CA1058194A - Substituted benzenedisulfonamides as anthelmintics - Google Patents

Abstract

Abstract of the Disclosure Novel substituted benzenedisulfonamides are disclosed which compounds are active anthelmintic agents being particularly useful against fascioliasis in sheep and cattle. Speci?ically the active compounds are 4-amino-1,3-benzenedisulfonamide compounds substituted at the 6-position with an unsaturated substituted alkyl group.
Compositions and methods containing the novel substituted benzenedisulfonamides for use in anthelmintic therapy particularly againt liver fluke are also disclosed.

Description

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~058~94 Description of the Prior Art Many sulfonamides, especially benzenesulfonamide compounds have been known in the art for many years. They have been generally prepared and studied for their activity as antibacterial and diuretic agents and much data is published concerning the bacteriostatic and diuretic activity of sulfonamide compounds. In addition, certain benzene-disulfonamides have been prepared as intermediates in the preparation of diuretic agents having substantial diuretic activity. Said diuretic agents have not been disclosed as having any anthelmintic activity. The instant benzene-disulfonamides, however, are novel compounds not having been disclosed in the prior art.

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1 Summar~ of the Invention The novel anthelmintic com~ounds of this invention 3 are classified generally as benzenedisulfonamides.
4 Specifically they may be described ~s 4-amino-6-substituted-1,3-benzenedisulfonamides. Said compounds have significant 6 and unexpected anthelmintic activity and in particular 7 demonstrate high activity against Fasciola or liver fluke in 8 animals. The instant compounds also possess significant 9 parasiticidal activity.
Thus, it is an object of this invention to provide 11 for novel anthelmintic compounds. A further object of this 1? invention is to provide for novel substituted benzenedi-13 sulfonamide compounds which have significant anthelmintic 14 and fasciolicidal activity. A still further object of this invention is to provide for processes for the preparation 16 of said novel substituted benzenedisulfonamides. Another 17 object is to provide for compositions and methods of treatment 18 which contain said novel substituted benzenedisulfonamides, 19 and which are useful in the prevention and treatment of ?O fascioliasis. Further objects will become apparent from the 21 following description.
~2~ Description of the Invention 23 The compounds of this invention which are active ~ anthelmintic agents are best described by the following structural formula:

l~N02S 1~[ No/2~Rl ~ ~ 15549 IA

lQ58~94 1 wherein

2 Each Rl and R2 are each hydrogen or loweralkyl,

3 R is a halogenated unsaturated alkyl group containing from

4 2 to 6 carbon atoms, one or two double bonds or single

5 triple bond and from 1 to 11 halogen atoms, and R3 and

6 R4 are independently hydrogen loweralkyl, benzyl,

7 furfuryl or phenyl; or R3 and R4 may be joined to form

8 a heterocyclic group of N4-loweralkyl piperazine morpholine g or thiomorpholine-l,l-dioxide.

The term "loweralkyl" refers to those alkyl 11 groups having from 1 to 5 carbon atoms in a straight or 12 branched configuration.
13 The preferred compounds of this invention are 14 realized when R is a carbon chain of from 2 to 4 carbon 15 atoms containing a single double bond and from 2 to 6 16 halogen atoms, 17 The most preferred compounds of this invention 18 are realized when the halogen atoms on the R group are 19 chlorine or fluorine or a mixture thereof.

Examples of the most preferred compounds of 21 this invention are:
22 4-amino-6-trichlorovinyl-1,3-benze;~edisulfonamide 23 4-amino-6-(~,~-difluoro-~-chlorovinyl-1,3-24 benzenedisulfonamide 4-amino-6-(a,~-dichloro-~-fluorovinyl)-1,3-26 benzenedisulfonamide 27 4-amino-6-trifluorovinyl-1,3-benzenedisul-28 fonamide.

lOS~194 The compounds of this invention wherein R3 and R4 are hydrogen are generally prepared by a process outlined in the following reaction scheme:

R ~ 2 ~ ~ NH2 ~ Cl 02S~s02cl N H' R 2 1~ N 2 S l~Cs 2 N~

wherein R, Rl and R2 are as previously defined.
In the first step of this process an appropriately substituted aniline compound is treated with chlorosulfonic acid. The reaction is carried out initially with external cooling due to a possible exothermic reaction as the starting material and the reagent are combined. Generally the amine is added dropwise or portionwise over a period of from 5 minutes to 2 hours, to the chlorosulfonic acid maintaining the reaction temperature at from -10 to 10C. When the addition is complete, the reaction temperature is raised to from 50 to 200C. for from 15 minutes to 4 hours. A solvent is optional and generally employed only when the reaction temperature is below 100C. It is preferred, however, to run the reaction without a solvent. The product benzenedisulfonylchloride is recovered from the reaction mixture by procedures known to those skilled in this art.

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10S~3194 The benzenedisulfonyl/chloride is then reacted with ammonia or a mono or diloweralkylamine to form the desired benzenedisulfonamide. The reaction may be carried out with aqueous solutions of ammonia or the mono or di10weralkylamine, non aqueous solutions of ammonia or the mono or diloweralkyl-amine in any non reactive organic solvent such as benzene, toluene, ether, chloroform and the like, or the reaction may be carried out in l;quid ammonia or amine. The reaction is somewhat exothermic and when an amine other than liquid ammonia is employed, external cooling is required. In liquid ammonia the reaction mixture is maintained at the temperature of liquid ammonia. The product is isolated and purified by techniques known to those skilled in this art.
The compounds of this invention may also be prepared by chlorosulfonating an appropriately substituted 0-amino benzenesulfonamide compound followed by amination as outlined in the following reaction scheme:

R ~ 2 '`R C102S ~ S32N\ R2 1 ~ N2S ~ C So2N~ R2 ` 15549 IA

` iO58~94 .
~ herein R, R and R are as previously defined. Chloro-;, ~, . -. ~ .
~ulfonic acid is generally preferred as the chlorosulfonating agent following the procedures outllned above. The ~ chlorosulfonic acid is then treated with ammonia or a mono-; ~ or di- loweralkylamine in the manner previously defined ~; 6 to obtain the desired product. The product is isolated by l techniques known to those skilled in this art. It is ' 8 readily apparent that the above described process is capable

9 of producing compounds wherein the -NRlR2 groups on each

10 of the sulfonamide moieties is different from the other.
; ll The compounds of this invention wherein R3 12 and R4 are other than hydrogen are prepared from the 13 compounds wherein R3 and R~ are hydrogen by the following 14 procedure:

~ ~.
~ R ~ NH2 R ~ Hal N025--~ S02N R ~ R2 /1~\~ 2~R

R ~ ~ ~

~N-H ~ N2S ~ 2 ~ R2 r 1058~4 1 wherein R " Rl~ R2~ R3 and R4 are as previously defined, 2 and Hal is a halogen, particularly chloro or bromo.
3 In the foregoing procedu~e the unsubstituted 4 amino starting material is diazotized with an alkali 5 metal nitrite, particularly sodium nitrite, in the 6 presence of an acid, and the diazonium salt treated with 7 an alkaline earth halide affording the 4-halo compound.
8 The diazotization is generally run in an aqueous medium 9 at from 0 to 25C. and the preferred acids are sulfuric 10 nitric and acetic.

11 The diazotized compound, still in aqueous

12 medium, is combined with an alkaline earth metal halide

13 in a hydro halide acid solution wherein the halide of the

14 salt and the acid are the same. The addition, at from

15 0C. to room temperature, is complete in from S minutes

16 to 1 hour and the reaction mixture is optionally stirred

17 for an additional period of time, conveniently up to

18 2 hours. The halide is isolated by techniques known to l9 those skilled in this art.
The halo compound is converted to the R3, 21 R4 substituted amino compound by treatment with an R3, 22 R4 substituted amine. The reaction is carried out 23 by heating at from 25 to 200C., however, it is preferred 24 to heat at from 75 to 125C. The reaction is complete 25 in from 15 minutes to 24 hours and the product isolated 26 by techniques known to those skilled in this art.

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1 The starting materials for the foregoing procedures 2 are generally known in the art or procedures are published 3 in the art which would enable one skilled in the art to 4 readily prepare said starting materials.
The meta substituted aniline of first described 6 synthesis wherein R is an unsaturated halogenated alkyl 7 group in which the unsaturation is in the a~ position 8 relative to the benzene ring, may be prepared according to 9 the following reaction scheme:

2 ~ ~ ~R-CXlX2 10 wherein Ph is phenyl, R3 is hydrogen, loweralkyl or 11 halogenated loweralkyl; and Xl and X2 are each halogen.
12 The starting material for this process is a 13 m-nitro benzaldedyle or a m-nitro phenyl-loweralkyl or 14 haloloweralkyl ketone. The reagent (Ph~ P=CXlX2 is 15 prepared by coupling triphenyl phosphine with a halo-16 genated methane such as carbon tetrachloride, carbon 17 tetrabromide, chloroform, bromoform and the like. The 18 reagent is not isolated but rather prepared in situ. The

19 preferred method is to combine all of the starting materials,

20 the triphenyl phosphine, the halogenated methane and the

21 benzaldehyde or ketone in a single reaction vessel at

22 a temperature o rom room temperature to 200C. Since

23 the phosphorous reagent is prepared in situ, the starting

24 material is readily available for reaction avoiding

25 problems of storage and stability of the reagent. The

26 reaction mixture is maintained within the above temperature

27 range for ~rom 1 to 24 hours and the product isolated by

28 techniques known to those skilled in this art. The 1(~58~9~

1 halogenated methane is generally used in excess so 2 that no additional solvent is required, however, a non 3 reactive solvent could optionally be employed.
4 The nitro compound of the above reaction is then 5 reduced to the corresponding amino compound using reduction 6 techniques such as iron and hydrochloric acid or zinc and 7 acetic acid. The amino compound thus obtained is treated 8 with chlorosulfonic acid followed by ammonia according to 9 the procedures already described to obtain the desired 10 product.
11 A variation of the above method starts with the 12 readily available unsubstituted benzaldehyde or phenyl 13 loweralkyl or halogenated loweralkyl ketone~

C R3 Ph3 ~ ~ C=CXlX2 ~=CXlx2 ~ C=CXlX2 02N~ ,~ 2 ~

2 ~ 2 2 ~ C~ CX1X2 -~ 2 ~ C=CX1X2 H2N02S ~J

14 wherein Ph, R3, X1 and X2 are as previously defined.
Benzaldehyde or the ketone is treated with the 16 Ph3P=C(R)2 reagent according to the procedures set forth 17 above. The halogenated vinyl or propenyl compound thus lV58:~94, 1 produced is then nitrated. The nitration is p-directing 2 and thus the p-nitro compound is recovered. The reaction 3 is run in excess nitrating agent such as nitric acid, fuming 4 nitric acid and the like in ~he presence of a dehydrating 5 agent such as concentrated sulfuric acid, acetic anhydride 6 and the like. The reaction mixture is maintained at from 7 0 to 50C. for from 15 minutes to 3 hours. The product is 8 isolated from the nitration reaction mixture by techniques 9 known to those skilled in this art.
The nitrated compound is then reduced to the 11 corresponding amino compound using standard reduction 12 techniques. In order to facilitate subsequent steps in 13 the synthesis, however, the amino group is generally 14 protected with a suitable protecting group such as an 15 acyl, preferably acetyl, function. The amino group is 16 acylated with any of the standard acylating reagents 17 available such as acid chlorides, anhydrides, carboxylic 18 acids and the like which correspond to the desired 19 protecting group.
The protected amine compound is then nitrated 21 using the nitration techniques described above. The 22 compound recovered is the m-nitro, p-amino compound. After 23 the nitration the protecting group is removed using 24 standard techniques known to those skilled in the art. In 25 the case of acyl protecting groups, acid or base catalyzed 26 hydrolysis readily recovers the free amine.
27 The free amine is then diazotized to prepare 28 the sulfonamide group.

1 The amine compound is diazotized in the presence 2 of agueous acid such as hydrochloric or sulfuric acid and 3 sodium nitrite at from 0 to 20C. The diazonium s~lt is 4 then treated with a solution of sulfur dioxide and 5 crystalline cupric chloride in acetic acid and 6 sufficient water to effect solution. The reaction 7 mixture is maintained at from 0 to 20C. for from 5 minutes 8 to 3 hours. The sulfonyl chloride group thus isolated from 9 the diazotization reaction is treated with ammonia or a 10 mono or di- loweralkylamine as described above affording the 11 mono sulfonamide which is chloro sulfonated and aminated 12 as described above.
13 A still further process for the preparation of 14 the 3-R-aniline starting materials utilizes m-nitro 15 aniline as precursor. The m-nitro aniline is diazotized 16 with a mineral or organic acid, sodium nitrite and water 17 as is fully described above. The diazonium salt is then 18 treated with an ethylene compound of the formula-R4R5C=CHX

19 in the presence of crystalline cupric chloride dihydrate 20 and acetone of other suitable non-reactive organic 21 solvent. In the above formula X is halogen and R4 and R5 22 are each halogen or one of R4 and R5 may be halogen and the 23 other i8 hydrogen, loweralkyl or halogenated loweralkyl.
24 The reaction is conducted initially at from -20 to 20C.
25 and following the initial reaction is maintained 26 substantially at room temperature for from 1 to 48 hours to 27 complete the reaction. The resultant product has the 28 ~ormula: H X
R4R5C-C ~ No2 ~058194 1 wherein X, R4 and R5 are as defined above. This 2 compound is then dehydrohalogenated to form:

R4R5C=C ~ No2 3 wherein R4 and R are as previously defined. The 4 dehydrohalogenation is carried out using an alkali metal 5 hydroxide or alkoxide or an organic base such as tri-6 ethylamine in the presence of a suitable solvent such as 7 a loweralkanol, prefe~ably methanol or ethanol. The nitro 8 group is then reduced using the reduction techniques 9 described above and the resultant amino compound chloro-10 sulfonated and aminated. Optionally the chlorosulfonation 11 and amination reactions may be conducted before the 12 diazotzation and dehydrohalogenation reaction steps.
13 Specifically 2-(3-aminophenyl)-1,1,2-trichloroethylene is 14 best prepared from the known starting material 2-(3-amino-15 phenyl) 1,1,1,2,2-pentachloroethane which is 16 dehalogenated using zinc in ethanol utilizing the above 17 reaction conditions. The foregoing process is also 18 applicable to the production of other compounds wherein 19 the unsaturation is at any other carbon atoms by utilizing the appropriate starting materials.
21 The compounds of the present invention have 22 utility in the field of animal therapy. They are effective 23 against both mature and immature liver fluke of the 24 species Fasclola gigantica and Fasciola hepatica, the common liver fluke in sheep and cattle. The preferred 26 dosage levels depend on the type of compound to be 27 employed, the type of animal to be treated, the particular lOS8~94 1 helminth to be combatted, and the severity of the 2 helminthic infestation. In general, effective fluke 3 eradication is achieved when the compounds are administered 4 in a single dose at dosage levels of from about 1 to 150 5 mg~kg of animal body weight and preferably from about 1 to 6 50 mg/kg of animal body weight. The compounds of the 7 present invention may be administered in a variety of 8 ways depending upon the particular animal employed, the g type of anthelmintic treatment normally given to such 10 animal, the materials employed and the particular helminths 11 being combatted. It is preferred to administer them in 12 anthelmintically effective amounts in a single or divided 13 oral or parenteral dose at a time when fluke infection is 14 apparent or suspected in the animal.
In addition to the inactive ingredients in the i6 composition, said composition may contain one or more other 17 active ingredients which may be selected from the compounds 18 of formula I or from other known anthelmintic agents.
19 Beneficial results are obtained when the compounds of 20 formula I are combined with an anthelmintic agent such as 21 2-(4-thiazolyl~benzimidazole (thiabendazole) or tetramisole 22 (dl-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole) or 23 other known anthelmintic agents.
24 In general, composition containing the active 25 anthelmintic compound are employed. The amounts of the 26 anthelmintic ingredient in the composition as well as the 27 remaining constituents vary according to the type of 28 treatment to be employed, the host animal and the particular

29 he]mintic infestation being treated. In general, however,

30 compositions suitable for oral administration, containing 1 a total weight percent of the active compound or compounds 2 ranging from 0.01 to 95~ will be suitable with the remainder 3 of the compositions being any suita~le carrier or vehicle.
4 A number of modes of treatment may ~e employed and each 5 to some extent determines the general nature of the 6 composition. For example, the anthelmintic compounds 7 may be administerd to domesticated animals in a unitary 8 oral dosage form such as a tablet, bolus, capsule, or 9 drench; a liquid oil base form suitable for parenteral 10 administration, or they may be compounded as a feed premix 11 to be later admixed with the animal food. When the 12 compositions are to be solid unit dosage forms as in 13 tablets, capsules, or boluses, the ingredients other than 14 the active compounds may be any other non-toxic vehicle 15 convenient in the preparation of such forms and preferably 16 materials nutritionally suitable such as starch, lactose, 17 tale, magnesium stearate, vegetable gums, and the like.
18 Moreover, when capsules are employed, the active compound 19 may be used in essentially undiluted form, the only 20 extraneous material being that of the capsule casing 21 itself which may be hard or soft gelatin or any other 22 orally acceptable encapsulating material. When the 23 dosage form is to be used for parenteral administration 24 the active material is suitably admixed with an acceptable 25 oil base vehicle preferably of the vegetable oil variety 26 such as peanut oil, cotton seed oil, and the like. In 27 all such forms, that is, in tablets, boluses, capsules, 28 and oil base formulations; the active compound conveniently 29 ranges from about 5 to 95% by weight of the total 30 composition.

105819~

1 When the unit dosage form is to be in the form 2 of a drench, the anthelmintic agents may be mixed with 3 agents which will aid in the subseq~nt suspending of the 4 active compounds in water such as beptonite, clays, water soluble starches, cellulose derivatives, gums, 6 surface active agents and the like to form a dry pre-7 drench composition, and this pre-drench composition is 8 added to water just before use. In the pre-drench 9 formulation, in addition to the suspending agent, such 10 ingredients as preservatives, anti-foam compounds, or 11 other suitable diluents or solvents may be employed.
12 Such a dry product may contain as much as 95~ by weight 13 of the active compound, the rest being excipient. Preferably, 14 the solid composition contains from 30 to 95% by weight of 15 the active compound. Enough water should be added to the 16 ~olid product to provide proper dosage level with a 17 convenient amount of liquid for a single oral dose. The 18 commonly used measure in the field is 1 fluid ounce of 19 material and thus that 1 fluid ounce of material should 20 contain enough of the anthelmintic compound to provide 21 an effective dosage level. Liquid drench formulations 22 containing from 10 to 50% by weight of dry ingredients 23 will, in general, be suitable with a preferred range being 24 from 15 to 25 weight percent.
When the compositions are intended to be used 26 in feeds, feed supplements or feed premixes, they will be 27 mixed with suitable ingredients of the animals nutrient 28 ration. Solid orally ingestible carriers normally used 29 for such purposes such as distiller dried grans, corn 30 shells, citrus meal, attapulgus cl-ay, wheat shorts, molasses

31 solubles, corn cob meal, vegetable substances, toasted lOS8~94 1 dehulled soya flour, soya bean meal feed, antibiotic 2 mycellia, soya grits, crushed limes~one and the like are 3 all suitable. The active compounds are intimately dispersed 4 or admixed throughout the active solid carrier by methods ~ as grinding, melting, or tumbling. By selecting a proper 6 diluent and by altering the ratio of carrier to active 7 ingredient, composition5 of any desired concentration may 8 be prepared. Feed supplement formulations containing from 9 about 5 to 30% of active ingredient are particularly suitable for addition to feeds. The active compound is normally 11 dispersed or mixed uniformly in the diluent but in some 12 i~stance~ may be adsorbed on the carrier.
13 These supplements are added to the finished 14 animal feed in an amount adequate to give the final concentration desired for controlling or treating the 16 helminth infection by wa~ of animal ration. Although the 17 preferred level in feeds will depend on the particular 18 compounds being employed, the active compounds of this 19 invention are normally fed at levels of 0.01 to 3~. As stated above, animals are preferably treated at a time 21 when the infestation is apparent or suspected and the most 22 preferred method of treatment is with oral doses. Thus, 23 administration of medicated feed is not preferred but may 24 be employed. Similarly, the amounts of drug present in the feed may be reduced to levels in the order of 0.01% to 26 0.5% by weight. Based on the weight of the feed and the 27 medicated feed administered over prolonged periods. This 28 could be in thè nature of a preventive or prophylactic 29 meaAure. Another method of administering the compounds of this invention to animals whose feeds are conveniently 31 pelleted such as sheep is to incorporate them directly - ~6 -1058i94 1 into the pellets. For instance, the anthelmintic compounds 2 are readily incorporated in the nutritionally adequateal-3 falfa pellets at levels of 2 to 10 g. per pound for thera-4 peutic use and lower levels for prophylactic use, and such pellets fed to the animals.
6 Examples of compositions suitable for 7 administration to animals are:
8 A typical bolus composition is as follows:
9 4-Amino-6-trichlorovinyl-1,3 10 benzenedisulfonamide 7.0 g.
11 Dicalcium phosphate 1.0 g.
12 Starch 0~7 g~
13 Guar gum 0.16 g.
14 Talc 0.11 g.
15 Magnesium stearate 0,028 g.
16 A typical drench compocition is as follows:
17 4-Amino-6-( a, ~-dichloro-~-18 fluorovinyl)-1,3-benzenedisulfonamide. 5.0 g.
19 Benzalkonium chloride 5.6 ml.
20 Antifoam emulsion 0.06 g.
21 Hydroxyethyl cellulose 0.3 g-22 Sodium phosphate 0.3 ml.
23 Water q.s. to 30 ml.
24 Examples of typical feed pxemix supplements are as follows:
26 A. 4-Amino-6-trifluorovinyl-1 t 3~
27 benzenedisulfonamide 10 lbs.
28 Wheat shorts 90 lbs.
29 B. 4-~mino-6-(1,1-dichloro-prop-1-ene-2-yl)-1,3-benzene-31 disulfonamide 15 lbs.

1058~94 1 Ground oyster shells 40 lbs.
2 Citru5 meal 45 lbs.
3 C. 4-Amino-6-(1,2-dichloro-3,3, 4 3-trifluoropropenyl)-1,3-benzenedisulfonamide 10 lbs.
6 Corn meal 90 lbs.
7 D. 4-Amino-6-(1,2-dichloro-1-8 propenyl)-1,3-benzene-9 disulfonamide 15 lbs.
Wheat shorts 50 lbs.
11 Corn meal 35 lbs.
12 The above feed premix supplements are combined 13 with the animals regular feed, intimately mixing therewith 14 such that the final concentration of the active ingredient is from 0.01 to 3% by weight.

17 EXAMPLE lA
18 4-Amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide 19 3~.8 G. of 2-(3-aminophenyl)-1,1,2-trichloro ethylene is added dropwise with stirring to 107 ml. of 21 chlorosulfonic acid maintained at +10C. W~len the addition 22 i9 completed, the reaction mixture i9 heated to 1~5-130 23 and stirred at this temperature for 2 1/~ hours. Then it 24 is cooled to ~0C. and 40.~ ml. of thionylchloride is added in portions. After this, the reaction mixture is 26 stirred at ~80C. for 1 1/2 hours and ihen cooled in ice to 27 +10C. The reaction mixture is poured onto ice and the 4-28 amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonylchloride 29 is extracted into methylene chloride, washed with water, 30 dried over MgSO and concentrated in vacuo to 52 g. of a 31 brown foam. The brown solid is dissolved in 60 ml. of 1058~94 1 CH2C12 and added in portions to 250 ml. of liquid ammonia.
2 The excess ammonia and the methylene chloride are allowed to 3 evaporate overnight. Water is added to the residue,and it is 4 carefully acidified with concentrated HCl, giving an amorphous precipitate. This is extracted into ethyl acetate, 6 washed with water, dried over MgS04 and concentrated 7 in vacuo to 45 g. of brown foam. This is extracted twice 8 with hot benzene leaving 38.5 g. of brown solids. The 9 residue is extracted three times by boiling with 1000 ml.
portions of ether, and the ether solutions are concentrated 11 in vacuo to 250 ml., and crystalline product is precipitated 12 by careful addition of hexane giving after filtration 13 20.8 g. of product - ether complex with melting point of 14 130-135. This is boiled with I75 ml. of water, without digsolving much of the compound for 1/2 hour then allowed 16 to come to room temperature, filtered washed with water, 17 dried in vacuo at 50C. to give 17.0 g. of 4-amino-18 6~ trichlorovinyl)-1,3-benzenedisulfonamide with 19 m.p. 188-193C. A small sample is recrystallized for analysis from aqueous methanol to melt at 205-207.

22 EXAMPLE lB

23 4-~mino-Nl, N3-dimethyl-6-(1,2,2-trichlorovinyl)-1,3-24 benzenedisulfonamide lOG. of 4-amino-6-(1,~,~-trichlorovinyl)-1,3-26 benzenedisulfonylchloride prepared as in example lA is 27 added to 150 ml. of liquid methylamine at -78C. When the 28 addition is completed, the cooling bath is removed and the 29 excess methylamine is allowed to evaporate. The solid lOS8194 1 residue is taken up in water and acidified with acetic acid.
~ A dark precipitate is collected by filtration and dried to 3 give 7.4 g. of crude product. Purification by chromatography 4 on a silica gel column and crystallization from ethanol gives 2.9 g. of 4-amino-N , N3-dimethyl-6-(1,~,2-trichlorovinyl)-6 1,3-benzenedisulfonamide with a m.p. of 2Ll to 212C.

7 EXAMPLE lC
8 4-Amino-Nl, Nl, N3, N3-tetramethyl-6-(1,2,2-trichlorovinyl)-9 1,3-benzenedisulfonamide 10 G. of 4-amino-6-(1,2,2-trichlorovinyl)-1,3-11 benzenedisulfonylchloride prepared as in example lA is treated 1~ with 1~5 ml. of dimethylamine. The reaction mixture is worked 13 up in a manner similar to example lB affording 5.2 g. of pure 14 4-amino-Nl,Nl, N3, N3-tetramethyl-6-(1,2,~-trichlorovinyl)-1,3-benzenedisulfonamide with a m.p. of ~38 to 2~9C.
16 EXAMPLE ~
17 4-Amino-6-(1,1-dichloroprop-1-en-~-yl)sulfonamide 18 a) 1,1-dichloro-7-ph~lnyl-1-propene 19 A mixture of 30 g. of acetophenone, 420 ml. of CCl and 196 g. of triphenylphosphine is stirred at 21 60C. for 9 hours. Then the liquid i5 decanted and the gummy residue washed well with ether. The solutions are 23 combined and the CC14 and ether is distilled out through ~4 a short vigreaux column. The residue is distilled in vacuo ~5 at 35 mm. Hg. pressure and the fraction boiling at 120C.
~6 is collected, representing 35.0 g. of l,l-dichloro-~-105t3194 1 phenyl-l-propene.
2 b) 1,1-dichloro-2-(4-nitrophenyl)-1-propene 3 A mixture of 33 ml. of concentrated H2SO4 and 4 28 ml. of concentrated HNO3 (70~) is stirred in an ice bath while 35.0 g. of l,l-dichloro-~-phenyl-l-propene 6 is added, keeping the reaction mixture 7 between 10 and ~0C. It is allowed to come to room 8 temperature and vigorous stirring is continued for 1 hour.
9 It is poured onto ice, extracted with ether, the ether extract washed with water several times, dried over 11 MgSO4 and concentrated in vacuo. Vapor phase chromatography 12 of the crude product indicates a mixture of two components 13 presumably 1,1-dichloro-~-(4-nitrophenyl)-1-propene 14 (major product) and its ~-nitro-isomer. The residue is distilled in vacuo at 1.0 mm. Hg. pressure and a 20.9 g.
16 fraction with boiling point 147-153C. is collected.
17 c) 1,1-dichloro-2-(4-acetylaminophenyl)-1-propene 18 30.0 G. of iron powder is added to a solution of 19 ~.7 g. of 1,1-dichloro-~-(4-nitrophenyl)-1-propene in 500 ml. of 50~ aqueous ethanol and stirred vigorously at ~1 reflux temperature. A solution of ~.~ ml. of concentrated ~2 HCl in 10.0 ml. of 50~ aqueous ethanol is added dropwise 23 and the mixture is refluxed for a total of 40 minutes, ~4 filtered hot and cooled to room temperature. 500 Ml. of chloroform i5 added, it is made basic with a little aqueous ~6 NaHCO3 solution and the layers are separated. The chloro-27 form-alcohol layer is washed with water, dried over MgSO~
Z~ and concentrated in vacuo to 28.5 g. of crude 1,l-dichloro-2~ ~-(4-aminophenyl)-1-propene. This is dissolved in 145 ml.
of pyridine and stirred in an ice bath while 35 ml. of 31 acetic anhydride is added over 5 minutes, then kept ` 10581~4 1 overni~ht at room temperature. Next morning it is concentrated in vacuo and high vacuo to a crystalline 3 residue. 30 Ml. of ethyl acetate is added and the slurry 4 is stirred 30 minutes at room temperature and 60 minutes in an ice bath. Then it is filtered, washed with little 6 ethyl acetate and ether and dried in vacuo to give 18.0 g.
7 of 1,1-dichloro-2-(4-acetylamino phenyl)-l-propene with 8 m.p. 164.5 to 165.5.
9 d) 1~l-dichloro-~--(4-acetylamino-3-nitrophenyl)--l-propene 6.0 G. of 1,1-dichloro-~-(4-acetylamino phenyl)-11 l-propene is dissolved in 120 ml. of acetic anhydride with 12 stirring at 50C., then quickly cooled to +5C. affording 13 a fine suspension. Then a mixture of 1.44 ml. of acetic 14 anhydride and 4,28 ml. of concentrated HN03 previously prepared at -2QC. is added slowly over 50 minutes. Then 16 the ice bath is replaced by an oil bath and the reaction 17 mixture is heated over 30 minutes to 50C., when everything 18 is dissolved, kept 30 additional minutes at 50C. and then 19 cooled in an ice bath for 2 hours. Then the yellow crystalline precipitate is filtered, washed well with 21 water and dried in vacuo to afford 3.14 g. of product 2~ with m.p. 142-143. The above filtrate is poured into 23 water, stirred for 1 hour, the precipitate filtered, ~4 washed with water, dried in vacuo to give 2.40 g. additional ~5 1,1-dichloro-2-(4-acetylamino-3-nitro phenyl)-l-propene of 26 m.p. 139-141.
27 e) 1,1-dichloro-~-(4-amino-3-nitrophenyl)-1-propene 28 A suspension of 7.55 g. of l,l-dichloro-29 ~-(4-acetylamino-3-nitro phenyl)-l-propene in 150 ml. of 6 n. HCl is stirred and heated at reflux for 30 minutes.

1051~94 1 It is cooled in ice bath, made basic with 2 50 ml. of 50% aqueous NaOH and extra~ted with ethyl 3 acetate. The extract is washed wit~ water, dried and 4 concentrated in vacuo to give 6.6 g. of crude 1,1-dichloro-2-(4-amino-3-nitro phenyl)-l-propene as a brown 6 oil.
7 f) ~-nitro-4-(1,1-dichloroprop-1-en-2~yl)benzene-8 disulfonamide 9 ~.1 Ml. of acetic acid is saturated with S02, 100 mg. of CuC12. 2H20 dissolved in ~ drops of water is 11 added, and SO~ is bubbled into the solution, which is 12 maintained at 10C. In a second flask, SOO mg. of 13 1,1-dichloro-2-(4-amino-3-nitro phenyl)-l-propene is 14 stirred in 3.6 ml. of concentrated HCl and warmed to about 80 and hen quickly cooled in ice. This suspension 16 is stirred at 0-5C., while a solution of 170 mg. of 17 NaNO~ in 0.6 ml. of water is added slowly over 30 minutes 18 and then the mixture is ~ept at 0 for one additional 19 hour. Then 100 mg. of sulfamic acid is used to destroy the excess of NaNO~. The reaction mixture is separated ~1 from some insoluble material by centrifugation and the 2~ clear solution is added rapidly to the acetic acid!SO~/
23 CuCl~ solution prepared before at 10C~ It is allowed to 24 come to room temperature over 30 minutes, then poured onto ice, extracted with methylene chloride, washed twice 26 with water, dried and concentrated in vacuo to 350 mg.
27 orange crystalline residue of 2-nitro-4-(1,1-dichloroprop-28 1-en-2-yl)benzenesulfonylchloride. This is dissolved in about ~ lOml. of liquid ammonia and left overnight~ To this is added 4 ml. of water and a few drops of ~.5 n. HCl, aged 31 for 1 hour at room temperature, the solid is separated by "j_ ~ `~

lOS8~94 1 centrifugation, washed with some water and dried to give 2 a80 mg. of crystalline ~-nitro-4-(1,1-dichloroprop-1-en-3 2-yl)benzenedisulfonamide. A part of this is recrystallized 4 from benzene benzene-hexane to afford an analytical sample of the product with m.p. 149 to 151.
6 g) ~-Amino-4-(1,1-dichloroprop-l-en-~-yl)benzenesulfonamide 7 1.02 G. of ~-nitro-4-(l,l-dichloroprop-l-en-2-yl) 8 benzenedisulfonamide i5 dissol~ed in 30 ml. of 50% a~ueous 9 ethanol at about 70C. While vigorously stirring, 1.0 g.
of iron powder is added and the reaction mixture is heated 11 to reflux. Three drops of concentrated ~Cl are added and 1~ the reflux is continued for 30 minutes, when the hot 13 reaction mixture is filtered, the solution cooled to room 14 temperature, 60 ml. of HCl and 15 ml. of ethanol is lS added, the organic layer is washed with water, dried and 16 concentrated in vacuo to 980 mg. of light oil, which 17 crystallizes from benzene petroleum benzene to give 410 mg.
18 2-amino-4~ -dichloroprop-l-en-7-yl)benzenesulfonamide with 19 m.p. 93 to 5C.
.0 h) 4-Amino-6-tl,l-dichloroprop-l-en-~-yl)-1,3-benzenedi-~l sulfonamide ~. 100 Mg. of the ~-amino-4-(l,l-dichloroprop-1-en-23 2-yl)benzenesulfonamide and 1.0 ml. of chlorosulfonic acid ~4 is mixed at 5 to lQC. and then immersed into an oil bath ~5 of l00 to 110 for 1 hour. The reaction mixture is cooled ~6 in ice, added onto ice, extracted into CH2C12, the solution 27 is washed twice with water, dried and concentrated in vacuo ~8 to yield 75 mg. of crude 4-amino-6-(1,1-dichloroprop-1-en-2~ 2-yl)-1,3-benzenedisulfonylchloride, identified by nuclear magnetic resonance and mass spectral analyses. lO0 Mg. of 1058~94 1 this disulfonylchloride is then dissolved in 4 ml. of tert-2 butanol and ammonia gas is bubbled into the solution for 3 about 10 minutes at room temperature. It is kept at room 4 temperature for 15 minutes and then concentrated in vacuo.
The residue is dissolved in ethyl acetate, washed with 6 dilute aqueous HCl, water, dried and concentrated in vacuo 7 to 87 mg. of crude product which slowly crystallized. It 8 is recrystallized from a methanol-benzene-methylene-9 chloride mixture to give 4-amino-6-(1,1-dichloroprop-1-ene-2-yl)-1,3-benzenedisulfonamide with m.p. 199 to 202C.
11 i) 4-Amino-6-(1,1-dibromo-1-Pent-en-2-yl)-1,3-benzenedi-12 sulfonamide 13 In example 2a) 37 g. of butyrophenone 14 is substituted for the acetophenone and the carbon tetrachloride iB replaced by carbon tetrabromide.
16 Succesively the same procedures are employed as set forth 17 in examples 2a) through 2h) to give 4-amino-6-(1,1-dibromo-18 1-penten-2-yl)-1,3-benzenedisulfonamide.
19 j) 4-Amino-6-(3,3,3-trifluoropropynyl) 1,3-benzene-disulfonamide 21 Following the procedures of Examples 2b) through 22 2h) utilizing 3,3,3-trifluoro-1-phenylpropyne in place of 23 1,1-dichlaro-2phenyl-1-propene there is obtained 4-amino-24 6-(3_3_3-trifluoropropynyl) 1,3-benzenedisulfonamide.

26 4-Amino-6-(2-chloro-1,2-difluorovinYl)-1,3-benzene-27 disulfonamide 28 a) (1,2-Difluoro-1,2,2-trichloroethyl) benzene 29 A solution of 86 g. of ~-chloro-a,~-difluoro styrene in 200 ml. of CC14 chlorinated at room 1 temperature with chlorine for 22 ho~rs. The reaction 2 mixture is then washed with water and aqueous sodium 3 bicarbonate solution, dried over magnesium sulfate and 4 concentrated by distillation of the solvent at atmospheric pressure through a vigreaux column. The liquid residue is ~ then distilled in vacuo at 20 mm. Hg. pressure to give 7 100 g. of (1,-difluoro-1,2,2-trichloroethyl) benzene 8 boiling at 96-7, N~5-1.5073.
9 b) 3-(1,2-Difluoro-1,2,2-trichloroethyl)-nitrobenzene 100 G. of (1,2-difluoro~1,2,2-trichloroethyl) 11 benzene is added dropwise over 30 mm. to a vigorously 12 stirred nitration mixture of 80 ml. of concentrated 13 nitric acid in 400 ml. of concentrated sulfuric acid 14 while the temperature is maintained between 15 and 25C.

by cooling with an ice bath. When the addition is 16 completed, stirring is continued at room temperature for 17 5 hours. It is then poured onto ice, and the product is 18 extracted with methylenechloride. This solution is washed 19 with water and aqueous sodium bicarbonate solution, dried and concentrated in vacuo to a yellow oil. The oily residue 21 is distilled n vacuo at 2.2 mm. mercury pressure to give 22 104 g. of 3-(1,2-difluoro-1,2,2-trichloroethyl)-nitrobenzene 23 with boiling point 122-4.
24 c) 3-(1,2-Difluoro-1,2,2-trichloroethyl)-aniline 104.4 G. of 3-(1,2-difluoro-1,2,2-trichloroethyl)-26 nitrobenzene is added over 10 min. to a solution of 325 g. of 27 crystalline stannous chloride (SnC12 ' 2H20) in 325 g. of 28 concentrated HCl and 325 g. of ethanol with vigorous 29 stirring, maintaining the temperature at 50C. Stirring 105819~

1 is continued for 3 additional hours. It is cooled in ice, 2 and the precipitate collected by filtration. The solids are 3 then suspended in 500 ml. water and 500 ml. of CH2C12, 4 the mixture is cooled in ice and made basic by the addition of 50% aqueous NaOH until almost all solids are dissolved.
6 The methylenechloride layer is separated, washed with water, 7 dried with Na2SO4 and concentrated in vacuo to 75 g. of 8 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline as yellow 9 oil.
d) 3-(2~Chloro-1,2-difluorovinYl)aniline 11 74 G. of zinc dust is added to a vigorously 12 stirred solution of 40 g. of 3-(1,2-difluoro-1,2,2-tri-13 chloroethyl)-aniline in 450 ml. of ethanol and heated at 14 r~flux for 2 hours. It is filtered hot, the solid residue washed with hot ethanol and the combined ethanol solution 16 cooled to room temperature. About 1000 ml. of chloroform 17 is added and the organic layer is washed with aqueous 18 NaHCO3solution and with water, dried over Na2SO4 and 19 concentrated in vacuo to 23.9 g. of oily 3-(2-chloro-1,2-difluorovinyl)aniline. This gives a single peak with a 21 retention time of 1.8 minutes at 200C. on a gas liquid 22 chromatography column packed with 5~ SE30, and the correct 23 values for C,H,N,Cl and F by combustion analysis.
24 e) 4-Amino-6-(2-chloro-1,2-difluorovinYl)-1,2-benzene-disulfonamide 26 2.0 G. of 3-(2-chloro-1,2-difluorovinyl) aniline 27 added dropwise to 20 ml. of ice cold and well stirred 28 chlorosulfonic acid. The 20 g. of dry sodium chloride is 29 added in portions over 30 minutes at room temperature. The reaction flask is immersed in an oil bath and heated at _ ,7 _ 105819~

1 115 to 120C. for 4 hours. It is cooled in ice and added 2 in portions to ice water. This is treated with methylene-3 chloride, the organic layer washed with water, dried and 4 concentrated in vacuo to give crude 4-amino-6-(2-chloro-1,2-5 difluorovinyl)-1,3-benzenedisulfonylchloride, identified by 6 a molecular ion peak of 385 in the mass spectrum with the 7 characteristic pattern expected for a trichloro compound.
8 This is immediately added to liquid ammonia and left 9 overnight, while the excess ammonia is allowed to evaporate.
10 The residue is dissolved in a small amount of water, 11 acidified with dilute HCl and extracted with ethyl acetate, 12 dried and concentrated in vacuo to 600 mg. of crude 4-amino-13 6-(2-chloro-1,2-difluorovinyl)-1,3-benzenedisulfonamide.
14 The nuclear magnetic resonance spectrum shows the two single 15 peaks at 7.35 and 8.25 J which are expected for this 16 product, representing the protons at the 5 and 2 position 17 of the 1,3,4,6-tetrasubstituted benzene ring. Further 18 purification of this product by preparative layer 19 chromatography on 2.0 mm. thick layers of silica gel with 20 a benzene-ethyl acetate-(l:l)-mixture as liquid phase gave 21 210 mg. of pure product, which gave from methylenechloride-22 ether mixture white crystalls, m.p. 184-187C., and a molecular 23 ion of 347 by mass spectrometry.

24 EX~PLE 4 25 4-Amino-6-(2,2-dichlorovinyl)-1,3-benzenedisulfonamide ._ 26 a) ~B-dichloro-3-nitrostyrene 27 A solution of 32.8 g. of tri;?henylphosphine in 28 70 ml. of carbon tetrachloride is stirred for 3 hours at 29 60C. to prepare in situ the reagent triphenylphosphine -- 2~ --l~S8194 1 dichloromethylene. A solution of 18.9 g. of 3-nitro 2 benzaldehyde in 60 ml. of carb~n tetrachloride is added 3 and the mixture is continued to be stirred at 60C. for an 4 additional two hours, when vapour phase chromatography 5 indicates that all the starting 3-nitrobenzenealdehyde has 6 disappeared and two new peaks in a ratio of 1:1 show 7 the formation of a mixture of ~-dichloro-3-nitrostyrene 8 and 3-nitrobenzalchloride. The reaction mixture is 9 decanted from the solid residues and concentrated in vacuo to an oil. This is treated with ether, and again separated 11 from some solid precipitate and the solution is again 12 concentrated in vacuo. The oily residue is then carefully 13 distilled in high vacuo to give essentially pure 14 dichloro-3-nitrostyrene.
b) ~,~-dichloro-3-aminostyrene 16 26,4 G. of ~,~-dichloro-3-nitrostyrene is 17 reduced according to the procedure of example 2c to give 18 the corresponding ~,~-dichloro-3-aminostyrene compound.
19 c) 4-Amino-6-(2,2-dichlorovinyl)-1,3-benzenedi-sulfonamide 21 2.0 G. ~,~-dichloro-3-aminostyrene is added 22 dropwise to 20 ml. of ice cold chloro sulfonic acid. As 23 soon as the addition is complete, the reaction flask is 24 immersed in a preheated oil bath of 110C. and kept there for 1 hour. It is then removed from the oil bath and cooled 26 in an ice bath. Then the reaction mixture is added dropwise 27 to a large excess of ice water and the disulfonylchloride is 28 extracted with methylenechloride, the methylenechloride 29 solution is dried over magnesium sulfate and concentrated in vacuo to about 5 ml. This concentrated solution is 1 added dropwise to about 50 ml. of liquid ammonia and left 2 overnight at ambient temperature. It is taken up the next 3 morning in little water, acidified with dilute HCl, and 4 extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo to a gummy 6 residue. 200 Mg. of this residue is dissolved in about 7 5 ml. ethyl acetate and applied to a preparative layer 8 chromatography plate 20 x 20 cm size and coated with a 9 2.0 mm. layer of silica gel. Development with a benzene-ethylacetate 1:1 mixture and extraction of one band 11 representing the product gives essentially pure 4-amino-12 6-(2,2-dichlorovinyl)-1,3-benzenediculfonamide.

14 1,2-Dichloro-1-(5-amino-2,4-disulfamYlPhenYl)-propene a) 1,1~2,2-Tetrachloro-1-(3-nitrophenyl)propane 16 47 G. of 1,1,2,2-tetrachloro-1-phenyl-1-propane 17 i8 added dropwise over 45min. to a well stirred nitration 18 mixture of 31.2 ml. of concentrated sulfuric acid and 19 16.9 ml. of concentrated nitric acid while the temperature is maintained between Z5 and 35C. Stirring is continued 21 for three additional hours at room temperature when the 22 reaction mixture is poured onto ice water, extracted with 23 CH2C12, concentrated in vacuo and crystallized from 125 ml.
24 of methanol to give 29 g. of yellow crystalline 1,1,2,2-tetrachloro-1-(3-nitrophenyl) propane with m.p. 75.5 to 26 77C.

27 b) 1,2-Dichloro-1-(3-aminophenyl)-1-propene 28 13 G. of 1,1,2,2-tetrachloro-1-(3-nitrophenyl) 29 propane and 7.9 g. of iron powder is stirred vigorously under reflux in 465 ml. of 50~ a~ueous ethanol. 5.6 Ml of 31 a solution prepared previously from 52 ml. of concentrated 1058~9~

1 hydrochloric acid and 250 ml. of 50~ aqueous ethanol are 2 added dropwise over 5 minutes. After an additional 2 hours 3 of stirring at reflux temperature, the hot reaction mixture 4 is filtered, cooled to room temperature, diluted with enough 5 chloroform to double the volu~e of the ethanol, and made 6 basic with saturated aqueous sodium bicarbonate solution.
7 The organic layer is separated, washed with water, dried 8 and concentrated in vacuo to give a mixture of essentially 9 pure cis and trans 1,2-dichloro-1-(3-aminophenyl)-1-propene 10 as a yellow oil.
11 c) 1,2-dichloro-1-(5-amino-2,4-disulfamylphenyl)-1-propene 12 1.0 G. of 1,2-dichloro-1-(3-aminophenyl)-1-propene 13 is added dropwise to 13 ml. of ice cold chlorosulfonic acid, 14 followed by 13 g. of dry sodium chloride NaCl over 35 minutes.
lS The reacti~n mixture is heated up to 125 C. over 30 minutes 16 and kept at this temperature for 1 1/2 hours. It is cooled 17 poured onto ice water, extracted with methylene chloride, 18 dried over magnesium sulfate and concentrated in vacuo to 19 900 mg. of crude intermediate disulfonylchloride. This is 20 added to liquid ammonia and left overnight. The crude 21 disulfonamide is isolated by addition of water, acidification 22 with dilute HCl, extraction with ethylacetate and 23 evaporation of the extract in vacuo. Further purification 24 by preparative layer chromatography on silica gel coated 25 plates gave 40 mg. of essentially pure 1,2-dichloro-1-26 (5-amino-2,4-disulfamylphenyl)-1-propene.

~058~94 2~4-Amino-6-(l,~-dichlorovinyl)-1,3-benzenedisulfonamide 3 a) l~ Trichloro-~-(3-nitrophenyl)ethane 4~ 13.8 G. of 3-nitroaniline are dissolved in a hot mixture of 30 ml. of concentrated HCl and 30 ml. of 6 water, cooled to room temperature, and 80 g. of ice is 7 added. Under vigorously stirring 24 ml. of a 30~ aqueous 8 sodium nitrate solution is added rapidly. Powdered sodium 9 bicarbonate is added to this solution until the pH is about 2, then the reaction mixture is cooled to 0C. This ll diazonium solution is added to a well stirred solution of 12 2Q g. of trans-1,2-dichloroethylene in 75 ml. of acetone 13 and ~.l g. of cupricchloride dihydrate and .75 g. of 14 calcium oxide at 0-~C. When addition is completed, the reaction mixture is allowed to come to room temperature and 16 stirred overnight. Workup is accomplished by addition of 17 methylene chloride,separation of the organic layer,and 18 concentration to a crude mixture of l,l,~-trichloro-~-l9 (3-nitrophenyl)ethane and 3-chloronitrobenzene from ~ which the product is isolated by fractional distillation 21 in high vacuo.
22 b) 1,2-Dichloro-2-(m-nitrophenyl)ethylene 23 A solution of ~.5 g. KOH in 30 ml. of ethanol 24 is added from a dropping funnel to a solution of 9.0 g.
of 1,1,~-trichloro-~-(3-nitrophenyl)ethane in ~0 ml. of ETOH
2~ during ~0 minutes and after that the reaction mixture is 27 boiled in the steam bath for 2 hours. It is cooled to room 2~ temperature poured an 100 ml. of water and extracted with 29 ether. After removel of the ether n vacuo the residue is distilled in high vacuo to yield pure 1,~-dichloro-2-(m-31 nitrophenyl)ethYlene-

-32 -10581~4 1 c) 1,2-Dichloro-2-(m-aminophenyl)ethylene 2 10.0 G. of iron powder i9 added to a solution of 3 8.7 g. of 1,2-dichloro-2-(m-nitrophenyl)ethylene 4 in 170 ml. of 50% aqueous ethanol and reduced analogous to 5 procedure 2c) to give crude 1,2-dichloro-2-(m-aminophenyl) 6 ethylene 6uitable for use in the next step.
7 d) 4-Amino-6-(1,2-dichlorovinyl)-1,3-benzenedisulfonamide 8 1.0 G. of 1,2-dichloro-2-(m-aminophenyl)ethylene 9 is added dropwise to 10 ml. of cold chlorosulfonic acid 10 followed by 10 g. of sodium chloride. The chlorosulfonation 11 workup and treatment with liquid ammonia is carried out 12 as described in example 3e) to give the 4-amino-6-13 (1,2-dichlorovinyl)-1,3-benzenedisulfonamide.

4-Bromo-6- (1! 2,2-trichlorovinyl)-1,3-benzenedisulfonamide 16 Nitrosyl sulfuric acid is prepared by addition 17 of 0.51 g. of powdered NaNO2 to 6.0 ml. cold (0), well 18 stirred concentrated H2SO4. Then 2.53 g. of 4-amino-6-19 trichlorovinyl-1,3-benzene disulfonamide is added in 20 po.rtions, followed by 6.0 ml. of glacial acetic acid. The 21 reaction mixture is then stirred`for 15 minutes at 15C. to 22 complete the diazotization reaction. A solution of 1.2 g.
23 of cuprous bromide (Cu2Br2) in 6.0 ml. of concentrated 24 hydrobromic acid is then added dropwise and the reaction 25 mixture is heated on a steam bath for 30 minutes after 26 completion of the addition. Addition of the reaction 27 mixture to 200 ml. of cold water results in a precipitate, 28 which is collected by filtration and dried to give 1.11 g. Of 29 essentially pure 4-bromo-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide which after one recrystallization

- 33 -1 from ethylacetate/benzene gives 0.86 g. pure product with 2 a m.p. of 228-229C.

4 _Chloro-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide If cuprous chl~ride and concentrated HCl in the 6 above procedure is substituted for the cuprous bromide 7 and concentrated HBr respectively, 0.76 g. of 4-chloro-8 6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide is 9 obtained which melts after one recrystallization from ethylacetate/benzene at 211-213C. (dec.) 12 4-Chloro-Nl, N3-dimethyl-6-(1, ~ 1,3-13 benzenedisulf~namide 14 The title compound is obtained if 4-amino-Nl, N -dimethyl-6-trichlorovinyl-1,3-benzenedisulfonamide is 16 used in the procedure of Example 7 as the amino compound 17 in place of 4-amino-6-trichlorovinyl-1,3-benzenedi-18 sulfonamide.

4-Benzylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedi-21 sulfonamide 22 A mixture of 0.31 g. of 4-bromo-6-trichlorovinyl-23 1,3-benzenedisulfonamide and 0.76 ml. of benzylamine is 24 stirred at 100c~or 2 hours and then added to 25 ml. of aqueous acetic acid and cooled in ice. A precipitate is 26 collected by filtration which weighs 0.26 g. after drying, 27 which gives after recrystallization from a ethylacetate/
28 benzene/petroleum benzene mixture 0.17 g. of 4-benzylamino-29 6-(1,2,2-trichlorovinyl)-1,3~benzenedisulfonamide with m.p.
188-1gooc.

- 34 -~ `" 15549 IA

105~194 ~ EXAMPLE 9 2 4-Furfurylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedi-3 sulfonamide 4 4-Bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and furfurylamine are reacted at 70C. for 10 hours in 6 analogy to above procedure to give 4-furfurylamino-6-7 (1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p.
~ 153-155C.
9 EXAMPI~ 10 4-Methylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisul-11 fonamide ~ . . _ 12 A mixture of 0.445 g. of 4-bromo-6-trichloro-13 vinyl-1,3-benz~nedisulfonamide, lS ml. of methanol and 5 to 14 10 ml. of methylamine is se~led in ~ steel tube and heated to 45C. for 2 hours. The reaction mixture is then concen-16 trated to a solid residue which is triturated with aqueous 17 acetic acid. This mixture is extracted with ethylacetate 18 and again concentrated in vacuo to 0.3 g. of an amorphous 19 solid. Crystallization from aqueous methanol gives 60 mg.
of 4-methylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisul-21 fonamide m.p. 239-240C. (dec.).
22 If the nucleophilic amino component in the previous 23 examples is replaced by isopropylamine, di-n-bu~ylamine, N-24 methylpiperazine, morpholine, thiomorpholine l,l-dioxide, or aniline the corresponding 4-isopropylamino; 4-N,N-di-n-26 butylamino; 4-(4-methyl-piperazinyl);4-(4-morpholinyl);4-27 (1,1-dioxy-4-thiomorpholinyl); or 4-phenylamino-6-trichloro-28 vinyl-1,3-benzenedisulfonamides are obtained.

- 35 -

Claims (15)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound having the formula:

wherein:
R1 and R2 are each independently hydrogen or lower-alkyl;
R is a halogenated unsaturated alkyl group contain-ing from 2 to 6 carbon atoms, one or two double bonds or a single triple bond, and from 1 to 11 halogen atoms; and R3 and R4 are independently hydrogen, loweralkyl, benzyl, furfuryl or phenyl, which comprises I. when R3 and R4 both stand for hydrogen: chlorosulfonating a compound of the formula:
or wherein R, R1 and R2 are as previously defined, to produce a compound having the formula:

or and reacting the latter with ammonia or a mono- or di-lower-alkylamine to form the desired product; or II. when R3 and R4 are not both hydrogen: reacting a compound of the formula:

wherein R, R1 and R2 are as previously defined and Hal is halogen, with an amine having the formula:

wherein R3 and R4 are as previously defined except that they may not both be hydrogen.

2. A process of Claim 1 for the preparation of a compound having the formula:

wherein each R1 and R2 is independently hydrogen or loweralkyl and R is a halogenated unsaturated alkyl group containing from 2 to 6 carbon atoms, one or two double bonds or a single triple bond, and from 1 to 11 halogen atoms; which comprises chlorosulfonating a compound having the formula:

to produce a compound having the formula:

wherein R is as previously defined which compound is treated with ammonia or a mono or diloweralkyl amine, to produce the desired product.

3. A process of Claim 1 for the preparation of a compound having the formula:

wherein each R1 and R2 is independently hydrogen or loweralkyl and R is a halogenated unsaturated alkyl group containing from 2 to 6 carbon atoms, one or two double bonds or a single triple bond, and from 1 to 11 halogen atoms; which comprises chlorosulfonating a compound having the formula:

to produce a compound having the formula:

wherein R, R1 and R2 are as previously defined which compound is treated with ammonia or a mono- or di-loweralkylamine to produce the desired product.

4. A process of Claim 1 for the preparation of a compound having the formula:

wherein each R1 and R2 is independently hydrogen or lower-alkyl; R is a halogenated unsaturated alkyl group containing from 2 to 6 carbon atoms, one or two double bonds or a single triple bond and from 1 to 11 halogen atoms; and R3 and R4 are independently loweralkyl, benzyl, furfuryl or phenyl, which comprises treating a compound having the formula:

wherein R, R1, R2, R3 and R4 are as previously defined and Hal is a halogen, with an amine having the formula:

wherein R3 and R4 are as previously defined.

5. The process of Claim 2, which comprises chloro-sulfonating 2-(3-aminophenyl)-1,2,2-trichloroethylene to form the 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonyl-chloride and reacting said compound with ammonia to form the 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide.

6. The process of Claim 5, wherein the 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonyl chloride obtained is reacted with methylamine to form the 4-amino-N1,N3-dimethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide.

7. The process of Claim 2, which comprises chloro-sulfonating 1,2-dichloro-1-(3-aminophenyl)-1-propene and reacting the product thus obtained with ammonia to form the 1,2-dichloro-1-(5-amino-2,4-disulfamylphenyl)-1-propene.

8. The process of Claim 4, which comprises reacting 4-bromo-6-trichlorovinyl-1,3-benzenedisulfonamide with benzyl-amine to form the 4-benzylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide.

9. A compound having the formula:

wherein:
R1 and R2 are each independently hydrogen or lower-alkyl;
R is a halogenated unsaturated alkyl group contain-ing from 2 to 6 carbon atoms, one or two double bonds or a single triple bond, and from 1 to 11 halogen atoms; and R3 and R4 are independently hydrogen, loweralkyl, benzyl, furfuryl or phenyl, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

10. The compound of Claim 9, wherein R3 and R4 are both hydrogen, when prepared by the process defined in Claim 2 or 3 or by an obvious chemical equivalent.

11. The compound of Claim 9, wherein R3 and R4 are not both hydrogen, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

12. The 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzene-disulfonamide, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

13. The 4-amino-N1,N3-dimethyl-6-(1,2,2-trichloro-vinyl)-1,3-benzenedisulfonamide, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

14. The 1,2-dichloro-1-(5-amino-2,4-disulfamyl-phenyl)-1-propene, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.

15. The 4-benzylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.