CH539026A - 1-Phenyl-3-carbalkoxy-2-thioureas - with anthelmintic pesticidal and antiviral activity - Google Patents

Abstract

Therapeutic compns., feedstuffs and feed concentrates contain at least one title cpd. of formula (I) and/or, when Y is NH2, an acid addn. salt thereof with a pharmaceutically acceptable anion: (where R5 is -N(R8)CSNHCOOR7 in which R7 is not >4C (un)satd. aliphatic hydrocarbyl opt. substd. by a halogen atom or is not >4C alkoxy gp. and R8 is H or CH3; R6 is H, halogen, is not >4C alkyl, 1-4C alkanoylamino opt. C-substd. by 3-6C cycloalkyl, 2-4C alkoxycarbonylamino, 2-4C alkanoyl, benzoyl or CH3SO2N(OH3)-; and Y is a group of the type defined for R5 or is NO2 or NR9R10 in which R9 and R10 are H or R9 is H or CH3 and R10 is 1-4C alkanoyl opt. substd. by 3-6C cycloalkyl, 2-4C alkoxycarbonyl or -COA1Z1 in which A1 is an (un)satd. straight chain is not >4C aliphatic hydrocarbon gp. opt. substd. by one or more CH3 gps. and Z1 is COOH, -NR11R12R13X2- or -NR12R13, where R11 is H or is not >4C alkyl, R12 is H, is not >4C alkyl or phenyl-(1-2C alkyl) and R13 is H or is not >4C alkyl, or NR12R13 is a 5- to 7-membered heterocyclic ring opt. contg. 1 or 2 further hetero atoms selected from N, O and S and opt. substd. by one or more 6 C alkyl gps., and X2- is a pharm. acceptable anion). (I) have anthelmintic, pesticidal (antifungal) and antiviral activity. Some cpds. (I) are new, and processes for the prepn. are claimed.

Description

       

  
 



   The present invention relates to a process for the preparation of products of general formula:
EMI1.1
 wherein R5 represents the group N (R8) CSNHCOOR7;
 R7 represents a saturated or unsaturated straight or branched aliphatic hydrocarbon radical comprising not more than 4 carbon atoms, unsubstituted or substituted by a halogen atom or an alkyloxy group comprising at most 4 carbon atoms;
 R8 represents a hydrogen atom or a methyl radical;
 R6 represents a hydrogen or halogen atom; an alkyl radical comprising at most 4 carbon atoms;

   an alkanoylamino group comprising from 1 to 4 carbon atoms, the alkanoyl portion of which is straight or branched, unsubstituted or substituted by a cycloalkyl radical comprising from 3 to 6 carbon atoms, a straight or branched alkyloxycarbonylamino radical comprising from 2 to 4 carbon atoms carbon, a straight or branched alkanoyl radical comprising from 2 to 4 carbon atoms, a benzoyl group or a CH3SO2N (CH3) group;
 Y represents a group -N <R8) CSNHCOOR7, the symbols
R7 and R8 having the definitions mentioned above;

   a nitro radical or a group -NR9R10 in which either R9 and R10 each represent a hydrogen atom, or R9 represents a hydrogen atom or a methyl radical while Rl represents a straight or branched alkanoyl group comprising from 1 to 4 atoms carbon, unsubstituted or substituted by a cycloalkyl group having from 3 to 6 carbon atoms;

   a straight or branched alkyloxycarbonyl group comprising from 2 to 4 carbon atoms, a COTA'XI group in which Al represents a saturated or unsaturated aliphatic hydrocarbon radical comprising at most 4 carbon atoms, unsubstituted or substituted by at least one group methyl and Z 'represents a carboxy group or a group of the general formula
EMI1.2
 in which R12 represents a hydrogen atom or an alkyl radical comprising at most 4 carbon atoms, a phenylalkyl radical in which the alkyl part contains 1 or 2 carbon atoms;

  ;
   R13 represents a hydrogen atom or an alkyl radical comprising at most 4 carbon atoms, or R12 and R13 with the nitrogen atom to which they are attached form a 5, 6 or 7-membered heterocycle, the ring of which may comprise a or two additional heteroatoms chosen from oxygen, nitrogen or sulfur, unsubstituted or substituted by one or more alkyl radicals comprising at most 6 carbon atoms as well as. when
Y represents the amino radical of their addition salts with acids.



   A subject of the invention is in particular the manufacture of the products of formula (VI) in which: a) R6 represents an alkyl radical comprising from 2 to 4 atoms
 carbon, alkanoylamino having from I to 4 atoms of
 carbon, alkanoyl having 2 to 4 carbon atoms,
 benzoyl or N-methylmethanesulfonylamino, alkyloxy
 carbonyl-amino having 2 to 4 carbon atoms;
 Y represents a group NR9Rt0 in which R9 represents
 a hydrogen atom or a methyl radical and
   R1 represents a hydrogen atom. an alkanoyl radical
 comprising from 1 to 4 carbon atoms or a radical
 alkyloxycarbonylamino, the alkyl group of which includes
 from 2 to 4 carbon atoms;
 R7 and R8 being defined as above.



   b) R6 represents an alkyl radical comprising from 2 to 4 atoms
 carbon, alkanoylamino containing from 1 to 4 carbon atoms
 carbon in position 3, 4 or 5 of the benzene ring,
 alkyloxycarbonylamino comprising from 2 to 4 atoms of
 carbon in position 3, 4 or 5 of the benzene ring,
 alkanoyl having 2 to 4 carbon atoms, benzoyl,
 or N-methylmethanesulfonylamino and
 Y represents a nitro group;
 R7 and R8 being defined as above.



  c) R6 represents an alkyl group having 1 to 4 atoms
 carbon, an alkanoylamino radical comprising from 1 to
 4 carbon atoms, an alkyloxycarbonylamino radical
 in which the alkyl radical contains from 2 to 4 atoms of
 carbon, alkanoyl having 2 to 4 carbon atoms,
 benzoyl, N-methylmethanesulfonylamino;
 Y represents a group NR9 CO Al Z 'in which R9 represents
 feels a hydrogen atom or a methyl radical and A
 and Z 'are defined as in claim,
 R7 and R8 being defined as above.



   The process, object of the present invention, is characterized in that one reacts an isothiocyanate of general formula
 SCNCOOR7 (VII) on a
EMI1.3


<tb> amine <SEP> of <SEP> general <SEP> formula <SEP> NHR8
<tb> <SEP> R6NHR8
<tb> <SEP> R6ÇÇy <SEP> (VIII)
<tb> <SEP> Y
<tb> in an inert organic solvent at a temperature between 0 C and 150 C, R6, R7, R8, Y being defined as above.



   The products of formula (VI1, the primary interest of which is anthelmintic and antivirus activity, have also been shown to be active as agricultural pesticides, in particular they exhibit a fungicidal action against pathogenic fungi of plants and also against certain pathogenic species of animals in especially Trichophyton mentagrophytes.



   The products of formula (VI) can in particular be used for combating Alternaria solani, Botrytis cinerea, Cercopora beticola.



  Cladosporium fulvum, Collectotrichum lagenarium, Corynespora -melongenae, Elsinoe fawcetti, Erysiphe graminis, Fusarium sambucinum, Glomerella cingulata, Helminthosporium species (e.g. H. signoideum and H. avenae), Mycosphaerella and species (e.g. M. pomi). Pellicularia sasaki, Penicillium species, Phaeoisariopsis vitis, Piricularia oryzae, Podosphaerea
 Leurcotricha, Pseudoperonospora humuli. Sclerotinia species (e.g. S. cinerea and S. sclerotiorum), Sphaerotheca species
 (eg S. fuliginea and S. humuli) and Venturia inaequalis.

 

   As anthelmintics and fungicides, the methoxycarbonyl-1 (2-dimethylaminoacetamido-phenyl3 thiourea
 (hydrochloride) methoxycarbonyl-1 (trimethylammoniumacetamido-2 phenyl3
 thiourea (iodide) 1-ethoxycarbonyl (2-dimethylaminoacetamido-phenyl3 thiourea
 (hydrochloride) ethoxycarbonyl-l (2-amino-4-fluorophenyl3 thiourea methoxycarbonyl-l (2-amino-4-butyl-phenyl3 thiourea l-methoxycarbonyl (2-nitro-phenyl3 thiourea
 methoxycarbonyl-1 (2-acetamido-4-butyl-4-phenylt3 thiourea methoxycarbonyl-1 (2-ethoxycarbonylamino-2-n-butyl-4-phenyl3
 thiourea
 methoxycarbonyl-1 (2-nitro-4-fluorophenylt3 thiourea
   1-ethoxycarbonyl (2-nitro phenyl5 thiourea
   ethoxycarbonyl- 1 [(N-benzyl N-methylaminoacetamido) -2
 phenyl] -3 thiourea

   (hydrochloride) ethoxycarbonyl-iodide (trimethylammonium 2-acetamido phenyl> 3 thiourea
   1-ethoxycarbonyl (2-di-n-butylaminoacetamido-2 phenyl3 thiourea
 (hydrochloride)
 ethoxycarbonyl-l [(N-methyl N-n-butyl aminoacetamidop2
   phenyll3 thiourea (hydrochloride) ethoxycarbonyl-l (piperidinoacetamido-2 phenylt3 thiourea
 (hydrochloride) methoxycarbonyl- 1 (dimethylaminopropionamido-2 phenylt3
 thiourea (hydrochloride) 1-ethoxycarbonyl (2-diethylaminoacetamido-phenylt3 thiourea
 (hydrochloride) ethoxycarbonyl-1 (morpholinoacetamido-2 phenyl) -3 thiourea
 (hydrochloride)
 Among these the following compounds have thus shown an interesting antiviral activity in particular against the influenza virus

   strain A2 Hong-Kong / 5/68: bis (allyloxycarbonyl-3 thio-2 ureidotl, 2 benzene ethoxycarbonyl-l [(N-methyl N-butylaminoacetamidot2 phé
   nyl3-3 thiourea (hydrochloride) methoxycarbonyl-l (acetamido-2 isopropyloxycarbonylamino-5 phenylt3thiourea methoxycarbonyl- 1 (acetamido-2 isopropyloxycarbonylamino-4
 phenylt3 thiourea ethoxycarbonyl-1 (2-amino-4-fluorophenyl> 3-thiourea (2-chloroethoxycarbonylkl (2-aminophenylt3 thiourea iodide of methoxycarbonyl-1 (trimethylammonium acetamido-2
 phenyl3 thiourea l-ethoxycarbonyl (4-acetamido-2-nitro phenyl3 thiourea l-methoxycarbonyl (methoxycarbonylamino-4-nitro-2 phenyl) W3
 thiourea

   methoxycarbonyl-1 (2-amino methoxycarbonylamino-4 phenyl3
 l-methoxycarbonyl thiourea (4-n-butyl-2-nitro-phenyl3-methoxycarbonyl-l-thiourea (4-chloro-2-nitro-phenyl-3-methoxycarbonyl-thiourea (2-cyclopropylcarbonamido-2-n-butyl-5 phe nylf3 thiourea bisyl-3 ureidoYl, 2-chloro-benzene-methoxycarbonyl-l (n-butyl-5 formamido-2 phenyl3 thiourea methoxycarbonyl-l (n-butyl-5 athoxycarbonylamino-2 phenyl} 3
 1-ethoxycarbonyl thiourea (2-acetamido isopropyloxycarbonylamino-5 phenylt3thiourea l-methoxycarbonyl (2-formamido-isopropyloxycarbonylamino-5
 phenyl3 thiourea (2-chloroethoxycarbonyltl (2-nitro-phenyl3 thiourea.



   The reaction which characterizes the process which is the subject of the invention is carried out in the presence of an inert organic solvent such as a lower alkanone (for example acetone or methyl ethyl ketone) a lower alkanol (for example methanol or ethanol), dioxane,
Acetonitrile or an aromatic hydrocarbon (for example toluene) at a temperature between 0 C and 150 ° C, preferably between 10 C and 60 ° C.



   When it is desired to obtain the product in the formula of which
Y represents the group N (R8) CSNHCOOR7, the reaction is carried out in the presence of an excess of the isothiocyanate of formula (VII).



   Isothiocyanates of general formula (VII) can be prepared by reacting an ester of general formula
   X3CO2R? (IX) (in which R7 is defined as above and X3 represents a bromine atom, iodine or preferably chlorine) and a thiocyanate of formula
 (NCS) qM (X) in which M represents a metal (preferably an alkali or alkaline earth metal) and q is the valence of this metal.



   The reaction can be carried out in the presence of an inert organic solvent such as a lower alkanone (eg acetone) or acetonitrile at a temperature between 0 ° C and 100 ° C, preferably between 20 ° C. and 50 C.



   The preparation of the compounds of formula (VII) can be carried out in situ for the subsequent reaction with the compounds of formula (VIII). The compounds of formula (VII) can also be isolated in known manner before reaction with the compounds of formula (VIII).



   When reacting equimolecular quantities of an isothiocyanate of formula (VII) and of an amine of formula (VIII) in which a) Y represents an amino radical and R8 a hydrogen atom or b) Y represents a methylamino radical, R represents a
 methyl radical, R6 being defined as above,
 we then obtain a compound in which Y represents
 an amino or methylamino radical respectively.



   The reaction can be carried out under the conditions described above. When R6 is other than a hydrogen atom in the compounds of formula (VIII) the reaction can give a mixture of compounds of formula (VI) isomers with respect to the relative positions of R6 and Y and Rs. These isomers can be separated in known manner, for example chromatography or fractional crystallization, therefore when Y represents an amino group, R6 is preferably hydrogen.



   The compounds of general formula (VIII) in which R6 is defined as above, R8 represents a hydrogen atom and Y is other than nitro. can be prepared by reduction of a compound of general formula:
EMI2.1
 in which R6 is defined as above and Y corresponds to the definition given above by the known methods of reduction of nitro aromatic groups, for example by hydrogenation in the presence of a catalyst (such as platinum) or using of a metal halide and reduced iron powder.



   The compounds of general formula (VIII) in which R6 and R8 are defined as above and Y represents the nitro radical, can be prepared by applying the known methods for the preparation of ortho nitro anilines and N-methyl-ortho-nitro anilines .



   It will be noted that the compounds of general formula (VIII) in which Y represents a group corresponding to the definition of R5 can be prepared by reduction of the compounds of general formula:
EMI2.2

 Compounds of formula (XXI) in which Y represents a group -NR9R10 (in which R9 is defined as above and R10 represents an alkanoyl or alkyloxycarbonyl group as defined) can be prepared by reaction of a compound of formula
EMI2.3


general <tb>:

  <SEP> 9 <SEP> NO
<tb> <SEP> R6 <SEP> (xxIr>
<tb> <SEP> NHR9
<tb> in which R6 and R9 are defined as above, with a compound of general formula:
 X3 CO R14 (XIII)
 in which X3 is defined as above and R14 represents a straight or branched alkyl radical comprising from 1 to 3 carbon atoms (optionally substituted by a cycloalkyl group comprising from 3 to 6 carbon atoms) or a cycloalkyl group comprising from 3 to 6 atoms carbon or an alkyloxy group having 1 to 3 carbon atoms or with formic acid. The reaction can be carried out in an inert organic solvent between 0 and reflux and preferably between 30 C and 100 C.



   The compounds of formula (XXI) in which Y represents a group -NR9R10 can be prepared by using known methods for the preparation of o-nitroanilines and N-methyl o-nitroanilines.



   The compounds of formula (XXI) in the formula of which Y represents the group -N (R9) COAZ1 (in which R9, A, Z 'are defined as above) can be prepared by reaction of a compound of formula:
EMI3.1
 in which R6, R4, Al and X3 are defined as above a) with a compound of general formula:
 HN R12 R13 (XVI) in which R12 and R13 are defined as above, an excess of which can be used as an acid acceptor:

   a product is obtained in which Y represents the group -NR9COA1Z1 (in which R9 and Al are defined as above) and Z represents a group of formula:
EMI3.2
 in which R11 is a hydrogen atom, R12 and R13 are
 defined as above and X2 / 3 is a halide anion corresponding to the halogen atom represented by X3 in the compound of general formula (XXIII); b) with a compound of general formula: NR11R12R'3 (XVII in which R12 and Rl3 are defined as above and R1 represents a straight or branched alkyl radical containing not more than 4 carbon atoms.

  The products of general formula (XXI) are obtained in the formula of which Y represents a group -N (R9) COA'Z 'in which R9 andAl are defined as above and Z' represents a group of formula:
EMI3.3
 in which R l is a straight or branched chain alkyl radical containing not more than 4 carbon atoms, R12 and R13 are defined as above and X2- is a halide ion corresponding to the definition of X3.



   Compounds of general formula (XXIII) can be prepared by reacting a compound of general formula (XXII) in which
R6 and R9 are defined as above, with a compound of general formula
   X'COA1X3 (XXIV) in which Al and X3 are defined as above.



   The reaction is preferably carried out in an inert organic solvent (for example a lower alkanone such as acetone, or an aromatic hydrocarbon (such as toluene) at a temperature between 0 C and 100 C.



   The compounds of formula (XXI) in which Y represents the group -N (R9) COA1Z1 in which R9 and A 'are defined as above and Z1 represents a group of general formula
EMI3.4
 (in which Roll, R1 2, Rl3, X2- are defined as above) can be prepared by reaction of a compound of general formula (XXI) in which Y represents a group -NR9COAZ1 (in which R9 and A are defined as above and Z 'represents the group -NR12R13 in which R12 and Rl3 are defined as above) with a compound of general formula:

  : R "X2 in which R" and X2 are defined as above.



   The compounds of formula (VIII) in which R6 is defined as above, R8 represents a methyl radical and Y represents the group -N (CH,) COAZ 'in which A and Z' are defined as above, can be prepared by reaction d 'a compound of general formula:
EMI3.5
 in which R6, Al and X3 are defined as above: a) with a compound of general formula (XVI) in which R'2 and Rl3 are defined as above, an excess of which can be used as an acid acceptor.



   The compound of formula (VIII) is obtained in which R6 is defined as above, R8 represents a methyl radical and
Y represents a group - N (CH,) COAZ 'in which R9 and Al are defined as above, Z' is a group:
EMI3.6
 wherein R "is a hydrogen atom, R'2 and R13 are defined as above and X2- is the halide anion corresponding to X '.



  b) with a compound of general formula (XVII) in which R'2 and
 RÚ are defined as above, and R '' represents a straight or branched alkyl radical comprising at most 4 carbon atoms.



   The compounds of formula (VIII) are obtained in which Y represents a group N (R9) COA'Z 'in which R9 and A' are defined as above, Z 'represents the group:
EMI3.7

   R '2, R13 being defined as above, X2? being the halide anion corresponding to X3 and R "representing a straight or branched alkyl radical comprising at most 4 carbon atoms.



   Compounds of general formula (XXV) can be prepared by reacting N, Nt-dimethyl-o-phenylenediamine with a molar equivalent of a compound of formula (XXIV) under the conditions described above for the reaction of compounds of formula (XXII ) and (XXIV).



   The compounds of general formula (VIII) in which Y represents a group of formula N (R9) COAZ 'in which R9 and A are defined as above and Z' represents the group of formula
EMI4.1
 in which Roll, R '2, Rl3 and X23 are defined as above, can be prepared by reaction of a compound of general formula (VIII) in which Y represents a group -N (R9) COA'Z' in which R9 and Al are defined as above and Z 'represents the group -NR'2R'3 in which Rl2 and R'3 are defined as above with a compound of formula (XIX) in which R "and Rl2 are defined as above.



   The reaction can be carried out under the conditions described for the reaction of the compounds of formulas (XIX) and (XVIII).



   The compounds of formula (VIII) in which R6 is defined as above, R8 represents a hydrogen atom and
Y represents the group -N (R9) COAZ '(R9, A and Z' being defined as above) can be prepared from compounds of general formula
EMI4.2
 in which R6, R9, Al and X3 are defined as above in the manner practiced for the preparation of the compounds of formula (VI) from the compounds of formula (XV).



   Compounds of formula (XXVI) can be prepared by reduction of compounds of formula (XXIII) using the methods
 reduction of nitro aromatic groups as has been described for the preparation of compounds of formula (XXI) in which
R6 is described as above and Y is defined as above except that corresponding to the group R5.



   The following examples illustrate the process of the invention:
 Example I
 The following are mixed beforehand with stirring at ambient temperature: 28.5 g of dry potassium thiocyanate, 27.5 g of methyl chloroformate and 150 ml of anhydrous acetone. Temperature
 of the mixture spontaneously rises to 40 ° C. Stirring is continued for 2 hours at this temperature.



   The mixture is then cooled in an ice bath to 15 ° C. and the solution is treated with the solution of 4-n-butylphenylene.
   1,2-diamine in 20 ml of acetone prepared as shown below added dropwise with stirring over 15 minutes while maintaining a temperature of 15 -20 during the addition. Stirring is then maintained at room temperature for eighteen hours and filtered. The solid residue is stirred with 100 ml of water; it is refiltered and dried under vacuum. 1.2 g of crude product are obtained.



   The filtrate is concentrated to reduced volume and the solid which precipitates is filtered off. It is washed with water and dried. 28 g of crude product are obtained. These two solid products are combined and crystallized from 320 ml of methanol. 11.5 g of bis (3-methoxycarbonyl thio-2 ureidoFl, 2 n-butyl-4 benzene, melting at 170 C-171 C (dec.) Are obtained.



   The 1,2-n-butyl-phenylene diamine-1,2 used as starting material was prepared as follows:
 12.5 g of n-4-n-butyl-2-nitro aniline, 0.75 g of platinum oxide and 125 ml of ethanol are mixed and stirred under an atmosphere
 of hydrogen at ambient temperature and pressure. After 6 hours, 5.2 liters of hydrogen have been absorbed. The mixture is filtered and the methanol is distilled off from the filtrate. 40 ml of benzene are added to the residual oil and removed by distillation. Crude 1,2-n-butyl-1,2-phenylenediamine is obtained which can be used directly
 ment as it was mentioned above.



   We prepare in the same way, replacing the chloroformate
 methyl by ethyl chloroformate, bis (3-ethoxycarbonyl
 2-thio ureido> 1,2 n-4-butylbenzene, mp 175 C-176 C (dec.).



   Is prepared in the same way, by replacing the n-butyl-4 phenylene diamine-1,2 by the corresponding quantity of diamino-1,2-isopropyloxycarbonylamino-4-benzene, bis (methoxycarbonyl-3-thio-2 ureidotl, 2 isopropyloxycarbonylamino -4
 benzene, melting at 196 C-197 C (dec.).



   The 1,2-diamino-isopropyloxycarbonylamino-4 benzene used as starting material was prepared as follows:
 Stirred under hydrogen at ambient pressure and temperature for several hours 17.9 g of 2-nitr'o-isopropyloxycarbonyl amine4 aniline (prepared according to the publication of Dutch application 69/09068) in 450 ml of methanol with 1.0 g of platinum oxide. It absorbs 5.04 liters of hydrogen.



   It is filtered off, the methanol is removed under vacuum and the brown residue obtained is recrystallized from benzene. 10.4 g of 1,2-diamino-isopropyloxycarbonylamino-4 benzene, melting at 108 C-i 10 C.



   Example 2
 42.8 g of dry potassium thiocyanate, 37.8 g of methyl chloroformate and 240 ml of anhydrous acetonitrile are mixed beforehand with stirring at room temperature. Stirring is continued for one hour at 40 ° C-45- C. The mixture is cooled in an ice bath to 15 ° C. and 12.6 g of fluoro-4 o-phenylenediamine are then added in portions over ten minutes while maintaining temperature at 15'C-20C.



   When the addition is complete, the mixture is stirred at 30 ° C-40 ° C for 2 hours, poured into 1 liter of water, the red-brown solid which separates is collected and washed with water.



   This crude product is recrystallized from methanol. We obtain
 14.6 g of bis (3-methoxycarbonyl-2-thio-ureidoSl, 2-fluoro-4 benzene, melting at 183OC-185JC (dec.).



   By operating in the same way but replacing the fluoro-4 o-phenylenediamine by the corresponding amounts of acetyl-4 o-phenylenediamine, benzoyl-4 o-phenylenediamine, methoxycarbonylamino-4 o-phenylenediamine and acetamido-4 o-phenylenediamine we obtain respectively the:

   bis (3-methoxycarbonyl-2-thio ureido> 3,4 acetophenone melting at 202 C-203 C (dec.), bis (methoxycarbonyl-3-thio-2 ureidot3,4 benzophenone melting at 187 C 188 C (dec. l methoxycarbonylamino- 4 bis (methoxycarbonyl-3-thio-2 ureidok 1,2
 benzene melting at 148 'C-150e C (dec.), acetamido-4 bis (methoxycarbonyl-3-thioureido-2F1,2 benzene
 melting at 183 C-185'C (dec.).



   By operating in the same way but by replacing beforehand the methyl chloroformate by the corresponding quantity of ethyl chloroformate, we obtain 4-fluoro-3-ethoxycarbonyl-2-thio-ureidoSl, 2 benzene melting at 191 C-193-C ( Dec.).

 

   Example 3
 14.3 g of 2-chloroethyl chloroformate are added dropwise to a stirred suspension of 11.7 g of potassium thiocyanate in 100 ml of anhydrous acetonitrile. The temperature spontaneously rises to 40 ° C. Stirring is continued for two hours at 30 ° C.-40 ° C. After filtration, the filtrate is added dropwise over fifteen minutes to a stirred suspension of 10.8 g of o- phenylenediamine in 50 ml of dried acetonitrile while maintaining the temperature between 15 C and 20 ° C by external cooling.



  When the addition is complete, the mixture is stirred at 30 "C-40" C for two hours, then poured into 1 liter of water. The solid product formed is separated by filtration, washed with water and crystallized from methanol. 149 g of (2-chloroethoxycarbonyl} 1 (2-aminophenyl} 3 thiourea are obtained, melting at 173 C-174 C with decomposition.



   By operating in the same way, but by replacing, in the previous operation, the 2-chloroethyl chloroformate by propargyl chloroformate and 2-ethoxy-methyl chloroformate, the following are obtained: propargyloxycarbonyl-1 (amino- 2 phenyl} 3 thiourea melting at 153 C-155GC (dec.), (2-ethoxyethyloxycarbonyl} 1 (2-amino phenyl} 3 thiourea melting at 128tC-130 C.



   Using methyl and ethyl chloroformate and the appropriate o-phenylenediamine derivatives, the following are prepared: 1-methoxycarbonyl (2-amino-4-butyl-4-phenyl-3-thiourea melting
 à157 C-159 C (dec), methoxycarbonyi-1 (2-amino isopropoxycarbonylamino-4
   nyl> 3 thiourea melting at 1983C-200iC (dec.), methoxycarbonyl-1 (2-amino methoxycarbonylamino-4amino-phenyl) 3
 thiourea melting at 190GC-1929C (dec.l methoxycarbonyl-1 (acetyl-4-2-aminophenyl} 3 thiourea melting at
   193 C-194GC (dec.), Ethoxycarbonyl-1 (2-amino-n-butyl-4-phenyl} 3 thiourea melting at 152tC-154-C (dec.);

  ; 1-ethoxycarbonyl (2-amino isopropoxycarbonyl-4-aminophenyl3
 thiourea melting at 204 "C-206 C (dec.).



   Example 4
 18.4 g of methyl chloroformate are added dropwise to a suspension of 20.8 g of potassium thiocyanate in 150 ml of dry acetonitrile while maintaining the temperature between 20GC and 22GC by light external cooling.



  Stirring is continued for a further two hours at 300C-35JC.



   The mixture is cooled to 15 ° C. in an ice bath and then 22.6 g of 2-cyclopropylcarbonamido-2-n-butyl-5 aniline are added in portions over ten minutes while maintaining the temperature between 155 ° C. and 20 ° C.



  When the addition is complete, the mixture is further stirred at room temperature for two hours and poured into one liter of water. A solid separates which is filtered, washed with water, dried and recrystallized from ethyl acetate. 25.7 g of methoxycarbonyl-1 (cyclopropyl carbonamido-2 n-butyl-5 phenyl-3 thiourea, melting at 178G C-180-C (dec.) Are obtained.



   By operating in the same way, but by replacing the cyclopropylcarbonamido-2 n-butyl-5 aniline by the corresponding quantities of acetamido-2 n-butyl-5 aniline, formamido-2 n-butyl-5 aniline, ethoxycarbonylamino- 2 n-butyl-5 aniline, formamido-2 isopropyloxycarbonylamino-5 aniline, acetamido-2 isopropyloxy carbonylamino-5 aniline, carboxyvinylènecarbonylamino-2 aniline, acetamido-2 isopropoxycarbonylamino-4 aniline, on-les-isbonil-2:

   1-methoxycarbonyl (2-acetamido-5-butyl-phenyl-3 thiourea melting at 178'C-180 C (dec.), 1-methoxycarbonyl (5-n-butyl-2-formamido-phenyl} 3 thiourea
 mp 167 C-169 'C (dec.), 1-methoxycarbonyl (n-butyl-5-ethoxycarbonylamino-2-phenyl3
 thiourea melting at 137- C-139 C, methoxycarbonyl-1 (2-formamido isopropoxycarbonylamino-5
 phenyle3 thiourea melting at 1985C-200 C (dec.),

   methoxycarbonyl-1 (2-acetamido isopropoxycarbonylamino-5
 phenyl} 3 thiourea melting at 211'C-213-C (dec.l methoxycarbonyl-1 (carboxyvinylene carbonylamino-2 phenyle3
 thiourea melting at 170 C-173'C (dec.), methoxycarbonyl-1 (2-acetamido isopropoxycarbonylamino-4
 phenyl} 3 thiourea, melting at 187GC-1880C (dec.) * methoxycarbonyl-1 (formamido-2 isopropoxycarbonylamino-4
 phenyl} 3 thiourea, melting at 194-C-195 ° C (dec.).



   By also operating in the same way, but by replacing, in the preliminary operation, the methyl chloroformate and the 2-cyclopropylcarbonamido-5-n-butyl-5 aniline respectively by the methyl chloroformate and of isopropyloxycarbonylamino-5 2-methoxy carbonylamino aniline, or 2-acetamido-isopropoxycarbonyl 4-amino aniline, 1-ethoxycarbonyl (isopropyloxy carbonylamino-5-methoxycarbonylamino-2-phenyl} 3 thiourea melting at 194 C-195 C (dec.) and 1 is obtained. '1-ethoxycarbonyl (2-acetamido-4-isopropoxycarbonylamino-4-phenyl} 3 thiourea melting at 201 - C-202G C.



   Cyclopropylcarbonamido-2 n-butyl-5 aniline used as starting material was prepared as follows:
 29.8 g of cyclopropylcarbonamido-2-n-butyl-5-nitro-1 benzene, 1.3 g of platinum oxide and 400 ml of ethanol are mixed.



  This mixture is stirred in an atmosphere of hydrogen at ambient temperature and pressure until absorption of hydrogen ceases. 7.8 liters of hydrogen were then absorbed.



   The ethanol is filtered off and then removed by evaporation under reduced pressure. We get a solid. The crude product is crystallized from benzene and 22.6 g of 2-cyclopropylcarbonamido-5-butyl-5 aniline are obtained, melting at 139 C-142-C.



   By operating in the same way but by replacing the cyclopropylcarbonamido-2 n-butyl-5 nitro-1 benzene by the equimolecular quantities of formamido-2 n-butyl-5 nitro-1 benzene, acetamido-2 n-butyl-5 1-nitro benzene, 2-ethoxycarbonylamino-butyl-5-nitro-1benzene, 2-formamido-isopropyloxycarbonylamino-5-nitro-lbenzene, 2-acetamido isopropyloxycarbonyl-5-amino-1-nitro-1benzene, methoxy carbonylamino-2-isopropyloxycarbonylamino-5-nitro-1-benzene 1 benzene, we prepare the:

   2-formamido-5-butyl aniline, m.p. 114 'C-116-C, 2-acetamido-5-butyl-5 aniline, 2-ethoxycarbonylamino-2-n-butyl-5 aniline, 2-formamido-isopropyloxycarbonylamino-5 aniline, m.t 175- C-177'C.



  2-acetamido isopropyloxycarbonylamino-5 aniline melting at 192'C-19j'C.



   2-methoxycarbonylamino-isopropyloxycarbonylamino-5 aniline.



   (Products for which no melting point is men
 are those for whom it has been difficult to
 purification as they quickly turn black on exposure to air;
 these products can however be used as such as material
 first).



   Cyclopropylcarbonamido-2-n-butyl-5-nitro-l benzene used
 as starting material was prepared as follows:
 Suspended in 200 ml of anhydrous toluene 20.0 g
 of n-butyl-4-nitro-2 aniline. We add drop by drop under
 stirring 12.0 g of cyclopropanecarbonyl chloride. On hand
 holds reflux for an hour and a half.



   On cooling, a yellow solid is formed from the clear solution, which is collected and crystallized from petroleum ether (fraction 60 C-80-C). 25.5 g of cyclopropylcarbonamido-2-n-butyl-5-nitro-1 benzene are obtained, melting at 83 C-84- C.



   By operating in a similar manner but by replacing the cyclopropane carbonyl chloride with the equivalent molecular quantities of acetyl chloride and ethyl chloroformate, the 2-acetamido-n-5-butyl-5-nitro-1 benzene, melting at 72- C, are respectively obtained. -73 C and ethoxycarbonylamino-2 n-butyl-5 nitro-1 benzene boiling at 136 C under 0.2 mm.

 

   By also operating in a similar fashion but replacing the cyclopropane carbonyl chloride with the equivalent molar amounts of acetyl chloride and methyl chloroformate and the n-4-n-butyl-2-nitro aniline with the equivalent molar amount of isopropyloxycarbonylamino-4 2-nitro aniline, the starting compounds are obtained: 2-acetarnido-isopropyloxycarbonylamino-5-nitro-l benzene fon
 before 163 C-166 C.



  2-methoxycarbonylamino-isopropyloxycarbonylamino-5 nitro-1
 benzene melting at 168 C-170 C.



   The 2-formamido-5-butyl-1-nitro-1benzene used as the starting material was prepared as follows:
 25 g of 2-nitro-n-butyl-4 aniline and 25 g of formic acid are mixed at room temperature and the mixture is maintained at reflux for forty minutes. The mixture is cooled to room temperature and the clear solution obtained is poured into 500 ml of water.



  An orange solid is prepared which is isolated by filtration, washed with water, dried and crystallized from petroleum ether (fraction 60 C-80G C).



  20 g of formamido-2-n-butyl-5 nitro-1 benzene are obtained, melting at 72C-73C.



   Analogously to that of 2-formamido-5-n-butyl-1-nitro-benzene, but by replacing the n-butyl-2-nitro aniline by the equimolecular amount of 4-isopropyloxycarbonylamino-2-nitro-aniline, we obtain 2-formamido 5-isopropyloxycarbonylamino-1-nitro benzene, mp 168 ° C-170 C.



   Example 5
 18.5 g of dry potassium thiocyanate are mixed beforehand with stirring at room temperature. 15.6 g of ethyl chloroformate and 65 ml of anhydrous acetonitrile. Stirring is continued for one hour at 455C-553C. Cooled in an ice bath to 15 C and then added in portions over 15 minutes while stirring 19.0 g of 2-nitro-4-butyl-aniline while maintaining the temperature between 15 C and 18 C.



   When the addition is complete, the mixture is stirred at 15- for 2 hours, poured into 1 liter of water, the yellow solid formed is isolated by filtration and washed with water. This crude product, recrystallized from cyclohexane, gives 26.9 g of 1-ethoxycarbonyl (2-nitro-4-butyl-4-phenyl-3-thiourea, melting at 121-C-123-C.



   Likewise, but replacing the 2-nitro aniline with the corresponding amounts of 4-isopropyloxycarbonylamino-2-nitro-aniline, isopropyloxycarbonylamino-5-nitro-2 aniline. 4-fluoro-2-nitro aniline, 4-acetamido-2-nitro aniline, the following are respectively prepared: 1-ethoxycarbonyl (isopropyloxycarbonylamino-4 2-nitro-phenyle3
 thiourea melting at 163-C-165-C (dec.), ethoxycarbonyl-1 (isopropyloxycarbonylamino-5 2-nitro-phenyl3
 thiourea melting at 137oC-139 C (dec.), ethoxycarbonyl-1 (4-fluoro-2-nitrophenyl3 thiourea melting at
 155- C-I 57- C (dec.), 1-ethoxycarbonyl (4-acetamido-2-nitro-phenyl) -3 thiourea flux
 at 202 C-204-C (dec.).



   Example 6
 42.8 g of dry potassium thiocyanate, 37.8 g of methyl chloroformate and 130 ml of dry acetonitrile are mixed beforehand with stirring at room temperature and stirring is continued for one hour at 35 ° C.-45 ° C. the mixture is cooled in an ice bath to 15 C and then added in portions in
 15 minutes, while stirring 38.8 g of n-4-n-butyl-2-nitro aniline, maintaining the temperature at 15 C-18 C during the addition.



   When the addition is complete, the mixture is stirred at 15 ° C. for 2 hours and then poured into 1 liter of water. The yellow solid which separates is collected by filtration and washed with water.



  It is recrystallized from ethanol and one obtains 47.8 g of metloxycarbonyl-1 (n-butyl-4-2-nitro-phenyl-3 thiourea, melting at
 164 C-165 C (dec.).



   By operating in the same way. but by replacing n-butyl-4
 2-nitro aniline by the corresponding amounts of isopropyloxy
 4-carbonylamino-2-nitro aniline, 4-amino-3-nitro-acetophenone.



   fluoro-4-nitro-2 aniline. 4-amino-3-nitro benzophenone,
 4-acetamido 2-nitro aniline, 4-cyclopropylcarbonamido-2-nitro
 aniline, cyclohexylacetamido-4-nitro-2 aniline. methoxycarbonyl
 4-amino-2-nitro aniline and N-methylmethanesulfonylamino-4
 2-nitro aniline, we obtain respectively the:

  :
 methoxycarbonyl-1 (isopropyloxycarbonylamino-4-nitro-2
   nylt3 thiourea melting at 180 C-181 C (dec.),
 methoxycarbonyl-1 (acetyl-4-2-nitro-phenyl-3 thiourea, melting
 181 C-182 C (dec.), Methoxycarbonyl-1 (4-fluoro-2-nitro-phenyl-3-thiourea, melting
   196'C-198GC (dec.), 1-methoxycarbonyl (4-benzoyl 2-nitro phenyl3 thiourea melting at 177C-179C, 1-methoxycarbonyl (4-acetamido-2-nitro-phenyl3 thiourea melting point
 at 215 C217 C (dec.), 1-methoxycarbonyl (4-cyclopropylcarbonamido-2-nitrophenyl3
 thiourea melting at 200 C-203- C (dec.), methoxycarbonyl-1 (4-cyclohexylacetamido-2-nitrophenyl3
 thiourea melting at 158'C-160'C.



  1-methoxycarbonyl (4-methoxycarbonylamino-2-nitro-phenyl3
 thiourea melting at 209 C-210 C (dec.), methoxycarbonyl-1 (N-methylmethanesulfonylaminot4 nitro-2
   phenyl3-3 thiourea, melting at 187 C-189; C (dec.).



   By operating in a similar fashion, but by replacing, in the preliminary operation, n-4-n-butyl-2-nitro aniline by 2-nitro aniline and methyl chloroformate by 2-ethoxy-ethyl chloroformate and d-chloroformate. 'allyl, (2-ethoxyethoxy carbonyl (2-nitrophenyl3 thiourea, mp 143 C-145'C (dec.) and allyloxycarbonyl-1 (2-nitrophenyl3 thiourea mp 127-128') are prepared.



   4-isopropyloxycarbonylamino-2-nitro aniline and 5-isopropyloxycarbonylamino-2-nitro-aniline used as starting materials in Example 6 and (N-methylmethanesulfonylamino> 4 nitro-2 aniline used as starting material in this example , were prepared as mentioned below.



   The other anilines used as starting products in these same examples are. unless otherwise stated, known commercial products.



  a) Preparation of isopropyloxycarbonylamino-4-nitro-2 aniline.



   To a stirred suspension of 60 g of 2,5-diamino-nitrobenzene in a solution of 49.4 g of sodium bicarbonate in 780 ml of water at 10 ° C., 48 g of chloroformate is added dropwise. isopropyl. Stirred for a further three hours at room temperature.



  The dark brown solid is isolated by filtration, washed well with water and dried. 90.0 g of isopropyloxycarbonylamino-2-nitro-aniline, melting point 158-160, are obtained, which can be used as is for the following phases. Recrystallization of a sample from toluene gives a product melting at 161 -163
 By operating in the same way. but by replacing the isopropyl chloroformate with the corresponding amount of methyl chloroformate, we obtain 4-methoxycarbonylamino-2-nitro-aniline, melting at 171 C-172 C.



  b) Preparation of isopropyloxycarbonylamino-5-nitro-2 aniline.



   To a stirred suspension of 3 g of 2,4-diamino-nitrobenzene and 2.5 g of sodium bicarbonate in 39 nil of acetone are added dropwise at room temperature 2.4 g of isopropyl chloroformate and one adds stir the mixture overnight at room temperature. The inorganic products are removed by filtration, and the solvent from the filtrate is evacuated under vacuum. A solid is obtained which is recrystallized from toluene. 2.34 g of isopropyloxycarbonylamino-5-nitro-2 aniline are obtained. yellow solid melting at
   142 C-145 C.



   By operating in the same way, but replacing the isopropyl chloroformate with equivalent amounts of cyclopropane carbonyl chloride and cyclohexylacetyl chloride. we
 obtains the 4-cyclopropylcarbonamido-2-nitro aniline melting at
 211-213 and 4-cyclohexylacetamido-2-nitro aniline melting at
 164 C-166 C.

 

   c) Preparation of (N-methylmethanesulfonylaminot4 nitro-2
 aniline.



   8.0 g of (N-methyl
   aminot4 2-nitro aniline, 8.05 g of sodium bicarbonate and 120 ml
 acetone. Cool to 15 in an ice bath and add
 5.6 g methanesulfonyl chloride drip over 10 minutes
 and the mixture is stirred for 6 hours at room temperature.



   A further 3.0 g of methane sulfonyl chloride and 4.2 g are added.
 of sodium bicarbonate and stirring is continued at temperature
 ambient for a further eighteen hours. The solids are removed from the dark solution obtained and the filtrate is evaporated. A dark solid is obtained. It is triturated with ether, filtered, washed well with ether, and crystallized from methanol after having passed over decolorizing charcoal. 8.5 g of (N-methyl methane sulfonylaminot4-2-nitroaniline, orange solid melting at 171 "C-173" C are obtained.



   Example 7
 In a vigorously stirred suspension of 4.8 g of
 N- (2-amino phenylt2 dimethylaminoacetamide in 20 ml
   dry acetonitrile 3.5 g of isothiocyanate are added dropwise
 methoxycarbonyl, maintaining the temperature between 150C and
   20 C by external cooling. We continue the agitation
 for a further 5 minutes then diluted with 500 ml of ether
 diethyl and an excess of a saturated solution of acid is added
 hydrochloric acid in ether. The precipitate is isolated by filtration,
 Dissolve it in the minimum of water and add an excess of soda
 aqueous 2N. The precipitate is isolated by filtration, recrystallized
 twice in benzene and obtains 3.5 g of methoxycarbonyl-1
 [(dimethylamino acetamido> 2 phenyl] -3 thiourea,
   F = 130 "C-131" C (dec.).



   By operating in the same way but replacing the
 N- (2-aminophenyl2 dimethylaminoacetamide by the amount
 equimolecular of N- (2-chloro-phenyl) 3-dimethylaminopropionamide, one obtains methoxycarbonyl-1 [(3-dimethylamino-propionamidot2 phenyl] -3.



   N- (2-aminophenyl) dimethylamino-2 acetamide used as a raw material can be prepared as follows:
 40 ml of a solution of dimethylamine in methanol (33% by weight) are added to a suspension of 14.9 g of N- (2-nitro phenyl) chloro-2 acetamide [prepared by the method described by
G. Tennant, J.C.S., (1963), 2428] in 70 ml of ethanol, and refluxed with stirring for 2 hours. After cooling, the ethanol and the excess of dimethylamine are evaporated off under reduced pressure and the solid residue is treated with 100 ml of 40% (weight / volume) aqueous potassium hydroxide solution. The resulting suspension is extracted with 3 x 100 ml of diethyl ether, the mixture of extracts is dried over magnesium sulfate and evaporated.

  13.8 g of
N- (2-nitrophenyl) dimethylamino-2 acetamide, M = 44 C-470 C, pure enough to be used as is in the following step:
 13.8 g of N- (2-nitro phenyl) dimethylamino-2 acetamide, 0.2 g of platinum oxide and 100 ml of ethanol are mixed, and the mixture is stirred in a hydrogen atmosphere at atmospheric pressure and temperature of. laboratory until the end of hydrogen absorption (or absorbs 45 liters in 2 hours). The mixture is filtered and the ethanol evaporated off under reduced pressure. The solid residue is recrystallized from cyclohexane and 9.3 g of N- (2-aminophenyl) -dimethylamino-2 acetamide is obtained. F = 121 C-123 C.



   This product can also be prepared as follows:
 A suspension of 0.15 g of platinum oxide is stirred in
 a solution of 4.29 g of N- (2-nitro phenyl) 2-chloroacetamide
 in 80 ml of ethanol in a hydrogen atmosphere, at high pressure
 atmospheric and laboratory temperature, until absorption
 of 1.5 liters of hydrogen. We filter. evaporates the filtrate under pressure
 reduced and triturated the solid residue with water. We separate by filter
 The solid obtained (Mp = 79 C-85 C) is dissolved and dissolved in ethanol.



   10 ml of a 20% (by weight) solution of dimethylamine are added
 in ethanol, and heated at reflux for 2 hours. We
 the ethanol is then evaporated off under reduced pressure and 20 ml are added.
 of water to the residue. The mixture obtained is extracted with 3 times 50 ml
 diethyl ether, dried the extracts over magnesium sulfate and
 evaporates to dryness. The solid residue is recrystallized twice from
 cyclohexane and obtains N- (2-aminophenyl) dimethylamino-2
 acetamide, F = 1195C-121-C.



   Methoxycarbonyl isothiocyanate, used as another
 raw material, can be prepared as follows:
 94.5 g of methyl chloroformate are slowly added to a stirred suspension of 106.7 g of dry potassium thiocyanate in 400 ml of dry acetone at 40 ° C., maintained at this temperature by external cooling. hour while allowing to return to the temperature of the laboratory. It is filtered and evaporated to dryness under reduced pressure. 500 ml of diethyl ether are added to the residue, the ether is filtered and evaporated off under reduced pressure: an oil is obtained which gives, by distillation , 30.0 g of methoxycarbonyl isothiocyanate, Eb, 5 = 32 C-33 C.



   Example 8
 6.4 g of ethoxycarbonyl isothiocyanate are added dropwise to a stirred suspension of 8.9 g of 2-N- (2-aminophenyl) dimethylamino-acetamide (prepared as in Example 7) in 50 ml of acetonitrile while maintaining the temperature at 15 "C-20" C by external cooling.



   When the addition is complete the solid has dissolved but after standing for 5 minutes another solid precipitates. It is filtered, washed with ice-cold acetonitrile and 9.4 g of ethoxy carbonyl [(2-dimethylamino-acetamido} phenyl] -3 thiourea, m.p. 159 C-160 C (dec.), Are obtained.



   By operating in the same way, but replacing the
 N- (2-aminophenyl) dimethylamino-2 acetamide by the starting compounds:
N- (2-aminophenyl) (N-benzyl N-methylamino} 2 acetamide,
N- (2-amino phenyl) piperidino-2 acetamide
N- (2-amino phenyl) (4-methyl piperazinyl> 2 acetamide,
N- (2-amino phenyl) (cisdimethyl-2,6 morpholinot2 acetamide,
N- (2-amino isopropoxycarbonylamino-4amino-phenyl) dimethylamino
 acetamide and
N- (2-amino phenyl) morpholino-2 acetamide, the:

   ethoxycarbonyl- 1 [(N-benzyl-N-methylamino-2 acetamidop2
 phenyl] -3 thiourea melting at 176 C-178 C (dec.), ethoxycarbonyl-1 (piperidino-2-acetamido phenyl3 thiourea
   melting at 154 "C-158" C (dec.), 1-ethoxycarbonyl [(4-methylpiperazinyl-1-acetamido> 2phenyl] -3
 thiourea melting at 183'C-185 C (dec.), ethoxycarbonyl-l [(cis-dimethyl-2,6 morpholinoacetamido t2
 phenyl] 3 thiourea whose hydrochloride melts at 198 C-200oC, 1-ethoxycarbonyl-dimethylamino-2-acetamido isopropyloxycar
 bonylamino-5 phenyl-3 thiourea, the hydrochloride of which melts at 159-C-161'C C (dec.),

   and
 1-ethoxycarbonyl (2-morpholinoacetamido-phenyl-3 thiourea including
 the hydrochloride melts at 187 C-189 C (dec.).



   Ethoxycarbonyl isothiocyanate (boiling at 55 "C-57 'C
 under 15 mm of mercury) was prepared as was said in Example 7 for methoxycarbonyl isothiocyanate by simply replacing the methyl chloroformate with the equivalent amount of ethyl chloroformate.



   The N- (2-aminophenyl) (N-benzyl, N-methylamino) -2 acetamide used as the raw material was prepared as follows:
 A mixture of 21.4 g of N- (2-nitrophenyl) chloro-2-chloroacetamide, 24.2 g of N-benzylmethylamine and 200 ml of ethanol is refluxed for two hours. The ethanol is removed under reduced pressure and 500 ml of water as a residue are added. Extracted with diethyl ether and the ethereal extract is dried over magnesium sulfate. It is evaporated to dryness and 29.9 g of N- (2-nitrophenyl) (N-benzyl N-methylamino) -2 acetamide is obtained, melting at 84C-85 C.

 

   By operating in the same way but by replacing the N-benzylmethylamine by the corresponding quantities of piperidine, morpholine and N-methyl piperazine we obtain the N- (2-nitro phenyl) piperidino-2 acetamide melting at 79 C-8 1 C, N- (2-nitro phenyl) morpholino-2 acetamide melting at 1335 C-135 'C (dec.),
N- (2-nitrophenyl) (4-methyl piperazinyl) -2 acetamide, melting at 56 C-58 C.



   Also by proceeding as previously but replacing the N-benzylamine with dimethylamine and N- (2-nitrophenyl) chloro-2 acetamide with N- (isopropyloxycarbonylamino-4-2-nitro-phenyl) bromo-2 acetamide, the preparation is N- (4-isopropyloxycarbonylamino-2-nitro-phenyl) -dimethylamino-2 acetamide, m.p. 1559 -C-16oC.



   The N- (4-isopropyloxycarbonylamino-2-nitro-phenyl) bromo-2-acetamide used above as the starting material was prepared as follows:
 18.6 g of bromoacetyl bromide are added dropwise with stirring to a solution of 22 g of isopropyloxycarbonylamino-4-2-nitroaniline in 300 ml of toluene. Maintained at reflux for one hour, cooled, filter the solid formed which is crystallized from benzene. 20 g of N- (isopropyloxycarbonylamino-4-nitro-2 phenyl) bromo-2 acetamide are obtained, melting at 195 C-197 ° C.



   30 g of N- (2-nitro phenyl) (N-benzyl N-methylamino> 2 acetamide and 0.3 g of platinum oxide in 500 ml of methanol) are stirred under a hydrogen atmosphere at ambient temperature and pressure until with complete absorption of hydrogen (6.6 liters have been absorbed). It is filtered and then evaporated to dryness. An oil is obtained which is extracted with boiling cyclohexane (1 liter). On cooling, 12.5 g of is obtained. N- (2-aminophenyl) (N-benzyl N-methyl aminot2 acetamide, almost white crystals melting at 75 'C-77 C.



   By operating in the same way but by replacing the N- (2-nitro phenyl> (N-benzyl, N-methylaminok2 acetamide by the N- (2-nitro phenyl) piperidino-2 acetamide, N- (2-nitro phenyl) 2-morpholinoacetamide, N- (2-nitrophenyl) (methyl4 piperazinyl- 1) acetamide and
N- (2-nitro isopropyloxycarbonylamino-4phenyl) 2-dimethylamino-acetamide,

   N- (2-aminophenyl) piperidino-2 acetamide, melting at 174 C-176- C, N- (2-amino-phenyl) morpholino-2 acetamide, melting at 198 C-200GC (dec.), are respectively obtained,
N- (2-aminophenyl) (4-methylpiperazinyl-1> 2 acetamide, melting at 138 C-140 C (dec.) And N- (2-amino isopropyloxycarbonylamino-4 phenyl) 2-dimethylamino acetamide, melting at 173'C -175 C.



   The N- (2-aminophenyl) (cis-dimethyl-2,6 morpholino) -2 acetamide used as starting material was prepared as follows:
 8.6 g of N- (2-nitrophenyl) chloro-2-chloroacetamide, 9.2 g of cis-2,6-dimethyl morpholine and 100 ml of ethanol are refluxed for 3 hours. Ethanol is removed by evaporation and 100 ml of water are added to the residue. The resulting suspension is filtered and the solid is recrystallized from ethanol. 8.5 g of N- (2-nitro phenyl) (cis-dimethyl-2,6 morpholinot2 acetamide are obtained (melting point at 127 "C-129" C (dec.)) Which is dissolved in 100 ml of methanol. .



  0.3 g of platinum oxide is added and the solution is stirred under hydrogen at ambient pressure and temperature until absorption of 1.9 liters of hydrogen. After filtering, the ethanol is evaporated off, recrystallized from water and 5.4 g of N- (2-aminophenyl) (cis-2,6-dimethyl-morpholino> 2 acetamide, melting at 104 ° C-106 C (dec. .).



   Example 9
 50 ml of petroleum ether (fraction 60 C-80 C) are added to a solution of 4.98 g of N- (2-amino-4-butyl-4-phenyl) dimethylamino-2 acetamide in 50 ml of benzene and The solution is stirred vigorously while 2.65 g of ethoxycarbonyl isothiocyanate is added dropwise, cooling the exterior so as to keep the temperature between 15 C and 20 C.



   After 10 minutes, the precipitate formed is collected by filtration and recrystallized from benzene. Ethoxycarbonyl-1 (n-butyl-5-dimethylamino acetamido-2 phenyl-3 thiourea is obtained, melting at 152 C-155 C (dec.).



   In the same way, but by replacing N- (2-amino-4-butyl-4-phenyl) dimethylamino-2 acetamide by N- (2-amino-phenyl) diethyl-2-amino acetamide, N- (2-amino-phenyl) ( N-methyl Nn-butylaminot2 acetamide, N- (2-aminophenyl) di-n-butylamino-2 acetamide and N- (2-aminophenyl) dimethylamino-2 propionamide, the following are obtained:

   1-ethoxycarbonyl (2-diethylaminoacetamido-phenyl3 thiourea
 mp 159 C-160 C (dec.), ethoxycarbonyl-1 (N-n-butyl N-methylaminoacetamido-2
   phenyl3 thiourea melting at 95 C-98 C, ethoxycarbonyl-1 (di-n-butylaminoacetamido-2 phenyl} 3 thiourea
 mp 137 'C-139i C, ethoxycarbonyl-l [(dimethylamino-l ethyl carbonylaminot2
   phenyl] -3 thiourea, melting at 143 C-144 C.



   N- (2-amino-4-butyl-4-phenyl) 2-dimethylamino-acetamide used as a raw material was prepared as follows:
 A suspension of 41 g of N- (2-nitro-n-butyl-4 phenyl) bromo-2 acetamide in 200 ml of ethanol is treated with 90 ml of a 20% solution of dimethylamine in ethanol.



   The mixture is maintained at reflux for one hour and the ethanol is evaporated off. 100 ml of water are added and extracted with three times 200 ml of ether.



  The ethereal extracts are dried over magnesium sulfate, filtered and evaporated. N- (2-nitro-4-butyl-phenyl) 2-dimethylamino acetamide is obtained, a yellow oil which can be used as a starting material without further purification.



   By replacing N- (2-nitro-4-butyl-4-phenyl) bromo-2-acetamide by N- (2-nitro-phenyl) bromo-2-propionamide, N- (2-nitro-phenyl) is prepared in the same way 2-dimethylamino propionamide, red oil usable as it is.



   By replacing N- (2-nitro-4-butyl-4-phenyl) bromo-2-acetamide with N- (2-nitro-phenyl) -chloro-2 acetamide and dimethylamine with diethylamine, N- (2-nitro-phenyl) is prepared. ) 2-diethylaminoacetamide melting at 68 C-71 'C.



   N- (2-nitrophenyl) (N-n-butyl N-methylaminot2 acetamide was prepared as follows:
 32.2 g of N- (2-nitrophenyl) chloro-2-chloroacetamide are dissolved in 350 ml of benzene and 26.1 g of N-n-butyl methylamine are added. The mixture is maintained at reflux for 22 hours, the benzene is evaporated off and 300 ml of water are added. Extracted with ether (3 times 200 ml, the ethereal extract is dried over magnesium sulfate.



  filter and evaporate the ether. N- (2-nitrophenyl) (N-n-butyl N-methylaminoF2 acetamide is obtained, a yellow oil which can be used as it is.



   By replacing Nn-butylmethylamine by di-n-butylamine, N- (2-nitro-phenyl) (di-n-butyl aminot2 acetamide, yellow oil) is prepared in the same way. Stirred in a hydrogen atmosphere at temperature. and ambient pressure until complete absorption of hydrogen 36 g of N (2-nitro-n-butyl-4 phenyl) 2-dimethylamino-acetamide, 0.2 g of platinum oxide and 100 ml of ethanol.



  It absorbs 8.2 l of hydrogen. The ethanol is filtered off and evaporated off. The solid obtained is recrystallized from petroleum ether (60 C-SOC fraction). 24.0 g of N- (2-amino-n-butyl-4-phenyl) -dimethylamin-2 acetamide are obtained, melting at 63 C-66- C.



   By operating in the same way, the starting compounds are prepared:
N- (2-amino phenyl) 2-diethylamino acetamide melting at 76 "C-77" C,
N- (2-amino phenyl) (N-n-butyl N-methylamino} 2 acetamide
 melting at 66C-68 C,
N- (2-aminophenyl) di-n-butylamino-2 acetamide, oil whose
 dihydrochloride melts at 189 ° C-191 ° C (dec.),
N- (2-aminophenyl) 2-dimethylaminopropionamide, oil.

 

   The N- (2-nitro N-n-butyî-4 phenyl) bromo-2 acetamide used as starting material was prepared as follows:
 33.3 g of bromoacetyl bromide is added to a solution of 29.1 g of 2-nitro-4-butyl-4 aniline in 100 ml of toluene. Maintained at reflux for three quarters of an hour and the toluene evaporated. An oil remains which is poured into 400 ml of petroleum ether (fraction 60-80 '). Crystals are deposited which are isolated by filtration. 41 g of N- (2-nitro-4-butyl-phenyl) bromo-2 acetamide are obtained, melting at 56 - C-57 - C.



   N- (2-nitrophenyl) bromo-2 propionamide, melting at 57 C-58 C., is prepared in the same way.



   Example 10
 5.6 g of ethoxycarbonyl isothiocyanate is added dropwise while cooling to maintain a temperature between 15 C and 20 C to a stirred solution of 10.75 g of N- (2-amino methoxycarbonylamino-4 phenyl } 2-dimethylaminoacetamide in 200 ml of anhydrous acetone Stirred for 30 minutes and poured into an excess of water.The precipitate formed is collected by filtration to give 1-ethoxycarbonyl [(dimethylamino acetamino) -2 5-methoxycarbonylamino-phenyl)] - 3 crude thiourea melting at 171 C-172 C.



   The N- (2-amino-methoxycarbonylamino-4-amino-phenyl) -dimethyl-2-aminoacetamide used as the starting material was prepared as follows:
 30 g of 2-nitro-4-methoxycarbonylamino-aniline are dissolved in 300 ml of toluene and 28.7 g of bromoacetyl bromide are added. Maintained at reflux for three hours and 300 ml of toluene are added. It is filtered hot and allowed to cool.



  30 g of N- [nitro-2 (methoxycarbonylaminot4 phenyl] bromo-2 acetamide, melting at 160 C-162 C.



   25 g of this N- [2-nitro (methoxycarbonylamino} 4 phenyl] bromo-2 acetamide in 250 ml of ethanol are treated with 35.5 g of a 30% solution by weight of dimethylamine in methanol and one maintained at reflux for one hour. The ethanol is evaporated off and the residual solid is stirred with water. The mixture is filtered and 21.1 g of N- [2-nitro (methoxycarbonylaminot4 phenyl] dimethyl amine-2 acetamide is obtained, melting at 186 C-189 C.



   25.3 g of this N- (2-nitro-methoxycarbonylamino-4-phenyl) dimethylamino-2 acetamide, 0.4 g of platinum oxide and 250 ml of methanol are mixed and the mixture is stirred under a hydrogen atmosphere at pressure. and ambient temperature until absorption of hydrogen ceased (6 liters of hydrogen were absorbed).



  The mixture is filtered and the ethanol evaporated off. The solid residue is recrystallized from isopropanol and 15.7 g of N- (2-amino-methoxycarbonylamino-4-phenyl) -dimethylamino-2 acetamide are obtained, melting at 1400 C-i 420 C.



   The 4-methoxycarbonylamino-2-nitro-aniline was prepared as follows:
 34 g of methyl chloroformate are added dropwise with stirring to a mixture of 50 g of 2-nitro-p.phenylenediamine, 44.5 g of sodium bicarbonate and 700 ml of water while maintaining the temperature at 53 C by external cooling.



   After addition the mixture is allowed to warm to room temperature and stirring is continued for two hours. The solid isolated is filtered off and recrystallized from isopropanol. 50 g of 2-nitro-4-methoxycarbonylamino-aniline are obtained, melting at 171 "C-172" C.



   Example he
 5.1 g of ethoxycarbonyl isothiocyanate are added dropwise with stirring, while cooling so as to maintain the temperature between 15 ° C. and 200 ° C. to a solution of 9.1 g of N- (amino-2 phenyl) trimethylammonium acetamide in 250 ml of ethanol. We stir for another fifteen minutes. The precipitated solid is separated by filtration and recrystallized from ethanol. 9.2 g of 1-ethoxycarbonyl chloride are obtained
 (trimethylammonium 2-acetamido phenyl} 3 thiourea melting at
   199 "C-200" C (dec.).



   Ethoxycarbonyl-1 iodide is prepared in the same way
 [trimethylammonium 2-acetamido-3-phenyl thiourea melting at 210 C-211 C (dec.) and methoxycarboyl-1 iodide [2-acetamido-phenyl] -3 thiourea melting at 176 Ce 1780 C
 (Dec.).



   N- (2-aminophenyl) trimethylammonium acetamide chloride used as the starting material was prepared as
 follows:
 32.1 g of N- (2-nitro phenyl) chloro-2 acetamide are heated,
 80 ml of a 33% by weight solution of trimethylamine in
 Ethanol and 150 ml of ethyl acetate at reflux for 1 hour.



   Petroleum ether (fraction 60 C-80 C) is added to the solution
 hot until slightly cloudy. Leave to cool. The solid precipitate, 19.5 g (melting point 120 ° C.
   124 C). It is suspended in 200 ml of ethanol, 0.5 g of platinum oxide is added and the suspension is stirred in a hydrogen atmosphere at ambient temperature and pressure until absorption ceases (4.8 liters of hydrogen). The ethanol is filtered off and the ethanol distilled until only a small quantity is retained (about 20 ml).



  The solid present is filtered off and 9.1 g of sodium chloride are obtained.
N- (2-aminophenyl) trimethylammonium acetamide melting at 210 ° C-211-C, usable as it is.



   Analogously, but replacing the chloride of
N- (2-amino phenyl) trimethylammonium acetamide starting with the hydrochlorides of
N- (2-aminophenyl) dimethyl-2-aminoacetamide,
N- (2-amino phenyl) (N-benzyl-N-methylaminot2 acetamide,
N- (2-amino phenyl) piperidino-2 acetamide,
N- (2-amino phenyl) (4-methyl piperazino} 2 acetamide,
N- (2-amino isopropoxycarbonylamino-4phenyl) 2 dimethyl
 2-aminoacetamide,
N- (2-amino phenyl) morpholino-2 acetamide,
N- (2-amino-4-butyl-phenyl) 2-dimethylamino-acetamide,
N- (2-amino phenyl) 2-diethylamino acetamide,
N- (2-amino phenyl) (N-methyl N-n-butylamino} 2 acetamide,
N- (2-aminophenyl) di-n-butylamino-2 acetamide,
N- (2-amino-4-methoxycarbonylamino-phenyl) 2-dimethylamino-2
 acetamide,
N- (2-amino phenyl) (cis-dimethyl-2,6 morpholino} 2

   acetamide,
N- (2-aminophenyl) di-methylamino-2 propionamide,
 the hydrochlorides of: ethoxycarbonyl-1 (2-dimethylaminoacetamido-phenyl) -3 thiourea are prepared
 mp 178 ° C-180 C (dec.), ethoxycarbonyl- 1 [(N-benzyl N-methylaminoacetamido t2
   phenyl] -3 thiourea melting at 187 C-188 "C (dec.), ethoxycarbonyl-1 (piperidinoacetamido-2 phenyl) -3 thiourea
 mp 179'C-180 C (dec.), ethoxycarbonyl-1 [(4-methylpiperazinylacetamidot2 phenyl] -3
 thiourea melting at 1933C-195'C (dec.), ethoxycarbonyl-1 (dimethylaminoacetamido-2

   isopropoxy
 5-carbonylaminophenyl) thiourea mp 159 C-161 "C (dec.), 1-ethoxycarbonyl (2-morpholinoacetamido phenylt3 thiourea
 mp 187 C-189eC (dec.), 1-ethoxycarbonyl (5-n-butyl-2-dimethylacetamido-2 phenyl) -3
 thiourea melting at 174 C-176 'C (dec.), ethoxycarbonyl-1 (2-diethylaminoacetamido-phenyl) -3 thiourea
 melting at 1770 C-179 C (dec.).



  ethoxycarbonyl-1 (N-n-butyl-N-methylaminoacetamido-2
 phenyl) -3 thiourea melting at 181 C-183nC (dec.), ethoxycarbonyl- 1 (di-n-butylaminoacetamino-2 phenyl} 3 thiourea
 melting at 192 C-194 C (dec.),
 1-ethoxycarbonyl (2-dimethylaminoacetamido-methoxycarbonyl
 5-aminophenyl) -3 thiourea melting at 21 ° C-2130C (dec.),
 ethoxycarbonyl-1 [(cis-dimethyl-2,6 morpholinoacetamidot2
 phenyl] -3 thiourea melting at 198 C-2000 C (dec.),
 ethoxycarbonyl- 1 [(dimethylamino- 1ethylcarbonylamino} 2
 phenyl] -3 thiourea melting at 194- C-195 C

   (Dec.).



   By replacing ethoxycarbonyl isothiocyanate with quan
 corresponding quantity of methoxycarbonyl isothiocyanate and N- (2-aminophenyl) trimethylammonium acetamide chloride by
 N- (2-aminophenyl) dimethyl-2-aminoacetamide hydrochloride
 and N- (2-aminophenyl) dimethyl-2-amino-methanesulfonate
 acetamide, hydrochloride is prepared
 methoxycarbonyl- 1 (2-dimethylaminoacetamido-phenyl) -3 thiourea
 melting at 187 "C-188" C (dec.) and the
 methoxycarbonyl-1 methane sulfonate (dimethylamino
 2-acetamido phenyl) -3 thiourea melting at 164 ° C-165 C (dec.).



   Products prepared as just mentioned may
 be used as anthelmintics, antivirus or pesticides,
 in particular fungicides in the form of formulations of the usual types.



   These formulations can be solid, pasty. liquids. Mention may in particular be made of tablets, capsules, bowls, granules, wettable or dispersible powders, pastes, gels, emul
 sions, suspensions, syrups, elixirs.



   The compositions for anthelmintic or antivirus use can be presented in all forms which can be administered orally or parenterally. Generally they contain 5% to 90% of active product.



   They can be prepared according to the usual methods.



   The compounds of formula VI are active as anthelmintics in oral doses generally between 25 and 250 mg per kilogram of body weight, sometimes even at lower doses of up to 5 mg per kilogram of body weight.



   In some cases it may be necessary to use higher doses of up to 500 and even 1000 mg per kilogram of
 body weight.



   As antivirus, especially against influenza virus A2 Hong
Kong 5/68 oral doses of between 50 and 250 mg per kilogram of body weight generally give good results.



   In veterinary medicine, the compounds of formula VI can also be administered in animal feed, feed supplements or drinking water. For this use the compounds of formula VI can be presented in the form of concentrates or supplements. Generally, processed foods contain between 0.000% and 3% of active product, concentrates from 5 to 90% of active product (by weight).

 

   All these compositions for anthelmic and antivirus use can naturally contain other known active products.



   As a pesticide, in particular an agricultural fungicide, the products are present in the form of compositions of the usual type such as powders, wettable powders, solutions, emulsions, ready-to-use or ready-to-use concentrates.



   Preferably, these compositions comprise between 0.005% and
 80% by weight of active product.



   They are used for their fungicidal action so as to obtain
 doses of product of formula VI generally between
 0.56 and 3.5 kg per hectare. Most often the products are
 applied as sprays of solutions or dispersions
 aqueous solutions obtained by diluting a powder concentrate with water
 or liquid.


    

Claims (1)

CLAIM Manufacturing process for compounds of general formula EMI10.1 in which R5 represents the group N (RB) CSNHCOOR7; R7 represents a saturated or unsaturated straight or branched aliphatic hydrocarbon radical comprising not more than 4 carbon atoms, unsubstituted or substituted by a halogen atom or an alkyloxy group comprising at most 4 carbon atoms; Rs represents a hydrogen atom or a methyl radical; ; R6 represents a hydrogen or halogen atom, an alkyl radical comprising at most 4 carbon atoms, an alkanoylamino group comprising from 1 to 4 carbon atoms (of which the alkanoyl portion is straight or branched, unsubstituted or substituted by a cycloalkyl radical comprising from 3 to 6 carbon atoms), a straight or branched alkyloxycarbonylamino radical comprising from 2 to 4 carbon atoms, a straight or branched alkanoyl radical comprising from 2 to 4 carbon atoms, a benzoyl group or a CH3SO2N group ( CH3); ; Y represents a group - N (Rs) CSNHCOOR7, the symbols R7 and R8 having the definitions mentioned above, a nitro radical or a group -NR9R'0 in which either R9 and R'O each represent a hydrogen atom, or R9 represents a hydrogen atom or a methyl radical while R'O represents a straight or branched alkanoyl group comprising from 1 to 4 carbon atoms, unsubstituted or substituted by a cycloalkyl group comprising from 3 to 6 carbon atoms, a straight or branched alkyloxycarbonyl group comprising from 2 to 4 carbon atoms , a COA'Z 'group in which Al represents a saturated or unsaturated aliphatic hydrocarbon radical comprising at most 4 carbon atoms, unsubstituted or substituted by at least one methyl group and Z 'represents a carboxy group or a group of general formula EMI10.2 in which R l 2 represents a hydrogen atom or an alkyl radical comprising at most 4 carbon atoms, a phenylalkyl radical in which the alkyl part contains 1 or 2 carbon atoms; ; R'3 represents a hydrogen atom or an alkyl radical comprising at most 4 carbon atoms, or R 12 and R'3 with the nitrogen atom to which they are attached form a 5, 6 or 7-membered heterocycle of which the ring may contain one or two additional heteroatoms chosen from oxygen, nitrogen or sulfur, unsubstituted or substituted by one or more alkyl radicals comprising at most 6 carbon atoms as well as, when Y represents an amino radical, the addition salts with acids of products of formula (VI), characterized in that one reacts an isothiocyanate of general formula SCNCOOR7 (VII) on an amine of general formula EMI10.3 in an inert organic solvent at a temperature between O "C and 150 C, R6, R7, R8, Y being defined as previously. SUB-CLAIMS 1. Method according to claim for the manufacture of products in the formula VI of which: R6 represents an alkyl radical comprising from 2 to 4 atoms of carbon, alkanoylamino having 1 to 4 carbon atoms, alkanoyl having 2 to 4 carbon atoms, benzoyl or N-methylmethanesulfonylamino, alkyloxycarbonylamino having 2 to 4 carbon atoms; Y represents a group NR9R'O in which R9 represents an atom of hydrogen or a methyl radical and Rl represents a hydrogen atom, an alkanoyl radical compor both 1 to 4 carbon atoms or an alkyloxy radical carbonyl having 2 to 4 carbon atoms; R7 and R8 being defined as in claim. 2. Method according to claim for the manufacture of products in the formula VI of which: R6 represents an alkyl radical comprising from 2 to 4 atoms of carbon, alkanoylamino having 1 to 4 carbon atoms in position 3, 4 or 5 of the benzene ring, alkyloxycarbonyl amltno comprising from 2 to 4 carbon atoms in position 3, 4 or 5 of the benzene ring, alkanoyl comprising from 2 to 4 ato carbon, benzoyl, or N-methylmethanesulfonylamino and Y represents a nitro group; R7 and R8 being defined as in claim. 3. Method according to claim for the manufacture of products in the formula VI of which: R6 represents an alkyl group comprising from 1 to 4 atoms of carbon. an alkyloxycarbonylamino radical comprising 2 to 4 carbon atoms, alkanoyl having 2 to 4 atoms carbon, benzoyl, N-methylmethanesulfonylamino; Y represents a group NR9 CO Al Z 'in which R9 represents a hydrogen atom or a methyl radical and A 'and Z' are defined as in the claim, R7 and R8 being defined as in claim.