BE578408A - - Google Patents

Description

       

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 EMI1.1
 



  "NEW DERIVATIVES OF% 4-GETANILIDE" ..

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   The present invention relates to novel acetanilide derivatives and to compositions containing such derivatives and suitable for the treatment of diseases.



   The compounds according to the invention are those of general formula:
 EMI2.1
 in which R 'denotes an alkyl radical (comprising not less than 4 carbon atoms), alkenyl (not comprising less than 4 carbon atoms), aryl (except unsubstituted phenyl), aralkyl, aralkenyl, alkoxyalkyl, cy- cloaliphatic, aryloxyalkyl, aryloxyalkenyl, aryloxy-aryl, heterocyclic, heterocyclicalcoyl, heterocyclicalcenyl, or the group -R COOR ', where R2 is an alkylene, arylene, cycloalkylene, arylenedocyclic or disubydialcoyl radical 4- (dichloroacet-N-methylamido) -phenyl, as well as the single substituted derivatives of compounds of general formula containing, for example, one or more substituent groups, such as halogen, nitro, amino, acylamino, alkyl, alkoxy,

   acyl and methanesulphonyl in the radical represented by R '.



   It has been found that the compounds of the general formula, the above-mentioned have valuable properties as amebicides.



   The compounds according to the invention can be prepared by methods well known in the art for the preparation of phenol esters. One of these methods is

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 occurs in the interaction of an alkali metal salt of
 EMI3.1
 . phenol (which is dichloroaceto-4-hydroxy-N-methylanilide, known commercially as hEntamide "(RTM) with an acid halide of general formula R4CO.X, in which R4 denotes an alkyl radical ( containing not less than 4 carbon atoms), an alkenyl radical (containing not less than 4 carbon atoms), an aryl radical (except the unsubstituted phenyl radical), an aralkyl radical, an aralkenyl radical, a cy- group cloaliphatiaue, an aryloxyalkyl radical, an aryl-oxyalkenyl radical,

   an aryloxyaryl radical, a heterocyclic group, a heterocyclocalcoyl radical, a heterocyclicalcenyl radical or the group -R2-CO.X, in which R2 has the meaning given above and X is halogen.



   Another method of preparing the compounds. according to the invention consists in reacting, in the presence of an acid binding agent, the basic phenol which is Entamide with an acid halogen of general formula R4CO.X, in which R4 and X have the meaning indicated above.



   Another process consists in reacting Entamide with an acid anhydride of general formula (R5CO) 2O, in which R5 denotes an alkyl radical (having not less than 4 carbon atoms), an alkenyl radical (not comprising bearing not less than 4 carbon atoms), an aryl radical (except the unsubstituted phenyl radical), an aralkyl radical, an aralkenyl radical, a cycloaliphatic group, an aryloxyalkyl radical, an aryloxyalkenyl radical, an aryloxyaryl radical, a group heterocyclic, a heterocyclicalkl radical, a heterocyclicalkenyl radical or the group of the general formula R2 (CO) 20, wherein R2 has the meaning given above.

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   Another method of preparing the compounds according to the invention consists in reacting the basic phenol which is Entamide with an acid of general formula R6COOH, in which R6 denotes an alkyl radical (containing not less than 4 carbon atoms) , an alkenyl radical (containing not less than 4 carbon atoms), an aryl radical (except the unsubstituted phenyl radical), an arylcoyl radical, an aralkenyl radical, a cycloaliphatic group, an aryloxyalkyl radical, an aryloxy radical alkenyl, an aryloxyaryl radical, a heterocyclic group, a heterocyclicalcoyl radical, a heterocyclic-alkenyl radical or a group of formula -R2COOH, in which R2 has the meaning indicated above, in the presence of a condensing agent, such as dicyclohexylcarbodiimide ,

   dimethylcyanamide or tetraphosphoric acid.



   Another process for the preparation of a compound of general formula I consists of protecting the amino group of p-aminophenol by forming a compound of general formula:
 EMI4.1
 in which -N = Y represents (a) the group -NHR7, in which R7 denotes a formyl, acetyl or dichloroacetyl radical, or (b) the group -N-CHR, in which R8 denotes a phenyl radical or a radical substituted phenyl, then carrying out esterification so as to form a compound of general formula:

   
 EMI4.2
 in which R 'and the group -N = Y have the meaning

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 indicated, in carrying out a methylation and, except in the case where R7 denotes a dichloroacetyl group, in selectively hydrolyzing the methylated product so as to form a compound of general formula
 EMI5.1
 in which R 'has the meaning indicated above and R9 denotes hydrogen or a dichloroacetyl group, and to carry out dichloroacetylation in the case where R9 denotes hydrogen. This process is shown schematically below:

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   TABLE 1
 EMI6.1
 The symbol -Ph- represents the phenylenē radical - <6 '% The symbol -Z represents the formyl or acetyl radical.



  HO-Ph-NH2 p-amino-phenol j,. Proté = és Protests i0-Ph-N = Y ^ HO-Ph-NHCOCHCl 2 HO-PH-NHZ H0- hN * CHR Esterify! Esterify Esterify, CRtC0.0-Ph-N = Y, = RtC0.0-Ph- NHCOCHC1 2 RtCO.0- Ph-NHZ R'CO.0-Ph-N = CHR \ i4 \ ethyler Yiethyler ,, 1 '/ Meth 1er and RrCO.0-Ph-NMeZ .. Hydrolyze! Selectively, 1 / * r ble ", R'c0.0-Ph-Nhijfl R'CO.O-Ph-NMeH R.C0.0 = Ph-N-R9> i dic- hloroacetyler RtCh-NMeCOCHC12 Entamide ester

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Another process for the preparation of compounds of general formula I consists of treating Entamide sulfite with an acid of general formula R6COOH, wherein R6 has the meaning given above, in the presence of an acid-binding agent.



   The amoebicidal activity of the compounds according to the invention has been demonstrated in animals as follows. The technique is essentially that described by Jones (Annals of Tropical Medicine and Par3sitology, 1946, 40, 130), in which newly weaned ra, ts are inoculated, intracaecally, with trophozoites of E. histolytica. The day after inoculation, 5 daily doses of the product tested are administered through a stomach tube to each rat of a group of rats and the animals are sacrificed the day after the day on which they have received the last dose. The cecum of each rat is examined microscopically and macroscopically and the degree of infection of each rat is determined on an arbitrary scale.

   The mean degree of infection ("A.D.I") is then calculated for each group. A compound is considered to exhibit promising amebicidal activity when the "A.D.I" of the treated group is less than half that of an untreated control group. In the case of highly effective compounds, the rats are completely free from amoebae and the "A.D.I" is then zero.

   Initial tests revealed that the preferred group of compounds is that consisting of the esters of Entamide with carboxylic acids containing a heterocyclic ring or an aryloxy group, such as Entamide furoa te; direct comparison revealed that this compound is approximately 4 times

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 as active as Entamide and 2 times as active as Entamide benzoate.



   Amoebiasis occurs clinically in acute and chronic form and only the chronic form has been combated by Entamide and the esters thereof, which are described in UK patents 767,148 and 794,762. It has now been found that the compound of the preferred group of compounds according to the present invention which has been selected for clinical trials, namely Entamide furoate, not only exhibits increased activity against chronic amebiasis, but is found to be equally effective. - active against the acute form of the disease, which can be completely cured by administration of Entamide furoate at a dose of 20 mg / kg per day for 10 days. The total dose may vary between 15 mg and 75 mg / kg per day, this dose preferably being 20 to 40 mg / kg / per day.

   This dose can be provided in the form of unit doses which can contain from 100 mg to 1000 mg of active material, the unit doses preferably being administered several times a day, for example 3 or 4 times a day.



   The compositions according to the invention are suitable for internal or external applications, although the preferred mode of administration is that by mouth.



   The compositions according to the invention which are suitable for administration by mouth can be provided in the form of solid compositions, such as tablets, pills, capsules or the like, or in the form of liquid compositions, in particular in the form of suspensions. .



  Diluents, which can be used in the preparation

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 compositions according to the invention may be made up of any non-toxic substance compatible with the compounds according to the invention. Among the diluents are fillers, solvents, suspending agents, binders, flavoring agents and the like. It has been found that the form suitable for the administration of the active compounds according to the invention is that of tablets. These tablets contain the active compound in combination with a suitable diluent normally employed in the manufacture of tablets. The icing sugar and cornstarch have been found to give a very satisfactory tablet, the total weight of which is preferably 5 or 10 grains.

   A granulating agent can also be incorporated into the composition and it is preferred to use acacia gum. Small amounts of a lubricant can be added if desired and the stearic acid has been found to be entirely satisfactory. Finally, the compositions can also contain, if desired, coloring and flavoring agents.



   Among the liquid compositions suitable for the oral administration of the compounds according to the invention, there may be mentioned suspensions and syrups containing the active ingredient in combination with compatible suspending agents and the like, which are well known in the art. the technique.



   The following non-limiting examples illustrate the invention: @
EXAMPLE 1.-
For the preparation of 4- (dichloroacet-N-methyl-amido) phenyl 2-furoate, 13.7 g of 2-furoyl chloride are slowly added to a stirred solution of 23.4 g of

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 dichloroacet-4-hydroxy-N-methylanilide in 50 ml of dry pyridine, water cooling being applied to maintain the temperature below 25 C. The reaction mixture is stirred for a further 40 minutes then diluted with 400 ml of. ice-cold water containing 100 mg of sodium hydrosulphite. The product is collected by filtration and recrystallized from 95% alcohol.

   4- (Dichloroacet-N-methylamido) phenyl 2-furoate is thus obtained in the form of a crystalline solid melting at 112.5-114 ° C.



  (Found: C = 51.2%; H = 3.4%. For C14H11Cl2NO4, the calculation gives: C = 51.2%; H = 3.35%).



   The following esters are prepared in a similar fashion:
4- (Dichloroacet-N-methylamido) phenyl 4-methoxy-phenoxyacetate. M.P .: 93-94.5 C. (Found: C = 54.6%; H = 4.4%. For C18H17Cl2NO5, the calculation gives: C = 54.2%; H = 4.3%).



   4- (Dichloroacet-N-methylamido) phenyl phenoxyacetate. M.p .: 108-109 C. (Found: C = 55.3%; H = 4.0%; For C17H15Cl2NO4, the calculation gives: 0 = 55.4%; H = 4.1%).



   4- (Dichloroacet-N-methylamido) phenyl 2-thenoate. M.P .: 134-135 C. (found: C = 49.1%; H = 3.0%. For C14H11Cl2NO3S, the calculation gives: C = 48.8%; H = 3.2%).



   4- (Dichloroacet-N-methylamido) phenyl ss-naphthoxyacetate; M.P.:121-122 C. (Found: 0 = 60.4%; H = 3.7%. For C21H17Cl2NO4, the calculation gives: C = 60.3%; H = 4.1%).



   4- (Dichloroacet-N-methyl-amido) phenyl 2-chlorophenoxyacetate; M.p. 102-104 C. (Found: C = 50.5%; H = 3.1%.



  For C17H14C13N04; the calculation gives: C = 50.7%; H = 3.5%).

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   4- (Dichloroacet-N-methylamido) phenyl 4-methyl-phenoxyacetate; Mp: 69-71 C. (Found: 0 = 56.6%; H = 4.4%.
 EMI11.1
 For C1 $ H17C12N04; the calculation gives: G - 56, 55%; H =., W5), 4- (dichloroacet-N -methylamido) phenyl d - (2-methyl-phenoxy) propionate; M.P.:107-lOF3 C.



  (Found: C = 57.7%; H = 5.2%. For C19H19C12NO4; calculation gives: C = 57.6%; H. 4.8%).



   4- (Dichloroacet-N-methyl- 5-bromo-2-furoate
 EMI11.2
 amido) phenyl; M.P .: 101-103 C. (Found: C = 10.9; H = 2, k. For C14H109rC1zN0; calculation gives C = 41.3%; H-2.5%).



   EXAMPLE 2.-
Working as described in Example 1, but after crystallization five times from alcohol and once from benzene, then dissolution in acetone, extraction in ice-cold 1N NaOH and final crystallization in 95% alcohol, 4- (dichloroacet-N-methylamido) -phenyl 4-nitrophenoxyacetate is obtained; M.P .: 133-135 C. ('Found: C = 49.5%; H = 3.6%. For C17H14Cl2N2O6, the calculation gives: C = 48.9%; H = 3.4%).



   EXAMPLE 3.-
By the method described in Example 1, but collecting the crude oily product by extraction with chloroform, washing the chloroform solution with 0.5N sulfuric acid, with aqueous sodium bicarbonate solution and With water, drying the solution with anhydrous magnesium sulfate, removing chloroform by distillation and crystallizing the residue from 95% alcohol, the following compounds are obtained as crystalline solids:

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 EMI12.1
 4- (Dichloroacet-N-methylamido phenyl y-phenoxybutyrate; PF 61-62 C. (Found: C = 57.8%; H = 5.0%. For C19H19Cl2NO4; calculation gives: C = 57.6% ; H = 4.8%).



   4- (Dichloroacet-N-methylamido) phenyl 3-chloro-phenoxyacetate; M.p. 80-81 C. (Found: C = 50.6%; H = 3.8%.
 EMI12.2
 For Cl 2 H14ClJN04 'the calculation gives: 0 = 50.7%; H-3.5%).



   4- (Dichloroacet-N-methylamide) phenyl 2-phenoxy-benzoate; M.p. 92-93 C (Found: C = 61.1%; H-4.0%.



  For C22H17Cl2NO4, the calculation gives: C = 61.4%; H = 3.95%).



    EXAMPLE 4.-
For the preparation of 4- (dichloroa- ket-N-methylamido) -phenyl nicotinate, 32.5 g of nicotinyl chloride (hydrochloride) is added to a stirred solution of 45 g of dichloroacet-4-hydroxy-N-methylanilide in 140 ml of dry pyridine. After stirring for 90 minutes, the reaction mixture was covered with ice-water and the product was isolated as in Example 1. There was thus obtained, in the form of a crystalline solid, 4- (dichloroacet- nicotinate. N-methylamido) phenyl melting at 167-170 C.
 EMI12.3
 



  (Found: C = 53.4; H = 3.510; N = 8.6%. For C15H1zC12IV203, the calculation gives: C = 53.1%; H = 3.5%; N = 8.3%).



   Similarly, 4- (Dichloro-acet-N-methylamido) phenyl picolinate is prepared; P.F. 130-131 C.



  (Found: C = 53.1% H = 3.7%. For C15H12C12N2O3, calculation gives: C = 53.1%; H = 3.5%).



   EXAMPLE 5.-
For the preparation of isonicotinate 4- (dichloro-
 EMI12.4
 acet-3-methylamiâo) phënyïe, 6.4 ml of benzene sulphonyl chloride are added to a sulution of 12.3 g of isonicotinic acid in 50 ml of dry pyridine, the temperature rising to 65 ° C. The solution is stirred at 45 ° C. for

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 15 minutes, then heated to 90 C. A solution of 11.7 g of dichloroacet-4-hydroxy-N-methylanilide in 20 ml of dry pyridine is slowly added to the stirred solution and stirring at 90 C is continued. during 30 minutes. The solution is cooled and poured into 300 ml of ice water. The crude product is filtered off and crystallized twice from 95% alcohol.

   This gives 4- (dichloroacet-N-methylamido) phenyl isonicotinate, melting at 125-.
 EMI13.1
 126.5 C. (Found: CK53.0%; H = 3.3%. For C15H12C12N20J 'the calculation gives C = 53.1%; H = 3.5%).



   In a similar manner, the following ester is prepared:
4- (dichloroacet-N-methylamido) 2-furylacrylate
 EMI13.2
 phenyl; PIF, 115-117 * 0. (Found: C = 54.4h; H = 3.6iâ. For C16H13C12N04, the calculation gives: C = 54.2%; He3je,).



  EXAMPLE 6.-
 EMI13.3
 For the preparation of 4- (dichloroacet-N-methylamido) phenyl o (-phenoxyisobutyrate), 11.7 g of dichloroacet-4-hydroxy-N-methylanilide are added slowly to a solution of 10 g of d- chloride. phenoxyisobutyryl in 50 ml of dry pyridine and the mixture is kept at about 20 C for 20 hours The reaction mixture is poured into 500 ml of ice-water and the crude product is filtered off, washed with dilute sulfuric acid. and with water and crystallized from methanol There was thus obtained, as a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl c (-phenoxyisobutyrate, m.p. 85-). 86 C. (Found:
 EMI13.4
 C, 57.5i; H = 4., 6; N =, 6ja. For C19H19C12N04 'the calculation gives: C = 57.6-; H = 4, e / .; N = 3.5).



   EXAMPLE 7. - By the method described in Example 6, but by

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 crystallization of the crude product twice from a mixture of chloroform and methanol to give, in the form of a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl coumarilate, melting point 151-153 ° C. (found : C = 57.4%; H = 3.4%; N = 4.0%. For C18H13Cl2NO4, the calculation gives: C = 57.1%, H = 3.4%; N = 3.7%) .



   EXAMPLE 8.-
By the process described in Example 6, but extracting the gummy product with ether, washing the ethereal solution with 5N sulfuric acid, with water, with water. Using 2N sodium hydroxide and water, evaporating the solvent and recrystallizing the gummy product in methanol, [alpha] -phenoxypropionate is obtained in the form of a crystalline solid. 4- (Dichloroacet-N-methylamido) phenyl mp 61-62 ° C. (Found: C = 56.6%; H-4.45%; N = 3.7%.



  For C18H17Cl2NO4, the calculation gives: C = 56.55%; H = 4.45%; N = 3.7%).



     EXAMPLE 9. -
By the process described in Example 8, the following esters of 4- (dichloroacet-N-methylamido) phenyl t-d-phenoxy-n-butyrate are obtained in the form of a gum. (Found: C = 57.9%; H = 5.2%; N = 3.9%. For C19H19C12N04, the calculation gives: C = 57.6%; H = 4.8%; N = 3.5 %).



     4- (Dichloroacet-N-methylamido) phenyl [alpha] -phenoxy-n-valerate. (Found: C = 58.8%; H = 5.2%. For C20H21Cl2NO4, the calculation gives: C = 58 , 5%; H = 5.1%). 4- (Dichloroacet-N-methyl-amido) phenyl (-phenoxy-n-hexanoate) (Found: C = 59.6%; H = 5.25%. For C21H23Cl2NO4, the calculation gives: C = 59, 4%; H = 5.4%).

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   EXAMPLE 10. -
For the preparation of 4- (dichloroacet-N-methylamido) -phenyl ss -phenoxypropionate, 9.3 g of thionyl chloride are added to a stirred suspension of 12.9 g of ss-phenoxypropionic acid in 50 ml of ss-phenoxypropionic acid. anhydrous ether and the mixture is maintained at about 20 C for 16 hours under anhydrous conditions. The solvent is distilled off at 20 ° C. under reduced pressure and 11.5 g of the gumous residue are dissolved in 60 ml of dry pyridine. To the solution is added a solution of 15 g of dichloroacet-4-hydroxy-N-methylanilide in anhydrous pyridine. The reaction mixture is immersed in water and the product is collected with ether and crystallized as described in Example 8.

   In this way, 4- (dichloroacet-N-methyl-amido) phenyl / 3 -phenoxypropionate is obtained in the form of a crystalline solid, melting at 61-62 ° C. (Found: C = 56.5%; H = 4.7 %.



  For C18H17Cl2NO4, the calculation gives C = 56.55%; H = 4.45%).



   EXAMPLE 11. -
For the preparation of 4- (dichloroacet-N-methylamido) -phenyl ss-phenoxypropionate, 2.32 ml of benzoyl chloride dissolved in 10 ml of anhydrous benzene are added dropwise at room temperature to a stirred suspension of 3 , 76 g of fine powdered sodium ss-phenoxypropionate in 40 ml of anhydrous benzene and stirring is continued for a further 90 minutes. To the solution of the mixed anhydride thus formed, a solution of 4.68 g of dichloroacet-4-hydroxy-N-methylanilide in 50 ml of dry pyridine is added and the reaction mixture is left to stand for a while. for about 16 hours, after which it is poured into 200 ml of water. The aqueous phase is washed with ether and the ethereal extract is added to the solvent phase.

   The gold phase

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        ganiquētotale is washed successively with 5N sulfuric acid, with water, with sodium hydroxide
2N and finally with water. It is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is crystallized twice from aqueous methanol and 4- (dichloroacet-N-methylamido) phenyl ss-phenoxypropionate is obtained in the form of a crystalline solid, melting point at 60-61 ° C. this compound mixed with that prepared according to the example
10 is also 60-61 C.



   EXAMPLE 12. -
For the preparation of tetrahydro-2-furoate
4- (dichloroacet-N-methylamido) -phenyl, 11.2 g of dicyclohexylcarbodiimide are added to a hot mixture of 6.27 g of tetrahydro-2-furoic acid, 12.6 g of dichloroacet-4- hydroxy-N-methylanilide and 100 ml of methylene chloride and the mixture is left to stand overnight at
C. To the mixture is added 1 ml of glacial acetic acid and after one hour the solution is filtered and the filtrate is washed with normal aqueous sodium carbonate solution, with ice-cold 2N hydroxide solution. sodium and with water. Then dried using anhydrous magnesium sulfate and evaporated until an oil is obtained, which is dissolved in a mixture of equal parts by volume of benzene and petroleum ether (60-80 C).

   The solution is cooled to 0 C for 3 hours, filtered and evaporated until an oil is obtained which is distilled under vacuum. There is thus obtained, in the form of an oil, 4- (dichloroacet-N-methylamido) phenyl tetrahydro-2-furoate which melts at 175 ° C. under a pressure of 0.01 mm Hg. (Found: C, 50.8%;
H, 4.5%. For C14H15Cl2NO4, the calculation gives: C = 50.6%; H = 4.5%) -

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   EXAMPLE 13.-
For the preparation of 4- (Dichbroa-ket-N-methylamido) phenyl 3-furoate, 6.75 g of dicyclohexylcarbodimide is added to a hot mixture of 3.6 g of 3- acid.
4-hydroxy-furoic, 7.7 g of dichloroaceous -N-methylanilide and 75 ml of methylene chloride and the mixture is left to stand at 20 ° C. overnight.

   To the mixture is added 2 ml of glacial acetic acid, and after standing for 5 hours, filtered and the filtrate washed with ice-cold 2N sodium hydroxide solution, then with water, after which it is dried. over anhydrous magnesium sulfate. The solvent is removed by distillation and the residue is crystallized twice from S.V.M. There is thus obtained, in the form of a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl 3-furoate, melting point at 105.5-107 C. (Found: 0 = 51.5%, H = 3, 6%. For C14H11Cl2NO4, the calculation gives: C = 51.2%, H = 3.35%).



   In a similar manner, the following esters are prepared: 4- (dichloroacet-N-methylamido) phenyl 4: 5-dibromo-2-furoate; M.p. 142-144 C. (Found: C = 34.8%; H = 1.8%.
 EMI17.1
 



  For C14H9Br2012N04 'the calculation gives: C = 34.6%; H = 1, $ 50).



   4- (Dichloroacet-N-methylamido) phenyl 5-methyl-2-furoate; M.P .: 129-131 C. (Found: C = 52.1%; H = 3.8%. For
 EMI17.2
 C15H13C12N0, the calculation gives: C = 52.6%; H = 3, $%). #: # -bis (fur-2-yl) -n-valerate of 4- (dichloroa- ket-N-methylamido) phenyl. (Found: C = 58.5%; H = 5.1%.
 EMI17.3
 C22H2IC12NOS 'the calculation gives: C = $ 5.66; H = 4.7f).



     [alpha]: 4- (dichloroacet-N-methylamido) phenyl c (-di- (5-methylfur-2-yl) propionate; m.p. 105-106 C. (Found:
 EMI17.4
 C, 58t3%; H, 5.0%. For C22H2IC12NOS 'the calculation gives:

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 C, 58.6%; H = 4.7%).



   EXAMPLE 14. -
By the procedure described in Example 1, except that the acid chloride is dissolved in acetone before addition to the solution of dichloroacet-4-hydroxy-N-methylanilide in pyridine , 4- (dichloroacet-N-methylamido) phenyl quinaldate is obtained in the form of a crystalline solid; M.P .: 143-145 C. (Found: C = 58.3%; H = 3.6%. For C19H14Cl2NO3, the calculation gives: C = 58.6%; H = 3.6%).



     EXAMPLE 15.-
By the procedure described in Example 14, but by crystallization from acetic acid, furan-2: 5-dicarboxylate of 4- (dichloroacet-N-methylamido) is obtained in the form of a crystalline solid. phenyl. P.F. 194-194.5 C.



  (Found: C = 48.6%; H = 3.0%. For C24H18Cl4N2O7, the calculation gives C = 49.0%; H = 3.1%).



   EXAMPLE 16. -
For the preparation of 4- (Dichloroacet-N-methylamido) -phenyl pyrazinoate, a solution of pyrazinoyl chloride (7.2 g) in acetone (70 ml) is added slowly to a stirred solution of dichloroacet-4-hydroxy-N-methylanilide (11.1g) in pyridine (35ml). Stirring is continued for 1/2 hour and the reaction mixture is poured into water (400 ml). The gum which deposits is collected with the aid of chloroform and the chloroform solution is washed successively with sulfuric acid diluted with aqueous sodium bicarbonate and with water. The solution is dried over anhydrous magnesium sulfate and evaporated, so that a gum is obtained which is dissolved in methanol.

   The methanolic solution

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 is evaporated to give a solid, which is recrystallized from alcohol. There is thus obtained, in the form of a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl pyrazinoate; M.p. 115-117 C. (Found: C = 49.0%; H = 3.5%; N = 12.0%.
 EMI19.1
 For C14HIICIZN303 'the calculation gives: 0 = 49.4%; H = 3.2; N = 12.4%).



   EXAMPLE 17. -
 EMI19.2
 For the preparation of 4- (Dichloroacet-N-methylamido) phenyl p-phenylenedioxydiacetate, a solution of p-phenylenedioxydiacetyl chloride (11.46 g) in acetone is added to a stirred solution of dichloroacet- 4- hydroxy-N-methylanilide (20g) in pyridine (50ml).



  After stirring for 2 hours at room temperature, the reaction mixture is poured into water and the gum which separates is extracted with chloroform. The chloroform solution is washed successively with water, with aqueous sodium hydroxide, with dilute sulfuric acid and with aqueous sodium carbonate solution, then dried over anhydrous magnesium sulfate and evaporated. to dryness. After crystallization from acetic acid, 4- (dichloroacet-N-methylamido) -phenyl p-phenylenedioxydiacetate is obtained; M.P .: 153-154 C (Found: C = 51.4%;
 EMI19.3
 H-3.7 '/ o. For C28H2, ci4N208, the calculation gives: C = 51.1 ;; H = 3.65%).



   EXAMPLE 18.-
For the preparation of 4- (di-chloroacet-N-methylamido) phenyl 5-nitro-2-furoate, 5-nitro-2-furoic acid (3.95 g) is heated under reflux for 24 hours. hours with thionyl chloride (5 ml), then an additional 5 ml of thionyl chloride is added and heating under reflux is continued for 8 hours. The solution is distilled

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 The crude acid chloride is dissolved in acetone and added to a stirred solution of dichloroacet-4-hydroxy-N-methylanilide (4.7 g) in pyridine ( 20 ml).

   The product is isolated and purified as described in Example 1 and 4- (dichloroacet-N-methylamido) -phenyl 5-nitro-2-furoate is obtained; M.p. 116-117 C. (Found:
 EMI20.1
 C, 45.19a; H, 2.9%. For C14HIOC12N206 'the calculation gives: C = 45.0%; H = 2.7%).



   EXAMPLE 19.-
For the preparation of 4- (Dichloroacet-N-methylamido) phenyl 5-methoxycoumarilate, 5-methoxycoumarilic acid (2 g) is heated with thionyl chloride (10 ml) under reflux for 1 hour, then distilled. to dryness. The crude acid chloride is dissolved in 30 ml of dry pyridine and 2.4 g of dichloroadet-4-hydroxy-N-methylanilide are added slowly, after which the reaction mixture is left at room temperature for 20 hours. The product is isolated and purified as described in Example 6. There is thus obtained in the form of a crystalline solid 4- (dichloroacet-N-methylamido) phenyl 5-methoxycoumarilate; P. F. 151-152 C. (Found: C = 55.5%;
 EMI20.2
 H, 3.6%.

   For C19H15ci 2NO 5y the calculation gives: 0 = 55.9%; H- 3.7%).



   In a similar manner, the following esters are prepared:
5: 7-dibromocoumarilate 4- (dichloroacet-N-med-
 EMI20.3
 thylamido) phenyl; M.p. 171 * C. (Found: 0 = 40.1%; Ho0%. For ClEH11Br2Cl2N04 'the calculation gives: 0 = 40.3%; H = 2.05%).



  4- (dichloroacet-N-methyl-amido) phenyl 7-methoxycoumai'3, late; M.p. 18 -1 $! R''C. (Troavé: C = 55.5%; H = 3, For C19H15Cl2NO5, the calculation gives 0 = 55.9%; H = 3.7%).

 <Desc / Clms Page number 21>

 



   EXAMPLE 20. -
For the preparation of 4- (Dichloroacet- N-methylamido) phenyl 2-furoatc, a mixture of dichloroacet-4-hydroxy-N-methylanilide (23.4 g), 2-furoic acid (11.2 g) and tetraphosphoric acid (55 g) is stirred and heated in a steam bath for 24 hours. The viscous product is triturated with water and the black solid obtained is kneaded with a dilute aqueous solution of sodium hydroxide, washed with water and drained. After extraction with boiling alcohol, the mixture is filtered and left to crystallize at 0 ° C. In this way, in the form of a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl 2-furoate is obtained. ; M.p. 111-112 C unreduced in admixture with the material prepared as described in Example 1.



   EXAMPLE 21.-
For the preparation of 4- (dichloroacet-N-methylamido) phenyl cinnamate, 17.3 g of cinnamon chloride is slowly added to a stirred solution of 23.4 g of dichloroacet-4-hydroxy-N-. methylanilide in 50 ml of pyridine. dries, cooling with water being carried out to maintain the temperature below 25 C. The conventional mixture is stirred for an additional 40 minutes, then diluted with 400 ml of ice water containing 100 mg of sodium hydrosulphite. The product is collected by filtration and recrystallized from 95% alcohol. 4- (Dichloroacet-N-methylamido) phenyl cinnamate is thus obtained in the form of a crystalline solid melting at 101-102 ° C. (Found: C = 59.55%; H = 4.2%.

   For C18H15Cl2NO3, the calculation gives: C = 59.35%; H = 4.1%).



   In a similar manner, the following esters are prepared:

 <Desc / Clms Page number 22>

 4- (Dichloroacet-N-methylami- 4-methoxybenzoate
 EMI22.1
 do) phenyl; M.p. 119-121 * C. (Found: C = 55, $%; H = 3.9%.



  For C17-15 ci 2NO 4y the calculation gives. C = 55.4; H = 4.1%) 4- (dichloroacet-N-methylamido) phenyl phthalate; mp 137-138 ° C (Found: C- 52p5%; H = 3.4% - For c26HZOC14NZQ6 'the calculation gives: C = 52.2%; H = 3.3%).



   4- (Dichloroacet-N-methylamide) phenyl 3-phenylpropionate; M.p. 76-77 C. (Found: C = 58.9%; H = 4.6%. For
 EMI22.2
 C1 calculH17C12NCJ 'the calculation gives: Ca59.0; H 4, 6 &).



   4- (Dichloroacet-N-methylamide) phenyl 2-acetylsalicylate; M.p. 175-177 C. (Found: C = 55.1%; H = 3.9%.
 EMI22.3
 For C1 $ H 1S012N05 'the calculation gives: C-54.6i; H3r) 4- (Dichloroacet-N-methylamide) phenyl hexahydrobenzoate; M.p. 76-78.5 C. (Found: C = 56.0%; H = 5.7%. For C16H19C12NO3, the calculation gives: C = 55; H-5.5%). 4- (Dichloroacet-N-methylamido) phenyl octanoate;
 EMI22.4
 M.p. 42-44 C. (Found: C = 56.7; Hn6.3a. For C17H23C12NOJ 'the calculation gives: C = 56.7%; H-6.4%).



     4- (Dichloroacet-N-methylamido) phenyl [alpha] -naphthoate; M.p. 140-141 C. (Found: C-61, 6%; H = 4.0%. For
 EMI22.5
 C20H15C12N03, calculation gives: C-6ly8%; H = 3, o; '). 4- (dichloroacet-N-methylamido) phenyl p-toluate; M.P .: 102.5-105 C. (Found: C = 58.0%; H = 4.3%.
 EMI22.6
 For C17H15C12N03 'the calculation gives: C = $ 5, 0; H = 4.3%).



   4- (Dichloroacet-N-methylamido) phenyl 4-nitrobenzoate; M.p. 145-147 C. (Found: C = 49.9%; H = 3.1%. For
 EMI22.7
 6H12C12N20S 'calculation gives: C-50y2%; H-3.1%).



   4- (Dichloroacet-N-methylamido) phenyl 4-dimethoxybenzoate; M.p. 156 C. (Found: C = 54.3%; H = 4.3%.
 EMI22.8
 For C18H17C12N05 'the calculation gives. C, 54.3%; H = 43%).

 <Desc / Clms Page number 23>

 



   4- (Dichloroacet-N-methylamide) phenyl 2-chloro-benzoate; M.p. 108-110 C. (Found: C = 51.2, ;; H = 3.3%. For
 EMI23.1
 C16H12cl 3 NO 3 the calculation gives: C = 51.6> '; H = 3.2%).



  4- (Dichloroacet-N-methylamide) phenyl 3-methoxy-benzoate; Mp 113-114 "C. (Found: C = 55.6i; H = 4.013. For C17H15Cl2NO4 'the calculation gives C-55e4%; H = 4.1%). 4- (dichloroacet-N-methylamido) hippurate phenyl; mp: 146-148 C. (Found: 0 = 54.6%; H = 4, (Y / o. For Cl $ H1bC12NZ04, calculation gives: Ca54.7; H = 4.05%). decanoate of 4- (Dichloroacet-N-methylamido) phenyl; mp: 47-49 "C. (Found: C = 58.9%; H = 6.8%. For
 EMI23.2
 C19H27C12N03 Calculation gives: C-58.8%; H = 7.0i).



  4- (dichloroac: t - methyldmido) phenyl 3-bromo-benzoate; M.p .: 108-109'C. (Found: 0 = 46.0%; H-3.0 '/ o. For C16H12BrC12NO), the calculation gives C = k6.0 ;; H-2.9 /).



   EXAMPLE 22. -
Following a similar procedure to that described in Example 21, but applying an isolation process consisting of dissolving the crude non-crystalline product in chloroform, washing the chloroform solution with sulfuric acid 0, 5 N, with aqueous sodium bicarbonate solution and with water, drying the solution with anhydrous magnesium sulfate, distilling off the chloroform and crystallizing the residue from 95% alcohol, then obtains the following esters as crystalline solids:
4- (Dichloroacet-N-methylamido) phenyl sebacate;
 EMI23.3
 M.p. 82-83'C. (Found: C = 53.2%; Hua. For C28H32C14N206, the calculation gives: C = 53.0%; H = 5.05%).

 <Desc / Clms Page number 24>

 
 EMI24.1
 



  4- (Dichloroacet-N-methyla ^ ida) phenyl diphenylacetate; M.p. 99-1010C. (Found: C = 64.2; ô; H = 4.6%. For c23H19 -12 NO3, the calculation gives. C = 64.5; 0; H = 4.4%).



  4- (Dichloroacet i3-methylamide) phenyl 2-benzoylbenzoate; M.P.:115-116 C. (Found: C = 62.2%; H = 4.0%. For
 EMI24.2
 C23, 17Cl2NO4, calculation gives: C = 62.4%; H = 3.8%).



  4- (Dichloroaeet-N-methylamido) phenyl hexanoate mp: 34-35 C. (Found: C = 54.2; H = 5.8%. For C15H19Cl2NO3, the calculation gives: C = 54.2%; H = 5.7%).



   EXAMPLE 23. -
By the process described in Example 22, but using ether instead of chloroform,
 EMI24.3
 4- (Dichloroacet-N-methylamido) phenyl oleate in the form of an oil; (Found: C = 64.5%; H = 8.3%. For C27H41Cl2NO3, the calculation gives: C = 65.1%; H = 8.2%).



   EXAMPLE 24.-
By the process described in Example 21, but by additional crystallization of the product from methyl propyl ketone, 4- (dichloroacet-N-methylamido) phenyl trephthalate is obtained in the form of a crystalline solid.
 EMI24.4
 at 174-177 C. (Found: C = 52, Oi; H = 3.6%. For C26H20C14N2O6 'the calculation gives: C = 52.2%; H = 3.3%).



   EXAMPLE 25.-
By the process described in Example 21, but using a reaction temperature below 10 ° C. and crystallizing the products from methanol, the following esters are obtained in the form of crystalline solids:
4- (Dichloroacet-N-methylamido) phenyl laurate;
 EMI24.5
 M.p. 52-54 C. (Found: C = 60.5%; H = 7.4%. For Cz1H31C1zN03, the calculation gives: C = 60.6%; H = 7.5%).

 <Desc / Clms Page number 25>

      
 EMI25.1
 4- (Dichloroacet-M-methylamido) phenyl stearate; H = 8-9%.



  PF 65-6 $ C. (Found: C = 65.7i; ß 3, o-> 5. For CH Cl NO, the calculation gives: C = 64.8, /; H = 8.6%; N = 2, $ o) z3 2 3
EXAMPLE 26.-
For the preparation of 4- (dichloroacet-N-methylamido) phenyl 4-methanesulfonylbenzoate, 22.0 g of 4-methar.esulfonylbenzoyl chloride are added over 10 minutes to a stirred solution of 21.5 g. dichloroacet-
 EMI25.2
 4-hydroxy-N-methylan it ide in 90 ml of anhydrous pyridine.



  At the end of this time, the mixture is heated to 40 ° C. and stirred at this temperature for 1 hour. The product is then isolated, as described in Example 21, so that 4- (dichloroa-acet-N-methylamido) phenyl 4-methanesulfonylbenzoate is obtained in the form of a crystalline solid melting at 166. -168 C. After crystallization from benzene; (Found: 0 = 49.4%; H = 3.7. For C17H15Cl2NO5S, calculation gives: C = 49.0%; H = 3.6%).



   EXAMPLE 27.-
For the preparation of 4- (dichlo-chloroacet-N-methylamido) -phenyl 4-chlorcbenzoate, a mixture of 5.9 g
 EMI25.3
 4-chlorobenzoic anhydride, 4.7 g of dichloroacet-4-hydroxy-N-methylanilide and 20 ml of dry pyridine is kept at 20 C for 3 hours then heated to 85 C for 30 minutes, cooled and poured in 200 ml of ice water.



  The product is collected by filtration and recrystallized from alcohol. This gives 4- (dichloroacet-N-methylamido) phenyl 4-chlorobenzoate in the form of a solid.
 EMI25.4
 crystalline melting at 98.5-1000C. (Found: C = 51,% µ; H = 3.3.



  For C16H12C'3 NO 3e the calculation gives: 0 = 51.6%; H = 3.2%).
EXAMPLE 28.- For the preparation of 4-chlorobenzoate of 4- (di-

 <Desc / Clms Page number 26>

   chlorbacet-N-methylamido) phenyl, an intimate mixture of 5.9 g of 4-chlorobenzoic anhydride and 4.7 g of dichloroaret-
 EMI26.1
 4-hydroxy-1-methylanilide is heated in an oil bath at 130-170 C for 3 hours. The cooled mixture is then crystallized from alcohol and kneaded in a mortar with 30 ml of a normal solution of sodium hydroxide and the solid is collected and recrystallized from alcohol, so that the 4- (Dichloroacet-N-methylamido) phenyl 4-chlorobenzoate is obtained identical to that prepared as described in Example 27.



   EXAMPLE 29.-
 EMI26.2
 For the preparation of 4- (dichloroa ket-N-methylamido) phenyl-cl-h1ethoxypropionate, II.7 g of dichloroadet-4-hydroxy-N-methylanilide are added, in fractions; to a solution of 6.2 g of c (-methoxy-propionyl chloride in 50 ml of dry pyridine and the mixture is kept at room temperature for 20 hours. The mixture is calcined by pouring it into 500 ml of dry pyridine. water and the product is collected by filtration, washed with dilute sulfuric acid and water and crystallized from methanol to obtain 4- (dichloroacet-N-methylamido) phenyl [alpha] - methoxypropionate as a crystalline solid melting at 110-111 C.
 EMI26.3
 



  (Found: C = $ 4.9%; H = 4.4%. For C13H15C12NO4, the calculation gives: C = 48.8%; H = 4.7%).



   EXAMPLE 30.-
For the preparation of 4- (Dichloroacet-N-methylamido) phenyl o-methylmandelate, 8.1 g of dichloroacet-
 EMI26.4
 4-hydroxy-N-methylanilide are added in portions to a solution of 6.4 g of o-methylmandelyl chloride in 32 ml of dry pyridine and the mixture is kept at room temperature for 20 hours and poured into 500 ml of 'water. The product

 <Desc / Clms Page number 27>

 gummy is extracted with 3 fractions of 100 ml of ether and the combined ethereal extracts are washed successively with 5N sulfuric acid, water, 2N sodium hydroxide and water.

   The solution is dried with anhydrous sodium sulphate and evaporated, until a gom-leux product is obtained which is crystallized twice from aqueous methanol. 4- (Dichloacet-N-methylamido) phenyl lte-methylmandelate is thus obtained in the form of an oristalline solid melting at 86-88 ° C. (Found: C = 56.7%; H = 4.7%. .   For
 EMI27.1
 Cl $ H17C12N04, the callus gives: C = 56, 557; li = 4.55 ,, ')
EXAMPLE 31.-
By the process described in Example 30, but by raising the ethereal extract with 50% aqueous methanol, with saturated aqueous Na bicarbonate solution and with water, 4- (dichloroacetate) methoxyacetate is obtained. -NOT-
 EMI27.2
 methylamido) phenyl; PiF. 52-54''C. (Found: C = 47.3%; H = 4.31 ;.



  For C12H 13 Cl2NO 41 the calculation gives i C = 4lli; H = 4.25%).



    EXAMPLE 32.-
By the process described in Example 30, but extracting with chloroform, instead of ether, and crystallizing from methanol, 4- (dichloreacet-N-methylamido) phenyl cyclop-ropane carboxylate is obtained. ; M.P .: 114-115 C. (Found: C = 50.5%; H = 4.6%; N = 4.3%.
 EMI27.3
 C13H13C12N03 'the calculation gives: C = 50.1%; H = i, 3; N = 4.6%).



   EXAMPLE 33.-
By the process described in Example 30 but by crystallizing the product in an ether / petroleum ether mixture (bp 40-60 C), the following esters are obtained: 4- (dichloroacét-N-methylamido) cyclobutane carboxylate phenyl; Mp 68-68.5 C (Found: C = 53.3%; H =
 EMI27.4
 5.0o. For C14H15 Cl2NO 3 the calculation gives: C = 53.2%; H = 4.7%).

 <Desc / Clms Page number 28>

 4- (Dichloroacet-N-methyl-amido) phenyl cyclopentanecarboxylate; M.p. 57-58 C. (Found: C = 54.0%; H = 5.2%. For C15H17C12N03, calculation gives: C = 54.2%; H = 5.1%).



     EXAMPLE 34.-
For the preparation of 4- (Dichloroacet-N-methylamido) phenyl 3: 4-dichlorobenzoate, a mixture of 3: 4-dichlorobenzoyl chloride (11.0 g), dichloroacet-4-hydroxy-N-methylanilide (11 , 7 g) and pyridine (30 ml) is stirred for one hour and poured into N / 4 sodium hydroxide solution (200-ml). The crude product is collected by filtration and crystallized three times from alcohol and twice from benzene. Thus obtaining, in the form of a crystalline solid, 4- (dichloroacet-N-methylamido) phenyl 3: 4-dichlorobenzoate; M.p. 113-114 C. (Found: C = 47.4%; H = 2.7%. For C16H11Cl4NO3 the calculation gives: C = 47.2%; H = 2.7%).



   EXAMPLE 35.-
For the preparation of 4- (dichloroacet-N-methylamido) -phenyl 4-aminobenzoate, a solution of 4- (dichloroacet-N-methylamido) phenyl 4-nitro-benzoate (9.57 g) in The ethyl acetate (180 ml) is hydrogenated at room temperature and at room pressure in the presence of a 10% palladium carbon catalyst (0.1 g). When the theoretical weight of hydrogen has been absorbed, the solution is filtered and concentrated in vacuo. The solid residue is crystallized from ethyl acetate, thereby obtaining 4- (dichloroacet-N-methylamido) phenyl. Mp 196.5-197 C. (Found: C = 54.2%; H = 3.8%; N = 8.0%. For C16H4C12N2O3, the calculation gives: C = 54.4%; H = 4, 0%; N = 7.9%).



   EXAMPLE 36, -
For the preparation of 4- (di-) phenylglyoxylate

 <Desc / Clms Page number 29>

 chloroacet-N-methylamido) phenyl, a mixture of dichloroacet-
 EMI29.1
 4-hydroxy-, M-methylan il ide (11.7 g), phenylglyoxylic acid (7.5 g), methylene chloride (40 ml) and pyridine (5 ml) is cooled to 0 C, and a solution of dicyclohexylcarbodiimide (10.3 g) in methylene chloride (20 ml) is added slowly with stirring. The mixture is left to stand at 0 C for 16 hours and is filtered after addition of an additional 0.5 g of phenylglyoxylic acid.



  The filtrate is diluted with two volumes of ether, washed with dilute acid, with water, (very quickly) with dilute alkali and finally with water, before being dried over water. sodium sulfate anhydrous and evaporated. The residue is crystallized from methanol and 4- (dichloroacet-N-methylamido) phenyl phenylglyoxylate is obtained as a crystalline solid; P. F. 87-88.5 C. (Found:
 EMI29.2
 C156.1%; H-3.5%. For C 17 H 13 Cl 2 NO 41 the calculation gives: C = 55.7%; H-3.55%).



   EXAMPLE 37.-
For the preparation of 4- (dichloroacet-N-methyl-amido) phenyl d-methoxyisobutyrate, a mixture of dichlo-
 EMI29.3
 roacet-4-hydroxy-N-methylanilide (11.2 g), d -methoxy-isobutyric acid (5.9 g), pyridine (5 ml) and methylene chloride (80 ml) is stirred at temperature ambient. A solution of dicyclohexylcarbodiimide (10.3 g) in methylene chloride (20 ml) is added and the mixture is allowed to stand at room temperature for 16 hours. After adding a further 0.5 ml of d-methoxyisobutyric acid, the mixture is filtered after 1 hour and the filtrate is washed successively with dilute sulfuric acid, water, hydrogen. dilute sodium droxide and water.

   After drying over anhydrous magnesium sulfate, the solution is evaporated and the

 <Desc / Clms Page number 30>

 gummy residue is triturated with benzene and light petroleum (60-80 C). The solution is filtered, then evaporated and the gummy residue is crystallized from aqueous methanol.



  There was thus obtained ltc (-methoxyisobutyrate 4- (dichloroacet-N-methylamido) phenyl; mp 56-57 C. (Found: C = 50.1%;
 EMI30.1
 H-5.2%. For 14HI7C12N04 'the calculation gives: C = 50.3; H = 5.1%).



   EXAMPLE 38.-
By a process similar to that described in Example 37, but by distilling the oily residue after evaporation of the methylene chloride solution, 4- (dichloroacet-N-methylamido) phenyl ethoxyacetate is obtained. in the form of an oil boiling at 167 C under 2.5 x 10-3 mm Hg.
 EMI30.2
 (Found: C-48.8%; H = 4.9%. For C13H15Cl2NO4 'the calculation gives: C - 48.8%; H = 4.7%).



   EXAMPLE 39.-
For the preparation of 4- (dichloroacet-N-methylamido) phenyl ss-benzoylpropionate, a mixture of /) - benzoylpropionic acid (8.9 g), dichloroacet-4-hydroxy-N-methylanilide, methylene chloride (100 ml) and di-cyclohexylcarbodiimide (10.3 g) is left to stand at room temperature for 18 hours. After adding 2 ml of acetic acid and standing for 1 hour, the mixture is filtered. The filtrate is washed with 2N aqueous sodium hydroxide and ice cold, then with water, after which it is dried over anhydrous magnesium sulfate and evaporated until a gum is obtained which slowly crystallizes. After recrystallization from ethyl alcohol, duss -benzoylpro-
 EMI30.3
 4- (Dichloroacet-E-methylamido) phenyl pionate m.p. 94.5-95.5 C. (Found: C = 57; H = 4.4%.

   For C19H17C1zNO4, the calculation gives: C = 57.9%; H-4.3%).

 <Desc / Clms Page number 31>

 



   EXAMPLE 40.-
For the preparation of 4- (Dichloroacet-N-methylamido) phenyl 4-chlorobenzoate, a mixture of dichloroacet-4-hydroxy-N-methylanilide (11.7 g), 4-chlorobenzoic acid (7.82 g) , dimethyl cyanamide (7.0 g) and carbon tetrachloride (50 ml) is heated under reflux for 24 hours, cooled, washed with an aqueous solution of sodium hydroxide and with sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution is evaporated and the residue is crystallized from alcohol. There is thus obtained, in the form of a crystalline solid material, 4- (dichloroacet-N-methylamido) phenyl 4-chlorobenzoate; P.

   F. 97-98 C unreduced in admixture with the material prepared by the process described in Example 27.



   EXAMPLE 41.-
For the preparation of 4- (Dichloroacet-N-methylamido) phenyl 4-chlorobenzoate, 4-chlorobenzoic acid (2.56 g) is added to a stirred solution of 4- (dichloroacet-N- sulfite. methylamido) phenyl (8.4 g) in pyridine (15 cc). After keeping the mixture at 20 C for 18 hours, the resulting solution is poured into a mixture of 1N sodium hydroxide (100 cc), ice (25 g) and sodium hydrosulphite (0.1 g ). The solid precipitate is collected by filtration, washed with water and dried, so that 4- (dichloroacet-N-methylamido) phenyl 4-chlorobenzoate is obtained as a crystalline solid; P. F. 96-98.5 C, identical to that prepared in Example 27.



   For the preparation of 4- (Dichloroacet- N-methylamido) phenyl sulfite, a solution of triethylamine (16.6 cc) in tetrahydrofuran (50 cc) is added dropwise to a stirred and ice-cooled solution of 4 - (dichloro-

 <Desc / Clms Page number 32>

 
 EMI32.1
 acet-N-methylamido) 'henol (23.4 g) and thionyl chloride (6.00 g) in tetrahydrofuran (85 cc) at a rate such that the temperature remains between 6 and 10 C.



  The mixture is then stirred at 20 ° C. for 45 minutes and, after filtration, it is evaporated under reduced pressure, so that 4- (dichloroacet-N-methylamido) phenyl sulfite is obtained in the form of a gum.



   EXAMPLE 42.-
For the preparation of 4- (dichloroacet- N-methylamido) phenyl 2-furoate, a mixture of 4- (di-chloroacetamido) phenyl 2-furoate (12.1 g), anhydrous potassium carbonate (12 g) , acetone (60 cc) and dimethyl sulfate (4 cc) is heated under reflux for 4 hours. The filtered solution is then evaporated under reduced pressure until an oil is obtained which crystallizes on cooling.



  After two recrystallizations from 95% alcohol, the desired compound is obtained in the form of a crystalline solid melting at 109-111 ° C., identical to that prepared in Example 1.



   For the preparation of 4-dichloroacetamidophenyl 2-furoate, 2-furyl chloride is added over 20 minutes to a stirred, ice-cooled suspension of 4-dichloroacetamidophenol (17.6 g). in pyridine (60 cc). After stirring for a further 20 minutes; the solution is poured into water (250 cc) and the precipitated solid matter is collected by filtration, washed with water, triturated with 95% alcohol (300 cc) and recrystallized from acetone (150 cc) with charcoal to obtain the desired compound in crystalline form; M.p. 201-202 C. (Found C = 49.6%; H = 2.9%. For
 EMI32.2
 C13H9C12NO4, the calculation gives: C = 49,, K /; H = 2.9%).

 <Desc / Clms Page number 33>

 



    EXAMPLE 43. - '
A batch of tablets is prepared with the following ingredients: 4- (Dichloroacet-N-methylamido) phenyl 2-furoate 30 pounds 13 ounces
Icing sugar 1 pound 8 ounces
Corn starch 7 pounds 8 ounces
20% Acacia Solution 75 oz (fluid)
3 oz Stearoid Acid
The 4- (Dichloroacet-N-methylamido) - phenyl 2-furoate, icing sugar and 1/2 pound of corn starch are mixed thoroughly and the mixture is granulated by adding the acacia solution to 20%.



   The granules are dried, sieved and added with 5 pounds of dried corn starch, followed by stearic acid.



  After a final kneading, the mixture is made into 28,000 tablets of 10 g each containing 0.5 g of active ingredient.

** ATTENTION ** end of DESC field can contain start of CLMS **.


    

Claims (1)

CLAIMS.- 1.- As new compounds, the compounds of the general formula: EMI33.1 in which R 'denotes an alkyl group (containing not less than 4 carbon atoms), an al cen yl group (containing not less than 4 carbon atoms, an aryl group (except an unsubstituted phenyl radical), an aralkyl group, an aralkenyl group, an alkoxyalkyl group, a cycloaliphatic group, an aryloxyalkyl group, an aryloxyalkenyl group, an aryloxyaryl group, a <Desc / Clms Page number 34> EMI34.1 heterocyclic, a heterocyclicalkyl group, a heterocyclicalkenyl group or a -RZCOOR3 group, in which R2 denotes an alkylene or arylene group, cycloalkylene or arylenedioxyalkyl or a disubstituted heterocyclic ring, and R3 denotes the 4- (dichloroacet-N-methylamido) phenyl radical, as well as the derivatives substituted by single groups of compounds of the general formula given above, containing, for example, one or more constituent groups, such as halo, nitro, amino, acylamino, alkyl, alkoxy, acyl and methanesulfonyl in the radical represented by R '. 2. - 4- (Dichloroacet-N-methylamido) phenyl 2-furoate. EMI34.2 3.- 4- (Dichloroacet-j-methylamido) phenyl phenoxyacetate. 4.- 4- (Dichloroacet-N-methylamido) nhenyl nicotinate. 5. - 4- (Dichloroacet-N-methylamido) - phenyl 2-thenoate. 6. - 4- (Dichloroacet-N-methylamido) c (-naphthoxyacetate). 7. - 4- (Dichloroacet-N-methylamido) phenyl 2-chlorophenoxyacetate. 8.- 4- (Dichloroacet-N-methylamido) phenyl 4-methylphenoxyacetate. 9. - 4- (Dichloroacet-N-methylamido) phenyl d- (2-methylphenoxy) propionate. EMI34.3 10.- 4- (Dichloroacet-DI-methyla- m # do) phenyl d-phenoxypropionate. 11.- - 4- (Dichloroacet-t3-methylamide) phenyl phenoxybutyrate. 12. - 4- (Dichloroacet-N-methylamido) phenyl isonicotinate. <Desc / Clms Page number 35> 13. - 4- (Dichloroacet-N-methylamido) phenyl 4-nitrophenoxyacetate. 14.- 4- (Dichloroacet-N-methylamido) phenyl 3-chlorophenoxyacetate. 15. - 4- (Dichloroacet-N-methylamine) phenyl 5-bromo-2-furoate. EMI35.1 16.- 4- (Dichloroacet-µ-methylamido) phenyl d-phenoxy-n-butyrate. 17. - c (-phenoxy-n-hexanoate 4- (dichloroacet-N-m- EMI35.2 % * Î # 1, #, thylamido) phenyl. ; ,,,,,.,. 1 <, <.. ...... 19.- c (-phenoxyisobutyrate 4- (dichloroacet-N-methylami do) phenyl e. '.., 19.-' d-phenoxy-n-valerate 4- (dichloroacet-N-methylamido ) phenyl. 20.- 4- (Dichloroacet-N-methylaido) phenyl coumarilate. EMI35.3 21.- 4- (Dichloroacet-I-methylamido) phenyl 3 -phenoxypropionate. 22. - 4- (Dichloroacet-N-methylamido) phenyl 2-furylacrylate. 23. - 4- (Dichloroacet-N-methylamido) phenyl tetrahydro-2-furoate. 24.- 4- (Dichloroacet-N-methylamido) phenyl 3-furoate. 25. - 4- (Dichloroacet-N-methylamido) phenyl 4-methoxyphenoxyacetate. 26. - 4- (Dichloroacet-N-methyl-amido) phenyl 5-methoxycoumarilate. EMI35.4 27.- 4: 5-dibromo -.- 4- (Dichloroacet-N-methylamido) phenyl. 28.- 4- (Dichloroacet-N-methylamide) phenyl 5-methyl-2-furoate. <Desc / Clms Page number 36> 29. - 5: 4- (Dichloroacet-N-methylamido) phenyl 7-dibromocoumarilate. 30. - 4- (Dichloroacet-N-methylamide) phenyl 2-phenoxybenzoate. 31.- 4- (Dichloroacet-N-methylamido) - phenyl picolinate. 32. - [alpha]: c (-di (5-methylfur-2-yl) propicnate of 4- (dichlo- EMI36.1 roacet.N-methylamido) phenyl. 33. - 4- (Dichloroacet-N-methylamido) phenyl quinaldate. EMI36.2 34.- Ë: 4- (Dichloroacet- -methylamido) phenyl e-bis- (fur-2-yl) -jj-valerate. 35. - 4- (Dichloroacet-N-methylamido) phenyl 7-methoxycoumarilate. 36. - Furan-2: 4- (dichloroacet-N-methylamido) phenyl 5-dicarboxylate. 37. - 4- (Dichloroacet-N-methylamido) phenyl pyrazinoate. 38. - 4- (Dichloroacet-N-methylamido) phenyl p-phenylene-dioxydiacetate. 39. - 4- (Dichloroacet-N-methylamido) phenyl 5-nitro-2-furoate. 40.- 4- (Dichloroacet-N-methylamido) phenyl laurate, 41. - 4- (Dichloroacet-N-methylamido) phenyl stearate. 42. - 4- (Dichloroacet-N-methylamido) phenyl d-naphthoate. 43.- 4- (Dichloroacet-N-methylamido) phenyl diphenylacetate. EMI36.3 44.- 4 .- (Dichlorcacet-N-methylamine} phenyl 4-chlorobenzoate. 4- (Dichloroacet - !! - methylamide) phenyl 4-methoxybenzoate. <Desc / Clms Page number 37> 46. - 4- (Dichloroacet-N-methylamido) phenyl cinnamate. 47. - 4- (Dichloroacet-N-methylamido) phenyl sebacate. 48.- 4- (Dichloroacet-N-methylamido) phenyl oleate. 49. - 4- (Dichloroacet-N-methylamido) phenyl phthalate. 50.- 4- (Dichloroacet-N-methylamide) phenyl 3-phenylpropionate. 51. - 4- (Dichlcrroacet-N-methylamide) phenyl 2-acetylsalicylate. 52. - 4- (Dichlordacet-N-methylamide) phenyl hexahydrobenzoate. 53.- 4- (Dichloroacet-N-methylamido) - phenyl terephthalate. 54. - 4- (Dichloroacet-N-methylamido) phenyl 4-nitrobenzoate. 55. - 4- (Dichloroacet-N-methylamido) phenyl p-toluate. 56. - 4- (Dichloroacet-N-methylamido phenyl 2-chlorobenzoate. 57. - 4- (Dichloroacet-N-methylamido) phenyl 4-methanesulfonylbenzoate. 58.- 4- (Dichloroacet-N-methylamido) phenyl 3: 4-dimethoxybenzoate. EMI37.1 59.- 4- (Dichloroacet-N-methvlamid do) phenyl 2-benzoylbenzoate. 60.- 4- (Dichloroacet-N-methylamide) phenyl 3-methoxybenzoate. 61.- 4- (Dichloroacet-N-methylamido) phenyl hippurate. 62.- 4- (Dichloroacet-N-methylamido) phenyl octanoate. 63.- 4- (Dichloroacet-N-methylamine) 3: 4-dichlorobenzoate. EMI37.2 64.- 4- (Dichloroacdt-N-methylamido) phenyl decanoate. <Desc / Clms Page number 38> EMI38.1 65.- 4- (Dichloraacet-N-methylamido) phenyl-α-methylmandelate. 66.- c (-4- (Dichloroacet-N-methylamide) phenyl-methoxypropionate. 67. - 4- (Dichloroacet-N-methylamido) phenyl hexanoate. 68.- 4- (Dichloroacet-N-methylamido) -phenyl methoxyacetate. EMI38.2 69.- 4- (Dichloroacet-N-methyl-amido) phenyl d -methoxyisobutyrate. 70. - 4- (Dichloroacet-N-methylamidd) phenyl ethoxyacetate. 71.- 4- (Dichloroacet-N-methylamido) phenyl phenylglyoxylate. EMI38.3 72.- 4- (dichloroacet - ethylamido) phenyl cyclopropanecarboxylate. 73.- 4- (Dichloroac6t-N-methylamido) phenyl 3-bromobenzoate. 74.- 4- (Dichloroacet-N-methylamido) phenyl cyclopentanecarboxylate. 75. - 4- (Dichloroacet-N-methylamido) phenyl cyclobutanecarboxylate. 76. - 4- (Dichloroacet-N-methylamido) phenyl 4-aminobenzoate. EMI38.4 77.- 4- (Dichloroacet-N-methyl-amido) phenyl j -benzoylpropionate. 78. A process for the preparation of a compound according to claim 1, wherein dichloro is esterified. EMI38.5 Acet-4.badroxy-N-methylanilide. 79. A process according to claim 7o, wherein dichloroacet-4-hydroxy-N-methylanilide is reacted <Desc / Clms Page number 39> with an acid halide of general formula R4CO.X in which R4 denotes an alkyl group (having not less than 4 carbon atoms), an alkenyl group (having not less than 4 carbon atoms), an aryl group ( except unsubstituted phenyl group), an aralkyl group, an aralkenyl group, a cycloaliphatic group, an aryloxyalkyl group, an aryloxyalkenyl group, an aryloxyaryl group, a heterocyclic group, a heterocyclicalkyl group, a heterocyclicalcenyl group or -R2-CO.X, in which R2 denotes an alkylene, arylene, cycloalkylene or arylenedioxyalkyl or a disubstituted heterocyclic ring and X is halogen, in the presence of an acid binding agent. 80. A process according to claim 78, in which dichloroacet-4-hydroxy-N-methylanilide is reacted with an acid ahydride of the general formula R5CO) 2O or of the formula R2 (CO) 20, in which R5 denotes an alkyl group (containing not less than 4 carbon atoms), an alkenyl group (containing not less than 4 carbon atoms), an aryl group (except an unsubstituted penyl radical), an aralkyl group, an aralkenyl group, an alkoxyalkyl group, a cycloaliphatic group, an aryloxyalkenyl group, an aryloxyalkenyl group, an aryloxyaryl group, a heterocyclic group, a heterocyclicalcoyl group, a heterocyclicalcenyl group and R2 denotes an alkylene group; an arylene group, a cycloalkylene group, an arylenedioxydialcoyl group or a disubstituted heterocyclic ring. 81. A process according to claim 78, wherein a compound of the general formula is reacted: EMI39.1 <Desc / Clms Page number 40> in which M denotes an alkali metal or an equivalent of an alkaline earth metal with an acid halide of general formula R4CO.X. in which R4 denotes an alkyl group (not containing less than 4 carbon atoms) an alkenyl group (containing not less than 4 carbon atoms), an aryl group (except an unsubstituted phenyl radical), an aralkyl group, an aralkenyl group, an alkoxyalkyl group, a cycloaliphatic group, an aryloxyalkenyl group, an aryloxyalkenyl group, an aryloxyaryl group, a heterocyclic group, a heterocyclicalkyl group, a heterocyclialkenyl group, or the group -R2¯CO.X in which denotes an alkylene, arylene, cycloalkylene or arylenedioxyalkyl group or a disubstituted heterocyclic ring and X is a halogen. 82. A process according to claim 78, wherein dichloroaceous L-4-hydroxy-methylanilide is reacted with an acid of the general formula R6COOH, wherein R6 denotes an alkyl group (containing not less than 4 carbon atoms, a group alkenyl (containing not less than 4 carbon atoms), an aryl group (except an unsubstituted phenyl radical), an aralkyl group, an aralkenyl group, an alkoxyalkyl group, a cycloaliphatic group, an aryloxyalkyl group, an aryloxy group - alkenyl, an aryloxyaryl group, a heterocyclic group, a heterocyclicalcoyl group, a heterocyclicalkenyl group, or the group -R2COOH in which R2 denotes an alkylene, arylene, cycloalkylene or arylenedioxyalkyl group or a disubstituyclic ring, in the presence of a condensing agent. 83. The method of claim 82 wherein the condensing agent is dicyclohexylcarbodiimide. <Desc / Clms Page number 41> 84. The method of claim 82 wherein the condensing agent is tetraphosphoric acid. 85. The method of claim 82 wherein the condensing agent is dimethylcyanamide. 86. A process for preparing a compound according to claim 1, in which the amino group of p-aminophenol is protected, so as to form a compound of the general formula: EMI41.1 in which -N = Y denotes (a) the group -NHR 'in which R7 is a formyl, acetyl or dichloroacetyl group or (b) the group -N = CHR8 in which R8 is a phenyl or substituted phenyl group, after which one performs an esterification, so as to form a compound of general formula: EMI41.2 in which R 'has the meaning given in claim 1 and the group-N = Y has the meaning given above, then a methylation is carried out and, except in the case where R7 is a dichloroacetyl group, the methylated product of so as to form a compound of general formula: EMI41.3 in which R 'has the meaning indicated in the claim. 1 and R9 denotes a hydrogen atom or a dichloroacetyl group, and, in the case where R9 denotes hydrogen, dichloroacetylation is carried out. <Desc / Clms Page number 42> 87. A process according to claim 86, wherein a compound of the general formula is prepared: EMI42.1 in which the group -N = Y represents the group -NHZ, in which Z denotes a formyl or acetyl group and R 'has the meaning given in claim 1, by formylation or acetylation of p-aminophenol, followed by introduction of the R'CO- group. 88. A process according to claim 86, wherein a compound of the general formula is prepared: EMI42.2 wherein the group-N = Y represents -NHCOCHCl2 and the group R 'has the significant indicated in claim 1, by dichloroacetylation of p-aminophenol followed by the introduction of the group R'CO-. 89. A process according to claim 86, in which a compound of the general formula is prepared: EMI42.3 in which -N = Y represents the group -N = CHR8 in which R8 denotes an optionally substituted phenyl radical and R 'has the meaning indicated in claim 1, by conversion of p-aminophenol into a Schiff base of general formula: EMI42.4 <Desc / Clms Page number 43> by reaction with an aldehyde of general formula R8CHO in which R8 has the meaning indicated above, then by introduction of the R'CO- group. 90. - The method of claim 86, wherein a compound of general formula: EMI43.1 wherein the group -N = Y represents the group -NHR7 in which R7 denotes a formyl group, an acetyl group or a dichloroacetyl group, and R 'has the meaning given in claim 1, is methylated by treatment with l' using a methylating agent in the presence of an alkali. 91. - The method of claim 90, wherein the treatment is carried out with methyl iodide in the presence of potassium hydroxide. 92. - The method of claim 90, wherein the treatment is carried out with di-dimethyl sulfate. presence of potassium carbonate. 93. The method of claim 86, wherein a compound of the general formula EMI43.2 in which the group -N = Y represents the group -N-CHR in which R8 denotes an optionally substituted phenyl radical, and R 'has the meaning given in claim 1, is methylated by treatment with a methylating agent appropriate. 94. The method of claim 93 wherein the methylating agent is dimethyl sulfate. <Desc / Clms Page number 44> 95. - A method according to either of claims 86 and 88, wherein the dichloroacetylation is effected by treatment with chloral cyanohydrin in the presence of an acid binding agent. 96. - A process according to claim 95, wherein the chloral cyanohydrin is prepared in situ. 97. - A method according to either of claims 86 and 88, wherein the dichloroacetylation is carried out by treatment with dichloroacetyl chloride. 98. A process according to claim 97, wherein the treatment is carried out in the presence of an acid binding agent. 99. - Process according to either of the claims 86 and 88, in which the dichloroacetylation is carried out by treatment with dichloroacetic anhydride. 100. A process according to either of claims 86 and 88, wherein the dichloroacetylation is carried out by treatment with? N: N-bis-dichloroacetamide. 101. A process according to either of claims 86 and 88, wherein the dichloroacetylation is carried out by treatment with dichloroacetic acid and phosphorus trichloride. 102. A process according to either of claims 86 and 88, wherein the dichloroacetylation is carried out by treatment with dichloroacetanitrile in solution in a lower aliphatic alcohol. 103. A process according to any of claims 90 to 92, wherein the methylated product of general formula: EMI44.1 in which Z is a formyl or acetyl group and R 'has the <Desc / Clms Page number 45> meaning given in claim 1 is hydrolyzed with dilute mineral acid to remove the Z group. 104. A process for the preparation of a compound according to claim 1, wherein 4- (dichloroacet-N-methylamido) phenyl sulfite is reacted with an acid of the general formula R6COOH, wherein R6 denotes a group alkyl (containing not less than 4 carbon atoms), an alkenyl group (containing not less than 4 carbon atoms), an aryl group (except an unsubstituted phenyl radical) an aralkyl group, an aralkenyl group, an alkoxyalkyl group, cycloaliphatic group, aryloxyalkenyl group, aryloxyalkenyl group, aryloxyaryl group, heterocyclic group, heterocyclicalcoyl group, heterocyclicalcenyl group, or -R2COOH group in which alkylene, R2 denotes a group , cycloalkylene or arylenedioxyalkyl or a disubstituted heterocyclic ring in the presence of an acid binding agent. 105. - Process for the preparation of a compound according to any one of claims 1 to 77, in substance, as described above in any of the examples. 106. Compounds according to any one of claims 1 to 77, when prepared by the process according to any one of claims 78 to 105 or by a chemically equivalent process. 107. Process for the preparation of 4- (di-chloroacet-N-methylamido) phenyl 2-furoate, in substance as described in Examples 1, 20 or 41. EMI45.1 108.- 4- (Dichloroacet-N-niethylamT.do) phenyl3 2-furcate when prepared by a process according to any of claims 78-105 and 107 or by a chemically equivalent process. <Desc / Clms Page number 46> 109. A therapeutic composition comprising a compound according to any one of claims 1 to 77, 106 and 108 in association with a pharmaceutically acceptable carrier or diluent. 110. The therapeutic composition of claim 109, wherein the active compound is 4- (dichloroacet-N-methylamido) phenyl 2-furoate and said compound is present at 100 to 1000 mg per unit dose. 111. A therapeutic composition according to either of claims 109 and 110, wherein the diluent or vehicle comprises icing sugar. 112. Therapeutic composition according to either of claims 109 and 110, wherein the diluent or carrier also comprises starch 113. Therapeutic composition according to either of claims 109 and 110, wherein the diluent or vehicle also comprises stearic acid. 114. A therapeutic composition according to any one of claims 109 to 113, also comprising acacia gum. 115. A method for combating amebiasis, wherein a human or an animal infected with amoeba is administered to a compound according to any one of claims 1 to 77-106 and 108. 116. A method for combating amoebiasis, wherein a human or animal infected with amoeba is administered a composition according to any of claims 109 to 114. 117. A method for combating amebiasis according to either of claims 115 and 116, wherein <Desc / Clms Page number 47> administers a total dose of 4- (Dichloroacet-N-methylamido) phenyl 2-furoate of 20 to 40 mg / kg / day.