JPS60248691A - Novel preparation of cephalosporin compound and its intermediate - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a fungicide, easily in high yield, by reacting a specific novel compound with a specific cephem compound in the presence of boron trifluoride, etc. CONSTITUTION:The novel compound (syn isomer) of formula I [R<1> is H, (substituted) alkyl, aralkyl, aryl or heterocyclic group; R<2> is lower alkyl] [e.g. 2-(2- aminothiazol-4-yl)-2-(syn)methoxyiminoacetic acid amide, etc.] is made to react with the compound of formula II [R<3a> is COOH-protecting group; R<4> is (substituted) heterocyclic group bonded with 3-exomethylene group through C-N bond] {e.g. pivaloyloxymethyl=7-amino-3-[(5-methyl-1,2,3,4-tetrazol-2-ylmethyl]- DELTA<3>-cephem-4-carboxylate} in the presence of boron trifluoride or its complex compound to obtain the objective compound of formula III (R<3> is H or COOH- protecting group). The starting raw material of formula I can be produced according to the reaction formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing cephalosporins and intermediates thereof, that is, a method for producing a cephalosporin (synisomer) represented by the general formula or a salt thereof useful as an antibacterial agent, and Specifically, the compound represented by the general formula (syn isomer) and the compound represented by the general formula J are reacted in the presence of boron trifluoride or its complex compound, and if necessary, the carboxyl protecting group is removed or The present invention relates to a production method for obtaining a cephalosporin (syn isomer) represented by the general formula [111] or a salt thereof by converting it into a salt, and a useful intermediate represented by the general formula [ID].

The present inventors have already discovered that the cephalosporin (synisomer) represented by the general formula [■] and its derivatives are extremely useful compounds as antibacterial agents, and have previously filed a patent application (Japanese Patent Application Laid-Open No. No. 57-99592, patent application No. 57-200
No. 382, No. 58-67871, No. 58-11356
No. 5, No. 58-114313).

After that, as a result of intensive research on the production method of the compound of the general formula [■] or its salt, we found that the compound of the general formula [ID] (synisomer) and the compound of the general formula [ID] were combined with boron trifluoride or its complex. React in the presence of a compound, the required anonymity,
By eliminating the carboxyl protecting group or converting it into a salt, useful cephalosporins of general formula [III] (
The present invention has been completed based on the discovery that the syn isomer) or a salt thereof can be easily obtained at high yield and pressure.

That is, by reacting an acid amide of the general formula CI or a monosubstituted acid amide having a free amino group with a compound of the general formula [■] in the presence of boron trifluoride or its complex compound, the general formula [ It has been found that the cephalosporin (syn isomer) or its salt III) can be easily obtained in high yield.

Therefore, the object of the present invention is to provide a cephalosporin (syn isomer) of general formula [I11] having an excellent antibacterial spectrum.
An object of the present invention is to provide a new method for producing a salt thereof, and a novel compound (syn isomer) of the general formula m.

In this specification, unless otherwise specified, the alkyl group refers to linear or branched C1-14 alkyl,
For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, see -7”thyl, t
ert - '7' tyl, pentyl, hexyl, heptyl, octyl, dodecyl, etc.; Aryl is, for example,
Phenyl, tolyl, naphthyl, indanyl, etc.; Aralkyl is, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl, etc.; Acyl is C
1-12 acyl, such as acetyl, propionyl,
n-butyryl, imbutyryl, valeryl, pivaloyl,
Pentane carbonyl, cyclohexane carbonyl, benzoyl, naphthoyl, furoyl, thenoyl, etc.; halogen atom means fluorine, chlorine, bromine, iodine atom, etc., respectively. Moreover, lower means having 1 to 5 carbon atoms.

Furthermore, among the various terms used in this specification, for example, terms such as alkyl, aryl, aralkyl, and acyl groups have the above-mentioned meanings unless otherwise specified.

R1 in the general formula CI] means a hydrogen atom or an optionally substituted alkyl, aralkyl, aryl, or a heterocyclic group, and specific examples of the heterocyclic group include, for example, pyrazolyl, imidazolyl, triazolyl, tetrazolyl.

pyridyl, pyrimidinyl, pyrimidinyl, pyrazinyl,
Examples include nitrogen-containing 5- or 6-membered heterocyclic groups such as triazinyl. Examples of these substituents for R1 include:
Halogen atom, nitro group, alkyl group, aryl group, alkoxy group, cyano group, amino group, alkylamino group,
dialkylamine group, acylamino group, acyl group, acyloxy group, acylalkyl group, carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, carbamoyl group, aminoalkyl group, N-alkylaminoalkyl group, N,N-dialkylaminoalkyl group, hydroxyalkyl group, hydroxyiminoargyl group, alkoxyalkyl group, carboxyalkyl group, sulfoalkyl group, sulfo group, sulfamoylalkyl group,
Examples include sulfamoyl group, carbamoylalkyl group, carbamoylalkenyl group, N-hydroxycarbamoylalkyl group, etc., and the above-mentioned alkyl, aralkyl, ring or heterocyclic group may be substituted with one or more of these substituents. It's okay. Among these substituents, the carboxyl group may be protected with a carboxyl protecting group as explained in R3B and R3 below.

R3a represents a carboxyl-protecting group, and R3 represents a hydrogen atom or a carboxyl-protecting group, and protective groups for these carboxyl groups include those commonly used in the field of penicillin and cephalosporin compounds. . Specifically, for example, alkyl, phthalidyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, l-acetoxyethyl, 1- acetoxy-n
-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl, benzoyloxymethyl,
Examples include 1-benzoyloxyethyl, α-pivaloyloxybenzyl, α-acetoxybenzyl groups, and the like.

Next, R4 represents an optionally substituted heterocyclic group that forms a carbon-nitrogen bond with the exomethylene group at the 3-position. represents a divalent group forming a 5-membered term or a 6-membered ring. ), for example, 1.2.6-thiadiazine-1,1-dioxide,
Examples include nitrogen-containing 5- or 6-membered heterocyclic groups such as isothiazolidine-1,1-dioxide groups. More specifically, 1-(1,2,3,4-tetrazolyl), 2-
(1,2,3゜4-tetrazolyl), 1-(1,2,
3-triazolyl), 2-(1,2,3-)riazolyl), 1-(1゜2.4-)riazolyl), 4-(1
, 2,4-triazolyl), 2,3-dioxo-1,2
, 3,4-tetrahydropyrazinyl, 3,6-thioxo-1,2,3,6-titrahydropyridazinyl, 6-oxo-1,6-cyhydropyridazinyl, 2-oxo-1
, 2-dihydropyrazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1,2-dihydropyrimidinyl, 1,2,6-thiadiazin-1,i-dioxide-2-yl, isothiazolidine -1,1-dioxido-2-yl group and the like.

Examples of the substituents in the heterocyclic group include the substituents described for R1. Among these substituents, the carboxyl group may be protected with a carboxyl protecting group as explained in %R3a and R3.

Salts of the cephalosporin (synthetic form) of the general formula Cm) include salts with basic groups or acidic groups conventionally known in the field of penicillin and cephalosporin compounds. Salts of such basic groups include, for example, salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, nitric or sulfuric acids; oxalic, succinic, formic, trichloroacetic or trifluoroacetic acids. Salts with organic carboxylic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfone W, 71 sitylenesulfonic acid (2,4
, 6-) Limethylbenzenesulfonic acid) salts with sulfonic acid, and salts with acidic groups include:
For example, salts with alkali metals such as sodium or potassium; salts with alkaline earth metals such as calcium or magnesium; ammonium salts; triethylamine, trimethylamine, aniline, N,N-dimethylaniline, pyridine, dicyclohexylamine, etc. Examples include salts with nitrogen-containing organic bases.

Next, embodiments of the method of the present invention will be described.

The compound of the general formula [IID or a salt thereof is the cephalosporin of the present invention, the general formula CI] and the compound of the general formula [■] are reacted in the presence of boron trifluoride or a complex compound thereof,
If necessary, it can be obtained by eliminating the carboxyl protecting group or converting it into a salt.

The compound of the general formula [■] can be prepared, for example, by a conventional three-position conversion reaction of 7-aminocephalosporanic acid in the presence of an acid. No. 206873, No. 58-67871, No. 5.8-113565, No. 58-114313, etc.) and then introducing a @ group into the carboxyl group at the 4-position.

Examples of boron trifluoride complexes used in the present invention include carboxylic acid ester complexes of boron trifluoride and ethyl formate or ethyl acetate; dialkyl ether complexes of diethyl ether or diisopropyl ether; Examples include sulfolane complex compounds with sulfolane; nitrile complex compounds with acetonitrile or propionitrile, etc., and preferably boron trifluoride sulfolane complex compounds, acetonitrile complex compounds, diethyl ether complex compounds, and ethyl acetate complex compounds. It will be done.

Further, in the present invention, it is preferable to carry out the reaction using an organic solvent, and examples of the organic solvents used include nitroalkanes such as tatoeha, nitromethane, nitroethane, and nitropropanato; diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, Ethylene 11
Ethers such as cold dimethyl ether, anisole, and dimethyl cellosolve; Esters such as ethyl formate, diethyl carbonate, methyl acetate, ethyl acetate, diethyl oxalate, ethyl chloroacetate, butyl acetate; methylene chloride, chloroform, and 1,2-dichloroethanat. Examples include halogenated hydrocarbons; nitriles such as acetonitrile and propionitrile; sulfolanes such as sulfolane; and preferred examples include nitroalkanes, esters, nitriles, halogenated hydrocarbons, and sulfolane.

Furthermore, if desired, two or more of these solvents may be used in combination. Furthermore, a complex compound formed with these organic solvents and boron trifluoride may be used as a solvent. The amount of the compound of general formula CI] to be used is usually 0.7 to 5 times the mole, preferably 1 to 5 times the mole of the compound of general formula [■].
It is 3 times the mole. In addition, the amount of boron trifluoride and its complex compound to be used is usually 1 to
It is 3 times the mole. Additionally, this reaction is generally carried out at -10 to 50°C.
It can be completed in 10 minutes to 20 hours.

In this reaction, the order of addition of the compound of general formula [I] and CIO and boron trifluoride (or complex compound of boron trifluoride) is not particularly limited, but preferably, the order of addition of the compound of general formula [I] and CIO is It is preferable to react the compound with boron trifluoride or a complex thereof, and then react with the compound of the general formula CIO.

Furthermore, it is preferable to isolate a compound obtained by reacting the compound of general formula CII with boron trifluoride or a complex compound thereof, and then react this with the compound of general formula [■]. In this case, the amount of the compound obtained by reacting the compound of general formula m with boron trifluoride or its complex compound is:
It is usually 1 to 2 times the mole of the compound of general formula [n] (calculated based on the compound of general formula m).

If water is present in the reaction system, it may cause undesirable side reactions such as cleavage of the β-lactam ring.
It is preferable to maintain the inside of the reaction system in an anhydrous state. In order to satisfy this condition, a suitable dehydrating agent such as calcium chloride, anhydrous sodium sulfate, anhydrous calcium sulfate, anhydrous magnesium sulfate, molecular sieve, etc. may be added to the reaction system.

The thus obtained cephalosporin of the general formula [111] or its salt can be isolated and purified by conventionally known methods, and if necessary, Bs can be replaced with a carboxyl protecting group by a conventional method. A certain compound of the general formula [■] can be easily converted into a compound of the general formula [■] in which R3 is a hydrogen atom or a salt thereof.

Next, a method for producing the compound of general formula [I] will be explained. This compound can be produced, for example, according to the production method shown below. In addition, the compound of general formula [I] in the diagram is a new compound and a useful intermediate.

Production method cH3coc-coNHn' [V:11 (1) Production of compound of general formula [V] The nitroso compound of general formula [V] is produced by reacting the compound of general formula (5) with a nitrosating agent. Obtainable.

This reaction is usually carried out in a solvent, and examples of the solvent used include solvents inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, and tetrahydrofuran.

Moreover, two or more kinds of these solvents can also be used as a mixture.

Preferred nitrosating agents used in this reaction include nitric acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide; alkali metal salts of nitrite such as sodium nitrite and potassium nitrite; Examples include alkyl nitrites such as butyl nitrate and bentyl nitrite. When a salt of nitrous acid is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic base such as hydrochloric acid, sulfuric acid, formic acid or acetic acid. Furthermore, when a nitrous acid alkyl ester is used as a nitrosating agent, it is preferably carried out in the presence of a strong base such as an alkali metal alkoxide.

This nitrosating agent reaction is carried out at 0°C to 30°C for 10 minutes to 1 hour.
Completed in 0 hours.

(2) Production of compound of general formula [■] The compound of general formula [■] can be obtained by reacting the compound of general formula N] with an alkylating agent.

This alkylation reaction can be carried out according to a conventional method,
It is usually completed in 5 minutes to 10 hours at -20 to 60°C. The solvent used here may be any solvent as long as it does not adversely affect the reaction, such as tetrahydrofuran, dioximethanol, ethanol, chloroform, methylene acetate, ethyl acetate, butyl acetate, N, N-
Examples include dimethylformamide, N,N-dimethylacetamide, water, and the like. Moreover, two or more kinds of these solvents can also be used as a mixture. Examples of alkylating agents used include lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, and p-)luene other than diazoethane. Examples include methyl sulfonate. When a compound other than diazomethane or diazoethane is used as an alkylating agent, it is usually an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, triethylamine, or pyridine. The reaction is preferably carried out in the presence of a base such as

The compound of general formula (1) can also be obtained by subjecting the compound of general formula (1) to a known amidation reaction with ammonia or a primary amine.

(3) Production of compound of general formula [■] The halogen compound of general formula [■] can be obtained by reacting the compound of general formula [VI] with a halogenating agent.

This reaction is usually carried out in a solvent, and the solvents used include halogenated hydrocarbons such as methylene chloride and chloroform; organic acids such as acetic acid and propionic acid; and ethers such as tetrahydrofuran and dioxane, which adversely affect the reaction. Examples include solvents that do not give Moreover, two or more kinds of these solvents can also be used as a mixture.

This halogen reaction is usually carried out at 0 to 50°C for 30 minutes to 2
Complete in 4 hours.

The halogenating agents used include halogens such as bromine and chlorine; sulfuryl halides such as sulfuryl chloride;
Hypochlorogenic acid or its salts such as hypochlorous acid, hypobromous acid, and sodium hypochlorite; N-halogenated imide compounds such as N-bromosuccinimide, N-chlorosuccinimide, and N-bromophthalimide Examples include perbromide compounds such as pyridinium hytropromite and 2-carboxyethyltriphenylphosphonium perbromide.

(4) Production of compound of general formula [1] The compound of general formula [I] can be obtained by subjecting a compound of the general formula to a ring-closing reaction with thiourea. This ring-closing reaction is usually carried out in a solvent, and any solvent may be used as long as it does not adversely affect the reaction. For example, water, methanol, ethanol, acetone, tetrahydrofuran, dioxane, N, N- Dimethylformamide, N,N-dimethylacetamide, N-
Examples include methylpyridone.

Further, two or more of these solvents can be mixed for use.

In addition, in this reaction, adding a deoxidizing agent may make the reaction proceed smoothly, so the deoxidizing agent used is
Examples include inorganic or organic bases such as alkali metal hydroxide salts, alkali metal salts of iced carbonate, triethylamine, pyridine, and N,N-dimethylaniline.

The reaction time is usually 1 to 48 hours, preferably 1 to 10 hours.

This ring-closing reaction is carried out at a temperature of o - ioo°C, and thiourea is preferably used in an amount of usually 1 to several times the molar amount of the compound represented by the general formula.

In addition, in this reaction, as an intermediate, the general formula (syn isomer) has the same meaning as above. ) was confirmed to be via the thiazoline compound. In this reaction, the thiazole compound of general formula CI) can also be obtained by isolating the above-mentioned thiazoline compound and then subjecting it to a dehydration reaction.

As described above, the syn isomer of the thiazole compound of the general formula [■] can be selectively obtained in high yield and at low cost.

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example 1 (1) Dissolve 101g of acetoacetamide in 35ml of water, add 6.9g of sodium nitrite under water cooling,
While stirring at °C, 4N sulfuric acid 25j17 was added dropwise over 30 minutes. After dropping, he reacted at the same temperature for 60 minutes.
Adjust the pH to 6.0 with a saturated aqueous sodium bicarbonate solution.

After removing impurities, water is distilled off under reduced pressure, and ethyl acetate 2041/ is added to the resulting residue to remove the precipitated crystalline P, which yields 2-hydroxyimino having a melting point of 96-97°C. 86 pieces of -3-oxobutyric acid amide (yield 66.2%) are obtained.

IR (KBr) cm, C=0 167 ONMR (d
a-DMSO) δ value; 2.26 (3H, s, CHiCO).

7.46 (IH, b++, -CON cutting).

\H 7,62 (IH, bs, -CON/H).

＼dan1260 (IH, u, = N-K0 (2) 2-hydroxyimino-6-oxobutyric acid amide 6
, 59 and anhydrous sodium carbonate 5.67 are dissolved in water 201117 at 20°C. Furthermore, dimethyl sulfate 66
was added at 20-25°C and stirred at the same temperature for 2 hours.

Then, a lot of the precipitate was collected, 10011j"q of methanol was added to the obtained phase product, and the mixture was stirred at 40 to 50°C for 30 minutes. Then, after removing the impurities 7, each section was distilled off under reduced pressure. Adding 20 ml of ethanol to the resulting residue and taking one crystal gives 2-(syn)- with a melting point of 156-157°C.
Methoxyimino-3-oxobutyric acid amide 529 (yield 7
22%).

IR (KBr) cm, C=0 1700. i67
ONMR (d6-DMSO) δ value; 2.26 (3H,s, CHiCO).

3.96 (3H, s, OCH*).

7.58 (IH, bs, -CON/H)\ group [312-(syn)-methoxyimino-6-oxobutyric acid amide 7,2 P 4 Tetrahydrofuran 36ml 1VC
At 40° C., add 0.87 g of bromine under stirring. After confirming that the coloring caused by bromine disappears, heat at 25-60°C.
Then, an additional 7.29 g of bromine is added under stirring. 1 at the same temperature
After reacting for some time, each section was distilled off under reduced pressure. Ethyl acetate 501 and water 20#J'7 are added to the obtained residue, and the pH is adjusted to 6.0 with a saturated sodium bicarbonate aqueous solution, and then the organic layer is separated and washed with 20 ml of saturated brine.

Then, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 d of diisopropyl ether-ethyl acetate (i:i) mixture is added to the resulting residue to obtain crystalline P, which yields 4-bromo-2-(syn)-methoxyimino-6 with a melting point of 112-113°C. - 92 g (yield 82.1%) of oxobutyric acid amide are obtained.

IR (KBr) cm, C=0 1715.166O
NMR (dr-DMSO) δ value: 4.02 (3)1. s, OCH*).

4.58 (2H, a, BrCH*CO).

7.72 (2H, bs, CO NHz) (4) 4-Flomo 2-(syn)-methoxyimino-6-oxobutyric acid amide 457 was suspended in 13.5 mK of ethanol, 1.59 mK of thiourea was added, and 20~ React at 30°C for 1 hour. Take 1 portion of the precipitated crystals, wash with ethanol, and then add 25 minutes of water;
[Suspend and adjust to pH 60 with saturated sodium bicarbonate water bath solution]
Adjust to. Next, the crystalline P was removed, and water-methanol (
If recrystallized with 15Rt mixed solvent of 1:1), the melting point will be 20
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetic acid amide at 209°C to 8 2.91
(yield 71.8%).

-1, ν IB(KBr) cm, C=0 1665NMR(a
s DMSO) δ value; 3.84 (3) I, s, -0 (J et al.).

6.75(IH,”,s][IIH).

7.26 (2H, ba, NHx).

Example 2 (112-(2-aminothiazol-4-yl)-2-
10.0 g of (syn)-methoxyiminoacetic acid amide is added to a mixed solvent of 10.2 g of boron trifluoride, 201 sulfolane, and 20 lj of anhydrous methylene chloride. 1 at room temperature
After reacting for some time, the crystals are collected. Next, the crystals were suspended in 100 d of ethyl acetate, stirred for 1 hour, and then P was collected. Washing twice with 20M ethyl acetate and drying yields 14.1 g of crystals.

IR, (KBr) an, 16B0.1650.1
620°1200-1000 (2) Hybaloyloxymethyl = 7-amino-3-[(
5-Methyl-1,2,3,4-tetrazol-2-yl)methyl]-Δ3-cephemu 4-carboxylate 4
．． 10g was dissolved in ethyl acetate 41 jj&c bath, (1)
Add the crystal 666v obtained in step 1 and allow the reaction to proceed at room temperature for 6 hours. Then, water 41117 was added to the reaction solution, and the pH was adjusted to 4.5 with sodium hydrogen carbonate. Take a portion of the organic layer,
After washing with water for 20 minutes, it is dried with anhydrous magnesium sulfate. Then, mesitylene sulfonic acid dihydrate 2.4
g and react at room temperature for 1 hour. 1 of the obtained crystals
If taken and washed with 511 tons of ethyl acetate, the melting point will be 218 ~
Pivaloyloxymethyl-7- showing 220°C (decomposition)
j2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-3-[(5-methyl-1°2, !l, 4-tetrazol-2-yl)methyl]- Mesitylene sulfonate of Δ1-cephemu 4-carboxy 1 note 7.189 (905% yield)
get.

Example 6 (112-(2-aminothiazol-4-yl)-2-
(Syn)-methoxyiminoacetic acid amide 6, Og was suspended in anhydrous methylene chloride 13a/[, and mixed solution of sulfolane-anhydrous methylene chloride (1:1) containing 2.729 boron trifluoride at 15-20°C i10 .3 Add red beni and boil at the same temperature.
Let it react for 0 minutes. Then, pivaloyloxymethyl-
Add anhydrous methylene chloride bath solution 13111 containing 7-amino-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-Δ3-cephemu-4-carboxylene) React for 2 hours and 60 minutes at ~35°C. Then, the reaction solution was introduced into ice water and heated to 80°C.
Adjust the pH to 5.5 with an aqueous sodium bicarbonate solution.

After removing insoluble matter, the organic layer was separated, washed with 15 az of saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was added with 60 Jl of ethyl acetate. After diluting and dissolving 2IO, mesitylene sulfonic acid dihydrate 2,369 was added and stirred for 60 minutes to precipitate crystals. If P is taken, the melting point is 218-220℃ (
pivaloyloxymethyl = 7-(2-(2
-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide 1)-3-(5-methyl-1,
2,5,4-tetrazol-2-yl)methyl-Δ3-
Cephemu 4-carboxylate mesitylene sulfonic acid q6.579 (yield 802%) is obtained.

IR(KBr)am, C-01782,1745,1
680(2) If the reaction is carried out in the same manner as in (1) above under the reaction conditions shown in Table 2, pivaloyloxymethyl =7-(
2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,3,4-tetrazol-2-yl)methyl-
Mesitylene sulfonate of Δ3-cephemu 4-carboxylate is obtained. In addition, the physical properties of the obtained product (melting point,
XR) were consistent with the physical properties of the compound obtained in (1) above.

(3) 2-(2-aminothiazol-4-yl)-2-
Table 6 instead of (syn)-methoxyiminoacetic acid amide
If the reaction is carried out in the same manner as in (1) above using the starting material compound shown in , pivaloyloxymethyl-7-(I2-(2-
aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide)-5-(5-methyl-1,2,
Mesitylene sulfonate of 5,4-tetrazol-2-yl)methyl-Δ1-cephemu 4-carboxylate is obtained. The physical properties (melting point, IR) of the obtained product are those of the compound obtained in (1) above, Example 4 (1) 2-(2-aminothiazol-4-yl)-2
Suspend 60 g of -(syn)-methoxyiminoacetic acid amide in 16 m of anhydrous methylene chloride [1:
Add 10.3μ of the mixed solution of 1) and react at the same temperature for 10 minutes.

Then, diphenylmethyl-7-amino-6-(5-methyl-1,2,5,4-tetrazol-2-yl)methyl-Δ3-cephemu-4-carpoxyle) 4.62
Add 9 g of anhydrous methylene chloride to 60 to 3
React at 5°C for 6 hours. After introducing the reaction solution into 5Q++u of water, the pH was adjusted to 5.5vc with sodium hydrogen carbonate. After removing impurities, separate the organic layer and add saturated saline solution 2
After washing under vacuum, it is dried over anhydrous magnesium sulfate. The residue was purified by column chromatography (Wako silica gel (Nie 200, bathing solvent: chloroform-methanol), with a melting point of 102-105°C (diphenylmethyl = 7-
[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-3-(5-methyl-1,2,5,4-tetrasoyl-2-yl)methyl-Δ3 -Cefemu 4-carboxinerate 4.2 g
(Yield 1; i65.1%) was obtained.

XR(KBr) cm, C-oi778.1720° 660 (2) Diphenylmethyl-7-42 obtained in (1)
-(2-aminothiazol-4-yl)-2-(syn)
-methoxyiminoacetamide)-3-(5-methyl-
1,2,s,4-tetrazol-2-yl)methyl-
645 g of Δ3-cephemu 4-carboxylate was dissolved in a mixed solvent of 35a+7 ketotrifluoro-11 acid and 1 Qm/anisole, and reacted at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystalline P was collected, thoroughly washed with diethyl ether, and then dried, showing a melting point of 123-125°C (decomposition). 7-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide]-5
-(5-methyl-1,2,3,4-tetrazole-2-
5.469 (yield: 92.1) of methyl-Δ3-cephemu-4-carboxylic acid nodorifluoroacetate is obtained.

-1, ν xn (xnr) cm, c-o 1790.1720 ~
1635 Example 5 The reaction was carried out in the same manner as in Examples 2, 6 or 4 to obtain the compounds shown in Table 5 in a yield of 65 to 85%.

Table 5 (Syn isomer) *Hydrochloride (reacted at room temperature to obtain vinyl hydrochloride)**
Diastereomer Integration Procedures Amendment Written April 27, 1985 Manabu Shiga, Commissioner of the Patent Office 1 Indication of the case 1982 Patent Application No. 104759 2 Title of invention New method for manufacturing cephalosporins 6 Amendment. Telephone: (03) 34B-6611 4. Date of amendment order Vol. “Claims” column 1v) “Detailed description of the invention” column 6 of the specification Contents of amendment (I) Amendment to the “Title of the invention” column of the application The description of ``intermediates thereof'' has been corrected to ``a new method for producing cephalosporins''.

(II) Amend the “Title of the Invention” column of the specification to include the description “Novel method for producing cephalosporins and intermediates thereof” [
"A new method for producing cephalosporins."

[Amendment to the "Claims 1" column of the specification As shown in the appendix (g) Amendment to the "Detailed Description of the Invention" column of the specification 1) Page 4, lines 3 to 4 of the specification The description of "and its intermediates" will be deleted.

2) The description of "and useful intermediates represented by general formula (I)" in lines 6 and 7 from the bottom of page 5 is deleted.

3) Page 5, bottom line to page 6, line 1 “Patent Application No. 57-200382, No. 58-7) 7871
No. 5B-113565, No. 58-114313). " has been corrected to "No. 59-95085, No. 59-193893, No. 60-4191, No. 60-6694).J.

4) Page 6, line 20 to page 7, line 1 “and a novel compound of general formula (1) (syn isomer)”
Delete the description.

5) Page 13, lines 6 to 9 “Patent Application No. 57-200382, No. 57-206875”
No. 5B-67871, No. 58-113565,
No. 58-114513” was changed to “No. 59-91085, No. 59-98089, No. 5
No. 9-193893, No. 60-4191, No. 60-6
No. 694” is corrected.

6) On page 16, lines 18 to 20, the statement ``In the diagram... is a useful intermediate.'' is deleted.

7) Page 18, line 16 The description of "nitric acid" has been corrected to "nitrous acid."

8) On page 23, line 18, "Examples" is corrected to "Reference Examples and Examples."

9) Page 24, line 1 Correct the description of “Example 1” to “Reference Example 1”0 10) Page 30, line 1 Correct the description of “Example 2” to “Example 1”0 11) Page 31, line 12 The description of "Example 3" is corrected to "Example 2."

12) The description of “Example 4” in the first line of page 66 is corrected to “Example 3”0 13) The description of “Example 5” in the first line of page 40 is corrected as “Example 4” 0 14) Page 40, line 2 - + -L + l ^ i]
Correct it to ``乑 え え え 1, 2, or 6''.

Above (Attachment) [2. Claims (1) A compound represented by the general formula (syn isomer) and a compound represented by the general formula are reacted in the presence of boron trifluoride or its complex compound. , A method for producing a cephalosporin (syn isomer) represented by the general formula or a salt thereof, which comprises, if necessary, eliminating a carboxyl group or converting it into a salt.

(2) Claim No. (1) in which R' is a hydrogen atom
A method for producing a cephalosporin (syn isomer) or a salt thereof as described in .

(s) The method for producing a cephalosporin (syn isomer) or a salt thereof according to claim (1), wherein R' is an optionally substituted alkyl group.

(4) The method for producing a salt of a cephalosporin (synisomer) according to claim (1), wherein R1 is an optionally substituted aryl group.

(5) Claim No. 1 in which the reaction is carried out in an organic solvent
) to (4) A method for producing a cephalosporin (syn isomer) or a salt thereof according to any one of the items.

(6) The cephalosporin according to claim (5), wherein the organic solvent is a nitroalkane, an ester, a halogenated hydrocarbon, a nitrile, or a sulfolane (
Synthetic isomer) Matakeso salt manufacturing method. ”

Claims (1)

[Claims] (1) A compound represented by the general formula (syn isomer) and a compound represented by the general formula are reacted in the presence of boron trifluoride or its complex compound, and if necessary, carboxyl protection is achieved. A method for producing a cephalosporin (syn isomer) represented by the general formula or a salt thereof, characterized by eliminating a group or converting it into a salt. Claim No. (1) in which f21 R1 is a hydrogen atom
A method for producing a cephalosporin (syn isomer) or a salt thereof as described in . (3) A method for producing a cephalosporin (syn isomer) or a salt thereof according to claim 11), wherein R'' is an optionally substituted alkyl group. (Even if 41R'' is substituted) A method for producing a cephalosporin (syn isomer) or a salt thereof according to claim (1), which is a good oryl group. (5) A method for producing a cephalosporin (syn isomer) or a salt thereof according to claim 1)
A method for producing a cephalosporin (syn isomer) or a salt thereof according to any one of items 1 to 4. +6) The organic solvent is nitroalkanes, esters,
The method for producing a cephalosporin (syn isomer) or a salt thereof according to claim (5), which is a halogenated hydrocarbon, a nitrile, or a sulfolane. (7) A compound represented by the general formula (syn isomer).