JP3121903B2 - Method for Carbamoylation of Deacetylcephalosporanic Acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

This invention relates to a process for preparing 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylates useful as oral cephalosporin antibiotics, especially 7-amino-3-hydroxymethyl. For the preparation of an organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid by acylating an organic amine salt of 3--3-cephem-4-carboxylic acid and carbamoylation of this product to give -Acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid is converted into an organic amine salt and then esterified to produce 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ester. About the method.

[0002]

BACKGROUND OF THE INVENTION Representative examples of esters of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acids 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 (German publication 22
No. 03653), 7- (p-hydroxyphenyl-2- (4
-Hydroxy-1,5-naphthyridine-3-carbonylaminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid pivaloyloxymethyl ester (U.S. Pat. No. 4,138,554), 7- (2-furyl-) 2-oxoacetamido) -3-carbamoyloxymethyl-3-
Cephem-4-carboxylic acid 1-acetoxyethyl ester (Japanese Patent Publication No. 3914672), 7- (2-furyl-2-methoxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 1-acetoxyethyl Ester (German Publication No. 2706413), 7- (2-furyl-
2-methoxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 1-oxide
1-acetoxyethyl ester (GB 2218094)
No.), 7- (2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido) -3-carbamoyloxymethyl-3-cephem-4-carboxylate pivaloyloxymethyl ester (Publication No. 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 Patent Publication No. 22245).

[0003]

[Problems to be Solved by the Invention] 7-Acylamino-3-
In the conventional method of carbamoylation of hydroxymethyl-3-cephem-4-carboxylic acid, the reaction system becomes acidic, so that the hydroxymethyl group at the 3-position and the carboxy group at the 4-position combine to form a partial lactonization. Rates were low.

[0004]

SUMMARY OF THE INVENTION The present inventors have now reacted the organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid with a reactive derivative of carbamic acid to give a yield. The present inventors have found that improvement in operability can be achieved by a smooth reaction as well as improving the operability.

[Compound] (Acyl group at 7-position) 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. Acyl group is aliphatic,
Acyl groups of carboxylic acids belonging to the alicyclic or aromatic series and constituting an amide side chain such as natural or synthetic cephalosporin are all included in this acyl group. The acyl groups of the following formula are representative examples. _{^{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 ¹¹ is a substituted hydroxy group, amino group, carboxy group, sulfo group, mercapto group, cyano group, etc., R ¹² is an oxo group, a thioxo group, an imino group, a hydroxyimino group, an 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 alkyl group, an alkenyl group and an alkynyl group which may have a substituent, and the aromatic group R ¹⁰ includes a phenyl group which may have a substituent.
The heterocyclic group includes a 5-membered or 6-membered monocyclic or bicyclic heterocyclic ring which may have up to 4 nitrogen atoms, an oxygen atom and a sulfur atom as a hetero atom, including a naphthyl group and the like. Including
The alicyclic group R ¹⁰ contains a cycloalkyl group which may have a double bond 1 or 2 of the four-membered ring-six-membered ring.

When the group represented by R ¹¹ is protected, there are synthetic protecting groups for preventing undesired changes in the synthetic process and pharmacologically active groups for changing the physiological or pharmacological properties. Representative examples of the protecting group R ¹¹ for synthesis include, when R ¹¹ is hydroxy, amino, or sulfhydryl, an alkyl or heterocyclic ring (such as t-butyl, tetrahydropyranyl, or tetrahydrofuranyl), or an alkenyl (enol ether-forming group). , Enamine-forming groups), alkylsilyls,
Alkoxysilyl, etc. stannyl, aralkyl (trityl, Jifuenirumechiru, etc. Fuenashiru), acyl (alkanoyl, alkenoyl, aroyl, and carbonic acyl); if R ¹¹ is carboxy, sulpho is like, ester-forming group (alkyl, aralkyl, ant - Etc.),
There are amide-forming groups (amino, alkylamino, dialkylhydrazino, etc.), which can be removed without adversely affecting other parts of the molecule. A typical example of the latter is R
^{When 11} is hydroxy, examples thereof include sulfo, carbamoyl, sulfamoyl, carboalkoxy, carbalkaloxy, cyano, alkanoyl, aralcanoyl, aroyl, and heterocyclic carbonyl. Further, when R ¹¹ is amino, there are alkylsulfonyl, alkylated oxoimidazolidinylcarbonyl, diketopiperazinylcarbonyl, alkylureidocarbonyl, thioureidocarbonyl and the like. When R ¹¹ is carboxy or sulfo,
Protecting groups that are removed in vivo may be available as pharmacologically active esters.

An alkoxyimino or alkylidene group R
^{The 12} substituents include carboxy, esterified or amidated carboxy, hydroxy, alkyl, alkoxy and the like, and any of them may be a 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 condensed ring, the second ring may not be an aromatic ring. Further, R ¹³ may be alkoxy, aralkoxy, aryloxy or the like, and the acyl group may constitute 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, they usually preferably have 20 or less carbon atoms. Typical acyl groups include alkanoyl having 1 to 8 carbon atoms (formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, etc.), and a heterocyclic ring in which the aryl moiety has a heteroatom such as nitrogen, oxygen, or sulfur. Monocyclic aroyl (benzoyl, nitrobenzoyl, etc.), alkoxycarbonyl having 2 to 12 carbons (where 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 (where the aralkyl moiety is benzyl, diphenylmethyl, nitrobenzyl, etc.), a dibasic acid having 3 to 10 carbon atoms Acyl (succinyl, phthaloyl, etc. , Halosulfonyl, 0 to the number of carbon atoms
And acyl groups such as 10 acyl phosphates (dialkoxyphosphoryl, dichlorophosphoryl, etc.).

(Ester Group) As the ester group in the organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid ester, the following pharmacologically active ester-forming groups can be exemplified.

Representative examples include 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.), etc., C8-C8 12 substituted aralkyl (phenacyl, phthalidyl, etc.), having 6 to 12 carbon atoms
Aryl (phenyl, xylyl, indanyl, etc.),
C2-C12 alkenyl (allyl, 2-oxo-1,
3-dioxolyl) methyl and the like.

(Organic amine) 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid or 7-acylamino-3-carbamoyloxymethyl-3-cephem
The organic amine in the organic amine salt of -4-carboxylic acid is preferably a secondary amine or a tertiary amine, and particularly preferably a secondary amine. Representative examples include the following organic amines having 1 to 18 carbon atoms. (Primary amine) methylamine, ethylamine, isopropylamine, isobutylamine, t-butylamine, cyclohexanemethylamine, tetrahydrofurfurylamine, benzylamine, p-methoxybenzylamine,
Phenethylamine, p-methoxyphenethylamine, homoveratrylamine, p-chlorophenethylamine, phenylpropylamine, furfurylamine, aniline,
p-Chloroaniline, (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 lower alkylamines, lower aralkylamines, cycloalkylamines, di-lower alkylamines, arylalkylamines, nitrogen-containing saturated ring compounds, saturated carbocyclic lower alkylamines, disaturated carbocyclic amines, tris Lower alkylamines, aryldialkylamines, aralkyldialkylamines, aromatic bases and the like.

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

(Range of Each Group) The alkyl portion 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, Heptyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, octyl, cyclooctyl, cyclohexylethyl, nonyl, dodecyl, etc. are typical examples. 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. An aralkyl group having 7 to 14 carbon atoms (benzyl, phenethyl, phenylpropyl, phenylisopropyl, diphenylmethyl, methoxydiphenylmethyl, naphthylmethyl, furylmethyl, thienylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, Representative examples include pyridylmethyl, indolylmethyl, benzimidazolylethyl, benzothiazolylmethyl, and quinolylmethyl. Each of these may have a substituent as described below.

The acyl moiety is an acyl group having the structure described above. Acyl groups having up to 14 carbon atoms, for example, acyl carboxylates (linear, branched or cyclic alkanoyl, aroyl, aralcanoyl, arylalkenoyl which may have a heteroatom in a monocyclic or bicyclic ring), acyl sulfonates ( Representative examples include alkylsulfonyl, arylsulfonyl, etc.), acyl carbonates (carbamoyl, carbalkoxy, carbalkalkoxy, etc.), sulfo and the like. Each of these may have a substituent as described below.

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

(Exemplary Substituents) Typical examples of the substituent which can be bonded to each group as described above include a carbon functional group (linear, branched or cyclic alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroalkyl). Ring group, acyl carboxylate, 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, carboxy Acid acyloxy,
Acyloxy sulfonate, acyloxy phosphate, etc.); sulfur functional group (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) And the like; stannyl groups (such as trialkylstannyl);

[Production Method] (Acylation reaction) The present invention always employs a reactive derivative of a carboxylic acid having an acyl group on an organic amine salt of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid. The present invention provides a method for producing an objective 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 ｛a symmetric acid anhydride, a mixed acid anhydride [a mineral acid (eg, phosphoric acid, sulfuric acid, carbonic acid half ester), an organic acid (alkanoic acid, aralkane). Mixed acid anhydride with 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.), Esters with N-hydroxy compounds, esters with diacylhydroxylamine (N-hydroxysuccinimidoyl Ter, N-hydroxyphthalimidoyl ester, etc.), thiol ester (aralkyl thiol ester, heterocyclic thiol ester, etc.), etc., active amide [aromatic amide (imidazole, triazole, 2-ethoxy-) Amide with 1,2-dihydroquinoline, etc.), diacylanilide, etc.], and other reactive derivatives. These reactive derivatives include acid scavengers [inorganic bases (oxides, hydroxides, carbonates, bicarbonates, etc. such as alkali metals and alkaline earth metals), organic bases (tertiary amines, aromatic bases, etc.) , Oxiranes (such as alkylene oxides and aralkylene oxides), pyridinium salts (such as tripyridinium triazine trichloride),
Adsorbents (such as celite) and others]. 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 a carboxylic acid having the acyl group.
Moles and 0 to 2 moles of an acid scavenger in a solvent. Acid halides and the like can also react in aqueous solvents.

(Additional carbamoylation reaction and esterification reaction) The present invention also relates to a method of preparing a reactive derivative of carbamic acid with an organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid by a conventional method. To produce the desired organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.

Reactive derivatives of carbamic acid include intramolecular anhydrides such as isocyanate and acid halide.
Tertiary amines, aromatic bases and the like can be added as acid scavengers. The amino group of carbamic acid is protected with a protecting group such as alkanesulfonyl, arylsulfonyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phospho, alkylphosphoryl, dialkylphosphoryl, and trialkylphosphoryl. You may keep it.

The reaction is preferably carried out in a solvent free of reactive hydrogen in the presence of an organic amine salt of 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acid. Act on moles. In the case of an acid halide, the reaction can be carried out even in an aqueous solvent.

Further, an esterification agent is allowed to act on an organic amine salt of 7-acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in a conventional manner to give a final product, 7-acylamino-3-carbamoyloxy. Methyl-3
Also provided is a method for preparing 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 an acid scavenger.

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

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

As a 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) ), Ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrohydrocarbons (nitromethane, nitrobenzene, etc.), nitriles (acetonitrile, benzonitrile, etc.), amides (formamide, Acetamide, dimethylformamide, dimethylacetamide, hexamethyl phosphorotriamide, etc.), sulfoxide (dimethylsulfoxide, etc.), carboxylic acid (formic acid, Acid, such as propionic acid),
Organic bases (diethylamine, triethylamine, pyridine, picoline, collidine, quinoline, etc.), alcohols (methanol, ethanol, propanol, hexano-
Octanol, benzyl alcohol, etc.), water, industrial solvents belonging to other series or mixtures thereof.

The desired product is obtained by removing contaminants (unreacted raw materials, by-products, solvents, etc.) from the reaction solution by a conventional method (extraction, evaporation,
After removal by washing, concentration, precipitation, filtration, drying and the like), isolation can be achieved by a combination of conventional post-treatments (adsorption, elution, distillation, precipitation, precipitation, chromatography, etc.).

[0030]

[Effects and effects] The desired 7-acylamino-3-acid is obtained by reacting a reactive derivative of a carboxylic acid having an acyl group with 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid by a conventional method. According to the prior art for producing hydroxymethyl-3-cephem-4-carboxylic acid, 7-amino-3-carboxylic acid is used.
Intramolecular esterification of hydroxymethyl-3-cephem-4-carboxylic acid proceeds to form 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, the production of lactone is less than 1%. The above two additional carbamoylation and esterification steps also each give a highly pure product in high yield.

[0031]

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 is dissolved in a mixture of 92 ml of ethanol and 45.6 ml of morpholine, and the mixture is dissolved in 910 ml of ethyl acetate at -10 ° C in the presence of 51.2 ml of triethylamine. 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 mixed anhydride of (-4-thiazolyl) -2-pentenoic acid methanesulfonic acid 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 give 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino. ] -Hydroxymethyl-3-cephem-4-carboxylic acid morpholine salt is obtained. IR ν _max cm ^-1 : 1770, 1720,
1660, 1630, 15555 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 the morpholine salt of 3-hydroxymethyl-3-cephem-4-carboxylic acid is added dropwise at about -40 ° C. in nitrogen. After stirring for 30 minutes, chlorosulfonyl isocyanate 2
After adding 5.2 ml dropwise over 3 hours, the mixture is stirred for 1 hour. The reaction is diluted with 200 ml of water and stirred for 1 hour. Separate the organic layer, add water and aqueous sodium bicarbonate to pH 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 are added to the remaining solution, 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 thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid morpholine salt 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-
Dissolve 89.9 g of the carboxylic acid morpholine salt in 300 ml of methyl isobutyl ketone and 150 ml of 4.5% aqueous sulfuric acid. The organic layer was separated, 150 ml of 7% aqueous sodium hydrogen carbonate was added, and the mixture was stirred for several minutes. The aqueous layer was separated, and 35 ml of methyl isobutyl ketone and 5.9 g of tetra-n-butylammonium bromide were separated.
And 41.0 g of pivalic acid iodomethyl ester are added sequentially. After stirring for 4 hours while keeping the mixture neutral, 280 ml of methanol is added, and the mixture is stirred for 3 hours, and the precipitated crystals are collected by filtration. Wash the crystals with cold methyl isobutyl ketone,
If dried under reduced pressure, 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino] -3-carbamoyloxymethyl-3-cephem-4-.
76.9 g of pivaloyloxymethyl carboxylate
Get. Colorless crystals. Yield: 82%. NMR δ (CD ₃ SOCD ₃ ) ppm: 1.07 (t, J = 7.5 Hz, 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 was mixed with 120 ml of methanol and 29 ml of diethylamine.
Dissolve into a 6 ml mixture, and 500 ml of ethyl acetate at -10 ° C.
In the medium, 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 and acylated to give 7β-[(Z) -2- (2-t-butoxycarbonylamino-). 4-thiazolyl) -2-pentenoylamino]
This gives diethyl-3-hydroxymethyl-3-cephem-4-carboxylic acid diethylamine salt. IR ν _max cm ^-1 : 1785, 1710, 1660, 1635, 1570. 2) Carbamoylation: This is dissolved in a mixture of 7.43 g of hydrogen chloride in 119 ml of ethyl acetate at about -10 ° C in nitrogen to give 14.8 ml of chlorosulfonyl isocyanate. After dropwise addition, the mixture is stirred for 1 hour to form carbamoyl. The reaction solution is diluted with 200 ml of water and stirred at 20 ° C. for 1 hour to dechlorinate sulfonylation. The reaction solution was adjusted to pH 2.4 with aqueous sodium bicarbonate, and 66 ml of acetone was added.
, The organic layer is separated, washed with water and concentrated under reduced pressure. The residue was diluted with ethyl acetate and concentrated under reduced pressure.
When 3.5 ml are 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, 15565 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoylamino]- 3-carbamoyloxymethyl-3-cephem-4-
50 g of diethylamine carboxylate are dissolved in 100 ml of methyl isobutyl ketone and 95 ml of 4.5% aqueous sulfuric acid. The organic layer is separated and back-extracted with 95 ml of 7% aqueous sodium bicarbonate. 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 stirred at 20 ° C. for 4 hours while maintaining neutrality to esterify the mixture. By crystallizing from the above A.I. 32.9 g of a compound identical to the product of are obtained. 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 add triethylamine 12 in 500 ml of ethyl acetate at -10 ° C. 0.3 ml and (Z) -2
-(2-t-butoxycarbonylamino-4-thiazolyl)-
23.9 g of 2-pentenoic acid and 6.6 m of methanesulfonyl chloride
A solution of a mixed anhydride of (Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid methanesulfonic acid in ethyl acetate (200 ml), which was synthesized from l, was stirred for 1 hour and acylated. 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, 155.2) Carbamoylation: This was added to a solution of 3.19 g of hydrogen chloride in 64 ml of ethyl acetate at about -40 ° C under nitrogen at -40 ° C, and 6.6 ml of chlorosulfonyl isocyanate was added. Is added dropwise and stirred for 1 hour to form a carbamoyl. Dilute the reaction solution with 4.2 ml of water,
Stir at 0 ° C. for 1 hour to dechlorinate. The reaction solution was adjusted to pH 2.4 with aqueous sodium bicarbonate, and 14 ml of acetone was 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 8.2 ml of dipropylamine was added 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, 15565 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pente Noylamino] -3-carbamoyloxymethyl-3-cephem-4-
Dissolve 21.5 g of dipropylamine carboxylate in 65 ml of methyl isobutyl ketone and 45 ml of 4.5% aqueous sulfuric acid.
The organic layer is separated and back extracted with 45 ml of 7% aqueous sodium bicarbonate. 6 ml of methyl isobutyl ketone, 1.3 g of tetra-n-butylammonium bromide and 9.1 g of pivalic acid iodomethyl ester were sequentially added to the extract, and the mixture was stirred at 10 ° C. for 4 hours while maintaining neutrality to esterify the extract. By crystallizing from the above A.I. 14.0 g of a compound identical to the product of are obtained. Colorless crystals. Yield: 64%.

D. (Diisopropylamine salt) 1) Acylation: 16.5 g of 7-aminodeacetylcephalosporanic acid was added to 50 ml of methanol and dipropylamine 2
Dissolve into a mixed solution of 2.1 ml and 500 m of ethyl acetate at -10 ° C.
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 for acylation to give 7β-[(Z) -2- (2-t-butoxycarbonylamino-4). -Thiazolyl) -2-pentenoylamino] -3-hydroxymethyl-3-cephem-4-carboxylic acid dipropylamine salt. IR ν _max cm ^-1 : 1790, 1690, 1660, 1625, 155.2) 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 was added. The mixture is dropped and stirred for 1 hour to form a carbamoyl. Dilute the reaction solution with 98 ml of water,
And stirred for 1 hour to dechlorosulfonylate. The reaction solution was adjusted to pH 2.4 with aqueous sodium bicarbonate, and 33 ml of acetone was 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 9.8 ml of dipropylamine was added 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 are obtained. Yield: 60%. IR ν _max cm ^-1 : 1780, 1730, 1680, 1650, 1620, 1565. Infrared absorption spectrum of isopropylamine salt produced under similar conditions. IR ν _max cm ^-1 : 1760, 1720, 1700, 1650, 1620, 15555. 3) Esterification: 7β-[(Z) -2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pente Noylamino] -3-carbamoyloxymethyl-3-cephem-4-
Dissolve 25.0 g of dipropylamine carboxylate in 100 ml of methyl isobutyl ketone and 50 ml of 4.5% aqueous sulfuric acid. Separate the organic layer and add 50% 7% aqueous sodium hydrogen carbonate
Back-extract with Methyl isobutyl ketone 25m in the extract
l, 1.6 g of tetra-n-butylammonium bromide and 11.8 g of pivalic acid iodomethyl ester were sequentially added,
If the mixture is stirred at 10 ° C. for 4 hours while maintaining neutrality and esterified, and crystallized from methanol, the above-mentioned A.I. 14.8 g of the same compound as the product are obtained. 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 dissolved, and 9.90 g of diisobutylamine was added in 150 ml of ethyl acetate at -10 ° C. 9ml and (Z)-
(Z) -2- (2-t-butoxycarbonylamino-4-) synthesized from 17.8 g of 2- (2-t-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid and 4.9 g of methanesulfonyl chloride. A solution of thiazolyl) -2-pentenoic acid methanesulfonic acid mixed anhydride in ethyl acetate was added, and the mixture was stirred for 1 hour and acylated to give 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 cooling in nitrogen, and 6.4 g of chlorosulfonyl isocyanate was added dropwise, followed by stirring for 1 hour to carry out carbamoylation. The reaction was diluted with 60 ml of water and stirred at 20 ° C. for 1 hour to dechlorinate. The reaction solution was adjusted to pH 2.4 with aqueous sodium bicarbonate, 25 ml of acetone was added, the organic layer was separated, washed with water and concentrated under reduced pressure. The residue was diluted with ethyl acetate, concentrated under reduced pressure, and 9.2 ml of diisobutylamine was added 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 diisobutylamine carboxylate are dissolved in 80 ml of methyl isobutyl ketone and 35 ml of 4.5% aqueous sulfuric acid. The organic layer is separated and back-extracted with 35 ml of 7% aqueous sodium bicarbonate. 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 esterification by stirring for 4 hours while maintaining neutrality, crystallize from methanol. Product 9.2 identical to
9 g are obtained. Colorless crystals. Yield: 57%.

F. (Other organic amine salts) The following organic amine was used in place of morpholine, diethylamine, dipropylamine, diisopropylamine or diisobutylamine, and the following organic amine was used. B. C. D. Or E. If the reaction of A. is performed, To give the same product. 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) (Diethylamine salt) 1) Acylation: 693 mg of 7-aminodeacetylcephalosporanic acid was added to 4 ml of methanol and 0.69 m of diethylamine.
The resulting mixture was dissolved in a mixture of the above and synthesized from 116 mg of (Z) -2- (2-furyl) -2-methoxyiminoacetic acid and 0.36 ml of methanesulfonyl chloride in 10 ml of ethyl acetate at −10 ° C. in the presence of 0.94 ml of triethylamine. A solution of the mixed anhydride of (Z) -2- (2-furyl) -2-methoxyiminoacetic acid methanesulfonic acid in 2 ml of 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-methoxyiminoacetamide] -3-hydroxymethyl-3-. -Cephem-4-carboxylic acid diethylamine salt is obtained. 2) Carbamoylation: 156 mg of hydrogen chloride was added to 5 parts of ethyl acetate.
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 ml in nitrogen. Add dropwise at ° C. After stirring for 30 minutes, 0.61 ml of chlorosulfonyl isocyanate was added dropwise over 3 hours, and 1
Stir for hours. The reaction is diluted with 8 ml of water and stirred for 1 hour. Separate the organic layer, add water and aqueous sodium bicarbonate to pH 2.4,
3 ml of acetone are added. The organic layer is separated, washed with water and concentrated under reduced pressure. The remaining liquid is diluted with ethyl acetate and concentrated under reduced pressure.
0.28 ml of diethylamine was added to the remaining solution, diluted with ethyl acetate and stirred at room temperature for 30 minutes. The residue was 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-)
Methoxyiminoacetamide] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid / diethylamine 798 mg was dissolved in a mixture of 7 ml of methyl isobutyl ketone and 2 ml of 4.5% sulfuric acid aqueous solution. The organic layer is separated, 1.7 ml of 7% aqueous sodium hydrogen carbonate solution is added, and the mixture is stirred for several minutes. The aqueous layer was separated, and 1 ml of methyl isobutyl ketone, 101 mg of tetra-n-butylammonium bromide and 928 mg of acetic acid 1-iodoethyl ester were sequentially added. After stirring the mixture at 20 ° C. for 4 hours while maintaining the mixture at pH 5, 6 ml of methanol was added.
The mixture is stirred for 1 hour and 2 hours at 5 ° C., and the precipitated crystals are collected by filtration. The crystals are washed with cold methyl isobutyl ketone and dried under reduced pressure to give 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -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 mixture of 2.5 ml of 5% aqueous propanol and 0.9 ml of dicyclohexylamine, and 0.1 ml of triethylamine was added in 12 ml of ethyl acetate at -10 ° C. 56 ml and (Z) -2- (2-furyl) -2-methoxyiminoacetic acid 72
A mixed anhydride of (Z) -2- (2-furyl) -2-methoxyiminoacetic acid methanesulfonic acid in ethyl acetate synthesized from 2 mg and 0.22 ml of methanesulfonyl chloride was added, and the mixture was stirred for 1 hour to effect acylation. To give β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt. 2) Carbamoylation: This was 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 was added dropwise and stirred for 1 hour to carry out carbamoylation. The reaction is diluted with 5 ml of water and stirred at 20 ° C. for 1 hour to dechlorinate. The reaction mixture was adjusted to pH 2.4 with aqueous sodium bicarbonate, and 1.5 ml of acetone was added. The organic layer is separated, washed with water and concentrated under reduced pressure. After concentrating the residual solution under reduced pressure, adding 0.35 ml of dicyclohexylamine and diluting with ethyl acetate gave 7β-[(Z) -2- (2-furyl) -2-methoxyiminoacetamido] -3-carbamoyloxymethyl.
This gives 710 mg of dicyclohexylamine-3-cephem-4-carboxylic acid salt. Yield: 63%. 3) Esterification: 7β-[(Z) -2- (2-furyl) -2-)
Methoxyiminoacetamide] -3-carbamoyloxymethyl-3-cephem-4-carboxylic acid 600 mg of dicyclohexylamine salt was added to 5 ml of methyl isobutyl ketone and 4.5
Dissolve in 1.5 ml of aqueous% sulfuric acid. The organic layer is separated and back-extracted with 1 ml of 7% aqueous sodium bicarbonate. 0.55 ml of methyl isobutyl ketone, 72.8 g of tetra-n-butylammonium bromide and 1-iodoethyl acetic acid 33 were added to the extract.
7 mg were added successively, and the mixture was stirred for 4 hours while keeping the mixture neutral, followed by esterification and crystallization from methanol. 313 mg of the same product are obtained. Yield: 62%.

C. (Other organic amine salts) The following organic amine was used in place of diethylamine or dicyclohexylamine. Or B. Is carried out, the reaction of Example 2. To give the same product. Isopropylamine, isobutylamine, t-butylamine, cyclohexylamine, dimethylamine,
-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.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 501/00-501/62 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] (1) 7-amino-3-hydroxymethyl-3-
7-acylamino-3-hydroxymethyl- produced by acylating an organic amine salt of cephem-4-carboxylic acid
The organic amine salt of 3-cephem-4-carboxylic acid 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-amine. A method for producing an ester of acylamino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. (2) 7-amino-3-hydroxymethyl-3-
Acylating an organic amine salt of cephem-4-carboxylic acid
-[(Z) -2- (2-t-butoxyca)
Rubonylamino-4-thiazolyl) -2-pentenoyl
Amino] -3-hydroxymethyl-3-cephem-4-
Carbamoylation of organic amine salt of carboxylic acid to give 7β-
[(Z) -2- (2-t-butoxycarbonylamino-
4-thiazolyl) -2-pentenoylamino] -3-ca
Rubamoyloxymethyl-3-cephem-4-carboxylic
An organic amine salt of an acid is produced, which is esterified to form 7β
-[(Z) -2- (2-t-butoxycarbonylamino
-4-thiazolyl) -2-pentenoylamino] -3-
Carbamoyloxymethyl-3-cephem-4-carbo
Producing pivaloyloxymethyl acid ester
Item 7. The method according to Item 1. 3. The organic amine salt is a secondary amine salt.
Item 3. The method according to Item 1 or 2.