~eneral Eormula
(II) or a sal-t ~hereoE can b~ procluced in the following
manner:
-- 7
~7Z5~
llll Halogena- 00 Halogena~
CE~3CCCH3 >- XlCH2CCCH3 ~- X C112CCCH2X a
(IV) (V) (VIaJ
Ring
closure
R CSNH2
~ (VII)
N CCH2X
R ~ ~ o
(II)
or a salt thereoE
1 whe.rein Xl and X2a, which may be the same or different, are
halogen atoms, and Rl is as defined above.
X2a in the general Eormula lVIa) represents
a halogen atom such as a fluorine atom, a chlorine atom,
a bromine atom, an iodine atom or the like.
The halogena-tion or obtaining a l-halogeno-
butane-2,3-dione represented by the general ormula
(V) ~rom.butane-2,3-cl.ione representecl by the
formula ~IV~ ancl the halogenatiorl ~or obtaining a
1,~ d.ihalogenobutane-2,3-dione represented by the
gerlera:l formula (VIa) Erom a l-halo~enobutalle-2,3-
dione representecl by the general :Eormula (V) are effected
under -t.he same conditions. For example, they are eEEected
in the absence of a solven-t or in the presence of a solvent
-- 8 --
7ZS~
1 iner-t to the reacti.ons, e.g., an aromatic hydrocarbon
such as benzene, toluene, xylene or the like, an etller such
as diethyl ether, diisopropyl e.tller, tetrahydrofuran,
dioxarle or the li]ce, a halogena-ted hydrocarbon such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane or the like, a carboxylic acid such as
acetic acid or the like, or a mixed solven-t -thereo~.
As the halogenating agent, there may be used a
halogenatlng agent which is usually employed for
halogenating a paraffin. For example, as chlorinating
agents, there may be used chlorine, suluryl chloride,
N-chlorosuccinimide, N~chlorophthalimide and the like,
and as brominating agents, there may be used bromine,
sulEuryl 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 Eorlnula
~V). Although the reaction condi-tions may vary depending
on -the kinds o~ halognnating agents to be used and
~0 the like, reaction is usuall~ eEfected at a temperature oE
10C to the reElux tempera-ture o~ the solvent for a periocl
oE 30 minutes to 10 hours.
When a compound of the general :Eormula (V~a)
in whicll Xl and X2a a.re the same haloyen atollls ls
produced, dihalocJerlation may be e.~Eected in one step
b~ di.rectly reacting a halogenating agent with a
compound represented by the ~ormula (IV), in
an amount oE about 2 moles per mole of said compound.
~L9372S~
1 The reaction conditions in this case are the same as
mentioned above.
Preferable halogena~ions are reac-tions in which
the compound represented by the formu].a (IV) is first
chlorinated with sulfuryl chloride to obtain a compound
represented by -the general formula (V) wherein Xl is a
chlorine atom~ which is then brominated with bromine
to ob-tain a compound represented by the general
formula ~VIa) wherein X2a is a bromine a-tom.
Subsequen-tly, in order to obtain a compound repre-
sented by the general formula (II) or a salt thereof by
reactin~ a 1,4~dihalogenobutane-2,3-dione, Eor instance,
l-bromo-4-chlorobu-tane-2,3-dione with a thiourea represent-
ed by the general formula (VII), -the reaction is effected
in the presence of a solvent inert to the reaction, Eor
example, an alcohol such as methanol, ethanol, isopropanol
or the like, an ether such as tetrahydrofuran, dioxane
or the like, an amide such as N,N-dimethylEormamide, N,N-
dimethylacetamide, hexamethyl phosphoramide or the like,
or a mixed solvent thereo:E or a mixed solvent oE one or
more of them and water. The amount of the -thiourea of
the general Eormula ~VII) used may be 0.90 mole or more
per mole oE the compound o~ tlle general formula (VIa),
and is particularly pre.Eerabl~ 0.95 to 1.00 mole per
mole oF said compound. This rin~ closure reaction is completed usually
in 5 minutes to 20 hours at a reaction temperature oF -50 to 10C.
In copending application No.~f75,3~filed on even date
there is provided herewlth
- 10 _
~7%5~
1 a compound represen-ted by the general formula (VI) and the present in-
vention provicles a compound of the general Formula (VIII) shown below
or a salt o-f the compound of the general Formula (VIII), s~id compound
or salt being a novel and useful intermediate, and to a process for
producing the same: a 1,4-dihalogenobutane-2,3-dione represented by
the general formula:
~ 2
X CH2CCCH2X (VI)
wherein Xl and x2 represent different halogen atoms,
a 2-aminothiazole deriva-tive represented by the general
Eormula or a salt thereof:
N C - R3
Rl~ ~ ~ (VIII)
wherein Rl is as defined above and R3 is a mono-
halogenomethyl, an alkylthiocarbonyl or an aralkylthio-
carbonyl group.
The compounds represented by ~he general formulas
(VI) and ~VIII) and salts o the compounds oE the general
formula (VIII) are obtained by the process described above.
The compound represented by the general
~orMula (VIII) or the salt thereof includes the
above-mentioned compounds represented by the general
Eormulas (II) and (III) o.r salts thereo:E.
As the monohalogenollle-thyl group in R3,
-there may be used, Eor example, a chloromethyl group,
- 11 -
s~
1 a bromomethyl group, an iodomethyl group and the like;
as the alky].thiocarbonyl group, there may be used,
for example, a me-thyl-thiocarbonyl yroup, an ethylthio--
carbonyl group, a n-propylthiocarbonyl group and the
like; and as the aralkylthiocarbonyl group, t.here may
be used, for e~ample, a benzylthiocarbonyl group and
the like.
Among the compounds of -the general formula
(VIII), particularly preferable are compounds in which
10 R is an amino yroup or a formylamino group and R is a
chloromethyl group or a methylthiocarbonyl group.
With respect to the N ~ group in each oE
the above-mentioned general formulas, tautomers exist
as shown in the following equilibrium formulas and the
tautomers also are included in -this inven-tion:
~ la~ ~ ~
wherein Rla is an imino group which may be protected,
and Rl is as definecl above.
~ s the protecting group ~or the imino group
in Rla, tllere may be used the monovalent aminoprotecting
c3roups exp.lained in the case o~ R1.
Tlle present invention is explained below
- 12 -
5~
l referrin~ -to E~amples, which are not by way oE limita-
tion but by way of illustration~
Example l
(l) To a mixed solution of 172 g of butane-2,3-
dione and 172 ml of benzene was added dropwise 163 mlof sulfuryl chloride wlth s-tlrring at 60C over a period
of 3 hours. After completion of -the addi-tion, the thus
obtained reaction mixture was stlrred at said tempera-
ture for 1 hour and then under reflux for 1 hour, and
thereaf-ter rectified under reduced pressure to obtain
12g g (51.5% yield) of 1-chlorobu-tane-2,3-dione having
a boiling point of 53.5 to 55.0C/14 mmHg.
IR (neat) cm : VC O 1720.
NMR (CDCl3) ~ values:
2.45 (3H, s, -CCII3),
4.71 (2~l, s, ClCH2C-
~
t2) To a mixed solut.ion of 120.5 g oE l-chloro-
butane-2,3-clione and 120 ml oE dichloroethane was
added dropwise 160 g o~ bromine w:ith stirrin~ under
reflux over a periocl o~ 2 hours. ~;e ter completion oE
the addition, the thus ob-tained reaction mixture was
~urther stirred under re.~lu~ for 30 minutes, and then
cool.ed to 20C. The depos.ited crystals were collected by
~iltration, washed with dichloroe~hane, and then dried
-to obtain lO~ g (54.6~ yield) of 1-bromo-4-chiorobutane-
- 13 -
zs~
1 2,3-dione having a melting point of 120 to 121.5C.
IR (KBr) cm : Vc 0 1760, 1735
NMR (CD30D) ~ values:
3.70 (lH, s), 3.83 (lH, s), 4.63 (l~l, s),
4.81 (lH, s)
13) A suspension 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 solu-tion was stirred at said -tem-
perature for 4 hours, and the temperature of the solution
was raised to -20C over a period of 30 minutes, after which
the solution was further stirred at said temperature for
2 hours. Thereafter, the temperature of -the reac-tion
solution was raised to lOC oVer a period of l hour and
30 minutes to deposit white crystals. The crys-tals were
collected by filtration, washed with e-thanol~ and then
dried to obtain 24.9 g 181.8~ yield) of l:l solva-te o~
ethanol and the hydrobromide salt oE 2-amino-4-chloro-
acetyl-thiazole having a melting poin-t o~ 191C (decomp.).
IR IKBr) cm 1 vc~O 1695
NMR (d6-DMS0) ~ values:
l.09 ~311, -t, J=7.~1æ, C}13C~120~1),
3,54 12~:[, cl, J=7.5~Iz, C~l3CN20H),
5.17 ~2II, s, -fCII~Cl),
', O
II~N~ S ~ II
Br
7~
l Example 2
A mlxed solu-tion of 30.4 g of l:l solvate of
ethanol and hydrobromide salt oE 2-amino-4-chloroacetyl-
-thiazole, 91 ml of dime-thyl sulfoxide and 11.9 g of
potassium bromide was heated to 30C, and 8.9 ml of dimethyl
disulfide was added. . The resulting reaction mixture
was s-tirred a-t 30 to 35C for 2 hours, and -then
poured into 300 ml oE ice water.
Subsequently, the resulting mi~ture was
adjusted to pH 5.5 with sodium hydrogencarbonate. The
deposited solid was collected by filtration and dis-
solved in 80 ml of l N hydrochloric acid, and a small
amoun-t of the insoluble material was removed thereErom
by filtration, after wh.ich the filtrate was adjusted to
pH 5.5 with sodium hydrogencarbonate. The deposited
crystals were collected by filtrat.ion, washed with
water, and then dried to obtain 11.7 g (61.4% yield) o~
2-~2-aminothiazol-4-yl)thioglyoxylic S-acid me-thyl ester
haviny a melting point of 130C (decomp.).
IR (KBr) cm l vc=O 1675, 1650
NMR (d6-DMSO) S values:
2.45 (3H, s, -CSCEl3),
7.60 (2E-I, bs, H2N-~,
8.2~ (I.H, s, N
- 15 -
2~
.
1 Example 3
To 10.1 g of 2~(2-aminothiazol-4-yl)thiocJlyoxylic
S-acicl methyl ester and 80 ml of water was added 10.6 g
of sodium carbon~te wlth ice-cooling, and the resul-ting
mixture was s-tirred at the same tempera-ture.for 1 hour.
Subsequen-tly, the thus ob-tained reaction mix-ture was
adjus-ted to pH 2.5 with 6 N hydrochloric acid at the
same temperature. The deposited crystals were collected
by filtration, washed with waterl and then dried to
obtain 6.2 g (67.8% yield) of 2-(2-aminothia~ol-4~yl)-
glyoxylic acid having a melting poin-t of above 200C.
IR (KBr) cm 1 vc O 1660
NMR (d6-DMSO) ~ values:
.11 (lH, s, N 1l ) ~
~ S ~ H N
7.50 - 8.30 (2H, bs, H2N ~ ~ )
~xample 4
A mixture of 40.3 g oE acetic anhydride and
18.4 g oE formic acid was stirred at 40 to ~5C Eor
1 hour. To the resulting mixtur~ was added 20.2 g of
2-(2-aminothiazol-~-yl)th.ioglyoxylic S-acicl metyl
ester, with wa-ter-cooling, a;Eter which the resultincJ
mixture was stirred at 25C Eor 1 hour. Subsequently,
160 ml of water was aclded clropwise to the thus ob-tained
reactlon mixture with ice-cooling, aEter wh.ich the
resulting mixture was stirred ~ith water-cooling Eor
30 minutes, and the deposited crystaLs were collected by
- 16 -
~72S~I
1 EiLtration. The crystals were washed successively wi-th
water and acetone and then dried to obta.in 21.9 g
(94O4% yield) of 2-(2-ormylamino-thiazol-4-yl)-thioylyoxyl.ic
S-acid methyl ester hav.ing a melting point of above 230C.
IR (KBr) cm 1 vc O 1690, 1670, 1650
E~ample 5
In 50 ml of water was suspended 7.8 g oE 1:1
solva-te of ethanol and hydrobromide salt of 2-amino-4-
chloroacetylthiazole, and to the suspension was gradually
added 2.3 y of sodium hydrogencarbonate At 20C with
stirring over a period of 15 minutes. The deposi-ted
crystals were collected by filtra-tion, washed with
10 ml of water, and then dried -to obtain 4.5 g (98.8
yield) of 2-amino-4-chloroacetylthiazole having a
melting point of 147C (decomp.).
IR (KBr) cm 1 vc=O 1675, 1600
NMR (d6-DMSO) ~ values:
5.0 a ( 21I, s, -CCEl2Cl)~
o
`20 7~47 (2H, bs, E12N-),
7.80 (lH, s,. N -~r- )
S~EI
- 17 -
1 Example 6
(1) In 200 ml of wa-ter is suspended 23 g of 2-(2-
formylamino-thiazol-4-yl)-thioglyoxylic S-acid methyl
ester, and 125 m] of a 2 N aqueous sodium hydroxide
5 solution was added -there-to dropwise with water-cooling
over a period of 30 minutes, after which the resulting
mixture was stirred at room temperature for 1 hour.
Af-ter completion of the reaction, the thus obtained
reaction mix-ture was adjusted to pH 2.5 with 6 N hydro-
chloric acid. The deposited crys-tals were collec-ted
by filtration, washed successively with 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.
I~ (KBr) cm 1 vc O 1660
NMR (d6-DMSO) ~ values:
8.31 (lH, s),
8.60 (lH, s),
12.8 (lH, bs)
(2) 2-(2-Formylaminothiazol-~-yl)glyoxylic acid
was hydrolyzed accorcling to a coslventional method ko
obtain 2-(2--aminothiaæol-~~yl)cJlyoxylic ac:id.
rrhe physical properties oE this compound were
idesltical with those of -the compouncl ob-kainecl in Example 3.
- ~8 -
