JPS5842194B2 - Cephalosporin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R is phenoxyacetyl, aminoadipoyl,
Alternatively, it represents aminoadipoyl in which the amino group is protected with acetyl or chloroacetyl, X represents hydrogen or acetoxy, and R1 represents hydrogen, an alkali metal, or p-nitrobenzyl.

The amino, carboxyl and hydroxy groups within the molecule are also protected.

) A method for producing a cephalosporin having a free 7-amino group by splitting the 7-carboxyamide group of a cephalosporin compound represented by
Protected by halogenating agent treatment at a temperature of ~-500C,
The iminohalide obtained here is treated with alcohol to produce an iminoether, and this iminoether is then hydrolyzed with water to produce a cephalosporin having a free 7-amine group. The reaction is carried out using tetrahydrofuran, bis(2 -methoxyethyl) ether, dimethoxyethyl acetate, ethylene glycol diacetate, ■.

The present invention provides a method characterized in that it is carried out in a single medium of an organic solvent miscible with water selected from 4-dioxane and 1,3-dioxane.

Cephalosporins are a well-known family of antibiotics, some of which are widely used in the treatment of diseases.

Cephalosporin C obtained by fermentation was defined to have the following structure, where R is HOOCCH(NH2)(CH2)3-.

It is also known as 7-(5'-aminoadipamide)-cephalosporanic acid.

It has weak antibiotic activity, but is important as a raw material for cephalosporin C, which has 7-aminocephalosporanic acid (7-ACA), which has the following structural formula.

Although the above formula is shown in the form of an intramolecular complex salt, an anionic or cationic salt may also be produced and used.

Cephalothin and medically important antibiotics such as cephaloridine and cephaloglycin are produced from 7-ACA by known methods.

A number of derivatives of antibiotics based on 7-ACA have been developed by converting the amino group at the 7-position of 7-ACA into an acyl group using a suitable acyl acid, acyl halide or other reactive form of such an acyl group. and/or by substituting the acetoxy group attached to the 3-methyl carbon of 7-ACA with a suitable nucleophilic group that is currently well cited in the literature.

It is thus clear that cephalosporin C is a very valuable fermentation-derived antibiotic and that it is of particular interest as a source of starting material for many other more potent antibiotics. Can be seen.

Desacetoxycephalosporin C described in U.S. Pat.
It is of interest as an intermediate for producing -ADCA).

Desacetoxycephalosporin C and its alkali metal salts can also be used as starting materials for the improved process of the invention.

One method of cleaving an amino group to obtain a free amine was described by Lander in the Journal of the Chemical Society (J.

Chem, Soc, 83, 320 (1903)).

According to Lander's method, the amide group is treated with a halogenating agent to form an aminohalide, and the aminohalide is then treated with an alcohol to yield the aminoethyl, which is then hydrolyzed to the free amine.

Applying this method to the cleavage of cephalosporin C, 7-A
CA is disclosed in Canadian Patent No. 770.125 and British Patent No. 1,041,985.

In order to successfully apply this series of reactions to cephalosporins, it is first necessary to protect the carboxyl groups in the molecule.

It is of particular importance to protect the carboxyl group in the 4-position of the cephalosporins.

In the past, these carboxyl groups were generally protected by converting them into esters.

With the exception of silyl esters, these esters are stable under the reaction conditions and generally the ester product must be subjected to more advanced processing to obtain the free acid.

Such treatments include hydrolysis with stronger acids or bases or, in some cases, hydrogenolysis.

These additional steps result in additional processing costs and, in the case of stronger acid hydrolysis, some of the acetoxy groups attached to the C3 methylene of the cephalosporin type C compound are hydrolyzed to desacetoxy. It becomes a cephalosporin, and in the case of hydrolysis with a base, there is a risk of isomerization of the double bond of the dihydrothiazine ring of the cephalosporin type C compound.

Additionally, many methods of making carbon esters result in isomerization of the double bonds of the cephalosporin solvate.

△2 product (incephalosporin) is obtained.

Silyl esters are more sensitive to moisture signatures and are therefore less stable than carbon esters throughout the reaction.

In fact in some cases they are too easily removed.

Moreover, the chemicals used in the production of silyl esters are expensive and not readily available in industrial quantities.

Robert R. Chauvette in U.S. Patent Application No. 117.043, filed February 19, 1971.
disclose an improved method for protecting the carboxyl group of cephalosporins throughout the cleavage reaction.

The improved method is to convert the carboxyl group to the formula % formula %, where R'' is C□-C8 alkyl, alkenyl or alkynyl, halogenated C1-C8 alkyl, alkenyl, or alkynyl, phenyl or formula, where Y is oxygen , sulfur or a carbon-carbon bond, n is an integer from O to 3, and when Y is oxygen or sulfur is at least 1, Z is oxygen, sulfur or N-H, and m is an integer from 1 to 3 This method is characterized in that the carboxyl group is protected by converting the compound into a mixed acid anhydride derived from the acid and the compound.

U.S. Patent No. 3.641, issued February 8, 1972
Harol (IB, Ha
Yes and Gerald L, Huff) disclosed an improved process for producing 7-aminocephalosporanic acid from cephalosporin C.

The method involves protecting the carboxyl group and converting the amide group at the 7-position to an iminohalide by treatment with a halogenating reagent.
Next, the following improvements were made when converting the iminohalide to an iminoether and hydrolyzing the iminoether to form 7-aminocephalosporanic acid.

That is, the improvement is to protect the amino group and adipamoyl side chain by α-halo or α,α
-Dihalo Acylation using a C2-C4 alkanoyl group is included.

In the production process using these cleavage reactions, water-immiscible organic solvents such as chloroform, methylene chloride, or similar substances are used in carboxyl group protection reactions, iminohalide production reactions, and imino production reactions of cephalosporin C or its derivatives. It was customary to use it when carrying out.

After these reactions, the reaction mixture obtained is treated with water to cleave the side chains and subsequently treated with the organic solvent/water reaction mixture to precipitate and separate the 7-aminocephalosporanic acid or other nuclei from the reaction mixture. The solution is treated with a base.

Emulsion problems were experienced during these operations.

These emulsions are sometimes difficult to break down in a reasonable amount of time.

To avoid this emulsion problem, those skilled in the art filtered the reaction mixture after the step of preparing the carboxyl-protected mixed acid anhydride.

This filtration step appeared to remove emulsion-forming material or at least not render the emulsion unmanageable.

In some cases, due to the scale of the operation, it is not desired to filter the reaction mixture, at least until the end of the water treatment step.

The emulsion, which has lasted through several reaction steps, can be filtered after the water treatment step.

If the strongly acidic reaction mixture is allowed to sit for 5 minutes, the emulsion appears to break down.

At laboratory scale, corrosion-resistant equipment such as glass centrifuge tubes is available.

For large-scale operations, equipment such as enameled centrifuges is difficult to obtain and expensive.

Such emulsion problems cause yield losses and increase the length of a plant cycle, as well as requiring extra operations or special equipment.

Furthermore, the use of chloroform solutions in field-scale operation of this method causes discomfort in field operations during hot fish festivals.

In an effort to avoid problems that arise in the case of the processing of cephalosporin C or its derivatives specifically derived from fermentation, such as the emulsion problem mentioned above, various water-miscible organic solvents have been developed. A cleavage reaction mixture was attempted.

Acetonitrile is a good solvent for the cleavage of cephalosporin C or its derivatives.

However, acetonitrile is such a good solvent for 7-aminocephalosporanic acid that its use requires that the acrylonitrile be removed, for example by distillation, in order to separate the 7-aminocephalosporanic acid from the final reaction mixture.

Cephalosporin cleavage technology simplifies the cleavage operation, avoids emulsion problems, reduces operator discomfort, and
Process improvements are needed to help reduce the requirements for special equipment and shorten the time of manufacturing operations.

Quinoline, isoquinoline, 3-picoline, 4-picoline, pyridine, or their salts with acids, or C2-
Tetrahydrofuran, bis(2-methoxyethyl) ether, 2-methoxy containing a catalytic amount of a complex with a C3 halogenated alkanoyl and an alkali metal salt of cephalosporin C or desacetoxycephalosporin C or other cephalosporins. Ethyl acetate, ethylene glycol diacetate, 1,4-dioxane, 1.
After the following series of reactions, i.e. mixed acid anhydride formation, iminohalide formation, iminoether formation and hydrolysis, the base obtained by mixing with 3 dioxane was obtained if the base was not mixed into the mixture. The inventors have discovered that the average yield of 7-aminocephalosporanic acid or 7-aminodesacetoxycephalosporanic acid is substantially increased compared to the obtained yield.

The present invention provides an improved process for cleaving the 7-carboxamide group of cephalosporins.

The improved method of the present invention involves the preparation of cephalosporin C in a diluted system with tetrahydrofuran, bis(2-methoxyethyl)ether, 2-methoxyethyl acetate, ethylene glycol diacetate, 1,4-dioxane, and 1,3-dioxane. It is specifically contemplated for use in a process for making 7-aminocephalosporanic acid (7-ACA) from an alkali metal salt.

It is also desacetoxycephalosporin C to 7-
Aminodesacetoxycephalosporanic acid (7-ADC)
A) or 3-methoxy-7-amino-3-cephem-4
-Carboxylic acid 7 (5'-aminoadipoylamino)-
Can be used to prepare other cephalosporin cores, such as from 3-methoxymethyl-3-cephem-4carboxylic acid, and cleavage of the 7-acyl side chain of the 7-azilamitodesacetoxycephalosporin ester. It can also be used to

The present invention involves carboxyl protection, iminohalide generation process,
and tetrahydrofuran (THF), bis(2-methoxyethyl) ether, 2-methoxyethyl acetate, ethylene glycol diacetate, 1°4-dioxane, or 1,3- It is characterized by the use of dioxane.

Tetrahydrofuran is preferred.

The resulting reaction mixture is mixed with water or other aqueous medium in a hydrolysis step. The hydrolyzed reaction mixture is treated with a base, such as ammonium hydroxide, at a pH such that the compound with the desired nucleus precipitates from the reaction mixture. Adjust the field to a certain isoelectric point.

The present inventors also present the 7-acyl group in the thread of 7-acylamidocephalosporanic acid, desacetate, xycephalosporanic acid, or 3-(substituted-methyl)cephalosporanic acid or easily cleavable ester thereof. It is anticipated that this method can be cleaved by a modified method.

Starting materials for this include cephalosporin C1, alkali metal salts of cephalosporin C (sodium and potassium being the most practical examples thereof), zinc and related metal complexes of cephalosporin C, desacetate. cicephalosporanic acid and its salts and esters,
In addition, 7-
Also included are azilamitodesacetoxycephalosporanic acid and its esters.

However, the most practical starting material for use in the improved process can be specified by the following formula.

(In the formula, R is phenoxyacetyl, aminoadipoyl,
Or it represents aminoadipoyl in which the amino group is protected with acetyl or chloroacetyl, X represents hydrogen or acetoxy, and R1 represents hydrogen, an alkali metal or p-nitrobenzyl.

The amino, carboxyl and hydroxy groups within the molecule are also protected.

) The cephalosporins used in this improved method can be obtained by the ring-opening reaction of penicillin sulfoxide esters cited in the above patents.

The penicillins used to produce such cephalosporins can be obtained by fermentation and precursor fermentation techniques, for example Behrens.
rens) U.S. Pat. No. 2,479,295, No. 2,
No. 479,296, No. 2,479,297, No. 2.5
No. 62,407, No. 2,562,408, No. 2.56
No. 2,409, No. 2,562,410, No. 2.562
, No. 411, and No. 2,623,876.

For example, cephalosporins with phenoxyacetyl side chains can be obtained, for example, from penicillin G (benzylpenicillin) and penicillin V (phenoxymethylpenicillin) by the penicillin sulfoxide ester conversion process described in the above-mentioned document.

2-chenyl and 3-chenylpenicillins and those found in U.S. Pat. No. 2,562,411 can be used to prepare cephalosporin starting materials where R is Here is an example of penicillin that can be used.

When R in the above formula is 5-aminoadipoyl and X is acetoxy and R1 is hydrogen, the cephalosporin is cephalosporin C.

When R is 5-aminoadipoyl, X is hydrogen, and R1 is hydrogen, the cephalosporin is named desacetoxycephalosporin C.

R may also be N-chloroacetamidoadipoyl or other similar groups.

In addition to being acetoxy, X in the above formula can be hydrogen.

It is to be understood that if the cephalosporin contains amino or hydroxy groups, such groups are protected prior to the cleavage reaction.

Groups that protect amino and hydroxy groups are well known to those skilled in the art.

If the amino group is on the 7-acyl side chain of the cephalosporin, it will be lost regardless of whether the protecting group is easily removed during the cleavage reaction.

The group protecting the amine group can be acetyl or chloroacetyl.

Mixtures of amine protecting groups can also be used for individual batches of cephalosporin to be cleaved.

Such a mixture is obtained when a mixed anhydride such as chloroacetic propionic anhydride is used as a reagent to form the amino protecting group.

Hydroxy groups are commonly protected by forming esters, and specifically by forming formyl esters.

Those skilled in the art will recognize that this list of protecting groups is merely an illustration and that many other amino and hydroxy group protecting groups may be used.

Cephalosporin C plus its alkali metal salts, N
-Acylated cephalosporin C quinoline salts can also be used in the method of the invention.

The present invention provides a method for preparing an alkali metal salt of cephalosporin C, desacetoxycephalosporin C or other cephalosporin C derivatives, such as tetrahydrofuran, bis( 2-methoxyethyl) ether, 2-methoxyethyl acetate, ethylene glycol diacetate,
■ Acid addition salts of quinoline, isoquinoline, 3-picoline, 4-picoline, pyridine or one or more of such bases with 4-dioxane or 1,3-dioxane mixtures, or with C2-C3 alkanoyls; It is still characterized by mixing a catalytic amount of the complex with the halide.

In the process of cleavage of the 7-(5'-aminoadipoyl) side chain from the alkali metal salt of cephalosporin C in tetrahydrofuran by the series of reactions of mixed acid anhydride, iminohalide, iminoether and hydrolysis described above, quinoline was It is the preferred base for catalytic purposes.

quinoline, isoquinoline, 3-picoline, 4-picoline,
The pyridine, acid addition salt or complex catalyst can be added to the reaction mixture at any time prior to the addition of the halogenating reagent, such as phosphorus pentachloride.

For example, before adding phosphorous pentachloride, alkali metal cephalosporin C salt, tetrahydrofuran, N, N
-diethylaniline, C2-C4-alkanoyl halide such as acetyl can be mixed in any order of addition.

We believe it is beneficial to stir or shake the mixture for about 15 minutes before the halogenating reagent is added to the mixture to allow the protection reaction to take effect.

Examples of such acid addition salts of catalytic bases include any of the readily available, non-oxidizing, economical hydrochloric, sulfuric, and phosphoric acids and similar acids.

Complexes of such bases with C2-C3-alkanoyl halides or halogenated alkanoyl halides, preferably chloride or bromide, acetyl chloride or acetyl bromide, propionyl chloride or bromide, chloroacetyl chloride can also be used.

This catalytic base enhances the first step acylation reaction, which helps the cephalosporin C alkali metal salt or related compound to dissolve in the solvent mixture, converting the cephalosporin C alkali metal salt into 7-aminocephalosporanic acid. Shorten the reaction time of the series of reactions required to remove insects.

Although the principles of the invention are generally applicable to processes for cleavage of side chains from cephalosporins, its direct economic application is to prepare an alkali metal (e.g., sodium or potassium) salt of cephalosporin C in a tetrahydrofuran solvent. cleavage in a system that uses a series of mixed acid anhydride, iminohalide, iminoether, and hydrolysis reactions currently known in the patent literature.

In carrying out the improved process, quinoline, 3-picoline, 4-picoline or pyridine or salts or complexes thereof, which increase the speed and/or yield of the process, may be used.
), may be used in any amount.

We prefer to use about 3 to 10 mmol of one of the catalytic bases per 20 mmol of cephalosporin C alkali metal salt in tetrahydrofuran or other solvent.

The present inventors have found that 8 to 9 mmol of a base, such as quinoline, to 20 mmol of an alkali metal salt of cephalosporin C, such as sodium cephalosporin C, in tetrahydrofuran is approximately optimal and more preferred for this step. I found it.

A 7-acylamide cephalosporin compound suitable as a starting material for the improved process of the present invention using a base as a catalyst is disclosed by the following formula: where R1-c(0) and is the carboxy ZJ to be cleaved. is an acyl group, is acetoxy or hydrogen, and R1 is hydrogen or an alkali metal cation.

The preferred starting material for use in the improved process is cephalosporin C sodium salt, although potassium and lithium salts of cephalosporin C can also be used.

The starting material in which R2-C(0)- is 5-aminoadipoyl, X is hydrogen, and R1 is an alkali metal such as sodium is desacetoxycephalosporin C.
It is.

Generally, in carrying out the process of the invention, the cephalosporin starting materials are tetrahydrofuran, bis(2methoxyethyl)ether, 2-methoxyethyl acetate, ethylene glycol diacetate, 1,4-dioxane, 1,3
- suspended or dissolved in dioxane or a mixture thereof having a freezing point below the lowest desired reaction temperature of the cleavage reaction.

desired catalyst, base such as quinoline, isoquinoline,
3-picoline, 4-picoline, pyridine or one or more acid addition salts of its bases, N,N di(C1-C3-alkyl)anilines and acyl halides which absorb hydrogen halides, 6-e.g. acetyl chloride. It is preferable to add it together to protect carboxyl groups and amine groups.

Tetrahydrofuran is the preferred reaction medium.

After the carboxyl group protection reaction is complete, if necessary, additional base is added and the mixture is cooled to the desired temperature before adding a halogenating agent such as phosphorous pentachloride.

Temperatures on the order of -25°C to -10°C using tetrahydrofuran are preferred, although lower temperatures can be used.

0°C to 30°C together with one or more other solvents
A temperature of 0.degree. C. may be preferred.

The mixture is stirred at a low temperature until the iminochloride formation reaction is substantially complete, and then the alcohol selected to form the iminoether is added to the cold reaction mixture.

Alcohols that can be used include methanol, ethanol, impropatol, isobutanol, hexanol, 2-ethylhexanol, as well as C1-C8 alcohols such as cyclohexanol, cyclopentanol, 2-methoxyethanol, ethylene glycol, 1
．． Examples include glycols such as 2 and 1,3 propylene glycol and glycerol and the like.

We found that ethylene glycol, 1,2- or 1,
It is preferable to use 3-propylene glycol, isobutanol, 2-ethyl-hexanol, methanol or 2-methoxyethanol in terms of availability and cost.

When the alcoholysis reaction is complete, water is added to accomplish hydrolysis of the cephalosporin side chains and form each cephalosporin core in an acidic medium.

If the alcoholysis reaction was carried out at 110 DEG C. or below, the reaction vessel was removed from the bath and stirred for 5 minutes without bath.

Before the water treatment step, the mixture was allowed to warm to a temperature above the freezing point of water.

In our experience, the initial pH of the reaction medium after addition of water was generally O~1.

The acidic reaction mixture in tetrahydrofuran-aqueous solution is then treated with a base to raise the pH of the reaction mixture to a pH (isoelectric point) at which most of the reaction products precipitate.

Although any economical base is suitable for this purpose, we prefer the use of concentrated ammonium hydroxide.

The invention is further disclosed by the following detailed examples, which are intended to illustrate but not to limit the scope of the claimed improvements.

Example 1 This example demonstrates the application of the improved method of the present invention to the process of cleavage of N-chloroacetyl cephalosporin C quinoline salt with phosphorus pentachloride.

14.1 of N-chloroacetyl cephalosporin C quinoline salt in 100 ml of tetrahydrofuran (THF)
1 batch was suspended.

In this suspension at 20°C, NS←dimethylaniline 1
4,9-1 followed by 10 ml of acetyl chloride. was added.

After stirring for 2 to 3 minutes, add 5.0 m of acetyl chloride again.
l, was added.

N,N-diethylaniline 10.9 mA' after stirring for 2-3 minutes to ensure completion of the reaction to form the mixed anhydride of N-chloroacetyl cephalosporin C.
added.

After cooling the mixture to -10.degree. C., 10.degree. O,! Added i'.

After the reaction had stopped, the temperature was raised to -20°C using carbon tetrachloride/dry ice, and after adding 50ml of methanol, the temperature rose to 15°C.

After cooling the temperature to -20° C. and stirring for about 35 minutes, 100 ml of water was added to the reaction mixture.

After stirring the mixture for 2 minutes, it was removed from the carbon chloride/dry ice bath and concentrated ammonium hydroxide was added to bring the pH to 0.
, 5 (before addition of NH40H) to 3.5 (the isocenter of 7-aminocephaloporanic acid in this mixture).

Approximately 24.5 ml of ammonium hydroxide was used.

The crystals of 7-aminocephalosporanic acid (7-ACA) were filtered off from the THF/H20 reaction mixture and the filter cake was washed with 50TfL11 of water and then 501R11 methanol.

The weight of wet 7-ACA was 4.3 g.

After drying overnight at 40° C. in a vacuum dryer (pressure 8-10107719 H), the weight of 7-ACA was 3.659.

A purity of 93.0% was obtained by ultraviolet spectroscopic analysis, and a purity of 94.3% was obtained by analysis with nicotinamide.

The yield was 63.3% (based on cotinamide analysis).

When this operation was repeated, the weight of the dried 7-ACA was 3.5 g (yield 58.6%).

Example 2 This example demonstrates the improved method of the present invention with a study of the effect of stirring the reaction mixture after addition of ethylene glycol.

In reaction vessel A, N-chloroacetylcephalosporin C quinoline salt in 10011 Ll of THF 14. IJ was suspended and then at 23°C 15.0 m71 of N,N-diethylaniline! added.

Then, when 10.0 TrLl of acetyl chloride was added, the temperature rose to 26.5°C.

After stirring for 15 minutes, the mixture was cooled to -10°C and then heated with N,N.
-diethylaniline11. Qml was added, during which time the temperature of the mixture rose to 0°C.

The mixture was cooled again to -15°C and then phosphorus pentachloride 10
．． 0g to THF cleaning solution 20m71! and added to the mixture.

The temperature rose from -15°C to 5°C.

Low temperature (-15 to -20°C) to ensure completion of the reaction.
) After stirring for 40 minutes, ethylene glycol 2
5.0 ml was added.

The temperature was increased from -20°C to 8°C and the mixture was cooled to -20°C and stirred for 1 hour.

The vessel containing the reaction mixture was transferred to an ice water bath for 2 minutes.

When the temperature rises to 110℃, water (room temperature) 1001rL
Added l.

The temperature of the mixture rose from -10°C to 21°C.

Then, after the temperature has decreased to 10°C, the pH of the mixture (
0,6) to 3.5 with 18TLl of concentrated ammonium hydroxide? ,,Crystals were observed at pH 2.8 to 3.0.

After filtering the crystalline product of 7-ACA from the reaction mixture, it was washed with cold THF/2050% mixture (25 r/L).

In reaction vessel B, the reactants were combined in the same proportions as described in the section for reaction vessel A above.

The difference in processing method was that after the addition of ethylene glycol, the mixture was stirred in a carbon tetrachloride/dry ice bath (-20'C) for 1 hour and 5 minutes (instead of 1 hour), and then further stirred in a water bath (5-10'C). ) for 32 minutes (instead of 2 minutes) before adding water and concentrated ammonia hydroxide (17 ml).

The reactants were mixed in reaction vessel C in the same proportions as described in the section for reaction vessel A above.

The only important difference in the process method is that after the addition of ethylene glycol, the reaction mixture is cooled in a -20°C bath for 1:23 minutes, then water and concentrated ammonium hydroxide (17d) are added in a water bath. It was stirred for 1 hour beforehand.

That's true. The wet 7-CAC in each experiment A, B and C was filtered off and dried.

The dry weight, purity and % yield of each 7-CAC product is displayed below.

BC Dry weight 1.97 3.73 4.2
3 Purity by ultraviolet light 91.9 92.6 92-1 Nicotinic acid amide 94.0 93.7 Purity by 94.1 % yield 34.064373.3 Example 3 This example includes the application of the improved method of the present invention. The effect of mixed anhydride protection chemicals on the yield of 7-ACA obtained is demonstrated.

14.1 g (20 mmol) of N-chloroacetyl cephalosporin C quinoline salt in THP'1007rLl
A suspension of N,N-diethylaniline 1 was prepared at 23°C.
5rrLl.

Then 10.0 ml of acetyl chloride was added.

The temperature of the mixture was about 23°C to 28.5°C.
After 0 minutes, an additional 5.01r11 portions of acetyl chloride were added.

The temperature went from 27°C to 29°C. After the acetyl chloride addition was complete, the mixture began to cool.

The mixture was mixed at -15°C with 11.0 ml of N,N-diethylaniline and then 10.0 g of phosphorus pentachloride and 257 Vl of THF. During the treatment, the temperature rose from -15°C to 2°C.

After stirring for 30 minutes, add 25 yd of engineered ethylene glycol to -20°C.
When the solution was added, the temperature rose to 8°C.

After stirring in the −20° C. bath for approximately 22 minutes, the reaction mixture vessel was transferred to a water bath (0° C. to 5° C.).

After stirring for about 80 minutes to complete the reaction, add 100% water.
TLl was added.

The pH thereafter was 0.3.

The mixture was then treated with concentrated ammonium hydroxide to adjust the pH.
7-A contained in it was increased to 3.5.
CA became crystal.

7-ACA crystals were filtered and then 'I'HF/I (20
Wash with 25TLl of 50% solution, then 25ml THF
I washed it again.

The weight of 7-ACA after drying was 4.5:l, the purity was 94.1% by nicotinamide assay, and the yield was 78.4% based on the purity assay value.

Example 4 This example demonstrates the use of the improved method of the present invention in combination with the study of the effect on the stability of 7-ACA in THF/H20 solution by standing for 2 hours after addition of water.

A suspension of 28.2 g (40 mmol) of N-chloroacetylcephalosporin C quinoline salt in 2001 rL of THF was mixed with 30.2 g (40 mmol) of N,N-diethylaniline. Oml and then acetyl chloride 20. Treated with Oml.

N,N-diethylaniline 22. after stirring to ensure optimal reaction. OTd! and followed by 20.0 g of phosphorus pentachloride
and THF 2 Oml were added.

After stirring for 45 minutes, ethylene glycol 50. Oml was added to the reaction mixture cooled with a carbon tetrachloride/dry ice bath.

The reaction mixture was stirred in a water bath for 90 minutes to complete the reaction.

After cooling the mixture to -10°C, the reaction mixture was diluted with 2 parts of water.
When treated with 00ml, the temperature changed from 110°C to 20°C.

The mixture was cooled to 10° C. and divided into two portions of 271 m each.

The pH of the first portion (4) was immediately adjusted to 3.5 with concentrated ammonium hydroxide (15 ml) from which 7-ACA was crystallized.

7-ACA was collected and washed as described above, and the dry weight was 4.31 (purity 93.9% as determined by cotinamide assay).
The yield was equivalent to 74.4%.

The second 271 portion was stirred for 2 hours at 0°C to 5°C and then treated with concentrated ammonium hydroxide (17.5m) to pH
was adjusted to 3.5, and the 7-ACA present therein was crystallized.

After filtration, washing and drying as described above, 4.38 g of 7-ACA with a purity of 91.4% and a yield of 73.6% was obtained by the nicotinamide method.

Example 5 14.1 g of N-chloroacetylcephalosporin C quinoline salt in 00 m7 of THFl were treated essentially as described in Example 1 to give a mixed anhydride, followed by phosphorous pentachloride io
, oy to produce iminochloride.

The reaction product obtained was treated at -20° C. with 65 g of isobutyl alcohol and subsequently with 100 g of water.

Thereafter, 22 ml of concentrated ammonium hydroxide was added to raise the pH of the reaction mixture to the isoelectric point.

The crystal 7-ACA was filtered, washed, and dried in the same manner as above to obtain a purity of 94.1% 7-ACA4.
06 g was obtained.

This corresponded to a yield of 70.4%.

Example 6 This example demonstrates the improved process of the invention using bis(2-methoxyethyl)-ether as the organic solvent for the phosphorus pentachloride cleavage reaction.

N- in 100 mJ of bis(2-methoxyethyl)ether
Chloracetyl cephalosporin C quinoline group 14.1
1 batch was treated with 26.0 mA of N,N-diethylaniline, 15.0 mA' of acetyl chloride, and then cooled to -20°C.

Thereafter, 10.0 g of phosphorus pentachloride and 25.0 mA' of ethylene glycol were added as described above, followed by 150 mA' of water.
Added M.

Add concentrated ammonium hydroxide (21yd) to adjust the pH to 3.
Raised it to 5.

7-aminocephalosporanic acid (7-aminocephalosporanic acid) with a purity of 81.4%
ACA) 1.4 g was obtained.

The yield corresponded to 25.7%.

Example 7 Cephalosporin C in 100 mA' of tetrahydrofuran
10 g of the sodium salt was dissolved at 24° C. in N,N-diethylaniline 26. Treated using OmJ.

The mixture was treated with 15.0 d of acetyl chloride to protect the carboxyl group in the form of a mixed anhydride.

The amine group in the side chain was probably also acylated at the same time.

After stirring to complete the reaction, phosphorus pentachloride 10
．． When the mixture was treated with 0 g, the temperature rose from 25°C to 30°C.

The iminochloride reaction mixture obtained after stirring was treated with 25.0 m7 of ethylene glycol at -15°C, the temperature rising to 10'°C.

After 45 minutes, 100 ml of water was added to the mixture at 15°C, and the temperature rose to 22°C.

The pH of the mixture was adjusted to 3.5 with concentrated ammonium hydroxide.

Crystals were formed at pH 3.5.

The crystalline precipitate of 7-ACA was separated by filtration, washed with 2511 L11 of water and then 251 L1 acetone, and then dried.

The weight of the dry product was 1.72mm, the purity was 73.2% by nicotinamide assay, and the yield was 23.2φ.

Example 8 This example demonstrates the use of the improved method of the present invention to prepare a PCl5/ethylene glycol/cephalosporin C sodium salt in THF.
Disclosed in conjunction with the use of quinoline as a catalyst for the H20 cleavage reaction.

The use of a catalytic amount of quinoline in the cleavage of the cephalosporin C sodium salt does not form part of this claimed invention.

A 9.8 g (20 mmol) of cephalosporin C sodium salt in 100 TLl of tetrahydrofuran were treated with quinoline 1M and then with 15.0-N,N-diethylaniline.

Next, 20.0 ml of acetyl chloride was added.

The temperature rose from 22°C to 35°C.

After stirring for 25 minutes, N,N-diethylaniline 11.
0 TLl followed by 1 o, og of phosphorous pentachloride to the mixture - 20
Added at °C.

After stirring to complete the reaction, 25% of ethylene glycol was added at -20°C. Om/? added.

Meanwhile, the temperature rose to 23°C.

After 2-3 minutes, transfer the mixture to a water bath and add 15 ml of water at 3°C.
0TIL1 was added.

The temperature of the mixture rose to 27°C. BN, N'-diethylaniline only 15. The above reaction was repeated except that only OmJ was added.

After addition of water, each reaction mixture was stirred for 3 minutes and the pH was adjusted to 3.5 using concentrated ammonium hydroxide.

The 7-ACA crystallized from each reaction mixture was filtered and water
r/lI! It was washed with a mixture of 25 m of acetone and dried.

The following yield was obtained. AB dry weight 4.39, 94.64. ! il'nicotinic acid amide, quantitative determination (purity) 92.0% 90.5% yield % 74.3% 77.1% Example 9 Cephalometric in a 500 mff 1 three-bottle round bottom flask with drying tube, thermometer and stopper. Sporin C sodium salt (20
Prepare about 10 g of millimoles).

The flask was then charged with THF5o11L11N, N-diethylaniline 35d and acetyl chloride 30rrL1.
Add.

Place the reaction mixture in a Cc 14 bath.

The temperature of the reaction mixture usually increases by about 40°C.

After the reaction appeared complete (approximately 15 minutes) dry ice was added to the CC1 bath.

After the temperature of the reaction mixture has decreased to about -15°C, N
, 11.01 rLl of N-diethylaniline and then 510.0 rL of PCl. Add Og.

The reaction mixture was placed in a CCl4-dry ice bath (-15°C to -
・Stir at 20°C for 1 hour.

Ethylene glycol 25M is then added to the reaction mixture and it is left in a Cc14-dry ice bath until the temperature drops to about 0°C.

The reaction mixture was then placed in a water bath (0-5°C) and stirred for 1 hour, with 150 m/? Add.

After stirring for 3-5 minutes, adjust the pH to 3.5 with concentrated NH,OH.

The precipitated 7-ACA crystals are collected, filtered, and washed on a funnel with 25 ml of water and then 25 ml of acetone.

7-ACA is dried in vacuo at 40° C. overnight.

Yield is usually 70-75%. Example 10 This example demonstrates the use of the improved method of the present invention in combination with the use of isobutyl alcohol as the alcohol reactant used in the cleavage reaction.

A suspension of 14.1 g of N-chloroacetylcephalosporin C quinoline salt in 1001 rLl of THF.

After treatment with 15.07 liters of N-diethylaniline and then with 15.0 mA of acetyl chloride, the mixture was cooled to 10°C and then 11.0 TL of N,N-diethylaniline.
Processed with.

The mixture was cooled in a carbon tetrachloride/dry ice bath and 10.0 g of phosphorous pentachloride and THFlomA were added.

After stirring for 50 minutes, add 15 rIL of isobutyl alcohol.
1 was added.

After the reaction appeared to be complete, the temperature was increased from -10°C to 20°C.

B. Another series of experiments essentially similar to the above except that 25 rILl of isobutyl alcohol was used.

Another series of experiments essentially similar to the above except that 50 C isobutyl alcohol was used was carried out.

The results are shown in the table below. ABC C 7-ACA Weight 2.08g 3.73g 4.05g
Nicotinamide assay (purity %) 83.8 81.6 85.3 Yield % 32.1 Bun 56.0% 63.5% Example 1
1 Cleavage of the 7-acyl side chain of p-nitrobenzyl 7phenoxyacetamidodesacetoxycephalosporinate ester in tetrahydrofuran.

p-Nitrobenzyl in 100d of tetrahydrofuran 7
- 10.2 g (20 mmol) of funinoxyacetamidodesacetoxycephalosporinate ester and N,
N-diethylaniline 11. OmJ mixture cooled in a carbon tetrachloride/dry ice bath was added with 10% phosphorous pentachloride.
0g was added.

The temperature rose from -11°C to -12°C.

The mixture was stirred for 75 minutes until the temperature had cooled to ensure completion of the reaction and then treated with 15.0 ml of ethylene glycol.

The temperature rose from -118°C to +20°C.

10 TLl of drained water was added for about 105 minutes. The temperature rose from 5°C to 18°C.

The mixture is treated with 3.81 g of p-toluenesulfonic acid to produce p-nitrobenzyl 7-aminodesacetoxycephalosporanate p-toluenesulfonate ester salt.

Some difficulty was experienced in isolating this ester-salt in good yield from this medium.

The crystals were redissolved and filtered off, the filtrate was brought to pH 0.5 with hydrochloric acid, and the solution was then brought to pH 4.0 with ammonium hydroxide.
Adjusted to 5.

Crystals of p-nitrobenzyl 7-aminodesacetoxycephalosporanate hydrochloride ester salt were filtered and weighed.

(4,95g). The yield was approximately 65%, and thin layer chromatography, ultraviolet and infrared analysis confirmed that the product was the product listed above.

Example 12 Cleavage of Cephalosporin C sodium salt in 1,4-dioxane Cephalosporin C in 100 rL1 of 1,4-dioxane
1.0 m of quinoline was added to a mixture of 9.3 g of sodium salt.

The temperature of the mixture was 25°C. 15.0 ml of N,N-diethylaniline was added to this mixture while stirring.

Then 20.011 Ll of acetyl chloride was added.

The temperature rose from 24.5°C to 38°C.

N,N-diethylaniline including cooling in a water bath11.
0- Then 10.0 g of phosphorus pentachloride was added.

The temperature rose from 15°C to 25°C, but then fell to +5°C.

20.0 d of ethylene glycol was added in two portions.

The temperature rose from -3°C to 25°C, then fell to 22°C and then rose to 26°C during the second addition of ethylene glycol.

After stirring to complete the reaction while cooling, add cold water (7
℃) 150 TLl were added.

The pH of the mixture was approximately 0.25. Ammonium hydroxide was added until 7-aminocephalosporanic acid precipitated (221 rL/liter).

The product was filtered and washed with 25 d of water and then 25 d of acetone.

After drying, we weighed 3.22 g (55.3% yield).

Ultraviolet spectroscopic analysis showed a purity of 95.4φ, and nicotinic acid amide analysis showed a purity of 93.4%.

Example 13 Cleavage of Cephalosporin C Sodium Salt in 1,3-Dioxane The procedure described in Example 12 was repeated except that the cephalosporin C sodium salt was suspended in 1,3-dioxane as the solvent.

Furthermore, propylene glycol was used instead of ethylene glycol as the alcohol.

At the end of the process, 7-aminocephalosporanic acid 2
．． 35 g (dry weight) (approximately 40% yield) was obtained.

Example 14 Cleavage of disacetoxycephalosporin C in tetrahydrofuran.

Following the procedure of Example 11, 25 TIJ of tetrahydrofuran
! Medium desacetoxycephalosporin C (purity approximately 50%)
) 1.98g mixture of quinoline 0.3m, N,N-diethylaniline 3.8rrL11 acetyl chloride 5.0m
l, N, N-diethyl 72 IJ: / 2.7 ml,
Phosphorus pentachloride 2.5g, ethylene glycol 5. Or
ILl, water 38rIIJ! , ammonium hydroxide 6o7
rL/! to produce a detectable solution of 7-aminodesacetoxycephalosporanic acid.

Example 15 Cleavage of cephalosporin C in tetrahydrofuran using cyclohexanol, glycerin or propylene glycol as alcohol Cephalosporin:/C in 100 TLl of tetrahydrofuran according to the procedure of Example 12
9,:1 (20 mmol scale) was treated with quinoline, N,N-diethylaniline, acetyl chloride, N,N-diethylaniline, and phosphorous pentachloride, then (A)
50 mA of cyclohexanol and then 50 mA of water (B) 20.0 mA of glycerin and 150 mA of water or (C) 1,2-propylene glycol and then 1 mA of water.
It was treated with 50M.

The resulting reaction mixture was adjusted to pH using ammonium hydroxide.
7-aminocephalosporanic acid was precipitated as 4,5.

The precipitate was filtered, dried, and weighed. The yield (dry weight) of 7-aminocephalosporanic acid was as follows.

BC Yield 3.33g4.00.9 4
．． 529 Yield 46.0% 66.6
78.4% Purity 75.1% 9
0.6 cup (94.4% cotinamide method) Footnotes Yield was calculated based on the indicated purity.

Example 16 2-methoxyethyl acetate 501 in a suitable container
To 9.8 g of Cephalosporin C sodium salt in rLl was added with stirring at room temperature 1.0 ml of quinoline and then 15.0 TLl of N,N-diethylaniline.

Then 20.0 TLl of acetyl chloride was added. The temperature rose from 23°C to 46°C.

Then N. N-diethyl 11.07 rlJ! added.

After the mixture was cooled to -15° C., 10.0 g of phosphorus pentachloride was added.

The temperature first rose to -4°C and then fell again to -15°C.

Then 50.011 Ll of methoxyethanol was added to the mixture.

The temperature rose from -15°C to +30°C.

Repeat the above operation with (a) 150 mJ of water or (b) 100 ml of water.
Two replicates were performed for treatment with rLl.

(a) The temperature of the reaction mixture treated with 150 rLl of water rose from 4°C to 13°C.

pH was 0.4. Concentrated ammonium hydroxide (241
rLl) to precipitate 7-aminocephalosporanic acid.

(b) The temperature of the reaction mixture treated with 1001 rLl of water rose from 5°C to 20°C.

Its pH was 0.2.

24 d of concentrated ammonium hydroxide was added to raise the pH of the mixture and precipitate the 7-aminocephalosporanic acid.

For each batch, the 7-aminocephalosporanic acid crystals were filtered out, washed with 25 TrLl of water and 25TLl of methanol, and dried at 35°C for 4 days in a vacuum dryer.

The weight purity and yield of the 7-aminocephalosporanic acid product for each batch was as follows.

Example 17 To a mixture of Cephalosporin C9,1 in 10011 Ll of tetrahydrofuran was added 1.0 ml of quinoline to 15.1 NtN-diethylaniline. Added OmJ.

20.0 ml of acetyl chloride was added to this mixture.

The temperature rose from 21°C to 35°C.

Cool the mixture and add 11.0 ml of N,N-diethylaniline.
added.

10.9 phosphorus pentachloride was added at -16°C.

The temperature rose to 12°C.

Then, 25.0 ml of methanol was added at -20°C.

The temperature rose to +16°C.

After stirring to complete the reaction, add water at +3°C.
011Ll was added.

The temperature rose to 10°C.

The pH of the resulting mixture was 0.5. Concentrated ammonium hydroxide was added to the mixture to raise its pH until the pH at which 7-aminocephalosporanic acid precipitated.

(Corc20d) After filtration, 7-aminocephalosporanic acid 3.82.9 was obtained, which had a purity of 9 by ultraviolet light.
The yield was 65.5% with a quantitative purity of nicotinic acid amide of 93.2%.

Example 18A Method for cleavage of cephalosporin C sodium salt by addition of quinoline.

Cephalosporin C (20 mmol, purity 84.5 mm) in a 500 TLl round bottom flask with thermometer and drying tube.
6%) 9.8,9. Tetrahydrofuran (THF) 10
0 mJ, 1.01 rLl (8.5 mmol) of quinoline and 15TfLl of diethylaniline were charged.

Acetyl chloride 20- was added to the above mixture at 25°C.

The resulting mixture was stirred vigorously for 15 minutes, during which time the temperature gradually rose to 35°C.

The temperature was maintained at or near 35°C.

After 15 minutes of reaction, the mixture was cooled to -15°C,
11 g of diethylaniline and 9.8 g of phosphorus pentachloride were added.

The reaction mixture was stirred at -20°C for 1 hour.

At the end of this time 251 rLl of ethylene glycol was added and the resulting mixture was stirred at 0 to +5°C for 1 hour.

150a of ice water was added to the above reaction mixture, and the resulting solution was stirred in a water bath for 10 minutes.

The pH of this solution was gradually adjusted to 3.5 using concentrated aqueous ammonia.
It was adjusted to

The 7-aminocephalosporanic acid (7-ACA) suspension was stirred in a water bath for 30 minutes, then separated, washed with water and then with methanol, and then dried.

The yield was 4.4 g (purity 93.1%, yield 75.2%).

The average yield of four identical experiments using this procedure was 7
It was 8.0%.

B. The cleavage operation without quinoline was carried out in the same manner as above, omitting the quinoline.

The yield was 2.4 g (purity 90.2%, yield 39.7%).

Example 19 Method for cleaving cephalosporin C with 3-picoline.

Cephalosporin C 9.8.9 (purity 84.6) was added to a 500 mJ round bottom flask fitted with a thermometer and drying tube.
%, 20 mmol), tetrahydrofuran (THF) 1
00TILl, 3-picoline 0.41 (4 mmol)
and diethylaniline 15TrLe were charged.

The mixture was cooled to 15°C and acetyl chloride 201rlI
! added.

The reaction mixture was stirred rapidly for 15 minutes, during which time the temperature gradually rose to about 32°C.

The mixture was then cooled to -15° C. and 11 mA' of diethylaniline and 9.8 g of phosphorus pentachloride were added.

The reaction mixture was then stirred at -20°C for 1 hour, at the end of which 25 drops of ethylene glycol was added and the resulting mixture was heated to 0-20°C.
The mixture was stirred at 5°C for 1 hour.

Ice water 1501111 was added to the above reaction mixture, and the resulting solution was stirred in water for 10 minutes.

The pH of this solution was gradually adjusted to 3.5 with concentrated aqueous ammonia.

A suspension of 7-aminocephalosporanic acid (7-ACA) was stirred in a water bath for 30 minutes, washed with water and methanol, and then dried.

The weight was 3.0 g, the purity was 95%, and the yield was 52.5%.

Example 20 Method for cleavage of cephalosporin C sodium salt with addition of pyridine.

Cephalosporin C sodium salt 9.8 g (20
mmol, purity 84.6%), tetrahydrofuran (T
HF) 100 g of viride 70.43 mA' (4 mmol) and 15 parts of diethylaniline were charged.

Cool the mixture to 15°C and add 20 mA' of acetyl chloride.
added.

The reaction mixture was stirred rapidly for 15 minutes and the temperature gradually increased to about 32°C.

The mixture was then cooled to -15 DEG C. and 9.8 g of diethylaniline 11- and phosphorus pentachloride were added.

After stirring the reaction mixture at -20°C for 1 hour, 25 m of ethylene glycol was added and the resulting mixture was stirred at -20°C.
Stir for 1 hour at 5°C.

150 rILl of ice water was added to the above reaction mixture, and the resulting solution was stirred in a water bath for 10 minutes.

The pH of this solution was gradually adjusted to 3.5 with concentrated aqueous ammonia.

The 7-aminocephalosporanic acid (7-ACA) suspension was stirred in a water bath for 30 minutes, separated, washed with water and then with methanol, and then dried.

The yield was 3.1 g, and the purity was 90.6% (yield 51.6%).

Example 21 Method for cleaving cephalosporin C sodium salt with 4-picoline.

In a 500 mA' round bottom flask fitted with a thermometer and drying tube, 9.8 g (2
0 mmol, purity 84.6%), tetrahydrofuran (
THF) 100d, 4-picoline 0.41111I! (
4 mmol) and 151 rLl of diethylaniline.

The mixture was cooled to 15° C. and 20 mg of acetyl chloride was added.

The temperature gradually rose to about 32° C. while the reaction mixture was stirred rapidly for 15 minutes.

The mixture was then cooled to -15°C before 1111 Ll of diethylaniline and 9.8 g of phosphorus pentachloride were added.

The reaction mixture was then stirred at -20°C for 1 hour, then 25 TrLl of ethylene glycol was added and the resulting mixture was stirred at 0-5°C for 1 hour.

150 mA of ice water was added to the above reaction mixture, and the resulting solution was stirred in a water bath for 10 minutes.

Gradually bring the pH of this solution to 3.5 using concentrated aqueous ammonia.
It was adjusted to

A suspension of 7-aminocephalosporanic acid (7-ACA) was stirred in a water bath for 30 minutes, washed with water and methanol, and then dried.

The yield was 3.4 g, and the purity was 96.4% (yield 60.3%).

Example 22 Method for cleavage of isoquinoline-doped cephalosporin C sodium salt.

Cephalosporin C sodium salt 9.8.9 in a 500TLe round bottom flask fitted with a thermometer and drying tube.
(20 mmol, purity 84.6%), 1 ooy of tetrahydrofuran (THF), 1.0 m7 of inquinoline (8,
5 mmol) and diethylaniline 15-.

Then 20 parts of acetyl chloride was added and the reaction mixture was reduced to 1 part.
After stirring rapidly for 5 minutes, the temperature dropped to about 40°C.
temperature, and then gradually decreased to 30°C.

The mixture was then cooled to -15°C, and 11m of diethyaniline and 9.8g of phosphorus pentachloride were added.

The reaction mixture was then stirred for 1 hour at -20°C, then ethylene glycol 257111 was added and the resulting mixture was stirred for 1 hour at 0-5°C.

A solution prepared by adding 150 TL of ice water to the above reaction mixture was stirred in a water bath for 10 minutes, and then the pH of this solution was gradually adjusted to 3.
No. 5 was adjusted using concentrated ammonia water.

The resulting suspension of 7-ACA was stirred in a water bath for 30 minutes, filtered, kept for a long time, washed with methanol, and then dried.

Yield 3.2 g of 7-aminocephalosporanic acid (purity 9
3.1%, yield 54.6%).

Example 23 To a mixture of 9.8 g of cephalosporin C sodium salt in 100 g of tetrahydrofuran was added 1.0 g of quinoline and N
, 15.0 d of N-diethylaniline were added.

To this mixture was added 20.01111 acetyl chloride.

The temperature rose from 21°C to 35°C.

After cooling the mixture to -16° C., 10 g of phosphorus pentachloride was added.

The temperature rose to -2°C. When 25.01 rLl of methanol was added at -20°C, the temperature rose to +16°C.

After stirring to complete the reaction, add 150 TL of water.
1 was added at +3°C, resulting in a temperature of +10°C.

The pH of the resulting reaction mixture was 0.5.

Ammonium hydroxide (20 TLl of concentrate) was added to raise the pH of the mixture to a pH at which 7-aminocephalosporanic acid precipitated.

3.82.9 of filtrate 7-aminocephalosporanic acid was obtained.

Its purity by ultraviolet analysis was 94.4%, the purity by nicotinamide method was 93.2φ, and the yield was 65.5%.

In summary, by practicing the improved process of the present invention, there is the benefit of a single phase in one reaction vessel after addition of the water reactant.

This system contains 7-ACA, 7-ADCA or other cephalosporin cores in solution.

The isoelectric point of the product (I for 7-ACA) H3,
When a base is added to raise the pH to a value corresponding to 5), the product crystallizes out, the yield being comparable to or even higher than that obtained by the prior art process with the selected starting materials.

This improvement over known cleavage methods thus offers the advantage of being a one-reaction vessel process without phase separation and without the need for difficult distillation or boiling down of the solvent.

Moreover, this method is used to generate 7-aminocephalosporanic acid from cephalosporin C or 7-aminodesacetoxycephalosporanic acid from desacetoxycephalosporin C during the cleavage reaction. A method of destroying penicillin N by mixing with phosphorus C is provided.

For example, we cleaved intentionally impure cephalosporin C with about 10 weight φ of penicillin N to obtain 7-aminocephalosporanic acid.

When the 7-ACA was converted to a sodium cephalothin antibiotic, the penicillin content of this antibiotic was tested using standard methods and no penicillin was detected.

Embodiments of the invention are as follows.

1. In the method defined in the claims, an alkali metal salt of cephalosporin C1 cephalosporin C;
or an N-acylated cephalosporin C compound is (1) suspended or dissolved in tetrahydrofuran and in which (2) C1 is added to protect the carboxyl of the cephalosporin C molecule with an anhydride group. (3) treating the cephalosporin C anhydride product from step (2) with base and phosphorous pentachloride at -25° to 30°C to obtain a cephalosporin producing an iminohalide of the phosphorus C molecule; (4) treating the iminohalide from the first step (3) with alcohol to produce a cephalosporin C imino ether; and (5) producing the cephalosporin C iminoether from the first step (4). Phosphorus C iminoether is treated with water to cleave the side chain of cephalosporin C, and (6) the reaction product from step (5) is treated with a base to adjust the pH of this mixture to 7-aminocephalosporin. Adjust the isoelectric point of acid (hereinafter abbreviated as 7-ACA) to 7-ACA.
A method characterized in that: (7) 7-ACA is then recovered from the reaction solvent.

2. In the method specified in the preceding paragraph 1, N-chloroacetyl cephalosporin C quinoline salt is suspended in tetrahydrofuran and then treated with N,N-bis(C1-C3-dialkyl)aniline and acetyl chloride. The carboxyl group is protected to form a mixed anhydride group, and the mixed anhydride is then cooled below 0°C and treated with phosphorous pentachloride in the presence of a base to form the imino chloride, followed by chloride. The imino is treated with a C1-C4 alkanol to form an imino-ether, which is then treated with an aqueous solvent to cleave the 7-acyl side chain into which the 7-amitsefalosporanic acid A method characterized in that the pH is adjusted with a base until it reaches a pH at which 7-amitusephalosporanic acid is precipitated.

3. In the method specified in the preceding section 1, an alkali metal salt of cephalosporin C is suspended or dissolved in tetrahydrofuran to obtain N,N-bis(C1-C3-dialkyl).
The carboxyl group is protected with a mixed anhydride group by treatment with aniline and acetyl chloride, the mixed anhydride is cooled below 0° C. and treated with phosphorus pentachloride in the presence of a base, and the imino chloride is treated with an alcohol. to form an imino-ether, and the imino-ether is treated with an aqueous solvent to form 7-
splitting the acyl side chain to form 7-amitscephalosporanic acid therein, and then adjusting the pH of this mixture with a base to a pH at which 7-amitscephalosporanic acid will precipitate. A method characterized by:

4. In the claimed method, 7-azilamitodesacetoxycephalosporinate ester is (1) suspended or dissolved in tetrahydrofuran; (2) then a base or phosphorus pentachloride is added therein; -25℃～3
(3) treating the iminohalide from step (2) with alcohol to produce an imino-ether; (4) First part (
The imino-ether from 3) is treated with water to cleave the imino-ether, and (5) the reaction product from step (4) is treated with a base to adjust the pH of the mixture to form the 7-amino-ether. A method characterized in that the desacetoxycephalosporinate ester cores are precipitated and then (6) the 7-amitudesacetoxycephalosporinate ester cores are recovered from the reaction medium.

5. In the process defined in paragraph 4 above, the 7-azilamitodesacetoxycephalosporinate ester starting material for producing p-nitrobenzyl 7-aminodesacetoxycephalosporinate as the product of the process is p- A method characterized in that it is nitrobenzyl 7-aminodesacetoxycephalosporinate.

6. In the method specified in the preceding paragraph 1, (1) mixing cephalosporin C sodium with tetrahydrofuran, (2) treating the mixture from the previous step (1) with quinoline, and (
3) treating the mixture from step (2) with acetyl chloride in the presence of chlorine to protect the cephalosporin C molecules with anhydride groups; (4) treating the anhydride product from step (3) with phosphorus pentachloride; (5) treating the halogenated imino from the previous step (4) with methanol to form a methylimino-ether; (6) the methylimino from the previous step (5); (7) Treating the mixture from step (6) with sufficient ammonium hydroxide to form 7-amitusephalosporanic acid in the reaction mixture; raising the pH of the mixture to the point that sporanic acid precipitates from the reaction mixture;
and (8) a method characterized in that the 7-amitsephalosporanic acid is recovered.

7. R in the method defined in the claims: R
2C(0)- (where R2-C(0) is a carboxyl acyl group to be split) X: hydrogen or acetoxy R1: hydrogen or an alkali metal cation with the general formula
/S\H2N-CH-cHCH2 1 C-N,, C-CH2X.

A method characterized by producing a 7-aminocephalosporin core represented by /'j''OOH, or a solution, salt or solvate thereof, wherein quinoline, isoquinoline, 3-picoline, 4
- catalytic amounts of picoline, pyridine or acid salts of one or more of these bases, or complexes thereof with C2-C3-halogenated alkanoyls, in tetrahydrofuran, bis(2-methoxyethyl) ether, acetic acid 2 -methoxyethyl, ethylene glycol diacetate, 1,4
- A method comprising mixing the halogenating agent into the medium containing dioxane or 1,3-dioxane before adding it.

8. An alkali metal salt of cephalosporin C is mixed in tetrahydrofuran in the method specified in paragraph 7 above and treated by the method described therein to obtain 7-
A method characterized in that it produces amitusephalosporanic acid.

9. The method defined in item 8 above, characterized in that quinoline or its acid salt is used as a catalyst.

10.Quinoline is 2 of alkali metal cephalosporin C
9. The method as defined in item 9 above, characterized in that it is added in a molar ratio corresponding to about 3 to 10 mmol of quinoline per 0 mmol of quinoline.

11. Halogenated C2-C4- where quinoline is a protective agent to the mixture of cephalosporin C and tetrahydrofuran
The method defined in item 7 above, characterized in that the alkanoyl is added prior to or simultaneously with the alkanoyl.

12. Mixing cephalosporin C sodium with tetrahydrofuran and hydrogen halide absorbing base; adding acetyl chloride to acylate the carboxyl and amino groups of cephalosporin C; acylated cephalosporin C; of cephalosporin C sodium by adding phosphorus pentachloride and base to produce the imino chloride, adding methanol to produce the imino-ether, and hydrolyzing the reaction product with water. (5'aminoadipoyl) In the method described in 1 above, in which the side chain is heated, quinoline, isoquinoline, 3-picoline, 4-picoline, pyridine or an acid addition salt or a base thereof and a C2-C3-chloride are added.
A process as defined in the claims characterized in that the complex with the alkanoyl is mixed into the reaction mixture before or simultaneously with the addition of the acetyl chloride to the mixture of cephalosporin C and tetrahydrofuran.

13. Process according to claim 1, characterized in that quinoline and acetyl chloride are mixed.

14. The method according to 7 above, wherein the catalyst is isoquinoline, 3-picoline, 4-picoline, pyridine, an acid addition salt, or a complex thereof.

Claims (1)

[Claims] 1 General formula (wherein R is phenoxyacetyl, aminoadipoyl,
Or it represents aminoadipoyl in which the amino group is protected with acetyl or chloroacetyl, X represents hydrogen or acetoxy, and R1 represents hydrogen, an alkali metal or p-nitrobenzyl. The amino, carboxyl and hydroxy groups within the molecule are also protected. ) A method for producing a cephalosporin having a free 7-amine group by splitting the 7-carboxyamide group of a cephalosporin compound represented by 1o℃
After protection by halogenating agent treatment at a temperature of ~-50'C, the resulting iminohalide is treated with alcohol to form the iminoether, which is then hydrolyzed with water to give the free 7 - A method for producing a cephalosporin having an amino group, in which a fission reaction is performed with quinoline, isoquinoline, 3-picoline, 4-picoline, pyridine, or an acid addition salt of one or more of these, or a C2-C3 Tetrahydrofuran, bis(2-methoxyethyl) in the presence of a complex with an alkanoyl halide
A process characterized in that it is carried out in a single medium of an organic solvent miscible with water selected from ether, 2-methoxyethyl acetate, ethylene glycol diacetate, 1°4-dioxane and 1,3-dioxane.