JPH0357104B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel synthetic intermediate of 1-dethia-1-oxacephalosporin. More details: General formula: [However, A is amino or protected amino; E is hydrogen or methoxy; Y is the formula:

【formula】

【formula】

[expression] or

[Formula] (However, COB is carboxy or protected carboxy; X is hydrogen or a nucleophilic group; Z is a leaving group.) A divalent group represented by; The wavy line represents an α or β bond; respectively. represent. ] It is related with the manufacturing method of the 1-dethia-1-oxacefam compound shown by these. 1-Dethia-1-oxacephalosporins are described by Christensen (Journal of the American Chemical Society, 96 , 7582).
(1974)), as well as other synthetic methods as shown in the reaction process diagram below. (However, A is amino or substituted amino; COB
(represents carboxy or protected carboxy; X represents hydrogen or a nucleophilic group; ph represents phenyl; and R′ represents aryl or alkyl). , depending on the direction of introduction of the oxygen functional group, the epimer isomer ratio is 1:1.
occurs at a rate of The epimer mixture has approximately 1/2 the activity of the 6-epimer form of 1-dethia-1-oxacephalosporins. The present inventors have completed the present invention as a result of intensive research aimed at finding an economical synthesis method to improve the above-mentioned disadvantages. In the above definition, a protected amino group is
For example, it means an amino group protected with the groups shown below. 1 _C1 - _C10 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropylacetyl, trimethylacetyl, valeryl, t-butylacetyl, caproyl, octanoyl, cyclohexylacetyl, dicanoyl, 2-ethylenantoyl, etc.) ; 2 C ₁ - C ₇ haloalkanoyl (e.g., chloroacetyl, chloropropionyl, chloroisovaleryl, dichloroacetyl, trichloroacetyl, trichloropropionyl, bromoacetyl, bromopropionyl, dibromocyclohexylcarbonyl, etc.); 3 azidoacetyl, cyanoacetyl , trifluoromethylthioacetyl. Cyanomethylthioacetyl, (4-pyridon-1-yl)acetyl; 4 Formula: Ar-CO- (However, Ar is aryl, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl,
Thiazolyl, isothiazolyl, thiadiazolyl,
Thiatriazolyl, pyrazolyl, imidazolyl,
Triazolyl, tetrazolyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, dihydrophenyl, tetrahydrophenyl, tetrahydropyrimidyl, naphthyl, benzothiazolyl, indolyl, quinolyl, isoquinolyl, benzopyrimidyl, cinnolinyl, pyridopyrimidyl, indanyl, etc. methyl,
Ethyl, propyl, hydroxymethyl, chloromethyl, trifluoromethyl, cyano, carboxy, carboxymethyl, aminomethyl, phenyl, chlorophenyl, fluorophenyl, amino, formylamino, acetamide, propionamide, butyrylamino, valeramide, isovaleramide, imino, nitro, hydroxy, methoxy, ethoxy, propoxy, methylenedioxy, ethylenedioxy, formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy, phenylacetoxy, benzoyloxy, methanesulfonyloxy, ethanesulfonyloxy, hensensulfonyl It may be appropriately substituted with oxy, bromobenzenesulfonyloxy, methoxycarbonyloxy, ethoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, carbamoyloxy, methylcarbamoyloxy, oxo, chloro, bromo, iodo, or the like. ); 5 Acyl represented by the formula: Ar-CQQ'-CO- (However, Ar has the same meaning as above; Q and Q' each represent hydrogen or methyl); 6 Formula: Ar-G Acyl represented by -CQQ'-CO- (Ar, Q, and Q' have the same meanings as above; G represents oxygen, sulfur, or imino); 7 Formula:

[Formula] (However, Ar has the same meaning as above; T ¹ is hydrogen or C ₁ - C ₆ alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isoamyl , t-pentyl, neopentyl, isopropylethyl, cyclopentyl, etc.); 8 Formula:

[Formula] (However, Ar has the same meaning as above; T ² is the following). Hydroxy or _C1 - _C10 acyloxy (e.g. formyloxy, acetoxy, propionyloxy, butyryloxy, valeryloxy, cyclopropylacetoxy, cyclopentylpropionyloxy, phenylacetoxy,
Thienylacetoxy, phenoxyacetoxy,
Glycoloyloxy, glyoxyloyloxy, glycyloxy, chloroacetoxy, bromoacetoxy, trifluoroacetoxy, benzoyloxy, methylbenzoyloxy, dimethylbenzoyloxy, nitrobenzoyloxy, methoxybenzoyloxy, cyanobenzoyloxy, methanesulfonylbenzyloxy, carbamoyl (oxy, methylcarbamoyloxy, ethylcarbamoyloxy, propylcarbamoyloxy, methoxycarbonyloxy, t-butoxycarbonyloxy, benzyloxycarbonyloxy, methoxybenzyloxycarbonyloxy, nitrobenzyloxycarbonyloxy, etc.); Carboxy or the COB column below protected carboxy as shown; sulfo or _C1 - _C5 alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, propoxysulfonyl, butoxysulfonyl, cyclopropylmethoxysulfonyl,
pentyloxysulfonyl, or cyclopropylethoxysulfonyl; or formula:

Group represented by [Formula] [W ¹ and W ² are each hydrogen or a C ₁ to C ₁₀ amino substituent, specifically, a C ₂ to C ₇ alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t -butoxycarbonyl, pentyloxycarbonyl, or methylhexylcarbonyl), _C3 - _C10 cycloalkyl -C2- _C3 -alkoxycarbonyl (e.g. cyclopropylmethoxycarbonyl, _{cyclopropylethoxycarbonyl} , cyclopentylmethoxycarbonyl, cyclohexylethoxycarbonyl) , cycloheptylmethoxycarbonyl),
_C5 - _C8 cycloalkoxycarbonyl (e.g.
cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclopropylcarbonyl), _C1 - _C4 alkylsulfonyl-
C1 _{- C4} alkoxycarbonyl (eg methanesulfonyl ethoxycarbonyl, ethanesulfonyl ethoxycarbonyl, methanesulfonyl butoxycarbonyl, butanesulfonyl butoxycarbonyl),
Halo- _C1 - _C3 alkoxycarbonyl (e.g.
Chloromethoxycarbonyl, chloroethoxycarbonyl, bromoethoxycarbonyl, iodoethoxycarbonyl, dichloroethoxycarbonyl,
trichloroethoxycarbonyl, trichloropropoxycarbonyl), aralkoxycarbonyl (e.g. benzyloxycarbonyl, methylbenzyloxycarbonyl, dimethylbenzyloxycarbonyl, aminobenzyloxycarbonyl, acetamidobenzyloxycarbonyl, nitrobenzyloxycarbonyl, methoxybenzyloxycarbonyl, Chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl, diphenylmethoxycarbonyl, diphenylethoxycarbonyl, thiazolylmethoxycarbonyl, pyridylmethoxycarbonyl, other Ar- _CH2
O-CO- (However, Ar has the same meaning as above)), C ₁ ~ C ₁₀
Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, t-valeryl, hexanoyl, heptanoyl, cyclohexanecarbonyl,
octanoyl, cyclopentanepropionyl, decanoyl), an acyl group represented by Ar-CO- (where Ar has the same meaning as above), or other acyl groups (e.g., pyronecarbonyl, thiopyronecarbonyl, pyridonecarbonyl, carbamoyl, anidylcarbonyl, ureidocarbonyl, methylimidazolidonecarbonyl, methanesulfonylimidazolidonecarbonyl, methyldioxopiperazin-1-ylcarbonyl, ethyldioxopiperazin-1-ylcarbonyl, butyldioxopiperazin-1-ylcarbonyl);

[Formula] is taken together to form a carbonyl compound that can be enolized with amino (e.g. C ₅ - _{C 10}
Acetoacetate (e.g. methyl acetoacetate,
ethyl, propyl, butyl, isobutyl, or pentyl ester), _C5 - _C10 acetoacetamide (e.g. amide, methylamide, anilide, or methylanilide of acetoacetic acid), acetylacetone, acetoacetonitrile, α-acetylbutyrolactone, 1,3-cyclo a group constituting a Schiff base or enamine derived from pentanedione, etc.), or

9 ₅ -aminoadipoyl, C _{1 -C} 5-aminoadipoyl, alkyl, whose amino group is protected with ₁₀ alkanoyl, aroyl, aralkanoyl, haloalkanoyl, or alkoxycarbonyl,
5-aminoadipoyl with carboxy protected with aryl, aralkyl, or alkylsilyl; 10 Formula: L-O-CO- (where L is appropriately substituted and easily removable)
C ₁ -C ₁₀ hydrocarbon groups (e.g. t-butyl, 1,
1-dimethylpropyl, cyclopropylmethyl,
Cyclopropylethyl, 1-methylcyclohexyl, isobornyl, 2-methoxy-t-butyl,
Acyls derived from polybasic carboxylic acids of 11 C ₄ to C ₁₀ ( (e.g., succinyl, maleoyl, phthaloyl, pyridine-2,3-dicarbonyl, etc.); 12 An optionally substituted _C1 - _C20 hydrocarbon group (e.g., methyl, ethyl, t-butyl,
Trityl, methylidene, benzylidene, hydroxybenzylidene, α-halobenzylidene, α
-methoxybenzylidene, α-ethoxybenzylidene, 1-methoxy-2-phenylethylidene, 3,5-di-t-butyl-4-hydroxybenzylidene, o-hydroxybenzylidene, etc.); 13 C ₃ - C ₁₀ organic silyl ( For example, trimethylsilyl, dimethylmethoxysilyl, _{chlorodimethylsilyl ,} methyldimethoxysilyl, methylethylenedioxysilyl); stannyl, methylethylenedioxystannyl); and 15 C ₁ -C ₁₀ sulfenyl (e.g. methylthio,
phenylthio, o-nitrophenylthio, etc.) Any of these groups can be a halogen (e.g. fluoro, chloro, bromo, etc.), a nitrogen functional group (e.g. amino, hydrazinyl, azide, alkylamino, arylamino, acylamino, alkylideneamino, acylimino, imino, nitro, etc.),
Oxygen functional groups (e.g. hydroxy, alkoxy,
aralkoxy, aryloxy, acyloxy,
oxo), sulfur functional groups (e.g. mercapto,
alkylthio, aralkylthio, arylthio,
Acylthio, thioxo, sulfo, sulfonyl, sulfinyl, alkoxysulfonyl, aryloxysulfinyl, carbon functional groups (e.g., alkyl, alkenyl, aralkyl, aryl, carboxy, carbalkoxy, carbamoyl, alkanoyl, aroyl, aminoalkyl, aralkanoyl, cyano, etc.) ), phosphorus functional groups (e.g. phospho,
phosphoroyl, etc.) may be substituted as appropriate. Among the above amino-protecting groups, the acyl group constituting the side chain in penicillin and cephalosporin is particularly important, but since it can be removed or introduced by conventional methods at any stage after the reaction, its composition varies between raw materials and final products. A wide range of changes are possible regardless of the structure, and the main focus is on stability against reactions. Also, groups that can be converted to amino or amide (e.g. enamino, amide, azide, isocyanato,
isocyano) and cyclic groups (e.g. 4-phenyl-2,2-dimethyl-5-oxoimidazolidin-1-yl, 4-p-hydroxyphenyl-2,
2-dimethyl-3-nitroso-5-oxoimidazolidin-1-yl, 4-p-hydroxyphenyl-2-phenyl-5-oxoimidazolidine-
1-yl, 4-thienyl-5-oxoimidazolidin-1-yl, etc.) are also included within the scope of A. The protected carboxy group represented by COB is
It is commonly used in the chemistry of β-raftam and can withstand the reaction conditions of this reaction.
Protecting group B includes 1 ester-forming group [e.g. _C1 - _C10 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, monohydroxy-t-butoxy, methoxy-t-butoxy, cyclopropylmethoxy) , pentyloxy, isopentyloxy, cyclopropylethoxy, cyclopentyloxy, hexyloxy, cyclohexyloxy, octyloxy,
decyloxy, etc.), _C1 - _C6 haloalkoxy (e.g. chloromethoxy, chloroethoxy, bromoethoxy, iodoethoxy, dichloropropoxy, trichloroethoxy, trichlorobutoxy, dibromocyclohexyloxy, etc.),
_C3 - _C10 acylalkoxy (e.g. acetonyloxy, acetyl ethoxy, propionylmethoxy, phenacyloxy, chlorophenacyloxy, bromophenacyloxy, nitrophenacyloxy, methylphenacyloxy, etc.),
_C3 to _C10 alkoxyalkoxy (e.g. methoxymethoxy, ethoxymethoxy, chloroethoxymethoxy, propoxyethoxy, butoxyethoxy, cyclohexyloxyethoxy, methoxyethoxymethoxy, butoxyethoxymethoxy, octyloxyethoxy, etc.), _C2 to _C10
Aminoalkoxy (e.g. aminomethoxy, aminoethoxy, dimethylaminoethoxy, ethylaminomethoxy, etc.), aryloxy (e.g. phenoxy, chlorophenoxy, nitrophenoxy, naphthyloxy, pyridyloxy,
indolyloxy, indanyloxy, pentachlorophenoxy), aralkoxy (e.g. benzyloxy, methylbenzyloxy, xylylmethoxy, chlorobenzyloxy, bromobenzyloxy, methoxybenzyloxy,
Ethoxybenzyloxy, nitrobenzyloxy, dibromobenzyloxy, phenethyloxy, phthalidyloxy, p-hydroxy-di-
t-butylbenzyloxy, diphenylmethoxy, trityloxy, etc.), _C1 - _C10 alkylsilyloxy, (e.g. trimethylsilyloxy,
₂ anhydride- _forming groups _{[ e.g.} Organic acyloxy (e.g. acetoxy, propionyloxy, sulfonyloxy, etc.), inorganic acyloxy (e.g. acyloxy such as sulfuric acid, perchloric acid, etc.); 3. Salt-forming groups [e.g. oxy, sodium oxy, potassium oxy, magnesium oxy), C ₁ -C ₁₅ hydrocarbyl ammonium oxy (e.g. triethylammonium oxy, dicyclohexylammonium oxy, etc.)]; 4 thiol ester-forming group (e.g. C ₁ -C ₁₀ hydrocarbylthio or mercapto) ); 5 amide-forming groups [e.g. _C1 - _C5 alkylamino (e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino, etc.), di- _C1 - _C5 alkylamino (e.g. dimethylamino, Diethylamino, piperidyl, morpholin-1-yl, methylmorpholine-1-
and 6 hydrazide or azide forming groups. Since these protecting groups are usually removed after the reaction, changes in their structure often have no important meaning for this invention. The nucleophilic group represented by X includes all groups that are substituted with an acetoxy group at the 3-position in the chemistry of cephalosporin. For example, halogen (chloro, bromo, etc.), hydroxy, optionally substituted C1 _{- C4} alkanoyloxy (formyloxy, acetoxy, propionyloxy, butyryloxy, malonyloxy, succinoyloxy, cyanoacetoxy, glycyloxy, alanyloxy, glycoloyloxy, glyoxyloyloxy, phenoxyacetoxy, sulfopropionyloxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, etc.), aroyloxy (benzoyloxy, naphthoyloxy, etc.), which may be substituted as appropriate Acyloxy of carbonic acid (chloroformyloxy, methoxyformyloxy, trichloroethoxyformyloxy, cyclopropylmethoxyformyloxy, methanesulfonylethoxyformyloxy, etc.), _C1 - _C6 alkoxy (methoxy,
ethoxy, propoxy, butoxy, s-butoxy, cyclopropylmethoxy, cyclohexyloxy, etc.), aralkoxy (benzyloxy, furfuryloxy, naphthylmethoxy, etc.), aryloxy (phenoxy, naphthyloxy, indanyloxy, etc.), mercapto, C ₁ ~ C ₅ alkanoylthio (acetylthio, propionylthio,
butyrylthio, etc.), aroylthio (benzoylthio, naphthoylthio, etc.), thiocarbamoylthio, methylthiocarbamoylthio, _C1 - _C6 alkylthio (methylthio, ethylthio, propylthio, butylthio, cyclopropylmethylthio,
cyclopropylethylthio, etc.), aralkylthio (benzylthio, picolylthio, phenethylthio, etc.), arylthio (phenylthio, triazolthio, thiadiazolylthio, oxadiazolylthio, tetrazolylthio, etc.), and the like. All of these groups include optionally substituted alkyl (methyl, ethyl, hydroxymethyl,
Hydroxyethyl, carboxymethyl, carboxyethyl, sulfoethyl, dimethylaminoethyl, dimethylaminopentyl, morpholinoethyl, etc.), nitrogen functional groups (amino, azido, hydrazinyl, acetylamino, methylamino, pyridinium, picolinium, 4-carboxypyridinium, carbamoyl) pyridinium, hydroxymethylpyridinium, carboxymethylpyridinium, chloropyridinium, etc.). The leaving group denoted by Z is the anionic part of the nucleophile, for example, halogen (chloro, bromo, iodo, etc.), hydroxy, acyloxy of _C1 - _C8 carboxylic acid (acetoxy, trifluoroacetoxy, etc.) ), acyloxy sulfonic acids (methanesulfonyloxy, ethanesulfonyloxy, toluenesulfonyloxy, bromobenzenesulfonyloxy, etc.), arylthio (phenylthio), arylsulfenyl (phenylsulfenyl, etc.), arylselenyl, arylsulfinyl Nyl, alkylsulfinyl, etc.
Since these leaving groups are eliminated during the reaction, their structure can vary widely and are often of no significance to the invention. The compound () of the present invention means a compound as shown below.

【formula】

【formula】

[expression] or

[Formula] (However, A, E, COB,
b), (c), or (d) can be easily produced by carrying out the following ring-closing reaction, methoxylation, addition reaction of XZ, etc. sequentially or in an appropriate combination. (The number inside the bracket indicates the position number of the bone nucleus.) 4 Other conversion reactions (In the above process formula, A, E, COB, X, and Z have the same meanings as above; Y ¹ is Y or

[Formula] R means a group obtained by removing carbonyl from acyl. ) In the above definition, the group represented by R, obtained by removing carbonyl from acyl, specifically means a group obtained by removing carbonyl from acyl, which is exemplified as an amino protecting group in the section A above. That is, R.C.O.
is included within the definition of A. According to the method of the present invention, by using the compound ( ) as a starting material, the oxygen atom of the hydroxyl group bonds from the opposite side of the ring bond during the ring-closing reaction, so that only the preferred stereoisomer (6β form) at the 6-position is present. can be obtained in high yield.
Therefore, the method of the present invention is an excellent method that improves the drawback of the conventional synthetic method that a 6-position isomer is produced. Each step will be explained in detail below. 1 Ring Closing Reaction When oxazolinoazetidines () are treated with an acid, the ring is closed to obtain the compound (). Examples of acids include mineral acids (hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid, etc.), sulfonic acid (methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
Toluenesulfonic acid, bromobenzenesulfonic acid,
trifluoromethanesulfonic acid, naphthalenesulfonic acid, etc.), strongly acidic carboxylic acids (trichloroacetic acid, trifluoroacetic acid, etc.), Lewis acids (boron trifluoride, zinc chloride, stannous chloride, stannic chloride, stannous bromide, etc.) Monotin, antimony trichloride, antimony pentachloride, titanium trichloride, etc.) can be used. The reaction is usually carried out in an inert solvent. Examples of inert solvents include hydrocarbon solvents (hexane, cyclohexane, benzene, toluene, etc.),
Halohydrocarbons (methylene chloride, chloroform,
dichloroethane, carbon tetrachloride, chlorobenzene, etc.), ethers (diethyl ether, diisobutyl ether, dioxane, tetrahydrofuran, etc.), esters (ethyl acetate, butyl acetate,
methyl benzoate, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), sulfoxides (dimethyl sulfoxide, etc.), nitriles (acetonitrile, benzonitrile, etc.)
These can be used alone or in combination. Solvents with hydroxyl groups, such as water, alcohols (methanol, ethanol, t-butanol,
(benzyl alcohol), acids (formic acid, acetic acid, propionic acid, etc.) are not preferable because they react with the raw material () and produce by-products, but they can be used if the reaction conditions are adjusted. The reaction is usually carried out at -30°C to 50°C, preferably from 15°C to
Achieved at 30℃, 5 minutes to 10 hours, usually 15 minutes to 3
It can be completed in a short period of time and the desired product () can be obtained in high yield. If necessary, the reaction may be conducted under stirring or under an inert gas (eg, nitrogen, argon, carbon dioxide, etc.). The terminal hydroxy group connected to Y ¹ of oxazolinoazetidine ( ) may be protected in advance with an easily removable hydroxy protecting group such as formyl, tetrahydropyranyl, etc. In this step, for example, oxazolinoazetidine () is mixed with a 5 to 10 times amount of a hydrocarbon solvent (chloroform, methylene chloride, etc.) and a 0 to 10 times amount of an ether solvent (ether, dioxane, etc.). After melting and adding 0.001 to 1 molar equivalent of acid (boron trifluoride etherate, toluene sulfonic acid, copper sulfate, zinc chloride, tin chloride, etc.), the solution is kept at 10 to 60℃ for 0.5 to 10 hours. Compound () can be obtained in yields of about 50-90%. The raw material () can be produced from 6-epipenicillin-1-oxide, for example, according to the following reaction process diagram. (R, COB, and
This can be achieved by adding methanol after forming (exo form at position 7). When A is amino or amide, when compound (a) is treated with an N-halogenating agent, a base is added to eliminate the hydrogen halide, and the resulting imino compound is treated with methanol, E becomes α - Obtain the target substance () which is methoxy. By adding the N-halogenating agent, other parts within the molecule may be halogenated to form a perhalogen, but excess halogen can be removed by reduction. This step is achieved by any of the following methods. The amino or amide is treated with an N-halogenating agent (e.g., molecular halogen, t-butyl hypochlorite) followed by an alkali metal methoxide (LiOCH ₃ , NaOCH ₃ , KOCH ₃ , etc.) in methanol.
or alkaline earth metal methoxide (Mg
(OCH ₃ ) ₂ , Ca(OCH ₃ ) ₂ , Ba(OCH ₃ ) ₂ , etc.). ; in the presence of a base and phenyllithium, optionally in a solvent (such as tetrahydrofuran), t-
Acts on butyl hypohalite and methanol. ; Bromine-DBU, phosphorus pentachloride-pyridine, base,
A methanolic base and trialkylsilyl chloride or tetraalkylammonium chloride are applied sequentially. or in methanol in the presence of sodium borate
- If a perhalogenated product is partially formed by the action of butyl hypohalite, reduce it with zinc, phosphite, etc. In addition, compound (a) (E=H, A=NH ₂ ) is a suitable aldehyde (benzuraldehyde, p-
Hydroxybenzaldehyde, 3,5-di-t
-butyl-4-hydroxybenzaldehyde)
The target compound () (E=OCH ₃ ,
A=NH ₂ ) is obtained. To describe this process specifically, amide (a) is
Dissolve in 10 to 50 times the volume of an inert solvent (dichloromethane, dioxane, ether, dipropyl ether, tetrahydrofuran, etc.) and add 1 to 5 molar equivalents of an N-halogenating agent (molecular halogen/carbon tetrachloride, t-butylhypochloride, etc.). -70
Stir at ~-10°C for 2-10 minutes, add 1-4 equivalents of a methanol solution of metal methoxide ( _LiOCH3 , Mg( _OCH3 ) ₂ , etc.) and stir at -50-0°C for 5-70 minutes. When the reaction mixture is neutralized with acetic acid or mineral acid and extracted with an organic solvent, a compound () in which E is methoxy is obtained. With such operations, yields are usually up to 95%. 3 Addition reaction Compound (c) having exomethylene at 3-position
is the addition reagent XZ [molecular halogen, peracid, peroxide, hypohalite salt, hypohalite ester, heavy metal peroxide] in an inert solvent (hydrocarbon, halohydrocarbon, ether, ester solvent, etc.) (such as osmium tetroxide), sulfenyl halide, etc.], Y becomes the formula:

[Formula] (However, COB, X and Z have the same meanings as above)
A compound (a) having a divalent group represented by is obtained. The addition reaction is carried out in an inert solvent, especially in a halohydrocarbon or ether solvent, at low temperature, i.e. -
It proceeds smoothly at 70-0°C and is completed in 5 minutes to 10 hours. Also, due to the high reactivity of the exomethylene double bond at the 3-position, the yield can reach up to 90%. When the reagent is a molecular halogen, halogenation can proceed by light irradiation or the addition of a catalyst (Cu, Cu ₂ S, Cu ₂ Cl ₂ , ph ₃ PO, etc.), and the yield can be increased. . 4. Other conversion reactions Compound () can be prepared by conventional conversion reactions in β-lactam chemistry (e.g. transfer of double bonds with bases, protection of carboxy represented by COB or deprotection of protected carboxy represented by A). Protection of amino or deprotection of protected amino, introduction or conversion of X or Z groups with nucleophiles, conversion of X or Z by conversion reactions such as acylation, hydrolysis, oxidation, reduction, etc.) It can be converted into the compound (). These reactions involve hydrocarbon solvents (hexane, toluene, etc.), halohydrocarbon solvents (dichloromethane, chlorobenzene, etc.), ether solvents (diethyl ether, dioxane, etc.), ketone solvents (acetone, cyclohexanone, benzophenone, etc.), Ester solvents (ethyl acetate, methyl benzoate, etc.), alcohol solvents (ethanol, t-butanol, benzyl alcohol, etc.),
It is carried out in a solvent commonly used for organic reactions such as amides and carboxylic acids. The compound () produced as described above is isolated from the solvent, unreacted substances, by-products, etc. by concentration, extraction, washing, drying, or other conventional methods, and then subjected to reprecipitation, chromatography, crystallization, adsorption, etc. Can be purified. Stereoisomers at the 3- or 7-position can be separated by chromatography, fractional recrystallization, and the like. The mixture of stereoisomers may be used in the next step or synthetic reaction without separation. During the above steps, double bond transfer, introduction of nucleophilic group,
Although side reactions such as elimination may occur during the reaction, these side reactions can also be effectively utilized and are within the scope of the present invention. The compound () of the present invention can be used as a raw material for the synthesis of known antibacterial agents, such as 1-oxacephalosporins (Japanese Patent Application Laid-open Nos. 49-133594 and 51-
149295). That is, operations such as transfer of the double bond to Δ ³ , conversion of the A group to a side chain suitable for exhibiting antibacterial activity, and/or deprotection of the protected carboxy represented by COB are performed on the compound (). It can be synthesized by applying For example, as shown in the process diagram below, when HZ is eliminated from compound (a), 1-dethia-1-oxacephalosporin () is obtained. b When compound (d) is treated with a base (such as trimethylamine) at 0 to 70°C for 5 hours to 3 days, the double bond is transferred and 1-dethia-1-oxacephalosporin () is obtained. C Compound (a) is treated with a Lewis acid (e.g. boron trifluoride) at 0°C to 50°C for 0.1 to 1 hour to cause ring closure and yield 1-dethia-1-oxacephalosporin (). Compound of the present invention () (A=7β-amide, COB
=COOH) or a pharmaceutically acceptable salt thereof is
It itself has a mild antibacterial effect, and with the addition of diluents, it can be used for one day to treat diseases caused by susceptible Glum-positive bacteria (e.g. (Streptococcus pyogenes)) or Gram-negative bacteria (e.g. Escherichia coli). It is sufficient to inject 0.1 to 10 g.The embodiments of the present invention will be clarified by giving examples below.The names and position numbers of the compounds in the examples are as follows. 1βH, 5βH- or (1R,5S)-7-oxo-
4-Oxa-2,6-diazabicyclo[3.2.0]
hept-2-ene 1-Dethia-1-oxacepham The configuration of the carbons at the 7- and 6-positions of oxacepham is the same as the configuration of the 1- and 5-positions of oxabicycloheptene. The stereochemistry at carbon 6 of the 1-dethia-1-oxacephame ring is consistent with the stereochemistry at carbon 6 of cephalosporin. Preferably, the stereochemistry of COB is the same as penicillin, ie the R configuration, but this need not be the case. The measurement error in the following examples is ±10 IR
cm ^-1 , NMR is within ±0.2 ppm, melting point is not accurate. Anhydrous sodium sulfate is used to dry the solution. The physical constants of the products are listed in the table. Ring Closing Reaction Examples -1 to 32 When oxazolinoazetidine is dissolved in a solvent and an acid is added, a 1-dethia-1-oxacefam compound is obtained. The reaction conditions are shown in the table. Taking No. 14 as an example, it will be shown in detail below. (1) 2-[(1R,5S)-3-phenyl-7-oxa-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-2-
12.0 g of diphenylmethyl isopropenylacetate,
Osmium tetroxide 1.0g and potassium chlorate
Dissolve 12.0g in a mixture of 400ml of tetrahydrofuran and 200ml of water, and stir at 58°C for 3.5 hours. After cooling, the reaction mixture is poured into ice water and extracted with ethyl acetate. The extract was sequentially washed with brine, 10% sodium thiosulfate solution, and sodium hydrogen carbonate solution, dried, and the solvent was distilled off, resulting in 2-
[(1R,5S)-3-phenyl-7-oxo-4-
12.88 g of diphenylmethyl oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl]-3,4-dihydroxybutyrate are obtained. IR: ν ^CHCl3 _nax 3500br, 1700br, 1742, 1636cm ^-1 (2) Add 10.88g of the above product to 300ml of diethyl ether
Add 75 μl of boron trifluoride etherate, stir at room temperature in a nitrogen stream for 3.5 hours, pour into cooled aqueous sodium bicarbonate solution, and extract with ethyl acetate. The extract is washed with brine and concentrated. Treatment of the residue with concentrated methylene chloride and ether gives 15 g of a mixture of isomers in the 3-position of diphenylmethyl 7α-benzamido-3ξ-methyl-3ξ-hydroxy-1-dethia-1-oxacefam-4α-carboxylate. IR: ν ^CHCl3 _nax 3560, 3445, 1774, 1739, 1670 cm ^-1 The isomer mixture is subjected to column chromatography on 10% hydrous silica gel and eluted with benzene-ethyl acetate (4:1). The stereoisomers can be separated by crystallizing the eluate with acetone-ether and acetone-methylene chloride, respectively. Example −33 (a) 2-[(1R,5S)-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)]-3-
Benzyl formyloxymethyl-2-butenoate
54 mg are dissolved in 2 ml of methanol, 19 μl of boron trifluoride etherate are added while cooling at -20°C, and the mixture is stirred at -20°C to 0°C for 40 minutes, at 0°C for 2 hours, and then at room temperature for 1 hour. 5% to this
Add aqueous sodium bicarbonate solution and extract with methylene chloride. The extract is washed with water, dried, and then the solvent is distilled off. The residue is crystallized from methanol to obtain 10 mg (yield 20%) of benzyl 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate.
mp.208-212℃ (b) Instead of boron trifluoride, add 5 μl of trifluoromethanesulfonic acid while cooling on ice and stir for 130 minutes, or add 0.38 N hydrochloric acid-methanol 0.5
ml, stirred for 3 hours, and otherwise performed the same procedure as above to obtain the same substance (14 mg; 5 mg) (yield
27.5%; 7%). mp.208~212℃ Methoxylation Example -1~24 7β-unsaturated-7α-amido-1-dethia-1-
When an oxacefam compound is dissolved in a solvent and an N-halogenating agent and a base are reacted in methanol,
A 7α-methoxy-7β-amide compound is obtained. The reaction conditions are shown in the table. (No. 5) 7α-benzamide-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4α-
Dissolve 486 mg of diphenylmethyl carboxylate in 20 ml of anhydrous methylene chloride, and dissolve t-butyl hypochlorite.
Add 0.15 ml and 1.1 ml of 2N lithium methoxide in methanol at -50°C and stir for 15 minutes.
Add 1.2 ml of acetic acid to this, stir for 5 minutes, dilute with ice-cooled aqueous sodium bicarbonate solution, and extract with methylene chloride. After washing the extract with an aqueous sodium hydrogen carbonate solution and then with water, the solvent was distilled off. The resulting colorless foamy residue was purified by silica gel chromatography to yield 7β-benzamide.
7α-methoxy-3α-hydroxy-3β-methyl-
250 mg (yield 48%) of diphenylmethyl 1-dethia-1-oxacefam-4α-carboxylate is obtained. 7α-benzamide-3ξ-bromo-3ξ-bromoethyl-1-dethia-1-oxacefam-4α
Dissolve 187 mg of diphenylmethyl carboxylate in 1 ml of anhydrous methylene chloride, add 46 ml of t-butylhypochlorite and 0.17 ml of a 2M methanol solution of lithium methoxide at -30°C, and stir at the same temperature for 1 hour. To this, 1-methyl-tetrazole-5
Add a solution of 100 mg of sodium ilmercaptide in 1 ml of acetone and stir at room temperature for 1.5 hours. The reaction solution is diluted with methylene chloride, washed with an aqueous sodium bicarbonate solution and then with brine, dried, and the solvent is distilled off. 180 mg of the residue was subjected to column chromatography on silica gel and eluted with benzene-ethyl acetate (1:1) to yield 7β-benzamide-7α.
-methoxy-3-(1-methyltetrazole-5
-yl)thiomethyl-1-dethia-1-oxa-
Diphenylmethyl 3-cephem-4-carboxylate
Get 108mg. Addition Reaction Examples -1 to 16 3,3-methylene-1-dethia-1-oxacepham compound is dissolved in a solvent, and addition reagent XZ is added. The reaction conditions are shown in the table. 7α-benzamide-3-exomethylene-1
-Dissolve 519 mg of diphenylmethyl dethia-1-oxacefam-4α-carboxylate in 5 ml of methylene chloride, add 1.6 ml of 0.76N chlorine/carbon tetrachloride solution, and stir at -20 to -30°C for 40 minutes while irradiating with a tungsten lamp. . Add this to 0.14ml of cyclopentene
Add and stir for an additional 5 minutes. 1,5 to the reaction mixture
Add 50.14 ml of -diazabicyclo[3.4.0]nonene, stir at -20°C for 10 minutes, wash with dilute hydrochloric acid and then with water, dry, and evaporate the solvent. Recrystallization of the crystalline residue from methanol yields 7α-benzamide-
3-chloromethyl-1-dethia-1-oxa-3
-Cefem-4-carboxylic acid diphenylmethyl
Obtain 484 mg (86% yield). mp.120-128℃ (No. 4) Dissolve 103 mg of diphenylmethyl 7α-benzamide-3-methylene-1-dethia-1-oxacefam-4α-carboxylate in 1 ml of methylene chloride,
Add 0.3 ml of 0.75N chlorine in carbon tetrachloride solution, -20 ~
After reaction under irradiation with a tungsten lamp for 30 minutes at −30°C, the solvent was distilled off under reduced pressure to produce 7α-benzamide-3ξ-chloro-3ξ-chloromethyl-1-
120 mg of diphenylmethyl dethia-1-oxacefam-4α-carboxylate are obtained. (No. 5) In the same manner, 141 mg of benzyl 7α-benzamide-3-methylene-1-dethia-1-oxacepham-4α-carboxylate and 1.4 equivalents of chlorine were reacted in 3 ml of methylene chloride at -50°C under light irradiation. If you let me
7α-Benzamide-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacefam-4α-
170 mg (yield 102%) of benzyl carboxylate is obtained. (No. 15) In the same manner as above, 1.77 equivalents of chlorine was added to 705 mg of diphenylmethyl 7α-phenylacetamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate in 7 ml of methylene chloride at -25°C or lower. If allowed to act, 7α-phenylacetamide-
3ξ-chloro-3ξ-chloromethyl-1-dethia-
Diphenylmethyl 1-oxacefam-4α-carboxylate is obtained. If 0.16 ml of pyridine is treated with this at 15°C for 40 minutes, 586 mg of diphenylmethyl 7α-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate (yield:
78.4%). mp.179-182℃ (decomposition). Example −17 1.405 g (3 mmol) of diphenylmethyl 7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate was dissolved in anhydrous methylene chloride cooled to -26°C, and 141 mg of copper powder was added under stirring in a nitrogen stream. In addition, 6.3 ml (2.5 equivalents) of 1.2M chlorine-chloroform solution was added dropwise over 10 minutes, and the mixture was stirred at -22 to -30°C for 3 hours. To this, sodium thiosulfonate pentahydrate (2.98 g; 4
Add an aqueous solution of the same amount) and extract twice with methylene chloride. The extract is washed with brine, dried over magnesium sulfate, and then the solvent is distilled off. Silica gel residue
Chromatographed 190g of benzene-
If eluted with ethyl acetate (3:1), 7α
-benzamide-3α-chloro-3β-chloromethyl-1-dethia-1-oxacepham-4α-diphenylmethyl carboxylate 1.541 g (yield 95.2%)
is obtained as a white foam. Other Conversion Reactions A Elimination Reaction Examples A-1 to 20 If the 1-dethia-1-oxacepham compound is dissolved in a solution and a desorption agent is used, 1-dethia-1-
Oxacefam compound is obtained. Table A shows the reaction conditions. 15.0 g of diphenylmethyl 7α-benzamide-3ξ-hydroxy-3ξ-methyl-1-oxadethiacefam-4α-carboxylate was added to 100 g of methylene chloride.
ml, add 6.8 ml of pyridine and 3 ml of thionyl chloride while stirring on ice, stir at the same temperature for 7.25 hours and at room temperature for 2.25 hours, and then pour into ice water. The organic layer is separated, washed with water, dried, and the solvent is distilled off. The residue was chromatographed on 350 g of 10% hydrated silica gel and benzene-ethyl acetate (9:
1), 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-
2.65 g of diphenylmethyl 4-carboxylate (yield:
25.2%) and 7α-benzamido-3-methyl-
1-dethia-1-oxa-2-cephem-4α-
Diphenylmethyl carboxylate 1.05g (yield: 10.8
%). (IR: ν ^CHCl3 _nax 3400, 1782, 1745, 1676, 1663
Sh cm ^-1 B Double bond transfer example B-1 Dissolve 100 mg of 7β-benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-carboxylic acid in 10 ml of acetone, and add 0.1 ml of triethylamine. ml and leave at room temperature for 6 days.
When the reaction solution is subjected to thin layer chromatography,
7β-Benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-3-cephem-4-
Carboxylic acid and raw material spots are shown. Example B-2 7α-benzamide-3,3-methylene-1-
Dissolve 5.0 g of diphenylmethyl dethia-1-oxacefam-4α-carboxylate in 25 ml of methylene chloride and add 0.5 ml of triethylamine. at room temperature
Stir for 80 minutes, add a small amount of benzene, and then concentrate. Crystallization of the residue from ether gives 4.5 g (yield: 90%) of diphenylmethyl 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate. After the mixture was left at room temperature for 15 hours, chromatographic separation revealed 50.8% of the Δ ² isomer and 38.3% of the Δ ³ isomer.
% and their mixture yields 4.1%. Example B-3 7α-benzamide-3,3-methylene-1-
Dethia-1-oxacefam-4α-carboxylic acid
Dissolve 100 mg in 10 ml of acetone, add 0.1 ml of triethylamine, and leave for 5 days. When the reaction mixture is subjected to thin layer chromatography, 7α-benzamido-3-methyl-1-dethia-1-oxa-
2-Cefem-4-carboxylic acid, 7α-benzamido-3-methyl-1-dethia-1-oxa-3
-Cefem-4-carboxylic acid and the spots of raw materials are shown. C Removal example of carboxy protecting group C-1 7β-benzamide-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacefam-4α-carboxylic acid diphenylmethyl 960
mg was dissolved in 4 ml of anisole, 10 ml of trifluoroacetic acid was added at 0°C, stirred for 15 minutes, and the solvent was distilled off under reduced pressure. Solidification of the residue from ether-n-hexane yields 7β-benzamide-7α-methoxy-
3α-methyl-3β-acetoxy-1-dethia-1
470 mg (yield: 70%) of -oxacefam-4α-carboxylic acid are obtained as a colorless powder. mp.203~208
℃ (Decomposition) The following carboxylic acids can be prepared from the corresponding diphenyl methyl esters in a similar manner. 7β-Benzamide-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylic acid, mp.100-105℃ (decomposition) 7β-Benzamide-7α-methoxy-3α-trifluoro acetoxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylic acid,
mp.108-113℃ 7β-benzamide-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4
-Carboxylic acid, mp.195-198℃ IR: ν ^KBr _nax 3250, 1766, 1742, 1642cm ^-1 7α-Benzamide-3ξ-chloro-3ξ-chloromethyl-1-dethia-1-oxacefam-4α
-Carboxylic acid, mp.118-122℃ (decomposition) Example C-2 7α-benzamide-3-exomethylene-1
-diphenylmethyl dethia-1-oxacefam-4α-carboxylate 1.125g in methylene chloride 15ml
A solution of aluminum trichloride (625 mg) in nitromethane (20 ml) was added to the solution of aluminum trichloride (625 mg) in nitromethane (20 ml) while stirring at -20°C, and the solution was heated to -10° C. in a nitrogen stream.
Stir for 30 min at ~-20°C. This is poured into an aqueous solution of hydrochloric acid and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium carbonate solution, the washings are acidified with concentrated hydrochloric acid, and extracted again with ethyl acetate. The organic layers were combined, washed with water, dried, and the solvent was distilled off to give 7α-benzamide-3-exomethylene-1-dethia-
623 mg of 1-oxacefam-4α-carboxylic acid are obtained. Similarly, 7α-benzamido-3-methyl-1
-diphenylmethyl dethia-1-oxa-2-cephem-4α-carboxylate (1.8 g) in methylene chloride
7α-benzamido-3-methyl-1-dethia-1-oxa-
2-cephem-4α-carboxylic acid 935 mg (yield 72.6
%). D Example of protection of amino group and removal of amino protecting group D-1 7α-amino-3-methylene-1-dethia-1
25 mg of diphenylmethyl -oxacefam-4α-carboxylate is dissolved in 0.5 ml of methylene chloride, 7 μl of pyridine and 10 μl of benzoyl chloride are added at −20° C. in a nitrogen stream, and the mixture is stirred for 1 hour. This is poured into ice water, stirred for 5 minutes, and then extracted with methylene chloride. The organic layer was separated, washed with water, an aqueous sodium bicarbonate solution, then water, dried, and the solvent was evaporated to give 28 mg of diphenylmethyl 7α-benzamido-3-methylene-1-dethia-1-oxacefam-4α-carboxylate. rate of 86%). This product was identified by thin layer chromatography and NMR. Example D-2 94 mg of diphenylmethyl 7α-benzamido-3-methylene-1-dethia-1-oxacefam-4α-carboxylate was dissolved in 4 ml of methylene chloride,
32 μl of pyridine and 0.37 M at −40°C in a nitrogen stream
Add 1.08 ml of a methylene chloride solution of phosphorus pentachloride, warm to room temperature, and stir for 1 hour. Cool again to -40℃, add 8 ml of methanol, warm to 0℃, and add water.
Add 0.8 ml and evaporate the solvent under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate, washed with water, extracted with an aqueous sodium bicarbonate solution and then with water. Combine the extract and washing liquid, cover with ethyl acetate, adjust the pH to 7.0, and extract with ethyl acetate. The organic layer was separated, washed with water, dried, and the solvent was distilled off to give 29 mg of diphenylmethyl 7α-amino-3-methylene-1-dethia-1-oxacefam-4α-carboxylate.
(yield: 40%). IR: ν ^CHCl3 _nax 3000, 1770sh, 1760, 1740cm ^-1 E Example of conversion reaction of X and Z E-1 (1) 7α-benzamide-3ξ-hydroxy-3ξ-
Diphenylmethyl bromomethyl-1-dethia-1-oxacefam-4α-carboxylate 108mg
Potassium carbonate dissolved in 5 ml of 10% aqueous acetone
After adding 50 mg and stirring at room temperature for 1.5 hours, dilute with brine and extract with methylene chloride.
The extract is dried over magnesium sulfate and the solvent is distilled off. When 90 mg of the residue was purified by silica gel thin layer chromatography (developing solvent: benzene-ethyl acetate (2:1)), 7α-benzamide-
40 mg of diphenylmethyl 3,3-epoxymethano-1-dethia-1-oxacefam-4α-carboxylate (isomer A) is obtained. Furthermore, from 140 mg of the stereoisomer of the raw material, 56 mg of the stereoisomer B at the 3-position is obtained. (2) 1-methyltetrazol-5-ylthiol
Dissolve 20mg in 2ml of tetrahydrofuran,
1.5Mn-butyllithium hexane solution 0.05ml
Add and stir for 30 minutes. I got this above
Add 56 mg of diphenylmethyl 7α-benzamide-3,3-epoxymethano-1-dethia-1-oxacepham-4α-carboxylate (isomer B) dissolved in 1 ml of tetrahydrofuran, stir for 1 hour, and add aqueous sodium bicarbonate solution. Extract with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and the solvent is evaporated. The residue was subjected to column chromatography on 1 g of 10% hydrous silica gel and eluted with benzene-ethyl acetate (9:1) to give 7α-benzamido-3-(1-methyltetrazol-5-yl).
Thiomethyl-3-hydroxy-1-dethia-1
43 mg of diphenylmethyl -oxacefam-4α-carboxylate (isomer B) are obtained. Example E-2 (1) 7α-benzamide-3α-hydroxy-3β-
Methyl-1-dethia-1-oxacefam-4
- Dissolve 100 mg of diphenylmethyl carboxylate in 5 ml of isopropenyl acetate, add 6 mg of p-toluenesulfonic acid hydrate, and heat at 60°C for 75 minutes. After cooling, the reaction mixture is poured into an ice-cooled aqueous sodium bicarbonate solution and extracted with methylene chloride. After separating the organic layer, washing with water and drying,
When the solvent was distilled off, diphenylmethyl 7α-benzamide-3α-acetoxy-3β-methyl-1-dethia-1-oxacefam-4α-carboxylate (yield: 30.5%) was obtained. (2) 7α-benzamide-3α-hydroxy-3β-
Methyl-1-dethia-1-oxacefam-4
- Diphenylmethyl carboxylate was added to a mixture of 1.1 equivalents of lithium diisopropylamide, 1.2 equivalents of acetyl chloride, and 20 times the volume of tetrahydrofuran, heated to -40℃ for 45 minutes, then heated to -20℃ for 15 minutes, and then heated to 0.
C. or treatment with a solution of 1 equivalent of pyridine and 1.2 equivalents of acetyl chloride in methylene chloride gives the same product as (1). (3) Dissolve 52 mg of diphenylmethyl 7β-benzamide-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacefam-4-carboxylate in 1 ml of dioxane, and add trifluoroacetic anhydride under ice cooling in a nitrogen stream. Add 0.1ml of
Stir at room temperature for 2 hours. Add 0.3ml of water to this,
Stir for 30 minutes, dilute with ice water and extract with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off to give 7β-benzamide-7α-methoxy-3α.
-trifluoroacetoxy-3β-methyl-1
64 mg of diphenylmethyl-dethia-1-oxacefam-4α-carboxylate are obtained as an oil. (4) 7α-benzamide-3ξ-hydroxy-3ξ-
Hydroxymethyl-1-dethia-1-oxacefam-4α-carboxylic acid diphenylmethyl 112
mg is dissolved in a mixture of 0.5 ml of pyridine and 0.3 ml of acetic anhydride, left overnight at 0°C, and then concentrated under reduced pressure. Pour the residue into water and extract with ethyl acetate. The extract was washed successively with water, dilute hydrochloric acid, aqueous sodium bicarbonate and water, dried and the solvent was distilled off to give 7α-benzamide-3ξ-hydroxy-3ξ-acetoxymethyl-1-dethia-
54 mg of diphenylmethyl 1-oxacefam-4α-carboxylate is obtained as crystals. mp.118~
120℃ (5) 7α-benzamide-3ξ-hydroxy-3ξ-
Hydroxymethyl-1-dethia-1-oxacefam-4α-carboxylic acid diphenylmethyl 350
Dissolve mg in 3 ml of methylene chloride and 78 μl of pyridine.
and 75 μl of methanesulfonyl chloride,
Stir at 0° C. for 1 hour and then at room temperature for 3 hours.
Pour this into ice water and extract with ethyl acetate. The extract is washed with water, an aqueous sodium bicarbonate solution and then with water, dried, and the solvent is distilled off. 370 mg of the resulting residue is subjected to silica gel chromatography to obtain 145 mg of diphenylmethyl 7α-benzamido-3ξ-hydroxy-3ξ-methanesulfonyloxymethyl-1-dethia-1-oxacefam-4α-carboxylate. Continuous Process Examples -1 to 8 7α-amino-7β-unsubstituted-3-exomethylene-1-dethia-1-oxacefam-4-carboxylic acid ester was dissolved in methylene chloride and treated with a halogenating agent and a base in methanol. Then, 3
-halo-3-halomethyl-7α-methoxy-7β-
Amino-1-dethia-1-oxa-3-cephem-4-carboxylic acid ester is obtained. The reaction conditions are shown in the table. 3-halomethyl may be substituted with other nucleophilic groups. 7α-p-cyanobenzamide-3-exomethylene-1-dethia-1-oxacefam-4α
-Dissolve 246 mg of diphenylmethyl carboxylate in 8 ml of methylene chloride cooled to -50℃, add 1.47 ml of 1.2M chlorine in carbon tetrachloride solution, and stir for 7 minutes while irradiating with a 300W tungsten lamp.7α-
Diphenylmethyl (N-chloro-p-cyanobenzamide)-3-exomethylene-1-dethia-1-oxacepham-4α-carboxylate is obtained. Add to this a 2M lithium methoxide methanol solution.
Add 1.57 ml and stir at -50°C to -60°C for 10 minutes.
After adding 0.2 ml of acetic acid to this, pour into ice water and extract with methylene chloride. The extract is washed with a dilute aqueous sodium bicarbonate solution and then with water, dried, and the solvent is distilled off. The residue (diphenylmethyl 7α-cyanobenzamide-7α-methoxy-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate) was dissolved in 6 ml of methylene chloride, and 1-methyltetrazole-5 - 100 mg of mercaptide and 20 mg of tetrabutylammonium bromide are dissolved in 3 ml of water and stirred for 1 hour at room temperature. The reaction mixture is poured into ice water, extracted with methylene chloride, washed with water, dried, and the solvent is distilled off. When 335 mg of the obtained residue was subjected to silica gel column chromatography, 7β-p-cyanobenzamide-7α-methoxy-3-(1-methyltetrazol-5-ylthio)methyl-1-dechia-1-oxa-3- 251 mg of diphenylmethyl cefem-4-carboxylate is obtained. Usage example 15.0 g of diphenylmethyl 7α-benzamide-3ξ-hydroxy-3ξ-methyl-1-oxadethiacefam-4α-carboxylate was added to 100 g of methylene chloride.
ml, add 6.8 ml of pyridine and 3 ml of thionyl chloride while stirring on ice, stir at the same temperature for 75 minutes, then at room temperature for 2.25 hours, and pour into ice water. The organic layer is separated, washed with water, dried and the solvent is distilled off. The residue was chromatographed on 350 g of 10% hydrous silica gel and eluted with benzene-ethyl acetate (9:1) to give 7α-benzamide-3-methyl-
2.65 g of diphenylmethyl 1-dethia-1-oxa-3-cephem-4-carboxylate (yield: 25.2
%, mp.144-146℃) and 7α-benzamide-
Diphenylmethyl 3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylate 1.05g
(Yield: 10.8%, IR: ν ^CHCl3 _nax 3440, 1782, 1745, 1676, 1663sh
We get cm ^-1 . Dissolve 512 mg of compound (a) in a mixture of 10 ml of benzene and 1 ml of methanol, and add triphenylphosphine.
Add 0.4g and stir at 65°C for 1.5 hours. This is 10
The product was subjected to column chromatography using 30 g of hydrated silica gel and eluted with benzene containing 20-30% ethyl acetate to obtain 202 mg of compound (b). IR: ν ^CHCl3 _nax 3370, 1782, 1755, 1635 cm ^-1 NMR: δ ^CHCl3 2.50-3.35 m 1H, 4.18S 2H,
5.08S1H, 5.25SIN, 5.28d (3Hz) 1H,
5.50S1H, 6.08d (3Hz) 1H, 6.93S1H, 7.20
~8.00m15H. (1) 2-(3-benzyl-7-oxo-2,6-
Diphenylmethyl diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-methyl-3-butenoate 4.6g Ethyl acetate 70ml
Add 3.8 ml of 2.74 M hydrochloric acid-ethyl acetate and 12 ml of 1.47 M hydrochloric acid-carbon tetrachloride, and stir at room temperature.
Stir for 15 minutes. To this were added 80 ml of 5% sodium thiosulfate, 3.4 g of sodium bicarbonate and 240 g of acetone, stirred at room temperature for 2.5 hours, and then extracted with ethyl acetate. The extract was dried with sodium sulfate and 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2-en-6-yl)-3-
Diphenylmethyl chloromethyl-3-butenoate
Obtain 3.33g. mp.82-83°C (2) Dissolve the above product in 25 ml of acetone, add 3.3 g of sodium iodide, and leave to stand at room temperature for 2 hours, then evaporate the solvent. The residue is extracted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and then with water, dried over sodium sulfate, and the solvent is distilled off to yield 3.0 g of the corresponding iodide. (3) Add 1.59g of the above product to 13ml of dimethyl oxide.
and dissolved in a mixture of 3 ml of water, cuprous oxide 0.77
g and stirred at 39°C for 1 hour, then filtered. The filtrate was extracted with ethyl acetate, washed with water, dried and the solvent was distilled off to give 2-(3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo[3.2.0]hept-2- en-6-yl)
0.35 g of diphenylmethyl-3-hydroxymethyl-3-butenoate is obtained. mp.40～55℃ Explanation of abbreviations -ph=phenyl -STert=1-methyl-1,2,3,4-tetrazol-5-yl -C ₆ H ₄ NO ₂ -p=p-nitrophenyl -C ₆ H ₄ CH ₃ -p=p-tolyl -C ₆ H ₄ CN-P=p-cyanophenyl -C ₆ H ₄ Cl-p=p-chlorophenyl -Bu-t=tertiary butyl -OAc=acetoxy Between X and Z ==CH ₂ X and Z together represent methylene. -O-=X and Z between X and Z represent epoxy. = CH ₂ = Weight of raw material 3-epoxymethylene compound EtOAC = Ethyl acetate THF = Tetrahydrofuran DMF = N,N-dimethylformamide c-H ₂ SO ₄ = Concentrated H ₂ SO ₄ Et ₂ O = Diethyl ether t-BuOCl = Tertiary butyl hypochlorite eq = equivalent DBN = 1,5-diazabicyclo[3.4.0]nonene-5 (CH ₂ ) ₅ NH = piperidine hν = light irradiation Δ ² or Δ ³ at Z = elimination at position 3 It means that a double bond is present at the 2(3) or 3(4) position in place of the group.

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[Table] Among the reagents, methoxide is used as a methanol solution.

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Claims (1)

[Claims] 1. General formula: [However, A is amino or protected amino; E is hydrogen or methoxy; Y is [formula] [formula] [formula] or [formula] (however, COB is carboxy or protected carboxy; X is hydrogen or halogen atom, hydroxy group, lower alkanoyloxy group, lower alkanesulfonyloxy group, lower alkylthio group or 1-lower alkyltetrazolylthio group; Z is a halogen atom, hydroxy group, lower alkanoyloxy group and halogenated lower alkanoyloxy group; A divalent group represented by ); The wavy line represents an α or β bond, respectively. ] A compound represented by: 2 General formula (However, A is amino or protected amino; Y is [formula] [formula] [formula] or [formula] (however, COB is carboxy or protected carboxy; X is hydrogen or halogen atom, hydroxy group, lower Alkanoyloxy group, lower alkanesulfonyloxy group, lower alkylthio group,
and a 1-lower alkyltetrazolylthio group; Z represents a halogen atom, a hydroxy group, a lower alkanoyloxy group, or a halogenated lower alkanoyloxy group; ) respectively represent divalent groups; ] The compound of Claim 1 shown by these.