JPS5835191A - Preparation of cephacetrile - Google Patents

Abstract

PURPOSE:To obtain cephacetrile at room temperature quickly in high yield useful for remedying diseases caused by Staphylococcus aureus, etc., by reacting a silyl derivative of 7-aminocephalosporanic acid with a cyanoacetic ester derivative, followed by removing the silyl group from the reaction product. CONSTITUTION:(A) 1mol silyl derivative of 7-aminocephalosporanic acid shown by the formulaI(R is trialkylsilyl) obtained by reacting 7-aminocephalosporanic acid with a silylating agent such as N,O-bistrimethylsilylacetamide, etc. is reacted with (B) 1-3mol cyanoacetic ester derivative shown by the formula CN- CH2-CO-Y (Y is halogen-substituted phenoxy having 4 or less substitution number, halogen-substituted phenylthio having 4 or less substitution number, 2- benzothiazolethio, etc.), and the reaction product is reacted with water or an alcohol and the silyl group is removed, to give the desired compound shown by the formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 7-(2,-cyanoacetamide)-3- represented by the following chemical structural formula (1) (1).
(Hydroxymethyl)-8-oxo-1-5-thia-1
-Azobicyclo(4,2,0)oct-2-ene-2-
The present invention relates to a method for producing carboxylic acid acetate (hereinafter referred to as the generic name cefacetril).

Cefacedryl sodium, which is the sodium salt of cefacedryl, is useful as a therapeutic agent for various human and animal diseases caused by Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, etc., and has been traditionally used with the chemical structural formula ( 2) (2) Using 7-aminocephalosporanic acid shown in C as a starting material, it is dehydrated and condensed with an acid halide of cyanoacid, a mixed acid anhydride of cyanoacetic acid, or cyanoacetic acid in the presence of a tertiary amine. cefacedolyl (1) t-J
&l! (1977-1987)
No. 47).

However, although the conventional method described above uses a tertiary amine to solubilize 7-aminocephalosporanic acid (2) in an organic solvent and thereby performs a homogeneous reaction, the reaction rate is low and the yield is low. is also low. In addition, since the purity of cefacedolyl (1) obtained by the reaction is low, it is necessary to purify it by means such as chromatography, which makes post-treatment complicated, especially for tertiary amines. There is a problem with removing.

Furthermore, when an acid/acid halogenated product of cyanoacetic acid is used in the reaction, there are problems in handling since the acid halide is an unstable compound that is prone to polymerization.

When mixed acid anhydrides are used, there are problems such as large amounts of by-products being produced and the reaction having to be carried out at low temperatures. Furthermore, when a dehydration condensation agent is used, there are problems in yield and post-treatment.

The present inventors have conducted various studies to solve the above problems, and found that when a silyl derivative of 7-aminocephalosporanic acid (2) is reacted with a specific ester derivative of cyanoacetic acid, a tertiary amine The present invention was completed based on the finding that cefacedolyl can be obtained rapidly at room temperature in high yield without the addition of gold, and almost no side reactions are observed.

That is, as shown in the reaction example below, the present invention provides 7-7 Z
A silyl derivative of nocephalospotic acid (3) is reacted with a specific cyanoacetate derivative (4) to obtain a silyl derivative of cefacedolyl, which is then desilylated to obtain cefacedril (1) f:.

(3) (4) (1) (In the formula, R is a trialkylsilyl group, Y is a halogen-substituted phenoxy group with 4 or less substitutions, a halogen-substituted phenylthio group with 4 or less substitutions, 2-penzothiazolethio group) ,
2-penzothiazolethio group, 2-benzoxazolethio group, or 2-benzoxazoleoxy group)
The present invention will be explained in detail below.

The starting material of the present invention, the silyl derivative of 7-a-denocephas-a-4anic acid (3), is known as 7-a-denocephaa-a-4anic acid (2) or its organic or inorganic salts. It can be easily produced by reacting a silylating agent using the method described in the following.

As the silylating agent, known silylating agents such as aN,O-bistrimethylsilylacetamide, trimethylchlorosilane, N-trimethylsilylacetamide, hexamethyldisiladene, or mixtures thereof can be suitably used.

The silylation reaction is carried out by mixing 7-ayanocephalos-42nic acid (2) or a salt thereof with a silylating agent, if necessary in the presence of a small amount of solvent.

The mixing ratio of the silylating agent differs depending on the type of silylating agent, but in the case of N,0-bistrimethylsilylacedoide, 1 mole of 7-aenocephalospotunic acid (2) or its salt is mixed. It is preferable to add 2 moles or more. The silyl derivative (3) of 7-arynosephalostetralanic acid thus produced can be isolated by a conventional method, or can be used as a starting material in the present invention as it is without isolation.

In the present invention, first, 7-
A silyl derivative (3) of aminocephalosporanic acid is subjected to a t-reaction with a cyanoacetic acid ester derivative (4).

The cyanoacetic acid ester derivative (4) is an ester consisting of a halodane-substituted phenol having a substitution number of 4 or less represented by the following general formula (wherein X represents hydrogen or a halogen such as fluorine, chlorine, or bromine) and cyanoacetic acid; An ester consisting of a 4-substituted thiophenol and cyanoacetic acid represented by the following general formula (in the formula, X indicates the same answer as above), and 2-mercaptobenzo represented by the following chemical structural formula. An ester consisting of thiazole and cyanoacetic acid, 2-
An ester consisting of hydroxybenzothiazole and cyanoacetic acid, an ester consisting of 2-mercaptobenzothiazole and cyanoacetic acid represented by the chemical structural formula below, and an ester consisting of 2-humanmixibenzoxazole and cyanoacetic acid represented by the chemical structural formula below. Ester etc. can be suitably used.

The reaction is carried out by mixing the silyl derivative (3) of 7-aminocephalosporanic acid and the cyanoacetate derivative in a t-solvent. The mixing ratio is preferably 1 to 3 moles per mole of the silyl derivative of 7-adenosephalostetralanic acid in terms of yield, post-treatment after the reaction, and the like. Examples of solvents include ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, halogen-containing OP-based solvents such as methylene chloride, dichloroform, carbon tetrachloride, ethylene dichloride, trichrene, and perchrene, ethyl ether, tetrahydrofuran, and dioxane. Ethers, esters such as ethyl acetate and butyl acetate, and others such as acetonitrile and dimethylsulfolane are desirable.

The reaction is preferably carried out at a temperature around room temperature, and side reactions do not occur even if the temperature is not particularly low. Reaction time is usually 30
It is preferable to set it as about 5 minutes to 5 hours.

The silyl derivative of cefacedolyl thus obtained is then reacted with water or alcohol to perform desilylation, and the target compound of the present invention, cefacedolyl (1
). Examples of alcohols include alcohol and ethyl alcohol.

Norobil alcohol, butyl alcohol, ethylene glycol, propylene glycol, glycerin, etc. can be used. 100 years old of the silyl derivative of cefacedolyl
Do not add more than twice as much water or alcohol.
The silyl group is decomposed and removed to yield cefacedolyl.

This desilylation reaction is accomplished extremely quickly in the presence of an acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an alkali such as sodium hydroxide, potassium hydroxide, or dipotassium hydrogen phosphate. The reaction temperature is preferably about 0 to 30°C, and the reaction time is about several minutes to 1 hour.

Cephacedryl thus obtained can be isolated and purified by conventional methods, and can also be derived into alkali metal salts, ammonium salts, salts with organic bases, etc. by known methods.

As detailed above, the present invention uses a silyl derivative of 7-adenosephalostetralanic acid as a starting material to produce cefacedolyl, and reacts it with a cyanoacetate derivative. If the reaction is mild and rapid, it will be easier to obtain the desired cefacedolyl in a high yield. Furthermore, since the cyano vinegar cast ester conductor is a stable compound, it does not require any special consideration during storage or handling. Furthermore, since this reaction does not use a tertiary amine unlike conventional methods, it can be easily purified without using chromatography, which is complicated and requires a small throughput. This has advantages such as simplification.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

[Example 1] 2.71 (ho mmol) of 7-aminocephalosporanic acid was suspended in 40-t-methylene chloride and dissolved in N,0-bistrimethylsilylacetamide 5 under a nitrogen atmosphere.
．． When 1 i (25 mmol) was added, the whole became a uniform droplet. Next, 2.3, 4.6-
(cytrachlorophenylcyanoacetate) 4.0 N
(13 mmol) was added, followed by stirring at room temperature for 2 hours. The resulting reaction mixture was kept under reduced pressure and the solvent was removed, and the residue was mixed with 100 dt of err-v ether and 100 dt of an aqueous solution of dipotassium hydrogen phosphate.
and stirred. The aqueous layer was separated and washed twice with 50% ethyl acetate.

Then, after adding 100 wt of ethyl acetate, the pH was adjusted to 62 with 17 wt of hydrochloric acid, and extraction was performed. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, and evaporated over the solvent under reduced pressure. After washing with isonorobyl ether, it was vacuum-dried to give cefacedolyl 2.
,911 (yield 861)'i was obtained. m, p, 168~
170℃ IR (KBr method) 2240m (CNN), 1770
m (C=O) [Example 2] 7-aminocephalosporanic acid 1.3 s tp (5
2.6 mmol) was suspended in acetonitrile (20 mmol) and 2.6 mmol of N-)limethylsilylacetate was suspended under a nitrogen atmosphere.
11 (20 mmol) was added to form a homogeneous solution. This K 2.4.5- ) 2.0 N (7,61 lmol) of acetate)=
-) It was added dropwise to 10 sd' of Ril solution at room temperature and stirred for 5 hours. Thereafter, the same procedure as in Example 1 was carried out to obtain cefacedolyl 1.3 b y (yield sog!I).

m, p, 168-170℃ Toho Pharmaceutical Research Institute Agent: Patent attorney Takashi Kojima Patent attorney Hanyo Takahata

Claims (1)

[Scope of Claims] l A halodane-substituted phenol having 4 or less substitutions on a silyl derivative of 7-7 minosephalos tetralanic acid, a halogen-substituted thiophenol having 4 or less substitutions, and 2-mercagutobenzothiazole. 2-Hydroxybenzothiazole, 2-Merka! 1. A method for producing cefacedolyl, which comprises reacting a cyanoacetate derivative consisting of topenzoxazole or 2-hydroxybenzoxazole and cyanoacetic acid to obtain a silyl derivative of cefacedryl, and then desilylating this. The silyl derivative of 27-7t nocephalosllanic acid is 7-
Amitusephalospora 7tR and N. The method according to claim 1, which is produced by reacting with a silylating agent selected from O-bistrimethylsilylacetamide, trimethylchlorosilane, and N-)limethylsilylacetamide.