JPS5826355B2 - 7- Aminocephalosporan sanyuudoutaino Seizouhouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides 7-acylamidocephalosporanic acid-1-
The present invention relates to a method for producing a 7-aminocephalosporanic acid derivative by deacylating and deoxygenating an oxide derivative.

More specifically, this invention relates to the general formula (■): (wherein R is a phenylacetyl, phenyloxyacetyl or thennylacetyl group, X is a hydrogen atom or an acetoxy group, -cooz is a carboxyl group or a protected carboxyl group) A 7-acylamide cephalosporanic acid-1-oxide derivative represented by (respectively) is reacted with an iminohalide-forming agent in the presence of a homolog of aniline in an inert organic solvent, and then an alcohol having 1 to 7 carbon atoms is reacted with an iminohalide-forming agent. is reacted and further hydrolyzed in an acidic region to form the general formula (
: (wherein -COOZ' means a carboxyl group or an esterified carboxyl group, and X has the same meaning as above) The present invention relates to a method for producing sporanic acid derivatives.

Converting the △2 cephem derivative produced when forming a cephem ring from penicillin through a ring expansion reaction or introducing a substituent to the methyl group at the 3-position of the cephem ring into a medicinally useful △3 cephem derivative In order to do so, △3-
It is necessary to lead to a cephemu 1-oxide derivative, and further to perform a deoxygenation reaction and a deacylation reaction at the 7-position.

A method for efficiently producing intermediates for producing cephalosporin antibacterial compounds of △3 value as pharmaceuticals is as follows:
It is extremely important industrially.

Conventionally, 7-acylamido-△3-carboxylic acid-1-oxide or its ester was converted into a 7-aminocephalosporanic acid derivative or its ester (after protecting the carboxyl group at the 4-position (in the case of an ester, it was used as it was). ),
First, (1) an organic acid halide, then a reducing agent is applied,
After taking out the generated cephalosporanic acid derivative, (ii) deacylation reaction at the 7-position was carried out again to obtain a 7-aminocephalosporanic acid derivative or its ester.

[For example, J. Am. Chem, SOC, Volume 91, No. 56
74 (1969); see J. Org, Chem, Vol. 35, p. 2430 (1970)].

However, the above step (1) was complicated, had a low yield, and was industrially unsatisfactory.

As a result of various studies on these steps, the inventor of this invention found that
This invention was completed.

In other words, it is a surprising finding that by using this new reaction, the reaction proceeds at a low temperature around 0°C without using a special reducing agent, and the desired product can be obtained in good yield with simple operations. .

The 7-acylamidocephalosporanic acid-1-oxide derivative of general formula (I) used in this invention will be explained.

The acyl group at position 7 may be an acyl group derived from any carboxylic acid, examples of which include phenoxyacetyl, phenylacetyl, benzoyl, chenylacetyl, chloroacetyl, bromoacetyl, acetyl,
Examples include propionyl and formyl.

However, industrially preferred examples include phenoxyacetyl, phenylacetyl, formyl, and chloroacetyl.

The protected carboxyl group in -cooz ultimately means a group that can be at least hydrolyzed or reductively decomposed, and further hydrolyzable or reductively decomposable groups include esters formed by alcohols and carboxyl groups,
There are mixed acid anhydrides formed by other acids and carboxyl groups.

Reagents that can form mixed acid anhydrides include the following.

Preferred examples include trimethylchlorosilane, dimethyldichlorosilane, trimethoxychlorosilane, dimethoxydichlorosilane, methylmethoxydichlorosilane,
Phosphorus trichloride, methoxydichlorophosphine, ethoxydichlorophosphine, 2-chloroto-3,2-dioxaphosphorane, 2-chloro-5-methyl-1,3,2-dioxaphosphorane, ethoxydichlorophosphine, acetic acid chloride , phosgene, etc.

Others methoxytrichlorosilane, methyldimethoxychlorosilane, propoxydichlorophosphonic acid, phthoxydichlorophosphate, propionic acid chloride, butyric acid chloride, methoxycarbonate chloride, ethoxycarbonate chloride, propoxycarbonate chloride, methoxydibromophosphine, phosphorus oxachloride, phosphorus pentachloride Examples include.

Preferred examples of alcohols that form esters include t-butanol, 2-chloroethanol, 2-furomonitanol, 2.2.2-trichloroethanol, 2.
-Methylsulfonylethanol, 2-ethylsulfonylethanol, benzoylmethanol, benzyl alcohol, p-nitrobenzyl alcohol, p-methoxybenzyl alcohol, triphenylmethanol, trimethylacetyloxymethanol, 3-hydroxy-3methyl-1・3-dihydroisobenzofuran-1-one, 5-hydroxy-5-methyltetrahydrofuran-2-one,
Examples include 1-i-petitoxybutanol and 5-hydroxy intaso.

Other examples include methanol, ethanol, propatool, butanol, p-furomobenzoylmethanol, 2,6-t-7' tilbenzene-1,4 diol, acetoxymethanol, benzhydrol, phenol, and the like.

Among the esters formed with the above alcohols, esters that can be reductively decomposed include p-nitrobenzyl ester, benzyl ester, benzhydryl ester, p-
There are methoxybenzyl ester, trichloroethyl ester, and halogen ethyl ester, and among these, p-nitrobenzyl ester and trichloroethyl ester are preferred.

A compound in which -cooz is a protected carboxyl group in general formula (I) can be prepared by a conventional method using a corresponding compound or a salt thereof in which -cooz is a carboxyl group as a raw material.

Note that when -COOz is a compound of general formula (I) with a carboxyl group (or a salt thereof in some cases) as a raw material, the carboxyl group is protected by a reaction to form an iminohalide with phosphorus oxyhalide or pentahalide. Therefore, the object of the present invention can be achieved without using a compound of general formula (I) having a previously protected carboxyl group.

The compound of general formula (I) is then reacted with an iminohalide forming agent in the presence of a congener of aniline in an inert organic solvent to form the corresponding iminohalide compound.

Preferred examples of inert organic solvents used here include methylene chloride, chloroform, ethylene chloride, propylene chloride, and the like.

Other examples include carbon tetrachloride, trichloroethane, trichloroethylene, tetrachloroethylene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like.

Particularly preferred examples of aniline homologs include dimethylaniline and diethylaniline.

Examples of the iminohalide forming agent include phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, and phosgene, but industrially it is preferable to use phosphorus oxychloride or phosphorus pentachloride.

When phosphorus pentachloride is used, the reaction is usually completed in 1 to 3 hours even at temperatures below 0°C, but if phosphorus oxychloride is used at around 0°C, it will take several days.

Next, alcohol is added to the above reaction solution to form an imino ether.

Examples of alcohol include methanol, ethanol,
Although propatool, butanol, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl glycol, etc. can be used, methanol, isobutanol, n-butanol, propylene glycol, etc. are preferably used industrially.

The iminoetherification reaction proceeds at -40 to 40°C, but is usually carried out at -30 to 30°C.

Generally, when the carboxyl group at position 4 of the compound of general formula (I) is protected in the form of a mixed acid anhydride, the temperature is below 0°C, and when it is protected in the form of a stable ester, it is around 0°C. It is often reacted with.

Furthermore, this reaction is faster for alcohols with smaller molecular weights, and slower for alcohols with larger molecular weights.

For example, in the case of methanol, the reaction is completed in about 2 to 3 hours at -80 to 10°C.

Next, the reaction solution is acidified, preferably adjusted to pH 3 or less, and subjected to a hydrolysis reaction.

For example, the iminoether can be hydrolyzed by placing the reaction solution in ice water, adjusting the pH to around 1, and stirring for about 30 minutes to 1 hour.

At this time, when the carboxyl group at the 4-position is protected with a mixed acid anhydride or an easily hydrolyzable ester, it is simultaneously hydrolyzed and -cooz' becomes the target object (2) of the carboxyl group. generate.

Easily hydrolyzable esters are esters formed from t-phthanol, triphenylmethyl alcohol, and the like.

Note that when compound (I) substituted with an acyloxy group at the 3-position is used as a raw material, hydrolysis at around pH 2 is preferred.

Then, when a base is added and a compound (2) having a carboxylic acid at the 4-position is formed, the target compound usually precipitates as crystals by adjusting the iso-point.

Also, a compound with a carboxyl group esterified at the 4-position (6
) is generated, it can be extracted with an organic solvent at around pH 7 and then obtained as a crystalline acid salt.

The bases used for neutralization include triethylamine,
Examples include ammonium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and aqueous ammonia.

Examples of ester acid salts include hydrochloric acid, sulfuric acid, alcoholic acid, citric acid, succinic acid, p-)luenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid,
Salts derived from ethanesulfonic acid and the like are also preferred because of their crystallinity.

In the above method, the target object (6) is 95% under optimal conditions.
% and can be used immediately for the next acylation step, i.e. for the production of cephalosporins of △3.

Next, an example will be explained. Example 1 7-phenylacetamide-3-methyl-3-cephem-
4-carboxylic acid-1-oxide 1.04? (3 mmol) was suspended in 107 nl of anhydrous methylene chloride and
Add 0.36P (3.6 mmol) of triethylamine and stir.

A clear solution is soon obtained.

To this were added 0.655' (6 mmol) of trimethylchlorosilane and 1.45f (12 mmol) of dimethylaniline, and after stirring for 30 minutes, the mixture was cooled to -30°C.

Phosphorus pentachloride 1.46? (7 mmol), -20~
-30 after stirring for 1 hour at -10℃ and 1 hour at -10~0℃
Cool to 0.degree. C. and add dropwise anhydrous methanol/L/2.24P (70 mmol).

React at -30 to -15°C for 1 hour and at -15 to -5°C for 1 hour, and leave in a -20°C cold room overnight.

10 ml of ice water was added to this, and after stirring for 30 minutes, ammonium carbonate was added to gradually raise the pH.Finally, the pH was adjusted to 3.5, and the mixture was kept in an ice chamber overnight.

Adjust the pH to 3.5 again, collect the precipitated crystals and add a small amount of 60%
Wash several times with cold ethanol and acetone, then dry.

0.611 (95%) of 7-amino-3-methyl-3-cephem-4carboxylic acid (abbreviated as 7-ADCA) was obtained.

Infrared absorption spectrum: 1800CrfL-1o ultraviolet absorption spectrum λ '265mμ (J'J ethyl ma
x'-yson, methanol).

Elemental analysis values, thin layer chromatography, etc. of the main island completely matched those of the specimen.

Example 2 The following reagents were used in place of trimethylchlorosilane (6 mmol) in the reaction of Example 1, and the reaction and treatment were carried out in the same manner.

Example 3 The following anhydrous alcohol was used in place of the anhydrous methanol (60 mmol) in Example 1, and the reaction was carried out according to Example 2.

Example 4 7-phenylacetamide-3methyl- in Example 1
According to Example 1, using 1.09 P (3 mmol) of 7-phenooxyacetamide 3-methyl-3-cephem-4-carboxylic acid 1-oxide in place of 3-cephem-4-carboxylic acid-1 oxide. Process after reacting.

7-ADCA was obtained with a yield of 94%.

Example 5 7-chenylacetamide-3-acetoxymethyl-3-
Cephem-4-carboxylic acid-1-oxide (cephalothin sulfoxide) 0.82P (2 mmol), triethylamine 0.31' (3-: rimole), dimethylaniline 0.97y' (8 mmol) in anhydrous methylene chloride lQ
ml and stir at 0°C.

Methoxydichlorophosphine 0.27f in clear solution
(2S IJ mol) was added and reacted for 30 minutes at 0°C, then -40°C.
Cool.

Add 1.04y (5 mmol) of phosphorus pentachloride to this reaction solution, react at -30 to -15°C for 1 hour, and at -15 to 5°C for 1 hour, and cool to -40°C.

Add 1.60P (50 mmol) of anhydrous methanol to this solution.
dropwise at -30 to -15℃ for 1 hour, -15℃ to 5℃
The mixture was allowed to react for 1 hour, and then kept in a cold room at -20°C overnight.

Ice water was added to this reaction solution, and while stirring, added ammonium oxide and reacted for 30 minutes at around pH 2.0, and then adjusted to pH 3.5.

Place in an ice chamber overnight to adjust pH to 3.5, and collect crystals by centrifugation.

Wash with 60% cold acetone, then dry with acetone.

7-amino-3-acetoxymethyl-3-cephem-4
-Carboxylic acid 0.47? (86%).

Infrared absorption spectrum: 1800cfn'.

Ultraviolet absorption spectrum λ: 263 mμ (water).

aX

Claims (1)

[Claims] 1 General formula (■): [In the formula, R is a phenylacetyl, phenyloxyacetyl or thienyl acetyl group, X is a hydrogen atom or an acetoxy group, and -COOZ is a carboxyl group or a protected carboxyl group. A 7-acylamidocephalosporanic acid-1-oxide derivative represented by The alcohol is reacted and further hydrolyzed in an acidic region to form the general formula (
6): (In the formula, -cooz' means a carboxyl group or an esterified carboxyl group, and X has the same meaning as above.) It is characterized by obtaining a 7-aminocephalosporanic acid derivative or a salt thereof represented by: A method for producing a 7-aminocephalosporanic acid derivative.