JPH05213968A - Carbamoylation of diacetylcephalosporanic acid - Google Patents

Abstract

PURPOSE:To effect high-efficient, high-yield production of an ester of acylaminocarbamoyloxymethylcephemcarboxylic acid by carbamoylating and esterifying an organic amine salt of acylaminohydroxymethylcephemcarboxylicacid. CONSTITUTION:An organic amine salt of 7-amino-3-hydroxymethyl-3-cephem-4- carboxylic acid is acylated and the resultant 7-acylamino-3-hydroxymethyl-3- cephem-4-carboxylic acid organic amine salt is carbamoyled to prepare an amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, which is esterified to give the corresponding 7-acylamino-3-carbamoyl- oxymethyl-3-cephem-4-carboxylic acid ester, the objective compound.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ester useful as an oral cephalosporin antibiotic, particularly 7-amino-3-hydroxymethyl ester. Method for Producing 7-Acylamino-3-hydroxymethyl-3-cephem-4-carboxylic Acid Organic Amine Salt by Acylation of Organic Amine Salt of 3-Cephem-4-carboxylic Acid and Carbamoylation of the Product -Acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid After forming an organic amine salt, it is esterified to produce 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ester. Regarding the method.

[0002]

BACKGROUND OF THE INVENTION Representative examples of esters of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid include the following compounds. That is, 7- (4-bromo-3-
Oxobutanamide) -3-carbamoyloxymethyl-3-
Cephem-4-carboxylic acid pivaloyloxymethyl ester (JP-A-63-277684), 7- (phenylacetamido) -3-carbamoyloxymethyl-3-cephem
-4-Carboxylic acid acetoxymethyl ester (published 22
03653), 7- (p-hydroxyphenyl-2- (4
-Hydroxy-1,5-naphthyridine-3-carbonylaminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (US Pat. No. 4,138,554), 7- (2-furyl- 2-oxoacetamido) -3-carbamoyloxymethyl-3-
Cephem-4-carboxylic acid 1-acetoxyethyl ester (German publication 3914672), 7- (2-furyl-2-methoxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 1-acetoxyethyl Ester (German publication 2706413), 7- (2-furyl-
2-Methoxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 1-oxide
1-acetoxyethyl ester (English Patent 2218094)
No.), 7- (2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (German publication 2727753) ), 7- (2- (2
-Amino-4-thiazolyl) -2-pentenamide) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (German publication 3610581
No.), 7- (2- (2-amino-1,3,5-thiadiazolyl) -2-methoxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester ( European publication 22245).

[0003]

[Problems to be Solved by the Invention] 7-Acylamino-3-
In the conventional method of carbamoylating hydroxymethyl-3-cephem-4-carboxylic acid, the reaction system becomes acidic, and the hydroxymethyl group at the 3rd position and the carboxy group at the 4th position are bonded to each other, resulting in partial lactonization. The rate was low.

[0004]

Means for Solving the Invention This time, the inventor has reacted by reacting an organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid with a reactive derivative of carbamic acid. It was discovered that improvement of operability can be achieved by improving smoothness and smooth reaction, resulting in the invention.

[Compound] (7-acyl group) 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid or 7-acylamino-
As the 7-position acyl group in the organic amine salt of 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, the following representative acyl groups can be exemplified. The acyl group is aliphatic,
An acyl group of a carboxylic acid belonging to a series such as alicyclic and aromatic, and an acyl group constituting an amide side chain such as natural or synthetic cephalosporin is included in this acyl group. The acyl group of the following formula is a typical example. _{^{1) R 10 CH 2 CO- 2}} ) R 10 OCH 2 CO- 3) R 10 SCH 2 CO- 4) R 10 CH (-R 11) CO- 5) R 10 C (= R 12) CO- 6) R ¹³ CO- (wherein R ¹⁰ is hydrogen, an aliphatic group, an aromatic group, a heterocyclic group,
R ¹² is a substituted hydroxy group, amino group, carboxy group, sulfo group, mercapto group, cyano group, etc. such as an alicyclic group, R ¹² is an oxo group, thioxo group, imino group, hydroxyimino group, alkoxyimino group, R ¹³ represents hydrogen, alkoxy, aralkoxy, aryloxy, heterocyclic oxy, aromatic group, heterocyclic group, etc. such as aryloxyimino group and alkylidene group)

The aliphatic group R ¹⁰ includes an optionally substituted alkyl group, an alkenyl group, and an alkynyl group, and the aromatic group R ¹⁰ includes an optionally substituted phenyl group,
Heterocyclic groups, including naphthyl groups, are heterocyclic rings of five-membered or six-membered monocyclic or bicyclic rings, which may have up to four nitrogen atoms and oxygen or sulfur atoms as hetero atoms. Including,
The alicyclic group R ¹⁰ includes a cycloalkyl group which may have a 4- to 6-membered double bond 1 or 2.

When the group represented by R ¹¹ is protected, there are synthetic protecting groups for preventing undesired changes in the synthetic steps and pharmacologically active groups for changing physiological or pharmacological properties. Representative examples of synthetic protecting group R ¹¹ include alkyl or heterocyclic ring (t-butyl, tetrahydropyranyl, tetrahydrofuranyl, etc.), alkenyl (enol ether forming group, when R ¹¹ is hydroxy, amino or sulfhydryl). , Enamine-forming groups, etc.), alkylsilyl,
Alkoxysilyl, stannyl, etc., aralkyl (trityl, diphenylmethyl, phenacyl, etc.), acyl (alkanoyl, alkenoyl, aroyl, acyl carbonate, etc.); When R ¹¹ is carboxy, sulfo, etc., ester-forming groups (alkyl, aralkyl, ari- , Etc.),
It has an amide-forming group (amino, alkylamino, dialkylhydrazino, etc.) and can be removed without adversely affecting other parts of the molecule. A typical example of the latter is R
^{When 11} is hydroxy, it includes sulfo, carbamoyl, sulfamoyl, carboalkoxy, carboaralkoxy, cyano, alkanoyl, aralkanoyl, aroyl and heterocyclic carbonyl. Further, when R ¹¹ is amino, it includes alkylsulfonyl, alkylated oxoimidazolidinylcarbonyl, diketopiperazinylcarbonyl, alkylureidocarbonyl, thioureidocarbonyl and the like. When R ¹¹ is carboxy or sulfo,
The protecting group in the form of being removed in vivo may be available as the pharmacologically active ester.

Alkoxyimino or alkylidene group R
^{The 12} substituents include carboxy, esterified or amidated carboxy, hydroxy, alkyl, alkoxy and the like, and each may be saturated or unsaturated chain or cyclic. The R ¹³ group is a monocyclic or bicyclic aryl group which may have a substituent, a heterocyclic ring and a corresponding R ¹³ oxy group. When R ¹³ is a fused ring, the second ring need not be an aromatic ring. Further, R ¹³ may be alkoxy, aralkoxy, aryloxy or the like, and the acyl group may form an acyl carbonate group.

Each of these R ^{10 to} R ¹³ groups may further have a substituent. When these acyl groups remain in the target antibacterial compound, it is usually preferable that the number of carbon atoms is 20 or less. Typical acyl groups include alkanoyl having 1 to 8 carbon atoms (formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, etc.), and heterocyclic rings in which the aryl moiety has a heteroatom such as nitrogen, oxygen or sulfur. May be monocyclic aroyl (benzoyl, nitrobenzoyl, etc.), alkoxycarbonyl having 2 to 12 carbon atoms (wherein the alkyl moiety is methyl, ethyl, propyl, cyclopropylethyl, isopropyl, butyl, pentyl, hexyl, isobutyl, Trichloroethyl, pyridylmethyl, cyclopentyl, cyclohexyl, etc.), aralkoxycarbonyl having 8 to 15 carbon atoms (wherein the aralkyl portion is benzyl, diphenylmethyl, nitrobenzyl, etc.), dibasic acid having 3 to 10 carbon atoms. Acyl (succinyl, phthaloyl, etc. , Halosulfonyl, 0 to the number of carbon atoms
Examples thereof include acyl groups such as 10-acyl phosphate (dialkoxyphosphoryl, dichlorophosphoryl, etc.).

(Ester Group) Examples of the ester group in the organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ester include the following pharmacologically active ester-forming groups.

Typical examples are 1-oxygen-substituted alkyl having 2 to 15 carbon atoms (linear, branched, cyclic or partially cyclic alkanoyloxyalkyl (acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl). , Pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl, etc.), alkoxycarbonyloxyalkyl having 3 to 15 carbon atoms (ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl, t-butoxy). Carbonyloxyethyl, isopentyloxycarbonyloxypropyl, cyclohexyloxycarbonyloxyethyl, cyclohexylmethoxycarbonyloxyethyl, bornyloxy Rubonyloxyisopropyl, etc.), C2-C8 alkoxyalkyl (methoxymethyl, methoxyethyl, etc.), C4-C8 2-oxacycloalkyl (tetrahydropyranyl, tetrahydrofuranyl, etc.)}, C8- 12-substituted aralkyl (phenacyl, phthalidyl, etc.), C6-12
Allyl (phenyl, xylyl, indanyl, etc.),
C2-C12 alkenyl (allyl, 2-oxo-1,
3-dioxolyl) methyl etc.) and the like.

(Organic amine) 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid or 7-acylamino-3-carbamoyloxymethyl-3-cephem
As the organic amine in the organic amine salt of -4-carboxylic acid, a secondary amine or a tertiary amine is preferable, and a secondary amine is particularly preferable. As typical examples, the following organic amines having 1 to 18 carbon atoms can be exemplified. (Primary amine) methylamine, ethylamine, isopropylamine, isobutylamine, t-butylamine, cyclohexanemethylamine, tetrahydrofurfurylamine, benzylamine, p-methoxybenzylamine,
Phenethylamine, p-methoxyphenethylamine, homoveratrylamine, p-chlorophenethylamine, phenylpropylamine, furfurylamine, aniline,
p-Chloraniline, (primary and tertiary diamines) 2-picolylamine. (Secondary amine) dimethylamine, diethylamine, dipropylamine, diisopropylamine, dicyclohexylamine, diphenylamine, piperidine, piperidine, morpholine. (Tertiary amine) trimethylamine, triethylamine,
Tri-n-butylamine, tri-n-pentylamine, tri
-n-octylamine, tribenzylamine, N, N-dimethylbenzylamine, N-ethyldiisopropylamine, N-methylmorpholine, pyridine, N, N-dimethylaminopyridine, α-picoline, β-picoline, 2,6 -Lutidine. Other examples include lower alkylamines, lower aralkylamines, cycloalkylamines, di-lower alkylamines, arylalkylamines, nitrogen-containing saturated ring compounds, saturated carbocyclized lower alkylamines, di-saturated carbocyclized amines, trialkylamines. Lower alkyl amine, aryl dialkyl amine, aralkyl dialkyl amine, aromatic base and the like.

The acyl group, ester group and organic amine may have a substituent described below. The carbon number includes a substituent.

(Range of each group) The alkyl moiety of each group is a linear, branched or cyclic alkyl. 1 to 1 carbon atoms
2 alkyl groups (methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tertiary butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, neopentyl, cyclopentyl, cyclopropylethyl, hexyl, cyclohexyl, cyclopentylmethyl, Representative examples are heptyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl and dodecyl. These may have an unsaturated bond or a substituent as described below.

The aralkyl moiety is a combination of an alkyl moiety and an aryl moiety. Aralkyl groups having 7 to 14 carbon atoms (benzyl, phenethyl, phenylpropyl, phenylisopropyl, diphenylmethyl, methoxydiphenylmethyl, naphthylmethyl, furylmethyl, thienylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, Pyridylmethyl, indolylmethyl, benzimidazolylethyl, benzothiazolylmethyl, quinolylmethyl, etc.) are typical examples. Any of these may have a substituent as described below.

The acyl moiety is an acyl group having the above structure. An acyl group having up to 14 carbon atoms, for example, a carboxylate acyl (linear, branched or cyclic alkanoyl, monocyclic or bicyclic aroyl which may have a hetero atom, aralkanoyl, arylalkenoyl, etc.), acyl sulfonate ( Typical examples are alkylsulfonyl, arylsulfonyl and the like), acyl carbonate (carbamoyl, carboalkoxy, carboaralkoxy and the like), sulfo and the like. Any of these may have a substituent as described below.

The aryl moiety is monocyclic or bicyclic, and has 5 to 6
It is a membered carbocyclic or heterocyclic aryl group. The heterocyclic group may have oxygen, nitrogen and sulfur as heteroatoms. An aryl group having 1 to 10 carbon atoms, for example, a carbocyclic aryl group (phenyl, naphthyl, indenyl, indanyl, tetralinyl, etc.) and a heterocyclic aryl group (furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, Thiadiazolyl, triazolyl, thiatriazolyl, tetrazolyl, pyridyl, pyranyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzothiazolyl, benzopyrazinyl, quinolyl and pyridopyridyl groups are typical examples. Any of these may have a substituent as described below.

(Exemplary Substituents) Typical examples of the substituents that can be bonded to the above groups include carbon functional groups (straight chain, branched or cyclic alkyl, alkenyl, alkynyl, aralkyl, aryl, and different compounds). Ring groups, acyl carboxylates, carbamoyl, carboxy, protected carboxy, cyano, etc.);
Nitrogen functional groups (amino, acylamino, guanidyl, ureido, alkylamino, dialkylamino, isothiocyano, isocyano, nitro, nitroso, etc.); oxygen functional groups (hydroxy, alkoxy, aryloxy, heterocyclic oxy, cyanato, oxo, carvone) Acid acyloxy,
Sulfuric acid acyloxy, phosphoric acid acyloxy, etc.); Sulfur functional groups (mercapto, alkylthio, alkylsulfonyl, arylthio, arylsulfonyl, heterocyclic thio, heterocyclic sulfonyl, acylthio, thioxo, sulfo, sulfamoyl, etc.); halogen (Fluorine, chlorine,
Bromine, iodine, etc .; Pseudohalogen (lower alkanesulfonyl, benzenesulfonyl, substituted benzenesulfonyl, trifluoromethanesulfonyloxy, trifluoroacetoxy, cyano, thiocyanato, isocyano, etc.); silyl group (trialkylsilyl, dialkylalkoxysilyl) Etc.); stannyl groups (trialkylstannyl, etc.) and the like.

[Production Method] (Acylation Reaction) The present invention is characterized in that an organic amine salt of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid is a reactive derivative of a carboxylic acid having the acyl group. There is provided a method for producing a desired organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid by acting by a method.

The reactive derivative of the carboxylic acid having an acyl group is an acid anhydride (symmetric acid anhydride, mixed acid anhydride [mineral acid (phosphoric acid, sulfuric acid, carbonic acid half ester, etc.), organic acid (alkanoic acid, aralkane). Acid, sulfonic acid, etc.)], intramolecular anhydride (ketene, isocyanate, etc.), acid halide (mixed acid anhydride with hydrogen halide), etc.}, acid halide, activity Ester [enol ester (vinyl ester, isopropenyl ester, etc.), aryl ester (phenyl ester, halophenyl ester, nitrophenyl ester, etc.), heterocyclic ester (pyridyl ester, benzotriazolyl ester, etc.), Ester with N-hydroxy compound, ester with diacylhydroxylamine (N-hydroxysuccinimidoyl ether Ter, N-hydroxyphthalimidoyl ester, etc.), thiol ester (aralkyl thiol ester, heterocyclic thiol ester, etc.) and others], active amide [aromatic amide (imidazole, triazole, 2-ethoxy- 1,2-dihydroquinoline, etc.), diacylanilide, etc.], and other reactive derivatives. These reactive derivatives are acid scavengers [inorganic bases (oxides of alkali metals, alkaline earth metals, hydroxides, carbonates, bicarbonates, etc.), organic bases (tertiary amines, aromatic bases, etc.). , Oxirane (alkylene oxide, aralkylene oxide, etc.), pyridinium salt (tripyridinium triazine trichloride, etc.),
Adsorbent (such as Celite), etc.]. This reaction is preferably carried out by reacting an organic amine salt of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid with a reactive derivative 1-2 of the carboxylic acid having the acyl group.
Moles and 0 to 2 moles of acid scavenger are allowed to act in the solvent. Acid halides and the like can react even in an aqueous solvent.

(Additional Carbamoylation Reaction and Esterification Reaction) Further, according to the present invention, an organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid is treated with a reactive derivative of carbamic acid in a conventional manner. Also provided is a method for producing a desired organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid by reacting with.

The reactive derivative of carbamic acid is an intramolecular anhydride such as isocyanate and acid halide.
A tertiary amine, an aromatic base or the like can be added as an acid scavenger. The amino group of carbamic acid should be protected with a protecting group such as alkanesulfonyl, arylsulfonyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phospho, alkylphosphoryl, dialkylphosphoryl, trialkylphosphoryl. You may keep it.

This reaction is preferably carried out in a solvent free of reactive hydrogen, wherein the reactive derivative 1-2 of carbamic acid is reacted with the organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid. Act moles. In the case of acid halide, the reaction can be carried out in an aqueous solvent.

Further, an esterification agent is allowed to act on the organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid by a conventional method to obtain the final product, 7-acylamino-3-carbamoyloxy. Methyl-3
Also provided is a method of making an organic amine salt of -cephem-4-carboxylic acid.

The esterifying agent is a reactive derivative such as a halide of the ester group. These reactive derivatives can also be used in the presence of acid scavengers.

This reaction is preferably carried out in a solvent free of reactive hydrogen, with 1 to 2 moles of the esterifying agent to the organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. Let it work.

[Reaction conditions, etc.] The above-mentioned synthesis methods are usually -30
~ 100 ° C, especially -20 to 50 ° C for 10 minutes ~
Often reacted for 10 hours. When the product is stable in the reaction solution, it may be left for a longer time. If desired, conventional methods such as reaction solvent, anhydrous conditions, inert gas, and stirring can be applied to each reaction.

As the reaction solvent, hydrocarbons (pentane,
Hexane, octane, benzene, toluene, xylene, etc., halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ether (diethyl ether, methyl isobutyl ether, dioxane, tetrahydrofuran) Etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitro hydrocarbons (nitromethane, nitrobenzene, etc.), nitriles (acetonitrile, benzonitrile, etc.), amides (formamide, Acetamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.), sulfoxide (dimethyl sulfoxide, etc.), carboxylic acid (formic acid, Acid, such as propionic acid),
Organic bases (diethylamine, triethylamine, pyridine, picoline, collidine, quinoline, etc.), alcohols (methanol, ethanol, propanol, hexanole)
, Octanole, benzyl alcohol, etc.), water, and other industrial solvents belonging to the series or mixtures thereof.

The desired product is obtained by extracting impurities (unreacted raw materials, by-products, solvents, etc.) from the reaction solution in a conventional manner (extraction, evaporation,
After removal by washing, concentration, precipitation, filtration, drying, etc.), a combination of conventional post-treatments (adsorption, elution, distillation, precipitation, precipitation, chromatography, etc.) can be combined to perform isolation.

[0030]

[Effects and Actions] 7-Acylamino-3-reacted by reacting 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid with a reactive derivative of a carboxylic acid having the acyl group by a conventional method. According to the prior art for producing hydroxymethyl-3-cephem-4-carboxylic acid, 7-amino-3-
Intramolecular esterification of hydroxymethyl-3-cephem-4-carboxylic acid progressed and 7-amino-3-hydroxymethyl-
3-cephem-4-carboxylic acid 4 → 3 lactone is the main component and cannot be used industrially. According to the invention, lactone formation is less than 1%. Each of the above two steps of additional carbamoylation and esterification also gives a highly pure product in high yield.

[0031]

EXAMPLES The embodiments of the present invention will be described below with reference to examples. Example 1 (Boc-S-1108)

A. (Morpholine salt) 1) Acylation: 61 g of 7-aminodeacetylcephalosporanic acid was dissolved in a mixed solution of 92 ml of ethanol and 45.6 ml of morpholine, and in the presence of 51.2 ml of triethylamine in 910 ml of ethyl acetate at -10 ° C. Z) -2- (2-t-
(Z) -2- (2-t-butoxycarbonylamino) synthesized from 101.9 g of butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid and 29.6 ml of methanesulfonyl chloride.
A solution of -4- (thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride in 950 ml of ethyl acetate is added, and the mixture is stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to remove methanol, and treated with ethyl acetate to obtain 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino. ] -3-Hydroxymethyl-3-cephem-4-carboxylic acid morpholine salt is obtained. IR ν _max cm ^-1 : 1770, 1720,
1660, 1630, 1555. 2) Carbamoylation: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino was added to a solution of 13.7 g of hydrogen chloride in 230 ml of ethyl acetate. ] The residue containing 3-hydroxymethyl-3-cephem-4-carboxylic acid morpholine salt is added dropwise under nitrogen at about -40 ° C. After stirring for 30 minutes, chlorosulfonyl isocyanate 2
After 5.2 ml was added dropwise over 3 hours, the mixture was stirred for 1 hour. The reaction solution is diluted with 200 ml of water and stirred for 1 hour. Separate the organic layer, add water and aqueous sodium hydrogen carbonate to bring the pH to 2.4, and add 85 ml of acetone.
Add. The organic layer is separated, washed with water, and concentrated under reduced pressure.
21.8 ml of morpholine was added to the residual liquid, diluted with ethyl acetate and stirred for 30 minutes. If the residual liquid is concentrated under reduced pressure, 7β
-[(Z) -2- (2-t-butoxycarbonylamino-4-
153 g of morpholine salt of thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid are obtained. Yield: 91%. IR ν _max cm ^-1 : 177
5, 1720, 1700, 1680, 1630, 1560. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-carbamoyl Oxymethyl-3-cephem-4-
89.9 g of carboxylic acid morpholine salt is dissolved in 300 ml of methyl isobutyl ketone and 150 ml of 4.5% sulfuric acid. The organic layer was separated, 150 ml of 7% aqueous sodium hydrogencarbonate was added and the mixture was stirred for a few minutes.
And 41.0 g of pivalic acid iodomethyl ester are added sequentially. After stirring the mixture for 4 hours while keeping the mixture neutral, 280 ml of methanol was added, the mixture was stirred for 3 hours, and the precipitated crystals were collected by filtration. Wash the crystals with cold methyl isobutyl ketone,
After drying under reduced pressure, 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-4-
Carboxylic acid pivaloyloxymethyl ester 76.9g
To get Colorless crystals. Yield: 82%. NMR δ (CD ₃ SOCD ₃ ) ppm: 1.07 (t, J = 7.5Hz, 3H), 1.23
(s, 9H), 1.56 (s, 9H), 2.47 (quint, J = 7.5Hz, 2H), 3.4
0, 3.56 (ABq, J = 18.0Hz, 2H), 4.79, 5.07 (ABq, J = 13.5H
z, 2H), 5.02 (d, J = 5.0Hz, 1H), 5.03 (s, 2H), 5.87 (s,
2H), 5.90 (dd, J = 5.0Hz, J = 8.5Hz, 1H), 6.41 (t, J = 7.5
Hz, 1H), 6.76 (s, 1H), 7.74 (d, J = 8.5Hz, 1H), 9.11
(s, 1H).

B. (Diethylamine salt) 1) Acylation: 33 g of 7-aminodeacetylcephalosporanic acid, 120 ml of methanol and 29.
Dissolve in 6 ml of mixed solution, 500 ml of ethyl acetate at -10 ° C
In the middle, 29.3 ml of triethylamine and (Z) -2- (2-t-
(Z) -2- (2-t-Butoxycarbonylamino-synthesized from 55.6 g of butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid and 14.6 ml of methanesulfonyl chloride.
A solution of 4-thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride in ethyl acetate was added, and the mixture was stirred for 1 hour to acylate, and 7β-[(Z) -2- (2-t-butoxycarbonylamino- 4-thiazolyl) -2-pentenoylamino]
-3-hydroxymethyl-3-cephem-4-carboxylic acid diethylamine salt is obtained. IR ν _max cm ^-1 : 1785, 1710, 1660, 1635, 1570. 2) Carbamoylation: This was dissolved in a mixture of hydrogen chloride (7.43 g) and ethyl acetate (119 ml) at about -10 ° C under nitrogen to give chlorosulfonyl isocyanate (14.8 ml). After dripping, the mixture is stirred for 1 hour to form a carbamoyl group. The reaction mixture is diluted with 200 ml of water and stirred at 20 ° C. for 1 hour to dechlorosulfonylate. The reaction mixture was adjusted to pH 2.4 with aqueous sodium hydrogen carbonate, and 66 ml of acetone was added.
Is added, the organic layer is separated, washed with water, and concentrated under reduced pressure. The residual liquid was diluted with ethyl acetate and concentrated under reduced pressure, then diethylamine 1
If 3.5 ml was added, 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-
64.5 g of 4-carboxylic acid diethylamine salt are obtained. Yield: 72%. IR ν _max cm ^-1 : 1785, 1725, 1660, 1565. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino]- 3-carbamoyloxymethyl-3-cephem-4-
50 g of carboxylic acid diethylamine salt is dissolved in 100 ml of methyl isobutyl ketone and 95 ml of 4.5% sulfuric acid water. The organic layer is separated and back extracted with 95 ml of 7% aqueous sodium hydrogen carbonate. 25 ml of methyl isobutyl ketone, 2.4 g of tetra-n-butylammonium bromide and 21.6 g of pivalic acid iodomethyl ester were sequentially added to the extract, and the mixture was esterified by stirring at 20 ° C. for 4 hours while maintaining neutrality. If crystallized from A. 32.9 g of a compound identical to the product of Colorless crystals. Yield: 65%.

C. (Dipropylamine salt) 1) Acylation: Dissolve 14.2 g of 7-aminodeacetylcephalosporanic acid in a mixture of 75 ml of 95% ethanol and 20.9 ml of dipropylamine, and dissolve triethylamine 12 in 500 ml of ethyl acetate at -10 ° C. 0.3 ml and (Z) -2
-(2-t-butoxycarbonylamino-4-thiazolyl)-
2-Pentenoic acid 23.9 g and methanesulfonyl chloride 6.6 m
(Z) -2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride 200 ml solution in ethyl acetate was added from 1 and stirred for 1 hour for acylation. For example, 7β-[(Z) -2- (2-t-
Butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-hydroxymethyl-3-cephem-4-
A carboxylic acid dipropylamine salt is obtained. IR ν _max cm ^-1 : 1790, 1695, 1660, 1630, 1565. 2) Carbamoylation: Add this to a solution of 3.19 g of hydrogen chloride in 64 ml of ethyl acetate at about -40 ° C under nitrogen to give 6.6 ml of chlorosulfonyl isocyanate. Is added dropwise and stirred for 1 hour for carbamoylation. Dilute the reaction solution with 4.2 ml of water, and
Dechlorosulfonylate by stirring at 0 ° C. for 1 hour. The reaction mixture is adjusted to pH 2.4 with aqueous sodium hydrogen carbonate, and 14 ml of acetone is added.
The organic layer is separated, washed with water, and concentrated under reduced pressure. The residue was diluted with ethyl acetate, concentrated under reduced pressure, and added with 8.2 ml of dipropylamine to give 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino. ]
27.4 g of -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid dipropylamine salt are obtained. Yield: 68
%. IR ν _max cm ^-1 : 1790, 1740, 1720, 1700, 1660, 1565. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pente Noylamino] -3-carbamoyloxymethyl-3-cephem-4-
21.5 g of carboxylic acid dipropylamine salt are dissolved in 65 ml of methyl isobutyl ketone and 45 ml of 4.5% sulfuric acid.
The organic layer is separated and back extracted with 45 ml of 7% aqueous sodium hydrogen carbonate. To the extract were added 6 ml of methyl isobutyl ketone, 1.3 g of tetra-n-butylammonium bromide and 9.1 g of pivalic acid iodomethyl ester, and the mixture was esterified by stirring at 10 ° C for 4 hours while keeping the neutrality. If crystallized from A. 14.0 g of a compound identical to the product of Colorless crystals. Yield: 64%.

D. (Diisopropylamine salt) 1) Acylation: 16.5 g of 7-aminodeacetylcephalosporanic acid, 50 ml of methanol and 2 of dipropylamine
Dissolve in a mixture of 2.1 ml, 500m ethyl acetate at -10 ° C
In 1 liter, 15.4 ml of trimethylamine and (Z) -2- (2-t-
(Z) -2- (2-t-butoxycarbonylamino-4-) synthesized from 27.8 g of butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid and 7.7 ml of methanesulfonyl chloride.
A solution of thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride in 200 ml of ethyl acetate was added, and the mixture was stirred for 1 hour to acylate, and then 7β-[(Z) -2- (2-t-butoxycarbonylamino-4 -Thiazolyl) -2-pentenoylamino] -3-hydroxymethyl-3-cephem-4-carboxylic acid dipropylamine salt is obtained. IR ν _max cm ^-1 : 1790, 1690, 1660, 1625, 1565. 2) Carbamoylation: This was added to a solution of 3.72 g of hydrogen chloride kept at -40 ° C in 80 ml of ethyl acetate, and 7.6 ml of chlorosulfonyl isocyanate. Add dropwise and stir for 1 hour to carbamoylate. The reaction mixture was diluted with 98 ml of water and kept at 20 ° C.
And dechlorosulfonylylate with stirring for 1 hour. The reaction mixture was adjusted to pH 2.4 with aqueous sodium hydrogen carbonate and 33 ml of acetone was added. The organic layer is separated, washed with water, and concentrated under reduced pressure. The residual liquid was diluted with ethyl acetate, concentrated under reduced pressure, and added with 9.8 ml of dipropylamine to give 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino. ] -3-
28.0 g of carbamoyloxymethyl-3-cephem-4-carboxylic acid dipropylamine salt is obtained. Yield: 60%. IR ν _max cm ^-1 : 1780, 1730, 1680, 1650, 1620, 1565. Infrared absorption spectrum of isopropylamine salt prepared under similar conditions. IR ν _max cm ^-1 : 1760, 1720, 1700, 1650, 1620, 1555. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pente Noylamino] -3-carbamoyloxymethyl-3-cephem-4-
25.0 g of carboxylic acid dipropylamine salt are dissolved in 100 ml of methyl isobutyl ketone and 50 ml of 4.5% sulfuric acid water. The organic layer was separated and 50 ml of 7% aqueous sodium hydrogen carbonate
Back extract with. 25m of methyl isobutyl ketone in the extract
1, 1.6 g of tetra-n-butylammonium bromide and 11.8 g of pivalic acid iodomethyl ester were sequentially added,
While maintaining neutrality, the mixture was stirred at 10 ° C. for 4 hours for esterification and crystallized from methanol. 14.8 g of a compound identical to the product of Colorless crystals. Yield: 58
%.

E. (Diisobutylamine salt) 1) Acylation: 10.6 g of 7-aminodeacetylcephalosporanic acid was added to a mixture of 32 ml of methanol and 17.6 ml of diisobutylamine and melted, and diisobutylamine was added to 150 ml of ethyl acetate at -10 ° C. 9ml and (Z)-
2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid synthesized from 17.8 g and methanesulfonyl chloride 4.9 g (Z) -2- (2-t-butoxycarbonylamino-4- Thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride solution in ethyl acetate was added, and the mixture was stirred for 1 hour to acylate, and 7β-[(Z) -2- (2-t-butoxycarbonylamino-4- Thiazolyl) -2-pentenoylamino] -3-hydroxymethyl-3-cephem-4-carboxylic acid diisobutylamine salt is obtained. 2) Carbamoylation: This was added to a solution of 2.38 g of hydrogen chloride in 50 ml of ethyl acetate under nitrogen in the cold, 6.4 g of chlorosulfonyl isocyanate was added dropwise, and the mixture was stirred for 1 hour for carbamoylation. The reaction mixture is diluted with 60 ml of water and stirred at 20 ° C. for 1 hour to dechlorosulfonylate. The reaction mixture is adjusted to pH 2.4 with aqueous sodium hydrogen carbonate, 25 ml of acetone is added, the organic layer is separated, washed with water, and concentrated under reduced pressure. The residual liquid was diluted with ethyl acetate, concentrated under reduced pressure, and added with 9.2 ml of diisobutylamine to give 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino]. 19.4 g of -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diisobutylamine salt are obtained. Yield: 62%. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-4-
52.1 g of carboxylic acid diisobutylamine salt are dissolved in 80 ml of methyl isobutyl ketone and 35 ml of 4.5% sulfuric acid. The organic layer is separated and back extracted with 35 ml of 7% aqueous sodium hydrogen carbonate. 10 ml of methyl isobutyl ketone in the extract,
0.77 g of tetra-n-butylammonium bromide and 7.52 g of pivalic acid iodomethyl ester were sequentially added,
After stirring for 4 hours while maintaining the neutrality, esterification, and crystallization from methanol, the above A. The same product as 9.2
9 g are obtained. Colorless crystals. Yield: 57%.

F. (Other organic amine salts) The following organic amines were used in place of morpholine, diethylamine, dipropylamine, diisopropylamine, or diisobutylamine to give A. B. C. D. Or E. The reaction of A. The same product is obtained. Dimethylamine, dibutylamine, methylisobutylamine, dicyclohexylamine, pyrrolidine, piperidine, diphenylamine, triethylamine, triethylamine
-n-butylamine, tri-n-pentylamine, tri-n-
Octylamine, N-methyldiisopropylamine, N-
Methylmorpholine, N-methylpiperidine, N, N-dimethylbenzylamine, tribenzylamine, pyridine,
N, N-dimethylaminopyridine, picoline, lutidine.

Example 2 (cefuroxime acetyl) A. (Diethylamine salt) 1) Acylation: 6-mg of 7-aminodeacetylcephalosporanic acid was added to 4 ml of methanol and 0.69m of diethylamine.
It was dissolved in 10 ml of ethyl acetate at -10 ° C in the presence of 0.94 ml of triethylamine and synthesized from 116 mg of (Z) -2- (2-furyl) -2-methoxyiminoacetic acid and 0.36 ml of methanesulfonyl chloride. A solution of (Z) -2- (2-furyl) -2-methoxyiminoacetic acid methanesulfonic acid mixed anhydride prepared in (2 ml) in ethyl acetate was added, and the mixture was stirred at -2.5 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove methanol, and treated with ethyl acetate to give 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-hydroxymethyl-3. -Cephem-4-carboxylic acid diethylamine salt is obtained. 2) Carbamoylation: 156 mg of hydrogen chloride and 5 of ethyl acetate
After dissolving in ml, the residue containing 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid diethylamine salt was dissolved in nitrogen at −30. Add dropwise at ° C. After stirring for 30 minutes, 0.61 ml of chlorosulfonyl isocyanate was added dropwise over 3 hours, and then 1
Stir for hours. The reaction solution is diluted with 8 ml of water and stirred for 1 hour. Separate the organic layer, add water and aqueous sodium hydrogen carbonate to bring the pH to 2.4,
Add 3 ml of acetone. The organic layer is separated, washed with water, and concentrated under reduced pressure. The residual liquid is diluted with ethyl acetate and concentrated under reduced pressure.
Diethylamine (0.28 ml) was added to the residual liquid, diluted with ethyl acetate and stirred at room temperature for 30 minutes. The residue is concentrated under reduced pressure to give 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl-3-.
1.05 g of cephem-4-carboxylic acid diethylamine salt are obtained. Yield: 70%. 3) Esterification: 7β-[(Z) -2- (2-furyl) -2-
Methoxyiminoacetamido] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid / diethylamine salt (798 mg) is dissolved in a mixture of methyl isobutyl ketone (7 ml) and 4.5% sulfuric acid (2 ml). The organic layer is separated, 1.7 ml of 7% aqueous sodium hydrogen carbonate is added, and the mixture is stirred for several minutes. The aqueous layer is separated and 1 ml of methyl isobutyl ketone, 101 mg of tetra-n-butylammonium bromide and 928 mg of acetic acid 1-iodoethyl ester are sequentially added. The mixture was stirred at 20 ° C. for 4 hours while maintaining the pH at 5 and after adding 6 ml of methanol,
The mixture is stirred for 1 hour and 5 ° C. for 2 hours, and the precipitated crystals are collected by filtration. The crystals were washed with cold methyl isobutyl ketone and dried under reduced pressure to give 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamide] -3-carbamoyloxymethyl-.
588 mg of 3-cephem-4-carboxylic acid acetoxyethyl ester are obtained. Colorless crystals. Yield: 72%. NMR δ (CD ₃ SOCD ₃ ) ppm: 1.51 (d, J = 6Hz, 3H), 2.08 (s,
3H), 3.77, 3.55 (ABq, J = 18Hz, 2H), 3.92 (s, 3H), 4.8
7, 4.65 (ABq, J = 12Hz, 2H), 5.31, 5.27 (d, J = 5Hz, 1
H), 5.94 (m, 1H), 6.6 ~ 6.8 (m, 2H), 6.8 (m, 2H), 7.0
4, 6.94 (m, 1H), 7.89 (m, 1H), 9.80 (d, J = 9Hz, 1H).

B. (Dicyclohexylamine salt) 1) Acylation: 429 mg of 7-aminodeacetylcephalosporanic acid was dissolved in a mixed solution of 2.5 ml of 5% water-containing propanol and 0.9 ml of dicyclohexylamine, and triethylamine was added to 0.2 ml of ethyl acetate at -10 ° C. 56 ml and (Z) -2- (2-furyl) -2-methoxyiminoacetic acid 72
Add (Z) -2- (2-furyl) -2-methoxyiminoacetic acid methanesulfonic acid mixed anhydride ethyl acetate solution synthesized from 2 mg and methanesulfonyl chloride 0.22 ml, and stir for 1 hour for acylation. , Β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt is obtained. 2) Carbamoylation: This is added to a solution of 97 mg of hydrogen chloride in 3 ml of ethyl acetate at about -40 ° C., and after 30 minutes, 378 ml of chlorosulfonyl isocyanate is added dropwise and stirred for 1 hour for carbamoylation. The reaction mixture is diluted with 5 ml of water and stirred at 20 ° C. for 1 hour to dechlorosulfonylate. The reaction mixture was adjusted to pH 2.4 with aqueous sodium hydrogen carbonate and added with 1.5 ml of acetone. The organic layer is separated, washed with water and concentrated under reduced pressure. The residual liquid was concentrated under reduced pressure, 0.35 ml of dicyclohexylamine was added, and diluted with ethyl acetate to give 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl.
710 mg of di-3-cyclophem-4-carboxylic acid dicyclohexylamine salt are obtained. Yield: 63%. 3) Esterification: 7β-[(Z) -2- (2-furyl) -2-
Methoxyiminoacetamide] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt (600 mg) and methyl isobutyl ketone (5 ml) and
Dissolve in 1.5 ml of% sulfuric acid water. The organic layer is separated and back extracted with 1 ml of 7% aqueous sodium hydrogen carbonate. Methyl isobutyl ketone (0.55 ml), tetra-n-butylammonium bromide (72.8 g) and acetic acid 1-iodoethyl ester (33) were added to the extract.
7 mg were sequentially added, and the mixture was stirred for 4 hours while maintaining the neutrality to esterify and crystallized from methanol. 313 mg of product identical to Yield: 62%.

C. (Other organic amine salts) The following organic amines were used in place of A. Or B. The reaction of A. of Example 2 is carried out. The same product is obtained. Isopropylamine, isobutylamine, t-butylamine, cyclohexylamine, dimethylamine, di
-n-propylamine, diisopropylamine, diisobutylamine, methylisobutylamine, dicyclohexylamine, pyrrolidine, morpholine, piperidine, diphenylamine, triethylamine, tri-n-butylamine, tri-n-pentylamine, tri-n-octylamine, N -Methyldiisopropylamine, N-methylmorpholine, N-methylpiperidine, N, N-dimethylbenzylamine, tribenzylamine, pyridine, N, N-dimethylaminopyridine, picoline, lutidine, 2-picolylamine.

Claims (2)

[Claims] 1. 7-Acylamino-3-hydroxymethyl-3
Organic salts of -cephem-4-carboxylic acid and 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. 2. A 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid prepared by acylating an organic amine salt of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid. The organic amine salt is carbamoylated to produce an organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, which is esterified to give the corresponding 7-acylamino-3-carbamoyloxymethyl- A method for producing an ester of 3-cephem-4-carboxylic acid.