CA1056828A - Preparation of 2,1,4-benzothiadiazine derivatives - Google Patents

Abstract

ABSTRACT

This invention is directed to the preparation of a 2,1,4-benzothiadiazine derivative by (a) a process in which an o-nitro-phenyl-thionocarbamoyl carbamate is reduced by means of an alkali metal dithionite in an alkaline solution or (b) a process in which a 2,1,4-benzothiadiazine having specific substituents is oxidized with a per-acid. These products are intermediates in the preparation of 2-carbalkoxy-amino-benzimidazoyl-5(6)-phenyl ethers and thioethers which are valuable chemotherapeutic agents for use in treating diseases caused by parasites in humans and animals.

Description

This invention relates to anthelmintically active benzimidazole derivatives, to a process for preparing th~m, to compositions containing them and to a method for combating helminths using them.

2-Carbalkoxy-amino-benzimidazole derivatives carrying alkyl or acyl groups in the 5~6) position are known to be anthelmintic agents (P. Actor et al.j Nature 215, 321 (1967);
DOS 2.029.637).
The present invention provides anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers of the formula (1) 2 ~ } ~ C-NH-COORl (1) in which Rl represents an alkyl group having from 1 to 4 carbon atoms, R2 and R3, which may be the same or different, each represents a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a halogen atom, a trifluoro-methyl group, an alkyl group having from 1 to 4 carbon atoms or a carbalko~y group having from 1 to 4 carbon atoms in the alkoxy group, R4 represents a hydrogen or chlorine atom and X represents oxygen or sulfur.
Compounds of the formula (13 in which Rl represents methyl, R2, R3 and R4 each represent hydrogen and X represents oxygen or sulfur are especially preferred.
The alkyl groups represented by Rl, R2 and R3 may be methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and 29 tert.butyl groups. The alkoxy groups represented by R2 and R3 :~. . . . . : , ,,. . : . ;, . ~ : - ., . :

., : --, . ., ; . . . : . , . . -:

may be methoxy, ethoxy, propoxy, isopropoxy and butoxy groups.
The hal~gen atoms represented by R2 and R3 may be fluorine, chlorine, bromine and iodine atoms. The carbalkoxy groups represented by R2 and R3 may be carbomethoxy, carboethoxy, carbopropoxy and carbobutoxy groups.
The present invention also provides (a) a process for the manufacture of 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers of the formula (1), in which Rl to R4 and X are defined as above, which comprises treating a 2,1,4~-benzothiadiazine derivative of the formula (2) l5 R3 ~ R4 ~ ~ (2) R2 \ NH-COORl in which Rl to R4 and X are defined as for formula (1), and ~5 represents a hydrogen atom, an acetyl or benzoyl group and n represents ~ero or 1, with an acid or tri-phenyl-phosphine or, if R5 represents the acetyl group, with a base. Reference is made to the fact that the position of the substituents R4 and X may also be ex-changed but, owing to the tautomer form of the imidazole ring, only one benzimidazole-carbamate of the formula (1) is obtained;
lb) a process for the manufacture of a 2,1,4-benzothiadiazine derivative of the formula (2~, in which Rl to R4 and X
are defined as for formula (1) and n represents zerol and R5 represents a hydrogen atom, which comprises reducing :..

an o~nitro-phenyl-thionocarbamoyl carbamate of the formula (3) ~3 4 ~ N3-CS-N~-COOR

in which Rl to R4 are defined as above, by means of an alkali metal dithionite in an alkaline solution;
(c) a process for the manufacture of a 2,1,4-benzothiadiazine derivativ~ of the formula (2), in which Rl to R4 and X are defined as for formula (1) and n represents zero and R5 an acetyl or benzoyl group, which comprises reac~ing a 2,1,4-benzothiadiazine derivatlve of the formula (2), in which Rl to R4 are defined as in formula (1) and n re-presents zero and R5 a hydrogen atom, with a carboxylic acid h~lide, especially a carboxylic acid chloride or anhydride derived from an acid of the formula R6-COOH, wherein R6 represents an alkyl group of 1 to 3 carbon ~ :
atoms or a phenyl group, preferably ln the presence of a ~ base:
; (d~ a process for the manufacture o~ a 2,1,4-benzothiadiazine derivative of the formula (2), in which Rl to R4 and X are .
: : defined as in formula (1~, n represents the integer 1 and ; R5 represents a hydrogen atom, which comprises oxidlzing a 2,1,4-benzothiadiazine of the formula :(2), in whlch Rl to R4 and X are defined as in formula~ and n represents i~

zero and R5 a hydrogen atom, with a per-acid; .
(e) a process for the manufacture of a 2,1,4-benzothiadiazine :-~

. .
-- 4 -- .

HOE 73/~ 184 ~5~
derivative of thc formula (2), in which R1 to R4 and X are ~efi~ed as in formula (1) 9 n represents 7ero and R5 a hydrogen atoms, an acetyl or benzoyl group, which comprise~
reacting a 2,1,4-benzothiadiazine derivative of the rormula (4) l5 . ~ R4 ~ N~ ~()n 2 ~ ~ N ~C NH~
"~X

' - . in which R2 to R4 and X are defined as in formula (1) and n represents zero and R5 a hydrogen atom, 2n acetyl or benzoyl group, with a carboxylic acid halide Or the formula R10-CO-Y, in whioh-R1 is defined as in formula (1) -. and Y represents a halogen atom, especially a chlorine atom; . ~ .
(f) a process for the manufacture of a nitrothiophenyl-urea derivative of the formula (3), in which R1 to R4 and X .
are defined as above in formula (1), which comprises reacting an o-nitro-aniline derivative of tbe ~ormula (5) . . .
R ~ ~ ~ 2 in which R2, R3, R4 and X are'defined as in formula (1), : with an alkyl-i60thiocyanato-formia*e of the formula (6) .
S = C - N - COORl : (6) in which R1 is defined as in formula (1).
, .
-5~

When the process of the invention is carried out in such a manner that a benzothiadiazine derivative of the formula (2), in which R5 represents a hydrogen atom, is reacted with an acid, the most advantageous method is to mix an at least equimolar amount of the acid with a solu~ion of the compound of formula (21, in which R5 represents a hydrogen atom. As solvents, there are especially suitable polar organic solvents, such as lower aliphatic alcohols, ethers, dioxan, acetone, acetonitrile, diethylene glycol ether, tetrahydrofuran, pyridine, dimethyl-formamide, as such or in mixture wi~h water. When mixed withwater, the p~-value is advantageously lower than 4~ The reaction temperature may vary within wide limits, it is prefer-ably between 15 and 60C. As acids, both inorganic acids, such as halohydric acids and other mineral acids, and strong organic acids, for example sulfonic acids, are suitable. ~ :
When the process of the invention is carried out by reacting a benzothiadiazine derivative of the formula (2), in which R5 stands for a hydrogen atom, with triphenyl-phosphine, the reaction components are heated in a solvent at an elevated temperature, preferably at the boiling point of the solvent used. As solvents, especially aprotic solvents, such as chloroform, benzene, methyl dichloride, tetrahydrofuran or dioxan, are useful.
When the process of the invention is carried out by reacting a benzothiadiazine derivative of the formula (2), in which R5 represents an acyl group, with a base, an at least equimolar amount of the base is mixed with a solution of the compound of formula (2). As solvents for this case, the same 29 solvents as mentioned :Eor the reaction with an acid, are usefulO

,, . ~ . . , . -, In the case of a mixture of the solvents with water, the pH-value of the reaction medium is advantageously above 8. As bases, both inorganic substances, such as alkali metal or alkaline earth metal hydroxides, alkali metal carbonate and 5 bicarbonates as well as phosphates, and organic substances, such as ~ertiary amines and quaternary ammonium hydroxides, are useful.
The reaction of a benzothiadiazine derivative of the formula (2) with triphenyl-phosphine in a solvent is especially preferred.
The novel 2,1,4-benzothiadiazine derivatives of the formula (2) used as starting material for the manufacture of the benzimidazole derivatives of the formula (1) as well as the likewise novel o-nitro-phenyl-thionocarbamoyl carbamates required for the preparation of compounds of formula (23 are prepared according to conventional methods as disclosed, for example, in German Offenlegungsschrift No. 2,215,733. The

3-amino-4-nitro-diphenyl ethers or thioethers of the formula (5), required for the preparation of the said o-nitrophenyl-thiono-carbamoyl carbamates of the formula (3) are obtained byreaction of a phenol or thiophenoi of ~he formula (7), in which R2 and R3 and X have the same meaning as that given for formula (1), with 5~chloro-2-nitroaniline or, if they are compounds of the formula (5) in which R4 stands for chlorine, with 4,5-dichloro-2-nitroaniline, suitably in the presence of agents having an alkaline reaction such ais potassium carbonate, at temperatures between 80C and the boiling temperature of ,i the solvent used, within a period of time of half an hour up 29 to 5 hours. Isolation is carried out by dilution of the _ 7 _ ~: . -, ' :

~5~ HOE 7~ ~ 184 reaction mixture ~ith water and separa$ion by filtration of the precipitate.

R~

R2 ~ XH ~ Cl ~ 2 ~~~~

. I I .
(7) X ~ ~2 (5) If in one of the amino-nitl-o-diphenyl ethers or thioethers R2 or R3 represent~ hydroxyl, such compoullds of the ~ormula (5) are used as ~tarting substances in ~lich R2 or R3 represents a methoxy group; these compounds are treated with an agent splitting off ether groups1 for example with concentrated hydrobromic acid.
Hellce~ *he following reaction is possible:
Reaction o~ an amino-nitro-diphenyl ether or thioether of the formula (53 ~ith an alkyl-isothiocyanato-formiate of the formula (6) to ~ield an o-nitrophenyl-thionocarb~moyl-carbamate of the formula (3~, in which R1 to R4 and X are defined as in formul~ ( 1 ), and reduction o~ ~.he co~pound of formula (3) by means of an alkali metal dithionite in an alkaline solution to yield a b~n~othiadiazine derivati~e of the formula (2), in which R5 represents a hydrogen atom, and n represents zero, ,.

-8- ~

as wel~ as reaction of compound (2) with an acid or triphenyl~
phosphine to yield a benzimidazole derivative of the formula (1).

2 ~ X ~ + S=C=N-COOR

(5) (6

4 NO2 X ~NR-CS-NH-COOR

- (3~

I-S-~ n 3 N=C-NH-COOCH3 ~ (2) R2 ~ R ~ / C - N~-COOR1 4 H (1) The 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers and thioethers of the present invention are valuable chemo-therapeutic agents and are suitable for combating diseases caused by parasites in humans and animals.
They are particularly active against a great number of h~lminths, for example Haemonchus, Trichlostrongylus, Oster-tagla, Strongyloides, Cooperia, Chabertla, Oesophagostomum, ' :: g Hyostrongylus, Ankylostoma, Askaris and Heterakis. Particularly marked is the activity against gastro-intestinal Strongylides, which are above all infesting ruminants~ The infestation of the animals by these parasites causes great economical damages, S so thak the compounds of the invention are mainly used in veterinary medicine.
The active substances ~ccording to the invention are ad-ministered together with suitable pharmaceutical solvents or carriers, perorally or subcutaneously, the one or the other form of administration being preferred in accordance with the prevailing circumstances.
The activity of the compounds of the invention was tested by chemotherapeutic experiments carried out on ewe-lambs having a weight of about 30 kg and which had been infested artificially with larvae of Haemonchus contortus or Trichostrongylus colubriformis. The test animals were kept in tiled stalls which were daily thoroughly cleaned. After termination of the prepatency period (time between infection and makurity of the parasites with beyinning excretion of eggs or larvae), the number of eggs per gram of faeces w~s determined with the modified McMaster process according to Wetzel (Tierarztliche Umschau 6, 209 - 210 (1951)). Directly therea~ter, the treat-ment of the sheep (in general 4 to 8 animals per active sub-stance, at least however 2) was begun. The animals obtained perorally, in one case also subcutaneously, a suspension of 2~5 or 5 mg/kg of body weight in, each time, 10 ml of a 1Tylose (regiskered Trade Mark) suspension. On the 7th, 14th and 28th day after the treatment, the number of eggs per gram 29 of faeces was determined according to the above-indicated i 0 --method and the percentage degree of decrease in comparison to the value determined before the beginning of the treatment was calculated.
The following Table indicates the activity of the new sub-stances of the invention determined according to the above-described method in comparison to two known compounds of similar structure; these compounds were Parbendazol (cf. P.
Actor et al., Nature 215, 321 (1967); D. Ross, Veterinary Record _ , 731 (1968); D. R. Johns et al., Australian Veteri-narian Journal 45, 460 (1969) and Mebendazol ~DOS 2.0Z9.637).
The novel active substances of the invention were desig-nated as follows: -A = 5-phenoxy-benzimidazole-2-methyl-carbamate B = 5~(4-chloro-phenoxy)-benzimidazole-2-methyl-carbamate C = 5-(3-chloro-phenoxy)-benzim}dazole-2-methyl-carbamate D = 5-(2-chloro-phenoxy)-benzimidazole-2-methyl-carbamate E = 5-(3-methoxy-phenoxy)-benzimidazole-2-methyl-carbamate F = 5-phenylmercapto-benzimidazole-2-methyl-carbamate The known active substances were designated as follows:
Comp. subst. 1 = Parbendazol Comp. subst. 2 = Mebendazol . :: .: , ,: . , , ~ . . ::. ~: :;: .: . . . . .
. . . . . . . . .
~.... . . . . .. . .

2~

T A B L E
.
Dos.cur.
Active min. in Adminis- Effect substance mg/kg tration in %
S A 2.5 peroral 100 B 5.0 peroral 94 C 2.5 peroral 100 D 5.0 peroral 96 E 2.5 peroral 100 F 2.5 peroral 100 F 2.5 subcu- 100 taneous Comp.subst.l 15.0 peroral 100 Comp.subst.2 10.0 peroral 76 - 100 As the Table shows, the new carbamates of the invention are s,uperior to known compounds of similar structure in that the Dosis curativa minima is essentially lower.
The Dosis tolerata maxima of the products of the invention is higher than 3200 mg/kg of body weight, upon peroral and sub-... . .
cutaneous administration.
Moreover, the 2,1,4-benzothiadiazine derivatives of the formula (2) and the o nitrophenyl-thionocarbamoyl carbamates of the formula (33 have also an anthelmintic activity.
~ The active substances of the formula I of the invention :: :
are administered, depending on the case, in doses ranglng ~5 between 0.5 and 50 mg per kg of body weight ~or a period of 1 to 14 days.
For oral application, there may be used tablets, dragées,' capsules, powders, granulates or pastes which contain the ~- 12 -.. . . . , . , ., , . j , . ~ .

active substance together with the usual excipients and adjuvants such as starch, cellulose powder, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely distributed silicic acid, carboxymethyl cellulose and similar substanres.
For parent~ral administration, there may be used solutions, for example oily solutions, prepared using sesame oil, castor oil or synthetic triglycerides, optionally with the addition of Tokopherol as anti-oxidation agent and/or using surface-active substances such as sorbitane fatty acid ester.
In addition, there may be used aqueous suspensions prepared with the use of ethoxylated sorbitane fatty acid esters, optionally with the addition of thickening agents such as poly-ethylene glycol or carboxymethyl cellulose.
The concentrations of the active substances of the in-vention in the preparations prepared therewith are preferably in the range of from 2 to 20 % by weight; for the use as medicaments for humans, the concentrations of the active substances are preferably in the range of from 20 to 80% by weight.
The following Examples illustrate the invention~
E X A M P L E 1:
. . .

5-Phenoxy-henzimidazole-2-methyl carbamate 315 Milligrams (0.001 mol) of 6-phenoxy~ 2,1,4-benzo-thiadiazinyl-3-methyl carbamate were dissolved in lOO~ml of boiling methanol~ and the solution was refluxed with 1 ml of 2N hydrochloric acid. The solution was allowed to cool and placed in a refrigerator overnight. Then the mixture was suction-filtered and the filtrate was Pvaporated to dryness.
29 The residue was dissolved in a mixture of 250 ml of chloroform .

and 250 ml of an aqueous sodium bicarbonate solution, the chloroform phase was washed away and the chloroform was evaporated after drying. The residue was recrystallized from methyl-glycol, whereupon 5-phenoxy-benzimidazole-2-methyl carbamate was obtained in a pure form, m.p. 248C
(decomposition).
The 6-phenoxy-lH-2,1,4-benzothiadiazinyl~3-methyl car-bamate used as starting material was obtained as follows:
23.4 Grams of 5-chloro-2-nitro-aniline were refluxed for 4 hours in ~0 ml of dimethylformamide with 12.8 g of phenol in the presence of 20 g of anhydrous potassium carbonate.
After cooling, the mixture was diluted with 150 ml of water, the precipitated 3-amino-4-nitro-diphenyl ether was suction-filtered and purified by recrystallization from isopropanol.
Yield: 15 g; m.p. 142C.

15 Grams of 3-amino-4-nitro-diphenyl ether and 24 g of methyl-isothiocyanato-formiate were heated to 100C for 1 hour. After cooling, 150 ml of ether were added and the 2-nitro-5-phenoxy-phenylthionocarbamoyl-methyl carbamate, which was already pure according to analysis, was suction-filtexed. Yield: 14 g, m.p. 142C (decomposition). From the mother-liquor, another 3 g of pure product could be isolated~
694 Milligrams (0.002 mol) of the 2-nitro-5-phenoxy-phenyl-thionocarbamoyl-methyl carbamate so obtained werP
dissolved in 20 ml of a 0.5N sodium hydroxide solution with the exclusion of oxygen~ and a solution of 1.0 g of sodium-dithionite hydrate in 10 ml of water was added thereto. The 29 solution was then neutralized using 2N hydrochloric acid.
. ' , ~ ,, . '' ~ ~ ' .; . ' ' ' . . ..
.

~3s~
The precipitated 6-phenoxy-lH-2,1,4-benzothiadiazinyl-3-methyl carbamate was suction-filtered and recrystallized from methanol; m.p. 135C
E X A M P L E S 2 TO 38:
.
In an analogous manner, the following compounds were prepared:
2. From 3-amino-4-nitro-4'-chloro-diphenyl ether (melting point 135C) over the 2-nitro-5-(4-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl carbamate and the 6-(4-chloro-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-chloro-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 197C.
3. From 3-amino-4-nitro-3l-chloro-diphenyl ether (melting point 114C) over the 2-nitro-5-(3-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl carbamate and the 6-(3-chloro-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3-chloro- :
phenoxy)-benzimidazole-2-methyl-carbamate, melting point 230C.
4> From 3-amino-4-nitro-2'-chloro-diphenyl ether (melting point 161C) over the 2-nitro-5-(2-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl carbamate and the 6-~2-chloro-phenoxy)-lH 2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2-chloro-phenoxy)-benzimidazole-2-methyl-carbamate, melting poin$ 206C.
5. From 3-amino-4-nitro-2',5'-dichloro-diphenyl ether (melting point 140C) over the 2-nitro-5-(2,5-dichloro-phenoxy)-phenyl-~thionocarbamoyl-methylcarbamate and the 6-(2j5-dichloro-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2,5-dichloro-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 244C.

6. From 3-amino-4-nitro-3',5'-dichloro-diphenyl ether 29 ~melting point 162~C) over the 2-nitro-5-(3,5-dichloro-phenoxy)-~ - 15 --:

~35~
phenyl-thionocarbamoyl-methyl-carbamate and the 6-(3,5-di-chloro-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3,5-dichloro-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 226C.

7. From 3-amino 4-nitro-4'-bromo-diphenyl ether (melting point 129~C~ over the 2-nitro-5-(4-bromo-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-bromo-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-bromo-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 248~C.

8. From 3-amino-4-nitro-3'-bromo-diphenyl ether (melting point 127C) over the 2-nitro-5-(3-bromo-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-t3-bromo-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3-bromo-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 232C.
lS 9. Fxom 3-amino-4-nitro-2'-bromo-diphenyl ether (melting point 152C) over the 2-nitro-5-(2-bromo-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(2-bromo-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2-bromo-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 211C.
10. From 3-amino-4-nitro-4'-methyl~diphenyl ethQr (melting point 128C) over the 2 nitro-5-(4-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-me~hyl-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-methyl-phenoxy)-benzimidazole 2-methyl-carbamate, melting point 251C.
11. From 3-amino-4-nitro-3'-methyl-diphenyl ether (melting point 110C) over the 2-nitro-5-(3-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(3-methyl-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3-methyl-29 phenoxy)-benzimidazole-2-methyl-carbamate, melting point 228C.

:

., . ~ ~: :

12. From 3-amino-4-nitro-2'-methyl-diphenyl ether (melting point 137C) over the 2-nitro-5-(2-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(2-methyl-phenoxy)-lH-2,1,4-benzthiadiazinyl-3-methyl-carbamate, the 5-(2-methyl-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 216C.
13. From 3-amino-4-nitro-4'-tert.butyl-diphenyl ether (melting point 94C) over the 2-nitro-5-(4-tert.butyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-text.-butyl-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-tert.butyl-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 250C.
14. From 3-amino-4-nitro-2',4'-dimethyl-diphenyl ether (melting point 116C3 over the 2-nitro-2-(254~dimethyl-phenoxy)-phenyl thionocarbamoyl-methyl-carbamate and the 6-(2,4-di-methyl-phenoxy)-lH-2,1,4-benzthiadiazinyl-3-methyl-carbamate, the 5-(2,4-dimethyl-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 239C~
15. From 3-amino-4-nitro-2'-chloro-4'-methyl-diphenyl ether (melting point 145C) over the 2-nitro-5-(2-chloro-4-methyl-phenoxy)-phenyl-thionocarbamoyl-methylcarbamate and the 6-(2-chloro-4-methyl~phenoxy)-lH 2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2-chloro-4-methyl-phenoxy)-benzimida-zole-2-methyl-carbamate, melting point 209C.
16. From 3-amino-4-nitro-2'-chloro-6'-methyl-diphenyl ether (meltiny point 164C) over the 2-nitro-5-(2-chloro-6-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(2-chloro-6-methyl phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2-chloro-6-methyl-phenoxy)-benzimida-29 zole-2-methyl-carbamate, melting point 300C.

.. . . ~ . , .

5~

17. From 3-amino-4-nitro-3'-chloro-4'-methyl-diphenyl ether (melting point 139C) over the 2-nitro-5-(3-chloro-4-methyl-phenoxy)-phenyl~thionocarbamoyl-methyl-carbamate and the 6-(3-chloro-4-methyl-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the ~(3-chloro-4-methyl-phenoxy)-benzimida-zole-2-methyl-carbamate, melting point 236Co 18. From 3-amino-4-nitro-3'-chloro-6'-methyl-diphenyl ether (melting point 141C) over the 2-nitro-5-(3-chloro-6-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(3-chloro-6-methyl-phenoxy)-lH-2~1,4-benzothiadiazinyl-3-.
. methyl-carbamate, the 5-(3-chloro-6-methyl-phenoxy)-benzimida-zole-2-methyl-carbamate, melting point 218C.
19. From 3-amino-4-nitro-3'-chloro-4~-carbethoxy-diphenyl ether (melting point 134C) over the 2-nitro-5-(3-chloro-4-carbethoxy-phenoxy) phenyl-thionocarbamoyl-methyl-carbamate and the 6-(3-chloro-4-carbethoxy-phenoxy)-lH-2,1,4-benzothia-diazinyl-3-methyl-carbamate, the 5-(3-chloro-4-carbethoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 194C.
20. From 3-amino-4-nitro-4'-c:hloro-2'-methyl-diphenyl ether ~melting point 142C) over the 2-nitro-5-(4-chloro-2-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-chloro-2-methyl-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-chloro-2-methyl-phenoxy)-benzimida-zole-2-methyl-carbamate, melting point 230C.
21. From 3-amino-4-nitro-4'-chloro-3'-methyl-diphenyl ether (melting point 135C) over the 2-nitro-5-(4-chloro-3-methyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-chloro-3-methyl-phenoxy)-lH~2,1,4-benzothiadiazinyl-3-methyl-29 carbamate, the 5-(4-chloro-3-methyl-phenoxy)-benzimidazole-2-~: ,, , ', ,, , ' ~; ', methyl-carbamate, melting point 253C.
22. From 3-amino-4-nitro-4'-chloro-3',5'-dimethyl-diphenyl ether (melting point 158~) over the 2-nitro-5-(4-chloro-3,5-dimethyl-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-chloro-3,5-dimethyl-phenoxy)-lH-2,1,4-benzothiadia-zinyl-3-methyl-carbamate, the 5-(4-chloro-3,5-dimethyl-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 239C.
23 From 3-amino-4-nitro-3',5'-bis-trifluoromethyl-diphenyl ether (melting point 129C) over the 2-nitro-5-(3,4-bis-tri-fluoromethyl-phenoxy)-phenyl-thionocarbamoyl-methylcarbamate, and the 6-(3,5-bis-trifluoromethyl-phenoxy)-lH-2,1,4-benzothia-diazinyl-3-methyl-carbamate, the 5-(3,5-bis-trifluoromethyl-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 238C.
24. From 3-amino-4-nitro-4'-methoxy-diphenyl ether (melting point 169C) over the 2-nitro-5-(4-methoxy-phenoxy)-phenyl-thionocarbamoyl-methylcarbamate andl the 6-(4-methoxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl.-carbamate, the 5-(4-methoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 246C.
25. From 3-amino-~-nitro-3'-methoxy-diphenyl ether (melting point 128C) over the 2-nitro-5-~3-methoxy-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(3-mathoxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3-methoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 203C.
26. From 3 amino-4-nitro-2'-methoxy-diphenyl ether (melting point 130C) over the 2-nitro-5-(2-methoxy-phenoxy)~phenyl-thionocarbamoyl-methyl-carbamate and the 6-(2-methoxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2 29 methoxy-phenoxy)-benzimidazole-2 methyl-carbamate, melting ~--- 1~ --., . , . .. . ..... ,, . . , . . : :

~s~
point 212C.
27. From 3-amino-4-nitro-4'-propoxy-diphenyl ether ~oily) over the 2-nitro-5-(4-propoxy-phenoxy)-phenyl~thionocarbamoyl-methylcarbamate and the 6-(4-propoxy-phenoxy)-lH-2,1,4 benzo-thiadiazinyl-3-methyl-carbamate, the 5-(4-propoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 218C.
28. From 3-amino-4-nitro-4'-isopropoxy-diphenyl ether (oily) over the 2-nitro-5-(4-isopropoxy-phenoxy)-phenyl-thiono-carbamoyl-methyl-carbamate and the 6-(4-isopropoxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-~4-iso-propoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 208C.
29. From 3-amino-4-nitro-4'-butoxy-diphenyl ether (oily) over the 2-nitro-5-(4-butoxy-phenoxy)-phenyl-thionocarbamoyl-methylcarbamate and the 6-(4-butoxy-phenoxy)-lH-2,1,4-benzo-thiadiazinyl-3-methyl-carbamate, the 5-(4-butoxy-phenoxy~-benzimidazole-2-methyl-carbamate, melting point 210C.
30. From 3-amino-4-nitro-4'-iso-butoxy-diphenyl ether (oily) over the 2-nltro-5-(4-isobutoxy-phenoxy)-phenyl-thiono-carbamoyl-methyl-carbamate and the 6-(4-isobutoxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(4-iso-butoxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 198C.
31. From 3-amino-4-nitro-6-chloro-diphenyl ether (melting point 131C) over the 2-nitro-4-chloro-5-phenoxy-phenyl-thionocarbamoyl-methyl-carbamate and the 6-phenoxy-7-chloro-lH-2,1~4-benzothiadiazinyl-3-methyl-carbamate, the 5-phenoxy-6-chloro-benzimidazole-2-meth~l carbamateS melting point 270C.
29 32. From 3-amino-4-nitro-~-chloro-4'-chloro-diphenyl ether .. . .
- ao ~

- . .. . ..

.. . ~., . . ~ . . . , ~ . . . I

.. . ..
. .

: . ~ , . :

(melting point 210C) over th~ 2-nitro-4-chloro-5-(4-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-chlorophenoxy)-7-chloro-lH-2,1,4-ben20thiadiazinyl-3-methyl-carbamate,the 5-(4-chlorophenoxy)-6-chloro-benzi-midazole-2-methyl-carbamate, melting point 305C.
33. From 3-amino-4-nitro-6-chloro-3'-chloro~diphenyl ether (melting point 126C) over the 2-nitro-4-chloro-5-(3-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6 (3-chloro-phenoxy)-7-chloro-lH-2,1,4-benzothiadiazinyl-3-methyl~carbamate/ the 5-(3-chlorophenoxy)-6-chloro-benzimida zole-2-methyl-carbamate, melting point 263C.
34. From -3-amino-4-nitro-6~chloro-2'-chloro-diphenyl ether (melting point 167C) over the 2-nitro-4-chloro-5-(2-chloro-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(2-chloro phenoxy)-7-chloro-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(2-chlorophenoxy)-6-chloro-benzimida-zole-2-methyl-carbamate, rnelting point 238C.
35. From 3-amino-4-nitro-4'-hydroxy-diphenyl ether (melting point 196C) over the 2-nitro-5-(4--hydroxy-phenoxy)-phenyl-thionocarbamoyl-methyl-carbamate and the 6-(4-hydroxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate/ the 5-(4-hydroxy-phenoxy)-benzimidazole-2-methyl-carbamate, melting point 238C.
For preparing the 3-amino-4-nitro-4'-hydroxy-diphenyl ether required as starting material, 11.7 g of 4-hydroxy-anisole in 40 ml of dimethylformamide were reacted under reflux for 4 hours with 16.3 g of 5-chloro-2-nitro-aniline in the presence of 13.2 g of anhydrous potassium carbonate.
29 After cooling, the mixture was diluted with 40 ml of water, .. :

the crude product was suction-filtered and after recrystalli-zation from methyl-glycol 15.1 g of 3-amino-4-nitro-4'-methoxy-diphenyl ether were obtained, m.p. 169C.
10 Grams of the 3-amino-4-nitro-4'-methoxy-diphenyl ether so obtained were heated at the boil for 4 hours with 100 ml of an 48 % hydrobromic acid. A clear solution was obtained, from which a precipitate separated after a short time. It was suction-filtered when cool and recrystallized from a mixture of 25 ml of ethanol and 15 ml of water, whereupon 6 g of 3-amino-4-nitro-4'-hydroxy-diphenyl ether were obtained, m~p. 196C.
36. From 3-amino-4-nitro-3'-hydroxy-diphenyl ether (melting point 137C) over the 2-nitro-5-(3-hydroxy-phenoxy)-phenyl-thionocarbamoyl-methyl carbamate and the 6-(3-hydroxy-phenoxy)-lH-2,1,4-benzothiadiazinyl-3-methyl-carbamate, the 5-(3-hydroxy-phenoxy)-benzimidazole-2-methyl carbamate, melting point 197C. The 3-amino-4-nitro-3'-hydroxy-diphenyl ether required as starting material was prepared in a manner analogous to Example 35 from 3-hydroxy-anisole over the 3-amino-4-nitro-3'-methoxy-diphenyl ether, melting point 128C.
37. From 3-amino-4-nitro-2'-hydroxy-diphenyl ether (melting point 134C) over the 2-nitro-5-(2-'hydroxy-phenoxy)-phenyl-thionocarbamoyl-methyl carbamate and the 6-(2-hydroxy phenoxy)-lH-2,1~-benzothiadiazinyl-3 methyl carbamate, the 5-(2-hydroxy-phenoxy)-benzimidazole-2-m~thyl carbamate, melting point 223C.
The 3-amino-4-nitro-2'-hydroxy-diphenyl ether used as startin~ material in this case was prepared in a manner 29 analogous to Example 35 from 2-hydroxy-anisole over the . ,, . - ............ , ,, ., ,., ~ , "' :

:, . . :, ~

~ 3~ ~W~
3-amino-4-nitro-~'-methoxy-diphenyl ether, melting point 130C.
38. From 3-amino-4-nitro-diphenyl thioether (melting point 112 DC) over the 2-nitro-5-phenylthio-phenyl-thionocarbamoyl-methyl carbamate and the 6-phenylthio-lH-2,1,4-benzothiadia-- 5 zinyl-3-methyl-carbamate, the 5-phenylthio-benzimidazole-2 methyl carbamate, melting point 233C.
E X A M P L E 39:
5-Phenoxy-benzimidazole-2-butyl carbamate The reaction was carried out as in E~ample 1, but the methyl-isothiocyanate-formiate was replaced by the equivalent amount of butyl-isothiocyanato-formiate. Thus, the 5-phenoxy-benzimidazole-2-bu~yl carbamate was obtained, melting point 188C.
E X A M P L E 40:
:
A solution of 315 mg (0.001 mol) of 6-phenoxy-lH-2,1,4-benzcthiadiazinyl-3-methyl carbamate and 430 mg of triphenyl-phosphine in 40 ml of chloroform was refluxed for 3 hours.
The mixture was allowed to cool and the precipitated 5-phenoxy-benzimidazole-2-methyl carbamate was suction-filtered. The product was identical with the material obtained according to Example 1 as to its melting ~oint and-properties.
E X A M P L E 41:
The reaction was carried out as in Example 40 using 20~ -mg of 1-acetyl-6-phenoxy-lH-2,1,4-benzothiadiazinyl-3-methyl 25 carbamate or 1-benzoyl-6-phenoxy-lH-2,1,4-benzothiadiazinyl-3-methyl carbamate. This reaction also yielded the 5-phenoxy-benzimidazole-2-methyl carbamate which was identical in its properties with the material obtained in Example 1.
29 The 1-acetyl-6-phenoxy-lH-2,1,4-benzothiadiazinyl-3-.. . j .,. .. ~., : . . . .
- , ,, ',. ' . ~

~Si6~
methyl carbamate or l-benzoyl-6-phenoxy lH-2,1,4 benzothia-dia~inyl-3-methyl carbamate used as starting material was pre-pared by dropwise adding, at 0C, 0.5 ml of acetyl chloride to a solution of 0.5 g of 6-phenoxy-lH-~,1,4-benzothiadiazine in 10 ml of pyridine and storing the mixture in an ice bath for some time. After another addition of 0.5 ml of acetyl chloride, it was diluted with water after an hour and worked up over ethyl acetate. The l-acetyl-6~phenoxy-lH-2,1,4-benzothiadiazinyl-3-methyl carbamate remained in the residue.
Using benzoyl chloride instead of acetyl chloride, the l-benzoyl-6-phenoxy-lH-2,1~ benzothiadiazinyl-3-methyl carbamate could be prepared in an analogous manner.
E X A M P L E 42:
50 Milligrams of l-acetyl-6-phenoxy-lH-2,1,4-ben70thia-diazinyl-3-methyl carbamate were dissolved in 5 ml of dioxan and a solution of 100 mg of sodium bicarbonate in 5 ml of water was added there~o. The mixture was allowed to stand for some time at room temperature and the solvent was then evaporated under reduced pressure. The residue was worked up over a mixture of chloroform and water. The 5-phenoxy-benzimidazole-2-methyl carbamate was obtained which was identical in its properties with the material obtained according to Example 1.
E X A M P L E ~3:

A solution of 50 mg of 6-phenoxy-lH-2,1,4-benzothia-dia~inyl-3-methyl carbamate S oxide in 10 ml of methanol was heated under reflux with 0.2 ml of 3N hydrochloric acid, and the mixture was then evaporated to dryness under reduced pressure after a quarter of an hour. The residue was taken 29 up in water, and after clarification with charcoal, sodium .. . , , ~ . ~ ' ' ' .

" , , :

HOE 73/~ 184 bicarbonate was used to yield 5-phenoxy-benzimidazolyl-2-methyl carbamate which was identical in its properties with the material obtained according to Example 1.
The 6~phenoxy-1H-2,1,LI-ben~othiadiazinyl~3-methyl carbamate S-oxide ~ras obtained from 6-phenoxy-1}I-2,1~4-benzothiadiazinyl-3 methyl-carbamate by Q ten minute6' o~idation with m-chloro-perb~nzoic acid in dioxan at room temperatule.
Thislapplication is a division o'f Canadian Application Serial No. 203,354, filed June 25, 1974.

. 25 .

.
:, ' , . . .
.
.. , . . . ~. .. . . .

... - . ~ . . ~ , . . ..

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a 2,1,4-benzothiadiazine derivative of the formula (2) (2) wherein R1 represents an alkyl group of 1 to 4 carbon atoms, R2 and R3, which may be the same or different, each represents a hydrogen atom, a hydroxy group, an alkoxy group of 1 to 4 carbon atoms, a halogen atom, a trifluoro-methyl group, an alkyl group of 1 to 4 carbon atoms, or a carbalkoxy group of 1 to 4 carbon atoms in the alkoxy, R4 represents a hydrogen atom, or a chlorine atom, X
represents an oxygen atom or a sulfur atom, n represents zero or 1, and R5 represents a hydrogen atom, an acetyl or benzoyl group, in which (a) when, in formula (2), n represents zero and R5 represents hydrogen, an o-nitro-phenyl-thionocarbamoyl carbamate of the formula (3) (3) wherein R1 to R4 are defined as above, is reduced by means of an alkali metal dithionite in an alkaline solution, or (b) when, in formula (2), n represents 1 and R5 represents a hydrogen atom, a 2,1,4-benzothiadiazine of the formula (2) wherein R1 to R4 and X are as defined in formula (2) and n represents zero and R5 a hydrogen atom is oxidized with a per-acid.

2. A process as claimed in claim 1 for the preparation of a 2,1,4-benzothiadiazine derivative of the formula (2) as defined in claim 1 wherein R1 to R4 and X are as defined in claim 1 and n represents zero and R5 represents a hydrogen atom, in which an o-nitro-phenyl-thionocarbamoyl carbamate of the formula (3) as defined in claim 1, wherein R1 to R4 are defined as above is reduced by means of an alkali metal dithionite in an alkaline solution.

3 A process as claimed in claim 1 for the preparation of a 2,1,4-benzothiadiazine derivative of the formula (2) as defined in claim 1 wherein R1 to R4 and X are defined as in claim 1, n represents the integer 1 and R5 represents a hydrogen atom, in which a 2,1,4-benzothiadiazine of the formula (2) wherein R1 to R4 and X are as defined in claim 1 and n represents zero and R5 a hydrogen atom is oxidized with a per-acid.