CA1216310A - Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates - Google Patents
Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediatesInfo
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- CA1216310A CA1216310A CA000475356A CA475356A CA1216310A CA 1216310 A CA1216310 A CA 1216310A CA 000475356 A CA000475356 A CA 000475356A CA 475356 A CA475356 A CA 475356A CA 1216310 A CA1216310 A CA 1216310A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Abstract for Divisional Application II
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for producing a novel compound represented by the following formula which are useful intermediate for 2-(2-aminothiazol-4-yl)glyoxylic acid derivative or a salt thereof,
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for producing a novel compound represented by the following formula which are useful intermediate for 2-(2-aminothiazol-4-yl)glyoxylic acid derivative or a salt thereof,
Description
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.
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:
. ~
.
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:
. ~
.
3;~
Dialkyl sulEoxide or diaralkyl 1 sulfoxide 2 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,
Dialkyl sulEoxide or diaralkyl 1 sulfoxide 2 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 , . .
.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 (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 X CH2CCCH2X (VI) wherein Xl and x2 represent different halogen atoms, a 2-aminothiazole derivative represented by the general formula or a salt thereof:
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, 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-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),
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 , . .
.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 (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 X CH2CCCH2X (VI) wherein Xl and x2 represent different halogen atoms, a 2-aminothiazole derivative represented by the general formula or a salt thereof:
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, 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-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 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
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 ~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, ~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.
--;~3 ' ~
Br 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
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 ~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, ~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.
Claims (5)
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a 1,4-dihalogenobutane-2,3-dione represented by the general formula:
(VI) wherein X1 is a halogen atom, and X2 is a halogen atom different from X1, which comprises reacting butane -2,3-dione with a halogenating agent, and then reacting the resulting compound represented by the general formula:
wherein X1 is as defined above, with a halogenating agent.
(VI) wherein X1 is a halogen atom, and X2 is a halogen atom different from X1, which comprises reacting butane -2,3-dione with a halogenating agent, and then reacting the resulting compound represented by the general formula:
wherein X1 is as defined above, with a halogenating agent.
2. A process according to Claim 1, wherein X1 is a chlorine atom and X2 is a bromine atom.
3. A process according to Claim 1, wherein the halogenations are effected at 10°C to the reflux temperature of solvent.
4. A compound represented by the general formula:
wherein X1 is a halogen atom, and X2 is a halogen atom different from X1, whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equivalent thereof.
wherein X1 is a halogen atom, and X2 is a halogen atom different from X1, whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equivalent thereof.
5. A compound of formula(VI) given in Claim 1, wherein X1 and X2 are as in Claim 2, whenever prepared or produced by the process as claimed in Claim 2 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000475356A CA1216310A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP103109/82 | 1982-06-17 | ||
| JP103108/82 | 1982-06-17 | ||
| JP57103108A JPS58222048A (en) | 1982-06-17 | 1982-06-17 | 1,4-dihalogenobutane-2,3-dione |
| JP57103109A JPS58222076A (en) | 1982-06-17 | 1982-06-17 | 2-aminothiazole derivative |
| JP58078201A JPS59204179A (en) | 1983-05-06 | 1983-05-06 | Preparation of (2-aminothiazol-4-yl)glyoxylic acid derivative or its salt |
| JP78201/83 | 1983-05-06 | ||
| CA000430079A CA1191512A (en) | 1982-06-17 | 1983-06-09 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
| CA000475356A CA1216310A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000475356A Division CA1216310A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000475356A Division CA1216310A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1216310A true CA1216310A (en) | 1987-01-06 |
Family
ID=27426372
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000475356A Expired CA1216310A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
| CA000475355A Expired CA1197251A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000475355A Expired CA1197251A (en) | 1982-06-17 | 1985-02-27 | Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1216310A (en) |
-
1985
- 1985-02-27 CA CA000475356A patent/CA1216310A/en not_active Expired
- 1985-02-27 CA CA000475355A patent/CA1197251A/en not_active Expired
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| Publication number | Publication date |
|---|---|
| CA1197251A (en) | 1985-11-26 |
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