JPS584030B2 - isothiazolone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing isothiazolone derivatives, and more specifically, the present invention relates to a method for producing isothiazolone derivatives. family,
Indicates an alicyclic group.

) is heat-transferred to a penicillin derivative represented by the general formula (where R and R' are the same as before) in the presence of an amine having a hydroxyl group.

), which is useful as an antibacterial agent.

The conventional method for producing intiazolone is the chlorination of 1.4 azepine (J.A.C., S86, 5307 (1964)).
), in the presence of a base such as pyridine or triethylamine,
Method by rearrangement of penicillin sulfoxide (J.C.S.
(c) 14.56, 1974), (J.C.S (c) 1
184, (1974)), but all of them are obtained as side reaction products rather than main products.
The yield is extremely low.

The present inventors have completed the present invention by discovering that penicillin derivatives can be specifically transferred to isothiazolone derivatives in extremely good yields only when an amine having a hydroxyl group is used as a catalyst.

The method of the present invention can be carried out using the general formula (wherein R represents phenoxyacetamide, pendylacetamide, or phthalimide, and R' represents aliphatic, aromatic, or alicyclic group).

) is a method in which an amine having a hydroxyl group is present in an organic solvent in a penicillin derivative represented by the formula (2), and the penicillin derivative is subjected to heat transfer.

The starting materials used in the present invention include esters such as penicillin V, penicillin G, and 6-phthalimidopenicillin, but the esters are not particularly limited. good.

Examples of the solvent used include organic solvents used in general organic reactions, such as benzene, toluene, xylene, dioxane, butyl acetate, dimethylformamide, and dimethylacetamide.

Examples of amines having a hydroxyl group include hydroxypyridines, pyridine alcohols (pyridine methanol,
pyridine ethanol, pyridine propanols), N-
Tertiary amines such as piperidine ethanol and 4-morpholine ethanol; secondary amines such as 1-piperazine ethanol and diethanolamine;
Although tertiary amines can be used, tertiary amines give particularly good results.

The amount of these amines used may be a catalytic amount, but if a larger amount is used, the reaction rate will be increased and the target substance can be obtained in a short time.

It is convenient to carry out the reaction at a temperature of about 70°C to 150°C, and therefore the reaction solvent may be selected from a solvent with a boiling point higher than that, but in some cases the reaction may be carried out under pressure. good.

The desired intiazolone derivative can be easily obtained as a crystal by heating a penicillin derivative to reflux using an organic solvent in the presence of an amine having a hydroxyl group, and then removing the solvent. Even higher purity can be obtained by purification by lamb chromatography.

Next, in order to show the effect of the catalyst of the present invention, a comparison with an amine having no hydroxyl group is listed in Table 1.

Example 1 Penicillin V sulfoxide trichloroethyl ester 5
．． 1.0 g of 2-pyridine methanol was dissolved in 30 ml of n-butyl acetate and heated under reflux for 2 hours.

After the reaction, the mixture is washed with dilute hydrochloric acid, water, and saturated brine, and then the solvent is distilled off.

Isothiazolone crystals begin to precipitate immediately.

Recrystallized from benzene-hexane, melting point 142-1
3.91 of intiazolone at 43°C is obtained.

Yield 80%. Analysis value C=45.18%, H=3.65%
, N-5.86%, S=6.54%, Cl=21.21
% Calculated value C=45.06%, H=3.54%, N-5.8
4%, S=6.68%, CI=21.28% NMR (inCD3COCD3): δ=1.93, 2.40, 4.73, 4.83, 6.8
7-7.47, 8.47, 8.97 (p.p.m) p-p・ ■R: νmax-3360, 3060, 1730, 16
90, 1630cIrL-1 (Nujol) Example 2 Penicillin G sulfoxide methyl ester 3.9 g, N
- Morpholine 1.0 g of ethanol is dissolved in 20 ml of toluene, heated under reflux for 2.5 hours, washed in order of diluted hydrochloric acid, water, and saturated saline, and then the solvent is distilled off.

The obtained oily residue was mixed with benzene/ethyl acetate (1/1
), and the distillate is recrystallized from benzene-hexane.

Yield 2.6g, yield 73%, melting point 230-232°C.

Analytical value C58.85% H5.26% N8.14% Calculated value C58.94% H5.10% N8.09% NMR: τ-1,02, 1.30, 2.68, 6.24
, 6.37, 7.82, 8.19 (p.p.m) IR:
ν=3270, 1710, 1680, maX 1619 cm-1 (Nujol) Example 3 3.6 g of 6-phthalimidopenicillin methyl ester,
1.0 g of N-piperidine ethanol is dissolved in 25 ml of dimethylformamide and reacted at 120-130°C for 1.5 hours.

After the reaction, the same treatment as in Example 2 is carried out to obtain intiazolone 2.21.

Yield 67%, melting point 254-256° Analysis value C56.83
%H4.01% N7.75%S8.87% Calculated value C56.98%H3.91% N7.82%88.94% NMR: δ(CDCl3)=1.97, 2.41, 3.
80, 7.94, 8.48 (p.p.m) ■R: νmaX=1781, 1730, 1715, 16
75cm-1 (Nujol)

Claims (1)

[Claims] 1 General formula (wherein R represents phenoxyacetamide, pendylacetamide, phthalimide, R' represents aliphatic, aromatic,
Indicates an alicyclic group. ) A method for producing an intiazolone derivative represented by the general formula (wherein R and R' are the same as above), which comprises subjecting the penicillary column derivative represented by the formula (R and R' to the same formula as above) to thermally transfer the penicillary column derivative represented by the formula in the presence of an amine having a hydroxyl group.