JPH0333711B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel oxazole compounds, salts thereof, and derivatives thereof, more specifically, the following general formula: "In the formula, R ¹ is a hydrogen atom or a hydroxyl protecting group, R ² is an optionally protected or substituted amino group, R ³ is a hydrogen atom or a halogen atom, and is a syn or anti isomer. The present invention relates to a novel oxazole compound, a salt thereof, and a derivative thereof. [Prior Art] The present inventors have already developed the general formula "In the formula, R ¹ , R ² , R ³ and have the same meanings as above, R ⁴ is a hydrogen atom or an alkoxy group, R ⁵ is a hydrogen atom or a carboxyl protecting group, R ⁶ is Hydrogen atom, halogen atom, alkyl group, alkoxy group or the formula -CH ₂ R ⁷ (wherein R ⁷
represents an aromatic hydrocarbon group with or without a substituent, an acylamino group, a heterocyclic group, an organic group bonded via an oxygen or sulfur atom, or a quaternary ammonium group. ), Z represents S or S→O, and the dotted line in the cefem ring means that a double bond exists between the 2nd and 3rd positions or between the 3rd and 4th positions. We discovered that cephalosporins and their salts represented by the following formula are extremely useful compounds as antibacterial agents, and filed a patent application (Japanese Unexamined Patent Publication No. 8087/1987). [Problems to be Solved by the Present Invention] An object of the present invention is to provide a novel compound of the general formula [] that has an excellent antibacterial spectrum and is a useful intermediate for cephalosporins of the general formula [] or a salt thereof. There is a particular thing. [Means for Solving the Problems] As a result of intensive research to achieve the above object, the present inventors have found that a compound of the general formula [ ] or a salt thereof or a derivative thereof, for example, a compound of the general formula Cephalosporins of the general formula ^{[ ] or} their The inventors discovered that the salt can be easily obtained in high yield, leading to the completion of the present invention. The present invention will be explained in detail below. The hydroxyl protecting group for R ¹ in the general formula [ ] includes protecting groups known in the art, such as alkyl groups with or without substituents; benzyloxycarbonyl, 4-
Nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl , tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl , 1-adamantyloxycarbonyl, 1-
Easily eliminated acyl groups such as cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, acetyl or trifluoroacetyl, and benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio groups, etc. Can be mentioned. Examples of the alkyl group with or without a substituent include methyl, ethyl, propyl, butyl, and the like. Furthermore, the substituents include, for example, a halogen atom, an alkyl group, an aryl group, a hydroxyl group,
Examples include an alkoxy group, a carboxyl group, a carbamoyl group, an alkoxycarbonyl group, a sulfamoyl group, an amino group, an alkylamino group, and a dialkylamino group. These hydroxyl groups, amino groups or carboxyl groups further include
It may be protected with the protecting groups described in R ¹ above and R ² and R ⁵ below. In addition, the protecting group for the optionally substituted or protected amino group of R ² in the general formula [ ] includes all groups that can be normally used as amino protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl , benzyloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-
Bromobenzyloxycarbonyl, o-nitrophenylsulfenyl, (mono-, di-, tri-)
Chloroacetyl, trifluoroacetyl, formyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)benzyloxycarbonyl, 4-(4- methoxyphenylazo)
Benzyloxycarbonyl, pyridin-1-oxide-2-yl-methoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl, phthaloyl, succinyl , 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and other easily eliminated acyl groups; trityl, 2-nitrophenylthio, 2,
4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene,
3-Hydoxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2
-Propylidene, 1-benzoyl-2-propylidene, 1-[N-(2-methoxyphenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)carbamoyl]-2-propylidene, 2 -Ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-
Groups that are easily eliminated such as dimethyl-5-oxocyclohexylidene; silyl groups such as di- or tri-alkylsilyl; substituents for amino groups include, for example, methyl, ethyl, n-propyl, etc. , isopropyl, n-butyl,
Straight and branched alkyl groups such as isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl; alkenyl groups such as allyl; cyclo such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl Alkyl group; Aryl group such as phenyl, naphthyl; benzyl, phenethyl,
Aralkyl groups such as 4-methylbenzyl and naphthylmethyl; furyl, thienyl, benzofuryl,
Benzothienyl, coumarinyl, triazolyl, tetrazolyl, pyridon-2-yl, pyridon-3
Examples include heterocyclic groups containing at least one heteroatom selected from oxygen, nitrogen and sulfur such as -yl; heterocyclic alkyl groups such as thienylmethyl and furylmethyl; It may be substituted with a substituent. These protecting groups and substituents may further include, for example:
Halogen atom, alkyl group, nitro group, hydroxyl group, alkoxy group, oxo group, thioxo group,
Alkylthio group, acylamino group, acyl group, acyloxy group, aryloxy group, carboxyl group, carbamoyl group, hydroxyalkyl group, alkoxyalkyl group, carboxyalkyl group, alkoxycarbonyl group, amino group, alkylamino group, aminoalkyl group, N - It may be substituted with one or more substituents such as an alkylaminoalkyl group, a sulfoalkyl group, a sulfo group, a sulfamoyl group, a carbamoylalkyl group, an aryl group, or a heterocyclic group such as furyl or thienyl. As substituents, the hydroxyl group, amino group and carboxyl group may be further protected with a commonly used suitable protecting group, and the protecting group for the hydroxyl group or amino group is the hydroxyl group or amino group explained above. Examples of the protecting group for carboxyl groups include those conventionally used in the field of penicillin and cephalosporin compounds, which will be explained in the section ^R5 below. Also, the general formulas [] and []

The oxime represented by the formula can include syn and anti isomers, and the present invention includes both isomers and mixtures thereof. General formulas [] and []

[Formula] In the group, tautomers exist as shown in the following balanced formula, and the present invention also includes these tautomers. "In the formula, R ² and R ³ have the same meanings as above, and R ^2a means an imino group corresponding to R ^2. " and salts with basic or acidic groups commonly known in the field of cephalosporins. Salts on basic groups include, for example, salts with mineral acids such as hydrochloric acid or sulfuric acid; salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid or trifluoroacetic acid; methanesulfonic acid, ethanesulfonic acid. acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylsulfonic acid), naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, enylmethanesulfonic acid, benzene-1,3-di-disulfonic acid, toluene-3,5-disulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,
6-disulfonic acid, naphthalene-2,7-disulfonic acid, benzene-1,3,5-trisulfonic acid, benzene-1,2,4-trisulfonic acid, naphthalene-1,3,5-trisulfonic acid, etc. and salts with acidic groups such as salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; procaine, dibenzylamine; , N-benzyl-β-phenethylamine, 1-ephenamine, salts with nitrogen-containing organic bases such as N,N-dibenzylethylenediamine, or triethylamine,
Trimethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine,
Mention may be made of groups with other nitrogen-containing organic bases such as N-methylmorpholine, diethylamine, dicyclohexylamine. In addition, as derivatives of the compound of the general formula [] of the present invention, there are those whose carboxyl group is protected with a carboxyl protecting group as explained in R ⁵ below, and reactive derivatives that are often used for acylation, esterification, etc. Specific examples thereof include acid halides, acid anhydrides, mixed acid anhydrides, active acid amides, active esters, and reactive derivatives of compounds of the general formula [] with the Vilsmeier reagent. Specifically, the mixed acid anhydride may be, for example, a mixed acid anhydride with a carbonic acid monoester such as carbonic acid monoethyl ester or carbonic acid monoisobutyl ester, or may be substituted with a halogen such as pivalic acid or trichloroacetic acid. Examples include mixed acid anhydrides with lower alkanoic acids. In addition, examples of the active acid amide include N-acylsactucalin,
Examples include N-acylimidazole, N-acylbenzoylamide, N,N'-dicyclohexyl-N-acylurea, and N-acylsulfonamide. Examples of the active ester include cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, and substituted thienyl ester. Furthermore, as the reactive derivative with the Vilsmeier reagent of the compound of the general formula [], the compound of the general formula []
and acid amides such as dimethylformamide, N,N-dimethylacetamide, phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, phosphorus oxochloride, phosphorus oxybromide, phosphorus pentachloride, trichloromethyl chloro Examples include derivatives reactive with Vilsmeier's reagent obtained by the action of a halogenating agent such as formate and oxalyl chloride. Next, a method for producing the compound of general formula [] will be explained. This compound can be manufactured according to the manufacturing method shown below. "In the formula, R ¹ , R ² , R ³ , R ⁵ and have the same meanings as above, R ^1a represents the same hydroxyl protecting group as R ¹ , and R ¹¹ represents a halogen atom." Examples of the carboxyl protecting group for R ⁵ include those conventionally used in the field of penicillin and cephalosporin compounds. These carboxyl protecting groups include ester-forming groups that have the property of being eliminated by treatment under catalytic reduction, chemical reduction or other mild conditions, or ester-forming groups that are easily eliminated in vivo;
Alternatively, various other known ester-forming groups may be mentioned, such as an organic silyl group, an organic phosphorus group, or an organic tin group, which have the property of being easily eliminated by treatment with water or alcohol. Among these types of protecting groups, suitable protecting groups include:
Specifically, the following can be mentioned. (i) Alkyl groups; especially straight-chain or branched _C1-14 alkyl groups such as methyl, ethyl, n ^- propyl, isopropyl, n _- butyl, sec-butyl, isobutyl, tert-butyl and pentyl. (b) At least one of the substituents is chloro, bromo,
Fluoro, nitro, carbalkoxy, acyl, alkyl, alkoxy, oxo, cyano,
Alkyl mercapto, alkyl sulfinyl,
Alkylsulfonyl, alkoxycarbonyl,
1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, succiimide, phthalimide, acetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N. lower alkylpiperazino, 2,5-dimethylpyrrolidino, 1 , 4,5,6-tetrahydropyrimidinyl, 4-methylpiperidino,
2,6-dimethylpiperidino, alkylamino, dialkylamino, acyloxy, acylamino, dialkylaminocarbonyl, alkoxycarbonylamino, alkoxycarbonyloxy or alkylanilino or chloro,
A substituted lower alkyl group that is alkylanilino substituted with bromo, lower alkyl or lower alkoxy. (c) Cycloalkyl or lower alkyl-substituted cycloalkyl or [2,2-dilower alkyl-1,3-dioxolan-4-yl]methyl group consisting of 3 to 7 carbon atoms. (d) Alkenyl groups having up to 10 carbon atoms. (e) Alkynyl groups having up to 10 carbon atoms. (f) A substituted phenyl group or a substituent in which the phenyl group or substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above, or a substituted phenyl group of the formula "In the formula, X is -CH=CH-O-,, -CH=CH
−S−, −CH ₂ CH ₂ S−, −CH=N−CH=N
−, −CH=CH−CH=CH−, −CO−CH=CH
-CO- or -CO-CO-CH=CH-. '' or a substituted derivative thereof (the substituents are arbitrarily selected from those exemplified in (b) above), or a group represented by the formula A group represented by "In the formula, Y is a lower alkylene group such as -(CH ₂ ) ₃ - or -(CH ₂ ) ₄ -" or a substituted derivative thereof (the substituents are exemplified in (b) above) an aryl group such as (g) An aralkyl group such as benzyl or a substituted benzyl in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (H) Furyl, quinoline, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolanyl,
3-(2-methyl-4-pyrrolinyl), 3-(4
pyrrolinyl) or N-methylpyridyl, or a substituted heterocyclic group in which the substituent is at least one substituent arbitrarily selected from the substituents exemplified in (b) above. (li) Alicyclic indanyl or phthalidyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro, alicyclic tetrahydronaphthyl and substituted derivatives thereof in which the substituent is methyl, chloro, bromo or fluoro, trityl; , cholesteryl, bicyclo[4,4,
0] Decyl etc. The carboxyl protecting groups exemplified above are representative examples, and protecting groups described in the following documents can be arbitrarily selected. U.S. Patent Nos. 3,499,909, 3,573,296 and
No. 3641018; West German Patent Publication No. 2301014,
Nos. 2253287 and 2337105. Particularly preferred carboxyl protecting groups include acyloxymethyl group, acyloxy-
Examples include a substituted methyl group or a carboxyl protecting group that is easily eliminated in vivo as represented by the following formula.

【formula】

【formula】

[Formula] "In the formula, R ⁸ is a straight chain or branched alkyl, alkenyl, aryl, aralkyl, alicyclic or heterocyclic group with or without a known substituent, and R ⁹ is A hydrogen atom or an alkyl group, R ¹⁰ is a hydrogen atom, a halogen atom, or an alkyl, cycloalkyl, aryl, or heterocyclic group with or without a known substituent, or -(CH ₂ ) _o COOR ⁸ (however, R ⁸ has the above meaning, n indicates 0, 1 or 2), m
means 0, 1 or 2. For example, acyloxymethyl groups such as acetoxymethyl and pivaloyloxymethyl groups; Substituted alkyl groups, alkoxymethyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl and isopropoxymethyl groups, alkoxycarbonyloxymethyl groups such as methoxycarbonyloxymethyl and ethoxycarbonyloxymethyl groups, 1-methoxycarbonyloxy-ethyl, 1
-alkoxycarbonyloxy-substituted-alkyl groups, such as -ethoxycarbonyloxy-ethyl groups,
Examples include alkoxycarbonylmethyl groups such as methoxycarbonylmethyl and ethoxycarbonylmethyl groups. (1) Production of compound of general formula [] Journal. of. Medicinal. Journal of Medicinal Chemistry, No. 16
Volume, No. 9, pp. 978-984 (1973), the compound of the general formula [] is subjected to conventional alkylation or acylation to form a compound of the general formula []. compound can be obtained.
In addition, this compound can be obtained by subjecting a compound of the general formula [] obtained by the method described in Nippon Kagaku Zasshi, Vol. 78, No. 9, pp. 1254-1256 (1957), etc., to ordinary halogenation. It can be obtained by (2) The compound of the general formula [] can be obtained by reacting the compound of the general formula [] with the urea of the production []. This ring-closing reaction is usually carried out in a solvent using the general formula []
Or, one to several equivalents of ureas are used with respect to the compound [ ]. Examples of the solvent used include one or a mixture of two or more of water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyridone. Preferably, N,N-dimethylformamide is used. In addition, the reaction time is 1 to 48
time, preferably 1 to 10 hours. At this stage, a protecting group can be introduced into or removed from the thus obtained compound of the general formula [] by a conventional method. Here, the protecting group includes the amino group protecting group and the hydroxyl protecting group explained in R ¹ and R ² . (3) Production of compound of general formula [] By halogenating the compound of general formula [], the compound of general formula [] can be obtained. (4) Production of compound of general formula [] A compound of general formula [] can be obtained by subjecting the compound of general formula [] to a usual hydrolysis reaction. Further, the compound of the general formula [] can be derived into a salt or a derivative thereof by a conventional method. [Examples] Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1 (1) 120 g of methyl 4-bromo-3-oxo-2methoxyiminobutyrate is dissolved in 700 ml of N,N-dimethylformamide, 151 g of urea is added, and the mixture is reacted at room temperature for 48 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue is introduced into a mixed solvent of 500 ml of water and 500 ml of diethyl ether. Then,
Separate the aqueous layer, add 700 ml of ethyl acetate, adjust the pH to 7.0 with sodium hydrogen carbonate, and separate the organic layer. After washing with 400 ml of water, drying over anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure.
Wash the residue with isopropyl alcohol and
If taken, 2- exhibiting a melting point of 148-150℃ (decomposition)
(2-aminoxazol-4-yl)-2-
35.2 g (yield 35.1%) of methyl (syn)-methoxyiminoacetate is obtained. IR (KBr) cm ^-1 ; ν _c=0 1735 NMR (d ₆ -DMSO) ppm value; 3.82 (3H; S; -COOCH ₃ ), 3.90 (3H; S; = N - OCH ₃ ), 6.40 (2H ;bs; _−NH2 ), 7.36(1H;S;

【formula】)

【table】

【table】

Claims (1)

[Claims] 1. General formula "In the formula, R ¹ is a hydrogen atom or a hydroxyl protecting group, R ² is an optionally protected or substituted amino group, R ³ is a hydrogen atom or a halogen atom, and is a syn or anti isomer. or a mixture thereof.'' An oxazole compound, a salt thereof, and a derivative thereof.