IE47309B1 - 2,6-bis-haloacylamino-benzol (1,2-d:5,4-d')-bisthiazole derivatives - Google Patents

Description

47309 The invention relates to derivatives of 2s6-bis-haloacylaraino-benzo-[l,2-d: 5,4-d‘]-bisthiazole useful as intermediates for the synthesis of 2,6-bis-aminobenzo-[1,2-d: 5,4-d']-bisthiazoles having antiarthritic and antirheumatic activities. Such 2,6-bis-airnnobenzo-[1,2-d: 5,4-d‘]-bisthiazoles and their 5 synthesis are described and claimed in our Patent Specification No. 47308 According to one feature of the present invention there are provided compounds of general formula R* *-n »1\ I i I R, <» 0 = ( i, ^ c=o i 1 I Hal Hal - 2 - 47309 (wherein each of the groups R^, which may be the same or different, represents a hydrogen atom or a or C^ alkyl group; R2 and R3, which may be the same or different, each represents a hydrogen, chlorine or bromine atom, a C1 to C3 alkyl, alkoxy or acyl group, a carboxy group, an alkoxycarbonyl group having from 1 to 3 5 carbon atoms in the alkoxy moiety thereof, or a carbamoyl, phenyl, trifluoromethyl, nitro, cyano or amino group; A represents a C1 or C2 alkylene group and Hal represents a halogen atom).

According to a further feature of the invention there is provided a process for the preparation of compounds of general formula I which comprises reacting a 2,6-10 diaminobenzo-bisthiazole of formula II N--N r3 (wherein Rj, R2 and R3 are as hereinbefore defined) with a haloalkanoyl halide or anhydride or with a p-nitrophenylhaloalkanoate. The reaction is conveniently effected in the presence of a solvent such as dimethylformamide or dioxan.

During the addition of the haloalkanoyl halide the temperature is generally kept low, e.g. between about 0 and +10°C. At the end of the addition the temperature is generally raised.

* Those 2,6-diaminobenzo-[1,2-d: 5,4-d']-bisthiazoles of formula II wherein - 3 - 47309 represents a hydrogen atom which are used as starting compounds may be obtained, for example, by reacting a ra-phenylene diamine with potassium thiocyanate in acetic acid as described in German Offenlegungsschrift Ho. 20 25 896.

The following Examples serve to illustrate the preparation of compounds according 5 to the invention.

EXAMPLE 1. 2,6-Di-(chloroacetylamino)-benzo-[l,2-d:5,4-d']-bisthiazole a) To a suspension of 15 g of 2,6-diamino-benzo-[1,2-d:5,4-d']-bisthiazole in 130 ml of dimethylformamide are added 20 ml of chloroacetyl chloride at 10°C while stirring vigorously. The mixture is then heated for one hour on a water-bath, and is subsequently cooled and filtered, washed with benzene and dried. 24 g of 2,6-di-(chloroacetylamino)-benzo-[1,2-d:5,4-d']-bisthiazole of m.p. 330'C are obtained (from dimethylformamide). b) A mixture of 222 mg of 2.6-diaRinobenzo-[1,2-d:5,£-d‘]-bisthiazole and 7 \i mixture ic vi :ra .fe sepa-^: crystals .‘.isc _,v. . _ 3..: ·-·. "f.i ' ~ thecr ' ? 1 7-ai · s'floroacetylaminoj-benzo-n, -.---7.5 ·:'·> s’.s'ji’.ucie o' 35v-C :i a ooti.·. c) 222 mg of 2,6-diir ino-n,2-d:5,4-d‘ j-c.st1" - and 513 mg .er.lcroacetV: 2o anhydride are refluxed in 2 r;l of dry dimethyl formanr»u; " 10 minutes. The suspension obtained is admixed with ethanol and the sepsr . 1 crystals are filtered off, washed erd -.nsd, 300 mg (60:7 of theory) of 2,6-di-(chlcroacsr'/laatno)-benzo-[1 jZ-drS^-d’J-tisthiazole of m.p. 330QC are obtained.

EXAMPLE 2. 2,6-Bis-[N-methyl-N-(chloroacetyl)-amino]-benzo-[1,2~d:5,4-d']-bisthiazole To f stirred, ice-cooled suspension of 6.5 g of 2,6-bis-(methylaroino)-benzo- - -2 - 47309 [1,2-d:5,4-d']-bisthiazole in 50 ml of dimethylformamide are added 8 ml of chloroacetyl chloride. The mixture is heated for 1.5 hours to 90°C and then poured into water. The resulting precipitate is filtered off, washed and dried. 10 g {95¾ of theory) of 2,6-bis-[N-methyl-N-(chloroacetyl)-amino]-5 benzo-[1,2-d:5,4-d’]-bisthiazole of m.p. 250°C (decomp.) are obtained (from di methylformami de).

EXAMPLE 3. 2.6- Bis-(chloroacetylamino)-4-chloro-8-trifluoromethylbenzo-[1,2-d:5,4-d‘]-bisthiazole 10 To a stirred mixture of 6 g of 2,6-diamino-4-chloro-8-trifluoromethyl-benzo-[1,2-d:5,4-d‘]- bisthiazole in 100 ml of dimethylformamide is added 10 ml of chloroacetyl chloride while cooling. The mixture is then heated for one hour to 60°C and allowed to stand overnight. The precipitate obtained is recrystallized from dimethylformamide.

Yield: 8.5 g (96¾ of theory), m.p. 350°C. 2.6- Diamino-4-chloro-8-trifluoromethyl-benzo-[1,2-d:5,4-d']-bisthiazole of m.p. 340°C is itself obtained by reacting a cooled mixture of 2-chloro-5-trifluoromethyl-m-phenylene-diamine (see German Offenlegungsschrift 20 25 896) and potassium thiocyanate in acetic acid and methanol with a solution of 20 bromine in acetic acid.

EXAMPLE 4. 2.6- Bis-(chloroacetylamino)-4-chloro-8-cyano-benzo-[1,2-d:5,4-d']-bisthiazole To a stirred suspension of 2.6 g of 2,6-diamino-4-chloro-8-cyano-benzo-[1,2-d: 5,4-d']- bisthiazole in 30 ml of dimethylformamide are added 4 ml of chloroacetyl 25 chloride at 10°C. The mixture is heated to 80°C for 4 hours, cooled and the precipitate is recrystallized from dimethylformamide. 2,6-Bis-(chloroacetyl-amino)-4-chloro-8-cyano-benzo-[1,2-d:5,4-d']-bisthiazole obtained melts at 330°C; - 5 -

Claims (6)

1. 4 Y 3 Ιί © Yisid: 2.3 g (ΐϊ · cr tJ'SC:'y}. 2,:£-3larniRo-4-c:;';orc-i'·-;.of n'.n. 2E-i· -2 used as starting -satsH.i 'a r.ii'i'x: i.- 1--::- ·.·. ;-2.-c/:co-i>-phe,-./ler.e- d1amir:e vase seraa: CffenTags.-mm· r: i. 25 c.-.-. :.-/.:55¾.¾ tniocyatsce 5 in acetic acid and «athcncl '.;U'· · : :1:,::-.,:: m:...: e -.cetic acid. EXAMPLE 5. 2,e“Bic-*:chloro2C3cyi?v.ir,o>‘'-'·:-^ ,-isr.ro-;.:,2--3:5,^-. j-oisthiazole A :.-1: '·'.: ·. 3 s :/ . ·.. · '·; rhyl-i:-3 · 2: '-i "“-ii = chiaZoie in % · · --:2 ain-ci-y r 2;ii(jsr:.-di - · -: 2 : :.: . chi.-,.· ,:et/i cn.cticfe. 1C The niri-jra i-„ nested for 2 i_ : :.' a wait. ;*: . .. . . .::2 . .-.- Xthloro- acetj-'.5..:iRo-4-r.sthy1-bSKz:-Li,2 ·· .-·-31 3-r·'.·:.ias-:·:a..--,-see 11ir i; cut. It is washed and recrysis-lized 2--:: -: : :*.ylfc ': :es. Yield: 6.5 g (66* of theory} m.p. 3304C. ; 2 .-. I P j 15 ' ’3i!30- r..-ii i*- ci.ep f2 n-r^S---... :* I 1 Ri\ , / s .. - V 0 fi n — r ^ 1 ^ C — 0 »-C, R. | A A 1 1 Hal - 6 - ! 47309 (wherein each of the groups Rj, which may be the same or different, represents a hydrogen atom or a or C2 alkyl group; R2 and R3, which may be the same or different, each represents a hydrogen, chlorine or bromine atom, a to C3 alkyl, alkoxy or acyl group, a carboxy group, an alkoxycarbonyl group having from 1 to 3 5 carbon atoms in the alkoxy moiety thereof, or a carbamoyl, phenyl, trifluoromethyl, nitro, cyano or amino group; A represents a or C2 alkylene group and Hal represents a halogen atom).

2. Compounds as claimed in Claim 1 as herein specifically described in any of the Examples. 10 3. A process for the preparation of compounds as claimed in Claim 1 which comprises reacting a compound of formula II -—rs—» ii 1/1 (n) R' ^ HN S S '^N^NH 1 P-3 (wherein R^, R2 and R3 are as hereinbefore defined) with a haloalkanoyl halide or anhydride or with a p-nitrophenylhaloalkanoate.

3. 4. A process as claimed in Claim 3 wherein the reaction is effected in the presence of a solvent.

4. 5. A process as claimed in Claim 4 wherein the solvent comprises dimethyl form-amide or dioxan. , 6. A process as claimed in Claim 3 substantially as herein described. - 7 -

5. 7. A process for the preparation of compounds as claimed in Claim 1, substantially as herein described in any of the Examples. 4?309 Dated this 18th day of May, 1983. BY:- TOMKINS & OL, Applicants‘/Sg^Rts, (Signed)

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