DE1545844A1 - Process for the preparation of N-substituted 3-aminobenzisothiazoles - Google Patents

Description

FARBENFABRIKEN BAYER AG

27 ° ^: 7ο 1965

Si / Rö

Process for the production of. ! «- substituted 3-Imino ™
benzisothiazolines

There is already an extensive literature on the antifungal effect of benzisothiazolones-3 ^ compilation!
Pharmaceutical research 14 * 13G1J1964) ^ 7

On the other hand, IT-substituted 5-imino-bis-isotiiasolias have not yet been described in the literature .

It has now been found that these compounds of general Formula I receives,

if you ϊϊ-substituted J-halogen-benzisothiazolium halides of the general formula II.

Reacts with ammonia.
Le A9571

BADORiGlNAt

- st -

Le A9571

In the general formulas, I and II, X stands for a halogen atom, especially Cl or Br- _s E ₁ for an alkyl radical with 1 to C atoms, a cycloalkyl, aralkyl or aryl best, which in turn is represented by halogen , Nitro, lower-alkyl, alkoxy or dialkylamino groups can be excluded. R "means one or more substituents of the following meaning: - - halogen, nitro, lower-alkyl

The new N-substituted 3-imino-benzisothiazolines are excellent antifungal agents. In terms of their effect, they are to be equated with the well-known Benziaothiazolonen-3, in some cases persistent. think. Opposite dan known Benzisothiazolonen-3 they siiid significantly less toxicity and are in Gegens & tss? Λι this on a recorded skin compatibility.

one N-methyl-3-chlorobenzisothiazolium chloride as A ^ starting material, ao the dReaktionverlauf can by the following Poreel scheme are reproduced.

egg

To carry out the inventive method dee 1 mole of N-BubBtituiertea 3-halo-benzisothiazoliumhalogenid at 5 to 10 ⁰ C in excess ammonia, preferably (1 liter 5 M NH,) was added in a methanolic NH, solution.

9098 51/1780

. 'BAD LOCATION

Le A9571

The Ausgangsraaterial used as N-3-suostituierten Halogenbenzisothiazoliumhalogenide _s preferably 3-ChlQr-benzisothiazoliumchloride be by DP. *. .ο. (Le A 9564) from .N-substituted dithiosalicylic acid amides and phosphorus pentahalpgenides

The N-substitTerieir ^^ isisasi ^ nziSQthiäzoline are farbloj crystalline compounds. ' They are weak bases as such only with strong acidic salts.

They show excellent inhibition values in T in vitro mentagrophytes, Candida albicans, -Penlcillium commune, Asper- gillti3 iiiger and Mikrosporium felineium. Some connections Also in the case of oral administration of the experimental 'guinea pig

öhvin Trichophjtie, a definite effect. -

The new compounds are intended to be used as antiraykotics in human and in veterinary medicine as well as pesticides

to serve" . -.

909-851 / 1 78 0 BAD ORIGINAL

fj. Le A 9571-

example 1 H- »methyl-3-iüiino-benziBothiazoline > HCl

110 g (0.5 MoI) H-methyl-3-chloro- "benziBothiazoliumchlorid (feinfippulvert) are at 5 quickly with vigorous stirring in 500 ml to 1O ⁰ C a saturated methanol / NEL solution (2.5 mol) was added. To complete the reaction, the mixture is stirred for a further 5 minutes, then the precipitated ammonium chloride is filtered off with suction and the piltrate is evaporated down. The syrup obtained is taken up in 150 ml of hydrochloric acid 1: 1 (0.75 mol). The initially clear solution continues to solidify After standing in an ice bath for a few minutes (30 minutes), the hydrochloride which has crystallized out is filtered off with suction, washed with a little cold water and dried, giving 55 g (55% of theory) of N-methyl-3-iminobenzisothiazoline. HCl. The compound crystallized from ethanol as colorless prisms rom melting point 220 ⁰ C (Subl.) '.

The compounds listed below are in the same Way made:

N-ethyl-3-imino-benzisothiazoline. HCl

The substance delivers to ümkristallisation from ethanol colorless gutausgeprägte, flaky prisms of mp. 171 ⁰ C (Subl).

N-propyl-3-imino-benziaothiazoline .HCl

Colorless prisms from methanol, mp. 111 ⁰ C.

909851/1780

BATH

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S '. . ■ .. ■ "- ■" ■ - ■:

N-butyl-3-imino-benzisothiazoline. HCl

Show the Verbindung..kristallisiert of acetonitrile in colorless, tough prisms, melting at 155 bie 157 ° C, then re-crystallize again and a second melting point. At 212 ⁰ C.

N-Iaobutyl-3-imino-bengiaothiazoline. HCl

The substance is obtained after recrystallization from methanol in large, colorless plates, melting at 187 ⁰ C, then -kristallisieren again and a second öchmp. at 216 ^° C.

M - ^ "s-chloroethyl7-3 - imino-benziaothiazolin. HCl

Colorless, coarse, well-defined prisms (methanol) from mp.

152 ⁰ c.

N-Cyclohexyl-3-imino ^ benzisothiazoline. HCl

Colorless from ethanol, massive prisms of mp. 166 ⁰ C.

N ~ ^ "4-methyl-cyclohexyl7-3-" imino benzi8othiazolin »HCl Recrystallization from A'thoxyäthanol colorless crystals of mp. 160 ⁰ C.

co *

co - ■ - ■. '■ - ""' "■. ' "■

cn N- » ^ 3-methyl-cyclohexyl / ~ 3 ~ imino-benzisothiazoline. HCl

^ Small needles, colorless from ethanol, m.p. 197 ⁰ C.

OO -: "■■" -.

N ^ 2Mthl lhl 7 "J3""imino-benz isothia2olin_ _{i. Tir} jtCl

When crystallized from DMSO, the compound is colorless BAD OBiGSNAL

Le A9571

Prisms of m.p. 210 C.

N-benzyl-3-imino-benziaothiazoline

The substance was isolated as the free base. The connection forms colorless, coarse prisms (methanol) with a melting point of 85 ° C.

H ~ phenyl-3-imino ~ benzisothiazoline

The compound was isolated as the free base. Colorless, nodular crystals (ethanol) mp. 99 C ⁰

The free base crystallizes from ethanol in long, yellowish Needles with a melting point of 144 ° C. ·

90 985Ί / 178 0

BATH ORIGINAL

Claims (1)

ie A 9571 Claim Process for the production of τοη N-substituted J-isfcrthiazolinen, dad-urch marked that one N ~ eubBti-tu- . ated 3-halide ben2i8otliiazolium halides of the general formula in which X stands for a halogen tom, _s S _{1 is} an alkyl radical with 1 to 7 carbon atoms, a. Aralkyl, Cjeloalkyl or aryl radical, which in turn can be substituted by halogen, nitro, lower-alkyl, alkoxy or dialkylamino groups, and R _{2 has} one or more lalsgena-o Htro, alkyl radicals 1 to 7 carbon atoms. Or Alkösy- © 2mmiQa IQaCiKtOa ₀ with aimealak at remote temperatures between 0 and 10 ⁰ G . BATH