NO142667B - PROCEDURE FOR MANUFACTURING ANTHELMINTICS. - Google Patents

Description

The present invention relates to the production of new substituted benzenedisulfonamides which are active anthelmintic agents which are particularly useful against fascioliasis in sheep and cattle. Particularly active compounds are 4-amino-1,3-benzenedisulfonamide compounds substituted in the 6-position with an unsaturated substituted alkyl group. Preparations containing the new substituted benzenedisulfonamides are useful in anthelmintic therapy, particularly against liver flukes.

Many sulfonamides, especially benzenesulfonamide compounds

has been known for many years. They have generally been prepared and investigated for their activity as antibacterial and diuretic agents, and much data has been published regarding the bacteriostatic and diuretic activity of sulfonamide compounds. In addition, certain benzenedisulfonamides have been prepared as intermediates in the preparation of diuretics with considerable diuretic activity. It has not been published that such diuretics have any anthelmintic activity. The benzenedisulfonamides produced according to the present invention are, however, new compounds that have not previously been discussed.

The new anthelmintic compounds produced according to the invention are generally classified as benzenedisulfonamides.

More specifically, they can be designated as 4-amino-6-substituted-1,3-benzenedisulfonamides. These compounds have considerable and unexpected anthelmintic activity and show particularly high activity against Fasciola or liver flukes in animals. The process compounds also have considerable parasiticidal activity.

It is thus an aim of the present invention to provide a method for the production of new anthelmintic compounds. A further aim of the invention is to provide new substituted benzenedisulfonamide compounds which have considerable anthelmintic and fasciolicidal activity.

The process compounds which are active anthelmintic agents are best represented by the following structural formula:

wherein each of and R~ is hydrogen or lower alkyl, and R is a halogenated unsaturated hydrocarbon group containing 2-6 carbon atoms, 1 or 2 double bonds or a single triple bond and from 1 to 11 halogen atoms.

The preferred compounds produced according to the invention are those where R is a carbon chain with 2-4 carbon atoms containing a single double bond and 2-6 halogen atoms.

The most preferred compounds produced according to the invention are those where the halogen atom on the R group is chlorine or fluorine or a mixture thereof.

Examples of the most preferred compounds produced according to the invention are

4-Amino-6-trichlorovinyl-1,3-benzenedisulfonamide

4-amino-6-(a,R-difluoro-S-chlorovinyl-1,3-benzenedisulfonamide 4-amino-6-(a,0-dichloro-0-fluorovinyl)-1,3-benzenedisulfonamide 4-amino-6 -trifluorovinyl-1,3-benzenedisulfonamide 4-amino-6-(2,2-dichlorovinyl)-1,3-benzenedisulfonamide 4-amino-6-(1,2-dichlorovinyl)-1,3-benzenedisulfonamide 4-amino- 6-(1,1-dibromo-1-penten-2-yl)-1,3-benzenedisulfonamide 4-amino-6-(3,3,3-trifluoropropynyl)-1,3-benzenedisulfonamide.

Method The compounds are generally prepared by a method indicated in the following reaction core:

where R, R 1 and R 2 are as indicated above.

In the first step of this process, an appropriately substituted aniline compound is treated with chlorosulfonic acid. The reaction is initially carried out with external cooling due to a possible exothermic reaction when the starting material and reagent are combined. In general, the amine is added dropwise or portionwise over a period of from 5 minutes to 2 hours, to the chlorosulphonic acid, the reaction temperature being maintained at from -10° to 10°C. When the addition is finished, the reaction temperature is raised to from 50° to 200°C for from 15 minutes to 4 hours. The use of a solvent is optional, and is generally only used when the reaction temperature is below 100°C. However, it is preferred to carry out the reaction without a solvent. The product, benzenedisulfonyl chloride, is recovered from the reaction mixture by methods known per se.

The benzenedisulfonyl chloride is then reacted with ammonia or

a mono- or di-lower alkylamine to form the desired benzenedisulfonamide. The reaction can be carried out with aqueous solutions of ammonia or the mono- or di-lower alkylamine, non-aqueous solutions of ammonia or the mono- or di-lower alkylamine in any unreactive organic solvent such as benzene, toluene, ether, chloroform and similar, or the reaction can be carried out in liquid ammonia or amine. The reaction is somewhat exothermic, and when an amine other than liquid ammonia is used, external cooling is required. In liquid

ammonia, the reaction temperature is maintained at the temperature for liquid ammonia. The product is isolated and purified by methods known per se.

The process compounds can also be prepared by chlorosulfonation of a suitably substituted O-aminobenzenesulfonamide followed by amination as indicated by the following reaction scheme:

where R, R 1 and R 2 are as previously indicated. Chlorosulfonic acid is generally preferred as the chlorosulfonating agent in the processes indicated above. The chlorosulfonic acid is then treated with ammonia or a mono- or di-lower alkylamine in the same manner as previously indicated to obtain the desired product. The product is isolated in a manner known per se. It is obvious that the method described above can give compounds in which the groups -NR^R^ on each of the sulfonamide units are different from each other.

The starting materials for the preceding methods are generally previously known, or methods have been published by which they can be easily prepared.

The meta-substituted aniline in the first described synthesis where R is an unsaturated halogenated alkyl group in which the unsubstituted is i i; The ,0 position in relation to the benzene ring can be prepared according to the following reaction scheme:

where Ph is phenyl, R 3 is hydrogen, lower alkyl or halogenated lower alkyl, and X 1 and X 2 are each halogen.

l't the starting material by i\miiv i"remganesmat o or ot n-n.it ro-benzaldehyde or a m-nitro-phenyl-lower alkyl- or -halogen-lower alkyl-ketone. The reagent (Ph), P=CX1\. . the starting materials, the triphenylphosphine, the halogenated methane and the aldehyde or ketone in a single reaction vessel at a temperature from room temperature to 200°C. As the phosphorus reagent is prepared in situ, the starting material is readily available for conversion, avoiding problems with storage and stability of the reagent. The reaction mixture is kept within the above temperature range for from 1 to 24 hours, and the product is isolated in a manner known per se. The halogenated methane is generally used in excess so that no further dissolution agent is necessary, but an unreactive solvent could possibly be used. The nitro compound from the above reaction is then reduced to the corresponding amino compound using reduction methods such as iron and hydrochloric acid or zinc and acetic acid. The amino compound thus obtained is treated with chlorosulfonic acid followed by ammonia according to the methods already described to obtain the desired product. A variant of the above method starts from the readily available unsubstituted benzaldehyde or phenyl-lower alkyl- or -haloaenert-lower alkyl-ketone: ;;where Ph, R , X and X are as indicated above. ;The benzaldehyde or ketone is treated with the Ph2P=C(R)2 reagent according to the methods indicated above. The halogenated vinyl or propenyl compound thus obtained is then nitrated. The nitration is p-directed, and thus the p-nitro compound is obtained. The reaction is carried out in an excess of nitrating agent such as nitric acid, fuming nitric acid or the like, in the presence of a dehydrating agent such as concentrated sulfuric acid, acetic anhydride or the like. The reaction mixture is kept at from 0° to 50°C for from 15 minutes to 3 hours. The product is isolated from the nitration reaction mixture in a manner known per se. The nitrated compound is then reduced to the corresponding amino compound by usual reduction methods. To facilitate the subsequent steps of the synthesis, however, the amino group is generally protected with a suitable protecting group such as an acyl, preferably acetyl, function. The amino group is acylated with any of the common acylating reagents available, such as acid chlorides, anhydrides, carboxylic acids, and the like, corresponding to the desired protecting group. The protected amine compound is then nitrated using the nitration methods described above. The recovered compound is the m-nitro, p-amino compound. After the nitration, the protective group is removed in a manner known per se. In the case of acyl-protecting groups, acid- or base-catalyzed hydrolysis readily affords the free amine. ;The free amine is then diazotized to obtain the sulfonamide group. ;The amine compound is diazotized in the presence of aqueous acid such as hydrochloric or sulfuric acid, and sodium nitrite at from 0° to 20°C. The diazonium salt is then treated with a solution of sulfur dioxide and crystalline cupric chloride in acetic acid and sufficient water to effect dissolution. The reaction mixture is kept at from 0° to 20°C for from 5 minutes to 3 hours. The sulfonyl chloride group thus isolated from the diazotization reaction is treated with ammonia or a mono- or di-lower alkylamine as described above, yielding the mono-sulfonamide as chlorosulfon<p>rn? and aminated as described above. Another method for preparing the 3-R-aniline starting materials uses an m-nitroaniline as a precursor. The m-nitro-aniline is diazotized with a mineral or organic acid, sodium nitrite and water as described above. The diazonium salt is then treated with an ethylene compound of the formula: ;R,RCC=CHX ;in the presence of a crystalline cupric chloride dihydrate and acetone or other suitable unreactive organic solvent. In the above formula, X is halogen, and R₂ and R₂ are each halogen, or one of R₂ and R₂ may be halogen and the other hydrogen, lower alkyl or halogenated lower alkyl. The reaction is initially carried out at from -20° to 20°C, and after the initial reaction is kept substantially at room temperature for from 1 to 48 hours to complete the reaction. The product formed has the formula: where X, R^ and R^ are as indicated above. This compound is then dehydrohalogenated to: ;where R^ and R^ are as indicated above. The dehydrohalogenation is carried out using an alkali metal hydroxide or alkoxide or an organic base such as triethylamine, in the presence of a suitable solvent such as a lower alkanol, preferably methanol or ethanol. The nitro group is then reduced using the reduction methods described above, and the amino compound formed is chlorosulfonated and aminated. Optionally, the chlorine-sulfonation and amination reactions can be carried out before the diazotization and dehydrohalogenation reaction steps. In particular, 2-(3-aminophenyl)-1,1,2-trichloroethylene is best prepared from the known starting material 2-(3-aminophenyl)-1,1,1,2,2-pentachloroethane, which is dehalogenated using zinc in ethanol at the above reaction conditions. The above method is also applicable to prepare other compounds where the substitution is on any other carbon atom by using the appropriate starting materials. The process compounds have applications in the field of animal therapy. They are effective against both fully developed and incompletely developed liver flukes of the species Fasciola gigantica and Fasciola hepatica, the common liver fluke in sheep and cattle. The preferred dosage amounts depend on the type of compound used, the type of animal being treated, the particular helminth being controlled, and the degree of helminthic infection. in general, effective icteric eradication is achieved when the compounds are administered in a single dose at dose amounts from approx. 1 to 150 mg/kg animal body weight and preferably from approx. 1 to 50 mg/kg animal body weight. Procedure - the compounds can be administered in a number of ways depending on the particular animal being treated, the type of anthelmintic treatment usually applied to such animals, the materials used; and in particular the helminths being controlled. It is preferred to administer them in anthelminthically effective amounts in a single or divided oral or parenteral dose at a time when ichthyosis infection is obvious or suspected in the animal. ;In addition to the inactive ingredients in the preparation, the preparation may contain one or more active ingredients which can be selected from the compounds of formula I or from other known anthelmintic agents Good results have been obtained when the compounds of formula I are combined with an anthelmintic agent such as 2-(4-thiazolyl)-benzimidazole ("Thia bendazo le") or "Tetramisole" (dl-2,3,5,6 -tetrahydro-6-phenylimidazo-[2,1-bJ-thiazole) or other known anthelmintic agents. Generally, preparations containing the active anthelmintic are used connection. The amounts of anthelmintic component in the preparation as well as the other components vary according to the type of treatment used, the host animal and the particular helminthic infection being treated. In general, however, preparations suitable for oral administration containing a total weight % of the active compound or compounds varying from 0.01 to 95% will be suitable, the remainder of the preparations being a suitable carrier or medium. A number of treatment methods can be used, and each determines to some extent the general nature of the preparation. For example, the anthelmintic compounds can be administered to livestock in a uniform oral dosage form such as a tablet, bolus, capsule or drench, a liquid oil base form suitable for parenteral administration, or they can be prepared as a premix for later addition to the animal feed. When the preparations are to be solid unit dosage forms such as in tablets, capsules or boluses, the ingredients apart from the active compounds may be any other non-toxic medium convenient for preparing such forms, and preferably materials suitable for being given as starch, lactose, talc, magnesium stearate, vegetable gums and the like. When capsules are also used, the active compound can be used essentially in undiluted form, the only inactive material being that in the capsule itself, which can be hard or soft gelatin or other orally acceptable encapsulating materials. When the dosage form is to be used for parenteral administration, the active material is suitably mixed with an acceptable oil base medium, preferably of a vegetable oil type such as peanut oil, cottonseed oil and the like. In all such forms, i.e. in tablets, boluses, capsules and oil base preparations, the amount of active ingredient is conveniently in the range from approx. 5 to 95% by weight of the total preparation. When the unit dosage form is to be in the form of a soak, the anthelmintic agents can be mixed with agents that will assist in the subsequent suspension of the active compounds in water, such as bentonite, clays, water-soluble starches, cellulose derivatives, gums, surfactants and similar, to form a dry pre-soak preparation, and this pre-soak preparation is added to water just before use. In the pre-soaking preparation, in addition to the suspending agent, such ingredients as preservatives, anti-foaming agents or other suitable diluents or solvents can be used. Such a dry product may contain as much as 95% by weight active compound, the remainder being excipient. Preferably, the solid preparations contain from 3<0 to 95% by weight of active compound. Sufficient water should be added to the solid product to provide appropriate dose levels with a convenient amount of liquid for a single oral dose. The commonly used measure in the area is 30 ml of material, and thus 30 ml of the material should contain sufficient anthelmintic compounds to provide an effective dose mirror. Liquid soaking preparations containing from 10 to 50% by weight of dry ingredients will generally be suitable, with a preferred range being from 15 to 25% by weight.

When the preparations are intended to be used in precursors, precursor additives or pre-premixes, they will be mixed with suitable components of the animal feed. Solid orally ingestible carriers commonly used for such purposes, such as dried berm, corn husks, citrus flour, attapulgite clay, wheat bran, molasses, corn cob meal, vegetable matter, toasted, dehulled soybean meal, soybean meal lining, antibiotic mycelia, soybean meal, crushed limestone and the like , is suitable. The active compounds are dispersed or intimately mixed with the active solid carrier by methods such as grinding, melting or tumbling. By choosing a suitable diluent and by changing the ratio between carrier and active ingredient, preparations of any desired concentration can be prepared. Additive preparations containing from approx. 5 to 30% active ingredient, is particularly suitable for addition to for.

The active ingredient is usually dispersed or mixed uniformly

in the diluent, but in some cases it may be adsorbed on the carrier.

These additives are added to the finished animal feed

an amount sufficient to provide the desired final concentration to combat or treat the helminth infection via the animal route. Although the preferred content will depend on the particular compounds used, the active compounds produced according to the invention are usually given in amounts of 0.01 - 3%• As stated above, the animals are preferably treated at a time when the infection is obvious or is suspected, and the most preferred method of treatment is with oral doses. Administration of medicine-containing for is thus not preferred,

mén can be used. In a similar way, the amounts of drug present in the feed can be reduced to amounts of the order of 0.01 - 0.5% by weight, calculated on the weight of the feed and the drug-containing substance for administration over longer periods of time. This can be in the form of a preventive or prophylactic precaution. Another method of administering the disclosed compounds to animals whose feed is conveniently pelletized, such as sheep, is to incorporate them directly into the pellets. For example, the anthelmintic compounds are easily incorporated into the nutritionally sufficient lucerne pellets in amounts of 4.4 - 22 g/kg for therapeutic use and smaller amounts for prophylactic use, and such pellets are fed to the animals.

Examples of preparations suitable for administration to animals are:

A typical bolus preparation is as follows:

A typical soaking preparation is as follows:

Examples of typical premixes for addition to lining are as follows:

The above premixes for addition to fodder are combined with the usual animal fodder and mixed intimately so that the final concentration of the active ingredient is from 0.01 to 3% by weight.

Example IA

4- 3mino- 6- fl, 2, 2- trichloroviny1)- 1, 3- benzenedisulfonamide

32.8 g of 2-(3-aminophenyl)-1,1,2-trichloroethylene are added dropwise with stirring to 107 ml of chlorosulfonic acid kept at +10°C. When the addition is finished, the reaction mixture is heated to 125 - 130°C and stirred at this temperature for 2.5 hours. It is then cooled to 20°C, and 40.2 ml of thionyl chloride is added in portions. After this, the reaction mixture is stirred at 80°C for 1.5 hours and then cooled in ice to +10°C. The reaction mixture is poured onto ice, and the 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonyl chloride is extracted into methylene chloride, washed with water, dried over magnesium sulfate and evaporated in vacuo to 52 g of a brown foam. The brown solid is dissolved in 60 ml of methylene chloride and added in portions to 250 ml of liquid ammonia. The excess of ammonia and methylene chloride is allowed to evaporate overnight. Water is added to the residue, and it is gently acidified with concentrated hydrochloric acid, which gives an amorphous precipitate. This is extracted in ethyl acetate, washed with water, dried over magnesium sulphate and evaporated in vacuo to 45 9 brown foam. This is extracted twice with hot benzene, leaving 38.5 g of brown solid. The residue is extracted by boiling with 3 x lOOO ml of ether, and the ether solutions are evaporated in vacuo to 250 ml, and the crystalline product is collected by careful addition of hexane, which after filtration gives 20.8 g of product-ether complex with melting point 130 - 135°C . This is boiled with 175 ml of water, without dissolving much of the compound for 1/2 hour, and it is then allowed to reach room temperature, filtered, washed with water, dried in vacuum at 50°C, whereby 17.0 g is obtained 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with melting point 188 - 193°C. A small sample is recrystallized for analysis from aqueous methanol and then melts at 205 - 207°C.

Example IB

4-amino-N 1 ,N 3-dimethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide 10 g 4-amino-6-(1,2,2-trichlorovinyl)-1,3 -benzenedisulfonyl chloride, prepared as in example IA, is added to 150 ml of liquid methylamine at -78°C. When the addition is finished,

the cooling bath is removed, and the excess methylamine is allowed to evaporate. The solid residue is taken up in water and made acidic with it

acetic acid. A dark precipitate is collected by filtration and dried, whereby 7.4 g of crude product is obtained. Purification by chromatography on a silica gel column and crystallization from ethanol gives 2,9 9 4-amino-N<1>,N<3->dimethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 211 - 212°C.

Example 1C

4-amino-N<1>,N<1>,N<3>,N<3->tetramethy1-6-(1,2,2-trichlorovinyl)-1,3~ benzenedisulfonamide

10 g of 4-amino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonyl chloride, prepared as in Example IA, is treated with 125 ml of dimethylamine. The reaction mixture is worked up in a similar way as in

113 3 example IB, whereby 5.2 g of pure 4-amino-N,N,N,N-tetramethyl-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with melting point 238 - 239° is obtained C.

Example 2

4- amino- 6-( 2 - chloro- 1, 2- difluorovinyl)- 1, 3- benzenedisulfonamide

a) (1, 2- difluoro-l f2 , 2- trichloroethyl)- benzene

A solution of 8^ g of 0-chloro-a,Ø-difluorostyrene in 200 ml

carbon tetrachloride is chlorinated at room temperature with chlorine for 22 hours. The reaction mixture is then washed with water and aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated by distilling off the solvent at atmospheric pressure through a Vigreaux column. The liquid residue is then distilled in vacuum at 20 mm Hg, whereby 100 g of (1,2-difluoro-1,2,2-trichloroethyl)-benzene is obtained which boils at 96 - 97°C, Ng5=1.5073.

b) 3-(1,2-difluoro-1,2,2-trichloroethyl)-nitrobenzene

100 g of (1,2-difluoro-1,2,2-trichloroethyl)-benzene is added

dropwise over 30 minutes to a vigorously stirred nitration mixture of 80 ml of concentrated nitric acid in 400 ml of concentrated sulfuric acid while the temperature is kept between 15° and 25°C by cooling with an ice bath. When the addition is finished, stirring is continued at room temperature for 5 hours. It is then poured onto ice and the product is extracted with methylene chloride. This solution is washed with water and aqueous sodium bicarbonate solution, dried and evaporated in vacuo to a yellow oil. The oily residue is distilled in vacuum at 2.2 mm Hg whereby 104 g of 3-(1>2-difluoro-1,2,2-trichloroethyl)-nitrobenzene with a boiling point of 122 - 124°C is obtained.

c) 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline

104.4 g 3-(1,2-difluoro-1,2,2-trichloroethyl)-nitrobenzene

is added over the course of 10 minutes to a solution of 325 g of crystalline stannous chloride (SnCl2-2H20) in 325 g of concentrated salt r acid and 325 g of ethanol with vigorous stirring, the temperature being kept at 50°C. Stirring is continued for a further 3 hours. It is cooled in ice, and the precipitate is collected by filtration. The solids are then suspended in 500 ml of water and 500 ml of methylene chloride, the mixture is cooled in ice and made alkaline by the addition of 50% aqueous sodium hydroxide until almost all the solids have dissolved. The methylene chloride layer is separated, washed with water, dried with sodium sulfate and evaporated in vacuo to 75 Q of 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline as a yellow oil.

d) 3~(2-chloro-1,2-difluorovinyl)-aniline

74 g of zinc dust is added to a vigorously stirred solution

of 40 g of 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline in 450 ml of ethanol and heated under reflux for 2 hours. There, it is filtered hot, the solid residue is washed with hot ethanol, and the combined/ethanol solutions are cooled to room temperature. About. 1000 ml of chloroform is added, and the organic layer is washed with aqueous sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated in vacuo to 23.9 n of oily 3-(2-chloro-1,2-difluorovinyl)-aniline. This gives a single peak with a retention time of 1.8 minutes at 200°C on a gas-liquid chromatography column packed with 5% "SE30", and the correct values for C, H, N, Cl and F by combustion analysis .

e) 4-amino-6-(2-chloro-1,2-difluorovinyl)-1,3-benzenedisulfonamide 2.0 g of 3-(2-chloro-1,2-difluorovinyl)-aniline are added dropwise

to 20 ml of ice-cold and well-stirred chlorosulfonic acid. 20 g of dry sodium chloride are added in portions over 30 minutes at room temperature. The reaction flask is immersed in an oil bath and heated at 115 - 120°C for 4 hours. It is cooled in ice and added in portions to ice water. This is treated with methylene chloride, the organic layer is washed with water, dried and evaporated in vacuo to give crude 4-amino-6-(2-chloro-1,2-difluoro-vinyl)-1,3-benzenedisulfonyl chloride, which is identified by a molecular ion peak at 385 in the mass spectrum with the characteristic pattern expected for a trichloro compound. This is immediately added to liquid ammonia and left overnight, while excess ammonia is allowed to evaporate. The residue is dissolved in a small amount of water, acidified with dilute hydrochloric acid and extracted with ethyl acetate, dried and evaporated in vacuo to 600 mg of crude 4-amino-6-(2-chloro-1,2-difluorovinyl)-1,3-benzenedisulf onamide. The nuclear magnetic resonance spectrum shows the two individual peaks at 7.35 and 8.25 if expected for this product, representing the protons in the 5- and 2-position of the 1,3,4,6-tetrasubstituted benzene ring. Further purification of this product by preparative layer chromatography on 2.0 mm thick layers of silica gel with a benzene-ethyl acetate mixture (1:1) as liquid phase gave 210 mg of pure product which from a methylene chloride-ether mixture gave white crystals with a melting point of 184 - 187 °C, and a molecular ion of 347 by the mass spectrometer ri.

Example 3

1, 2- dichloro- 1-( 5- amino- 2, 4- disulfamoylphenyl)- propene

a) 1, 1, 2, 2- tet raclor- 1- f3-" it ropheny1)- propane

47 g of 1,1,2,2-tetrachloro-l-phenyl-l-propane are added dropwise

during 45 minutes to a well-stirred nitration mixture of 31.2 ml of concentrated sulfuric acid and 16.9 ml of concentrated nitric acid while maintaining the temperature between 25° and 35°C. The stirring is continued for a further 3 hours at room temperature, after which the reaction mixture is poured into ice water, extracted with methylene chloride, evaporated in vacuo and crystallized from 125 ml of methanol, whereby 29 g of yellow crystalline 1,1,2,2-tetrachloro-1-(3-nitrophenyl) are obtained )-propane with a melting point of 75.5 - 77°C.

b) 1, 2-dichloro-1-(3-aminophenyl)-1- propert

13 g of 1,1,2,2-tetrachloro-1-(3-nitrophenyl)-propane and 7.9 g

iron powder is vigorously stirred under reflux in 465 ml of 50% aqueous ethanol. 5.6 ml of a solution prepared in advance from 52 ml of concentrated hydrochloric acid and 250 ml of 50% aqueous ethanol are added dropwise over the course of 5 minutes. After an additional 2 hours of stirring at reflux temperature, the hot reaction mixture is filtered, cooled to room temperature, diluted with sufficient chloroform to double the volume of ethanol, and made alkaline with saturated aqueous sodium bicarbonate solution.

The organic layer is separated, washed with water, dried and evaporated in vacuo, whereby a mixture of essentially pure cis- and trans-1,2-dichloro-1-(3-aminophenyl)-1-propene is obtained as a gu1 oil.

c) 1, 2- dichloro- 1-( 5- amino- 2, 4- disulfamoylphenyl)- 1- propene

1.0 g of 1,2-dichloro-1-(3-aminophenyl)-1-propene is added dropwise to 13 ml of ice-cold chlorosulfonic acid, followed by 13 g of dry sodium chloride over the course of 35 minutes. The reaction mixture is heated to 125°C within 30 minutes and held at this temperature for 1.5 hours. It is cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate and evaporated in vacuo to 900 mg of crude disulfonyl chloride intermediate. This is added to liquid ammonia and left overnight. The crude disulfonamide is isolated by adding water, acidified with dilute hydrochloric acid, extracted with ethyl acetate, and the extract evaporated in vacuo. Further purification by preparative layer chromatography on silica gel coated plates gave 40 mg of essentially pure 1,2-dichloro-1-(5-amino-2,4-disulfamoylphenyl)-1-propane.

Claims (1)

Procedure for the preparation of a compound with the formula: where and R2, which are the same or different, are hydrogen or lower alkyl, R is a halogenated unsaturated hydrocarbon group with 2-6 carbon atoms, 1 or 2 double bonds or a single triple bond, and 1-11 halogen atoms, characterized in that a compound of the formula : above, is reacted with chlorosulfonic acid to form a compound with the formula: above, which compound is treated with ammonia or a mono- or di-lower alkylamine.