JPS5851956B2 - Method for producing cephalosporin compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7β-amino-3- by cleaving the amide group at the 7-position of a compound represented by the formula (wherein R represents a protected amino group). This invention relates to a method for producing (3-oxobutyryloxymethyl)cef-3-emu-4-carboxylic acid.

Conventionally, the most common method for cleaving the 7-position acylamide group of cephaloaporins was disclosed in Japanese Patent Publication No. 41-138.
62 (Dutch Patent No. 640142) is known.

That is, this is a method in which an amide bond is converted into an imino-ride, which is further converted into an imino ether, and the resulting imino ether is hydrolyzed to form an amino compound.

However, this method cannot be carried out unless the carboxyl group at the 4-position is protected in advance.

In the above-mentioned patent, this protective group includes a benzyl group,
A benzhydryl group is indicated.

Removal of the protecting group is necessary to restore the carboxylic acid, but this removal requires a method using trifluoroacetic acid and anisole, or strong conditions such as catalytic reduction, so cleavage of the β-lactam ring is necessary. As a result, the yield is poor.

As a result of various studies on the method for cleaving the acyl group at the 7-position of a compound CI) having a substituent more chemically active than a methyl group or an acetoxymethyl group at the 3-position, the present inventors found that acetyl chloride or propionyl chloride, etc. Protecting the carboxyl group with propionyl halide at -10°C to -5°C gives good yields from CI) to ([,l
It was found that this could be obtained, and the present invention was completed.

As disclosed in JP-A No. 51-98296 and JP-A No. 52-83869, the raw material compound CI) has a protected amine 7 group represented by the formula (wherein R represents a protected amino group). It can be produced by reacting deacetylcephalosporin C and diketene.

This reaction is equimolar, and it is sufficient to use an equimolar amount of diketene for [IV], but since diketene decomposes in the presence of water or alcohol, in order to control such decomposition, Diketene may be used in excess.

Usually, this reaction is easily accomplished by combining [IV,) and diketene in a suitable inert solvent at a reaction temperature of -30°C to 40°C.

Suitable inert solvents include, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, dimethylformamide, dimethylacetamide,
Tetrahydrofuran, acetonitrile, ethyl acetate, acetone, dioxane, ether, mixtures thereof, and the like are used.

The reaction of diketene with CIV) is very fast, but is somewhat dependent on the reaction temperature and is usually run for 0.5 to 15 hours to complete the reaction.

Further, if necessary, a lower trialkylamine such as triethylamine may be added to the reaction system.

In compound [■] and CIV, 1, R represents a protected amino group, and the protecting group generally used in peptide chemistry is used. All of the protecting groups for amino groups are applicable, but since removal of the protecting group is not necessary in the method of the present invention, it may be difficult or impossible to remove the protecting group, such as the acylamino group, where as acyl For example, phthaloyl, bensoyl, p
-Nitrobensoyl, toluoyl, naphthoyl, p-
Tert-butylbenzoyl and the like are frequently used.

When [■] is produced from CIV), [■] can be used as it is in the reaction for producing (II,) without any particular isolation and purification.

CI,) to (ID is produced as follows.

First, CI) is reacted with acetyl or propionyl halide such as acetyl chloride or propionyl chloride to protect the carboxyl group.

Compound [■] can be subjected to the reaction in free form or as a salt with an alkali metal, alkaline earth metal, organic amine, etc.

In this reaction, for example, dichloromethane, chloroform, 1
For example trimethylamine, triethylamine, quinoline, pyridine, N- in an inert solvent such as 2-dichloroethane, tetrahydrofuran, etc. under anhydrous conditions
N-dimethylaniline, N-N-diethylaniline, N
- Advantageously carried out in the presence of a tertiary amine such as methylmorpholine.

[■] forms salts with these amines and dissolves in solvents.

This protection reaction can be carried out at temperatures above -50°C, but since side reactions occur and high purity products cannot be obtained using a dish towel at room temperature, -50°C to 0°C, preferably -10°C to
Preferably it is carried out at 50°C.

Further, it is preferable to use the protective agent in a molar amount of 2 times or more.

Next, the above reaction product is reacted with an imino-ride forming agent (for example, phosphorus pentachloride, etc.) to convert it into an imino-ride form.

This reaction is preferably carried out in the above-mentioned inert organic solvent in the presence of a tertiary amine such as N-N-dimethylaniline or N-N-diethylaniline.

The reaction temperature is not particularly limited, but is preferably -55°C to 0°C.

A lower alcohol such as methanol, ethanol, n-propanol, n-butanol, or imbutanol is added to the iminohalide thus obtained to convert it into an iminoether.

The above reactions are carried out according to conventional techniques.

[II,) is precipitated by subjecting the obtained iminoether compound to solvolysis with water, a lower alcohol, etc. to bring the reaction solution near the isoelectric point of (II).

When a lot of this is collected, washed with an organic solvent such as acetone or dichloromethane, and dried, [II] is obtained.

The thus obtained [[[] is an important intermediate for the production of antibacterial substances.

For example, as shown in JP-A No. 52-83869, 3-(4-carbamoyl-1 -pyridiniomethyl)-7β-(D-α-sulfophenylacetamide)cef-3-emu 4-carboxylate monosodium salt is a compound that exhibits strong antibacterial activity against Pseudomonas.

Example 1 7β-(D-5-carboquine-5-phthalimidovaleramide)-3-hydroxymethylcef-3-em-4-
Citriethylamine carboxylic acid salt (8,25P) was dissolved in diolmethane (120ml), triethylamine (2,3Ill) and diketene (3,orfLO) were added, and the mixture was stirred at 20°C for 1 hour.

Cool to -20°C, acetyl chloride (11.5ml
) and stir for 20 minutes at -10°C to 0°C.

Add N-N-dimethylaniline (19 ml) to -50
Cool to ℃, add phosphorus pentachloride (12, (1)) and stir for 20 minutes.

Add methanol (50 rnl) at -30°C or lower, -2
Stir for 20 minutes at 0°C to -15°C, add water (100 ml), stir vigorously for 5 minutes, let stand, and separate the aqueous layer.

Add methanol (55rrLl) to this, adjust to pm 3.4 with a saturated potassium carbonate aqueous solution at room temperature while stirring,
Stir for 30 minutes under water cooling.

Collect a lot of precipitated crystals, wash with water, acetone, and dry.7
β-amino-3-(3-oxobutyryloxymethyl)
Cef-3-emu-4 carboxylic acid is obtained.

Yield 4.46? . IR(KBr)crfL':
3200.1800.1745.1720.1622 NMR (D20+Na0D) δ: 2.27 (3H, s
), 3.48 (2H, ABq, J = 18H
z), 4.6-5.6 (4H, m) Example 2 7β-CD-5-(pt-butylbenzamide)-5
-carboxyvaleramide io-3-hydroxymethylcef-3-em-4-carboxylic acid ditriethylamine salt (
6,55P) was suspended in dichloromethane (60wLl), triethylamine (1,1m) and diketene (1,
5ml) and stir for 60 minutes.

Then, it was cooled to -50°C, and acetyl chloride (7.6d
) and N-N-dimethylaniline (9, smA') are added sequentially and stirred at -45°C to -40°C for 30 minutes.

Then, at -50°C, add phosphorus pentachloride (6,01) to -45
Stir for 25 minutes at ~-40°C, add methanol (25ml
) slowly.

During this time, keep the internal temperature below -30°C. Then water (50r
rLl) and stir vigorously for 5 minutes at -5°C to 0°C, and separate the aqueous layer.

The organic layer is further extracted with water (5 ml).

The aqueous layers were combined, methanol (25 m) was added, and while stirring, a 40% aqueous potassium carbonate solution was added to adjust the pH to 3.4.
Stir for 30 minutes at 0°C to 5°C, take one precipitate, wash with water and acetone sequentially, and dry to obtain 7β-amino-3-(3
-oxobutyryloxymethyl) cef-3-em 4-carboxylic acid is obtained.

Yield 2.21S'. The IR spectrum of the crystal matches well with that obtained in Example 1.

Example 3 When the same reaction as in Example 1 was carried out using propionyl chloride (14rIll) instead of acetyl chloride, 7β-amino-3-(3-oxobutyryloxymethyl)cef-3-emu-4-carvone was obtained. Get acid.

Yield: 4.31fo The IR spectrum of this product matches well with that obtained in Example 1.

Claims (1)

[Scope of Claims] A compound represented by formula 1 [wherein R represents a protected amino group] is combined with acetyl or glopionylnolide.
After reacting at 0°C to -50°C, it is reacted with an iminohalide forming agent to form an imino)lide, this is reacted with a lower alkanol to form an iminoether, and then this is solvolyzed. A method for producing a compound represented by the formula characterized by: