WO1997017325A1 - Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments - Google Patents

Derivates of n,n-dimethyl-2-(arylthio)benzylamine, their salts, methods of preparation and their use in pharmaceutical medicaments Download PDF

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WO1997017325A1
WO1997017325A1 PCT/CZ1996/000022 CZ9600022W WO9717325A1 WO 1997017325 A1 WO1997017325 A1 WO 1997017325A1 CZ 9600022 W CZ9600022 W CZ 9600022W WO 9717325 A1 WO9717325 A1 WO 9717325A1
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dimethyl
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benzylamine
mixture
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Zdene^¿k POLÍVKA
Karel Dobrovsky
Alexandra S^¿ILHÁNKOVÁ
Karel S^¿INDELÁR^¿
Ruz^¿ena MÍC^¿KOVÁ
Vladimír VALENTA
Ivan KREJC^¿Í
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Farmak A.S.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/27—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton

Definitions

  • the invention relates to the derivatives of N,N-dimethyl-2-(arylthio)benzylamine and their salts, which selectively inhibit serotonin re-uptake in the brain structures It is also concerned with the methods of preparation and pharmaceutical medicaments on their basis suitable for treatment of depression and other diseases of the central nervous system, based on serotonin transport defects and serotonin metabolism imbalance in the brain.
  • N,N-dimethyl-2-(2-hydroxymethyl)phenylthio)benzylamine (VO 93/12080, and particularly N,N-dimethyl-2-(4-(trifluoromethyl)-2-(hydroxymethyl)phenylthio)benzylamine.
  • the aim of the invention is to find the modification of the compound on the basis of N,N-dimethyl-2-(phenylthio)benzylamine, which would show higher selectivity and better effects than compounds having been applied up to the present.
  • substituents R 1 or R 2 in the A ring in 4 and 5 positions is an hydrogen atom
  • the other substituent R 1 or R 2 in the A ring is either a fluorine atom or chlorine atom
  • two to three among the substituents R 3 to R 6 in the B ring in the 2 to 5 positions are hydrogen atoms
  • the other substituent R 1 or R 2 in the A ring is either a fluor
  • N,N-dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzylamine N,N-dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzylamine, N,N-dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzylamine, or N,N-dimethyl-2-(2-amino-4-(trifluoromethyl)phenyIthio)-5-fluorobenzylamine
  • the advantageous compound is N,N-dimethyl-2-(2-amino-4-(trifluoromethyI)phenylthio)benzylamine, and among its salts particularly oxalate, dihydrochloride and maleate.
  • This compound shows the highest selectivity regarding the comparison of inhibition of serotonin re-uptake and noradrenaline re-uptake in the brain structures, which is apparent from the Table of biological activity (see below).
  • substituents R 1 to R 6 are identical to those in formula (I), and besides that, in the B ring can also he a formyl or dimethylaminocarbonyl group.
  • these amides are reduced by e.g. complex hydrides of the lithium aluminium hydride type, or by diborane, which is advantageously used "in situ", so that in the reaction mixture it is generated by the reaction of sodium borohydride with boron trifluoride etherate.
  • any of the substituents R 3 to R 6 in the B ring is a formyl, dimethylaminocarbonyl or carboxyl group, according to the invention also such a group is reduced at the same time and provide the derivative of the compound of general formula (I) with a hydroxyl or dimethylaminomethyl group.
  • Another method of preparation of the derivatives of the compound (I) according to the invention uses benzy lhalogenides of general formula (III) as an intermediate product in the last step
  • Hal is an chlorine or bromine atom and the substituents R 1 to R 6 are identical to the substituents in formula (I).
  • These benzylhalogenides are brought into reaction with dimethylamine in an organic solvent - advantageously in toluene at room temperature.
  • one of the substituents on the B ring of the compound of general formula (I) according to the invention shall be methylsulfinyl
  • the corresponding methyl thioderivative is oxidised by hydrogen peroxide in acetic acid at room temperature.
  • one of the substituents on the B ring of the compound of general formula (I) according to the invention shall be esterified carbonyl, i.e. methoxycarbonyl or ethoxycarbonyl
  • the corresponding carboxyderivative is esterified by methanol or ethanol - advantageously in the presence of hydrogen chloride, or the corresponding trifluoromethylderivati ve is used, which is hydrolysed with sulfuric acid at 90 to 110oC and then is esterified with the corresponding alcohol.
  • salts of compounds of general formula (I) according to the invention can anvantageously be prepared via neutralisation of bases with pharmacodynamically harmless inorganic or organic acids.
  • All derivatives of the compound of general formula (I) according to the invention are of an alkaline nature and their bases are insoluble in water, and mostly are of oily appearance. Neutralisation of all of them with suitable acids yields their crystalline salts, usually also badly soluble in water; their examples can be hydrochlorides, oxalates or maleates. Providing one substituent on the B ring is carboxyl, the final products are amphoteric, but, however, they also provide the crystalline salts due to the presence of a strong basic amino group.
  • N,N-Dimethyl-5-fluoro-2-(3,4-difluorophenylthio)benzylamine N,N-Dimethyl-5-fluoro-2-(3,4-difluorophenylthio)benzylamine.
  • N,N-Dimethyl-2-(2,4-dichlorophenylthio)benzylamine 20 ml of thionylchloride was added to a solution of 13.6 g of 2-(2,4-dichlorophenylthio) benzoic acid (Sindelaf K. et al.: Collect. Czech. Chem. Commun. 38, 3321 (1973)) in 100 ml of toluene and the mixture was refluxed for 3 h.
  • the benzene phase was dried with magnesium sulfate and evaporated i n vacuo , to obtain 13.7 g of N,N-dimethyl-2-(2,4-dichlorophenylthio) benzamide, which after crystallisation from a mixture of benzene and petroleum ether melted at 120-122oC.
  • a suspension of 3,5-dichloroaniline hydrochloride obtained from 29.0 g of 3,5-dichloroaniline and 75 ml of diluted hydrochloric acid (1:1) was diazotized under stirring at 0-5oC with a solution of 13.7 g of sodium nitrite in 30 ml of water.
  • 0.2 g of nickel sulfate was added to a solution of the diazonium salt and the cooled mixture was added in small amounts to a solution of 35 g of potassium xanthate in 45 ml of water kept between 40-45oC. After having added everything, this temperature was kept for a further 1 h.
  • Example 14 N,N-Dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzylamine.
  • a) A reaction of 5.7 g of potassium hydroxide in 65 ml of water with 5.52 g of 2,4-dichlorothiophenol, 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper, carried out in analogy to example 1 /a , yielded 2- ( 2 , 4 - dichlorophenyl thio)-5-fluorobenzoic acid, which was filtered by suction and recrystallised from ethanol, which yielded 8.32 g of the acid, m.p. 198.5-199.5°C.
  • N,N-Dimethyl-4-fluoro-2-(4-isopropylphenylthio)benzylamine One drop of dimethylformamide was added to a suspension of 22.0 g of 4-fluoro-2-(4-isopropylphenylthio)benzoic acid (Protiva M. et al.: Collect. Czech. Chem. Commun.
  • N,N-Dimethyl-2-(4-(fluoro-3-methoxyphenylthio)benzylamine A mixture of 18.5 g of thiosalicylic acid, 150 ml of dimethylformamide, 33.15 g of potassium carbonate, 24.6 g of 5-bromo-2-fluoroanisole (EP 175,452; JP 61/27,768; Chem. Abstr. 105, 42658 (1986)) and 2.2 g of copper was refluxed for 12 h. After cooling, the reaction mixture was diluted with 1.1 1 of water, filtered and washed with benzene.
  • the water phase was acidified with hydrochloric acid, the precipitated crude 2-(4-(fluoro-3-methoxyphenylthio)benzoic acid (20.6 g) was filtered by suction and after crystallisation from ethanol melted at 222-224°C.
  • N,N-Dimethyl-2-(4-fluoro-3-hydroxyphenylthio)benzylamine A solution of 7.0 g of N,N-dimethyl-2-(4-fluoro-3-methoxyphenylthio)benzylamine hydrochloride (see example 27) in 50 ml of 46% hydrobromic acid was heated up to 120oC under stirring for 8 h. After cooling, the mixture was diluted with 100 ml of water, its pH was adjusted up to 8 using 20% solution of sodium hydroxide, and the mixture was extracted with chloroform. The extract was filtered over a 100 g silica gel column, which was eluted with chloroform.
  • the reduction of the acid into alcohol is more suitably carried out in the following way: 323 g of 70% solution (toluen) of sodium dihydridobis(2-methoxyethoxo)aluminate (NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 in 300 ml of toluene was under stirring over a period of 75 min added dropwise to a solution of 125 g of 2-(2-amino-4- (trifluoromethyl)phenylthio)benzoic acid in 2 l of toluene and the mixture was stirred at room temperature for 4 h. Under external cooling and under stirring then it was decomposed by adding 2000 ml of 10% solution of sodium hydroxide.
  • the toluene phase was separated, the aqueous phase was extracted with toluene and the toluene solutions were put together, dried with magnesium sulfate and after filtration the toluene evaporated off i n vacuo .
  • the residue was 101 g (92%) of crude 2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl alcohol, which after crystallisation from cyclohexane melted at 88-89oC and was identical to the product of the previous reduction.
  • the residue was 41 g of crude 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzylalcohol to which 40 ml of thionylchloride was added dropwise under cooling with ice and under stirring. The mixture was stirred at room temperature for 2 h and left standing for 16 h The excess thionylchloride evaporated off i n vacuo The residue was crude 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzyl chloride hydrochloride.
  • N,N-Dimethyl-2-(4-amino-2-(trifluoromethyl)phenylthio)benzylamine 0.93 g of thiosalicylic acid and 1.6 g of 2-bromo-5-nitrobenzotrifluoride (Filler R., Novar H.: J. Org. Chem. 26, 2707 (1961)) were added to a solution of 0.48 g of sodium hydroxide in 25 ml of ethanol and the mixture was refluxed under stirring for 2.5 h. The ethanol evaporated off i n vacuo and the residue was dissolved in 25 ml of hot water. After cooling, the mixture was acidified under stirring with 2.5 ml of 3M hydrochloric acid.
  • the residue was 4.42 g (90%) of the crude base, which was purified by crystallisation on a silica gel column gradually eluted with a mixture of chloroform and ethylacetate, chloroform and a mixture of methanol and chloroform saturated with ammonium at last.
  • the residue of the chloroform eluate was an oily base whose neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2-(4-(hydroxymethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 96-98oC.
  • this aldehyde can be converted to crystalline 2,4-dinitrophenylhydrazon in a familiar way, which after crystallisation from a mixture of ethylacetate and ethanol melted at 216-222°C.
  • N,N-Dimethyl-2-(2-(dimethylaminomethyl)phenylthio)benzylamine N,N-Dimethyl-2-(2-(dimethylaminomethyl)phenylthio)benzylamine.
  • thionylchloride in 20 ml of benzene was added dropwise under stirring to a solution of 4.11 g of diphenylsulfido-2-2 -dicarboxylic acid (Mayer F.: Ber. Dtsch. Chem. Ges. 43, 588 (1910)) in 40 ml of benzene and the mixture was refluxed for 4 h.
  • Example 43 N,N-Dimethyl-2-(2-carboxyphenylthio)benzylamine. a) A mixture of 30 ml of dimethylformamide, 7.7 g of thiosalicylic acid, 7.0 g of 2-chlorobenzaldehyde, 14 g of potassium carbonate and 1.2 g of copper (I) chloride was heated up to 100oC under stirring in 5 min and then stirred at 110-120oC for 6 h. After 16 h of standing, the mixture was diluted with 220 ml of water at 60oC and the resulting cloudy liquid was filtered with 1 g of filtration charcoal. After cooling, the filtrate was acidified with 5M HCl under stirring. The precipitate was filtered off by suction, washed with water and dried, which yielded 9.11 g of crude 2-(2-carboxyphenylthio)benzaldehyde with melting point 167-169°C.
  • a suspension of 5.0 g of N,N-dimethyl-2-(2-(amino-4-(trifluoromethyl)phenylthio)benzylamine oxalate (see example 34) was made alkaline with aqueous ammonium and the free base was extracted with chloroform. The extract was dried with magnesium sulfate and evaporated. The residue base was heated with 8 ml sulfuric acid for 3 h up to 100°C. After 16 h of standing, 40 ml of methanol was added and the mixture was refluxed for 9 h. After pouring on the ice, it was made alkaline with aqueous ammonium and the free base was extracted with ether.
  • the following Table contains the values of serotonin re-uptake inhibition (5HT), noradrenaline re-uptake inhibition (NA) and paroxetine binding inhibition (PA) for some compounds prepared via the methods described in Examples hereinbefore in relation to the known compounds mentioned in the Background of the Invention hereinbefore.
  • 5HT serotonin re-uptake inhibition
  • NA noradrenaline re-uptake inhibition
  • PA paroxetine binding inhibition
  • this compound does not show the affinity towards alpha-adrenergic muskarine and benzodiazepine receptors, so that it does not inhibit binding of [ 3 H] preparatives (prazosin, quinuclidinnyl benzilate and flunitrazepam) onto the receptors in the corresponding brain structures. This suggests a low probability of occurrence of some cardiovascular anticholinergic and central neurotropic effects of the benzodiazepine type compounds.
  • Derivatives of general formula (I) and their pharmaceutically acceptable salts are suitable for the production of pharmaceutical medicaments designed primarily for treatment and prophylaxis of depression, anxious states, migraine and other diseases of the central nervous system, in which the brain serotonin plays an important role.

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Abstract

Derivatives of N,N-dimethyl-2-(arylthio)benzylamine of general formula (I), wherein the substituents R1 and R2 in the A ring in the 4 and 5 positions are hydrogen, fluorine, or chlorine atoms, while at least one of them must be a hydrogen atom and further, among the substituents R3 to R6 in the B ring two to three are hydrogen atoms, another one is either one fluorine or chlorine atom (only if at least one of the substituents R¿1¿ to R2 in the A ring is a fluorine or chlorine atom), further, two fluorine or two chlorine atoms, an alkyl with one to three carbon atoms, trifluoromethyl, methylthio, methylsulfinyl, methoxyl or hydroxyl (only if in the B ring there is also a fluorine or chlorine atoms as a substituent), nitro, amino, hydroxymethyl - except the 2 position, carboxyl - except the 3 position, methoxycarbonyl or ethoxycarbonyl group, as well as their salts with pharmacodynamically harmless acids. Methods of preparation of these compounds have been described, as well as some of their pharmacological characteristics and ways of their use in pharmaceutical medicaments based on their ability to selectively influence serotonin transport in the central nervous system.

Description

Derivatives of N,N-Dimethyl-2-(arylthio)benzylamine, Their Salts, Methods of Preparation and Their Use in
Pharmaceutical Medicaments.
Field of Technique
The invention relates to the derivatives of N,N-dimethyl-2-(arylthio)benzylamine and their salts, which selectively inhibit serotonin re-uptake in the brain structures It is also concerned with the methods of preparation and pharmaceutical medicaments on their basis suitable for treatment of depression and other diseases of the central nervous system, based on serotonin transport defects and serotonin metabolism imbalance in the brain.
Background of the Invention
Besides other compounds, in depression pharmacotherapy tricyclic amines are also used, recently plus some tetracyclic compounds, with a characteristic complex of behavioural features expressed in the term "thymoleptic activity" These compounds, some of which have undesirable cardiotoxic and anticholinergic side effects, are still widely used and are called First-Generation Antidepressants The progress in biochemical pharmacology, which has led to the knowledge that the influence of antidepressants on the fate of some biogennic amines in brain, noradrenaline in particular, plays its role in the antidepressant effect mechanism, resulted in the synthesis and testing of a large number of monocyclic and bicyclic amines; some of them came to be used in pharmacotherapy of depression and are called Second-Generation Antidepressants. Since the second half of the 70s, the serotonin transport role in the brain structures in depression ethiology have become understood, and compounds, which besides inhibiting noradrenaline presynaptic re-uptake also substantially inhibit serotonin re-uptake, have been gradually discovered. There has been an effort to find selective inhibitors of serotonin re-uptake with minimum influence on noradrenaline re-uptake. This type of antidepressants is called Third-Generation Antidepressants, and also here a number of monocyclic or bicyclic amines have been found, e.g. citalopram, fluoxetine, paroxetine, fluvoxamine and sertraline (Owen R.T. : Drugs of Today, 28, 439 (1992)), which have been already applied in pharmacotherapy of depression. An accidental discovery of serotonin and noradrenaline re-uptake inhibition (non-selective effect) in case of the plain N,N-dimethyl-2-(phenylthio)benzylamines (Jilek J. et al. Collect. Czech. Chem. Commun. 54, 1995 (1989)) aroused a bigger interest concerning compounds of this type and manipulation of the structure of the above mentioned basic compound first led to the series of N ,N-dimethyl-2-(methoxy- and hydroxyphenylthio) benzylamines, (Jilek J. et. al: Collect. Czech. Chem. Commun. 54, 3294 (1989)), where some compounds clearly suggested selectivity in effect. It was a case of N , N-dimethyl-2- (3-hydroxyphenylthio) benzylamine, in particular, called "moxifetin" (Protiva M. Drugs of the Future 16, 911 (1991); CS 276004; EP 396,827).
Another selective inhibitor of serotonin re-uptake in the brain structures is N,N-dimethyl-2-(2-hydroxymethyl)phenylthio)benzylamine (VO 93/12080, and particularly N,N-dimethyl-2-(4-(trifluoromethyl)-2-(hydroxymethyl)phenylthio)benzylamine.
However, even in case of this compound, [3H]serotonin and [3H]noradrenaline re-uptake inhibition in synaptosomal frac tions in particular e.g. of rat cerebral cortex, is not sufficient.
The aim of the invention is to find the modification of the compound on the basis of N,N-dimethyl-2-(phenylthio)benzylamine, which would show higher selectivity and better effects than compounds having been applied up to the present.
Disclosure of the Invention
The grounds of the invention lie in the new derivatives of N,N-dimethyl-2-(arylthio)benzylamine of general formula (I)
Figure imgf000005_0001
or their salts with inorganic or organic acids which are pharmacodynamically harmless, wherein at least one of the substituents R1 or R2 in the A ring in 4 and 5 positions is an hydrogen atom, while the other substituent R1 or R2 in the A ring is either a fluorine atom or chlorine atom and wherein two to three among the substituents R3 to R6 in the B ring in the 2 to 5 positions are hydrogen atoms, while if the both substituents in the A ring are hydrogen atoms, the substituents in the B ring are either three hydrogen atoms and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms, one fluorine or chlorine atom and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or are two hydrogen atoms and each of the two remaining substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms and two fluorine or chlorine atoms, or in case that one substituent in the A ring is either an fluorine atom or chlorine atom, the substituents in the B ring are either two hydrogen atoms and two fluorine or chlorine atoms, or two hydrogen atoms and one fluorine or chlorine atom and one subsituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or are three hydrogen atoms and one fluorine or chlorine atom, or one of the substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group.
The anvantageous derivatives of the compound of general formula (I) according to the invention are:
N, N-dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl amine,
N,N-dimethyl-5-chloro-2-(4-(methylthio)phenylthio)benzylamine,
N,N-dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzylamine, N,N-dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzylamine, N,N-dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzylamine, or N,N-dimethyl-2-(2-amino-4-(trifluoromethyl)phenyIthio)-5-fluorobenzylamine
and their salts with inorganic, or organic acids which are pharmacodynamically harmless.
The structure of the above mentioned compounds suggests that the said specificity of substituents on a diphenylsul fide fragment lies particularly in the presence of a halogen atom in the 5 position of the A ring and in the presence of a 2-amino group or a 4-(methylthio) group in the B ring.
According to the invention, the advantageous compound is N,N-dimethyl-2-(2-amino-4-(trifluoromethyI)phenylthio)benzylamine, and among its salts particularly oxalate, dihydrochloride and maleate. This compound shows the highest selectivity regarding the comparison of inhibition of serotonin re-uptake and noradrenaline re-uptake in the brain structures, which is apparent from the Table of biological activity (see below).
Derivatives of the compound of general formula (I) can be prepared via various procedures which use the methods of organic synthesis. As for the fundamental procedure, the key intermediate products are N,N-dimethylamides of general formula (II)
Figure imgf000007_0001
wherein the substituents R1 to R6 are identical to those in formula (I), and besides that, in the B ring can also he a formyl or dimethylaminocarbonyl group. In the last step of synthesis these amides are reduced by e.g. complex hydrides of the lithium aluminium hydride type, or by diborane, which is advantageously used "in situ", so that in the reaction mixture it is generated by the reaction of sodium borohydride with boron trifluoride etherate. If any of the substituents R3 to R6 in the B ring is a formyl, dimethylaminocarbonyl or carboxyl group, according to the invention also such a group is reduced at the same time and provide the derivative of the compound of general formula (I) with a hydroxyl or dimethylaminomethyl group.
Another method of preparation of the derivatives of the compound (I) according to the invention, uses benzy lhalogenides of general formula (III) as an intermediate product in the last step
Figure imgf000008_0001
wherein Hal is an chlorine or bromine atom and the substituents R1 to R6 are identical to the substituents in formula (I). These benzylhalogenides are brought into reaction with dimethylamine in an organic solvent - advantageously in toluene at room temperature.
In yet another advantageous procedure according to the invention, the benzal dehydes of general formula IV
Figure imgf000008_0002
wherein the substituents R1 to R6 are identical to the substituents in formula (I), in the last step react with dimethylformamide and formic acid at higher temperatures - the advantageous temperature is between 110 and 120ºC.
If one of the substituents on the B ring of the compound of general formula (I) according to the invention, shall be methylsulfinyl, the corresponding methyl thioderivative is oxidised by hydrogen peroxide in acetic acid at room temperature.
If one of the substituents on the B ring of the compound of general formula (I) according to the invention, shall be esterified carbonyl, i.e. methoxycarbonyl or ethoxycarbonyl, the corresponding carboxyderivative is esterified by methanol or ethanol - advantageously in the presence of hydrogen chloride, or the corresponding trifluoromethylderivati ve is used, which is hydrolysed with sulfuric acid at 90 to 110ºC and then is esterified with the corresponding alcohol.
Finally, if one of the substituents R3 to R6 in the B ring of the compound of general formula (I) according to the invention, is hydroxyl, the corresponding methoxyderivative demethylates - anvantageously via heating with hydrobromic acid.
Further, the salts of compounds of general formula (I) according to the invention can anvantageously be prepared via neutralisation of bases with pharmacodynamically harmless inorganic or organic acids.
All derivatives of the compound of general formula (I) according to the invention are of an alkaline nature and their bases are insoluble in water, and mostly are of oily appearance. Neutralisation of all of them with suitable acids yields their crystalline salts, usually also badly soluble in water; their examples can be hydrochlorides, oxalates or maleates. Providing one substituent on the B ring is carboxyl, the final products are amphoteric, but, however, they also provide the crystalline salts due to the presence of a strong basic amino group.
These salts, or the above mentioned amphoteric "amino acids" are suitable for preparation of oral medical forms, which can be used advantageously in human pharmacotherapy. The affinity of the compounds according to the invention, to serotonergic system conditions the potential use of compounds according to the invention not only in treatment of depression, but also in treatment of migraine, fear or anxiety states, or as anorectics in treatment of obesity.
Examples of the Methods According to the Invention
Some advantageous methods of preparation of the derivatives of compound of general formula (I) according to the invention are demonstrated in the following examples.
Example 1:
N,N-Dimethyl-4-fluoro-2-(3-fluorophenylthio)benzylamine. a) 8.0 g of 3-fluorothiophenol (Rajsner M. and Protiva M. Collect. Czech. Chem. Commun. 32, 2021 (1967)) was gradually added to a solution of 9.0 g of potassium hydroxide in 80 ml water and after 10 min of stirring, 1.0 g of powdered copper and 10.6 g of 4-fluoro-2-iodobenzoic acid (Rajsner M. et. al: Collect. Czech. Chem. Commun. 40, 719 (1975)) were added and the mixture was refluxed under stirring for 6 h. After partial cooling, the insoluble fractions were filtered off by suction and the filtrate was acidified with diluted hydrochloric acid (1:1) under stirring. After 16 h of standing, the product was filtered, washed with water and dried, which yielded 7.5 g of 4-fluoro-2-(3-fluorophenylthio)benzoic acid, which after crystallisation from ethanol melted at 198.5-200°C.
b) 7.6 g of thionylchloride was added under stirring dropwise to a suspension of 7.35 g of 4-fluoro-2-(3-fluorophenylthio) benzoic acid in 60 ml of benzene. After adding two drops of dimethylformamide, the mixture was refluxed for 2 h. The volatile constituents evaporated off i n vacuo , the residue was added 2x80 ml of benzene and evaporated i n vacuo .
Crystallisation of the residue from cyclohexane yielded 7.3 g of 4-fluoro-2- (3-fluorophenylthio) benzoyl chloride with the melting point 91-93°C.
c) A solution of 7.2 g of 4-fluoro-2-(3-fluorophenylthio)benzoyl chloride in 50 ml of benzene was added dropwise under intensive stirring at 20 C over a period of 5 min to 25 ml of 40% aqueous solution of dimethylamine and the mixture was stirred at room temperature for 3 h. The benzene layer was separated, washed with 2×40 ml of water, dried with potassium carbonate and evaporated i n vacuo , which yielded 8.2 g of crude oily N,N-dimethyl-4-fluoro-2-(3-fluorophenylthio)benzamide.
d) 2.8 g of sodium borohydride was added to a solution of 8.2 g of crude N,N-dimethyl-4-fluoro-2-(3-fluorophenylthio)benzamide in 70 ml of tetrahydrofuran and then 10.4 g of boron trifluoride etherate was added dropwise under stirring at room temperature over a period of 15 min. The mixture was stirred at room temperature for 1 h and then was refluxed for 3 h. After cooling, 30 ml of diluted hydrochloric acid (1:1) was added dropwise and the mixture was refluxed for a further 3 h. After cooling, the mixture was alkalised with 20% solution of sodium hydroxide and the product was extrac ted with ether. The extract was dried with anhydrous potassium carbonate and was evaporated. The residue (9.2 g) was dissolved in ether and the solution was neutralised with a solution of maleic acid in ether. After 16 h of standing, 6.3 g of N,N-dimethyl-4-fluoro-2-(3-fluorophenylthio)benzylamine hydrogen maleate precipitated. This, after recrystallisation from a mixture of acetone and ether, melted at 159-160°C.
Example 2:
N,N-dimethyl-2-(3,4-difluorophenylthio)benzylamine.
10.0 g (0.068 mol) of 3,4-difluorothiophenol (Cervena I.et al.: Collect. Czech. Chem. Commun. 41, 881 (1976)) was gradually added to a solution of 12.65 g of potassium hydroxide in 135 ml of water at 50°C. After 10 min of stirring, 1.0 g of powdered copper and 16.62 g of 2-iodobenzoic acid were added to the mixture. The mixture was refluxed under stirring for 9 h and processed in analogy to example 1/a to obtain 14.20 g (80%) of 2-(3,4-difluorophenylthio)benzoic acid, which after recrystallisation from ethanol melted at 196-198°C.
20.3 g of thionylchloride was added dropwise under stirring to a suspension of 14.0 g of 2-(3,4-difluorophenylthio)benzoic acid (0.052 mol) in 115 ml of benzene and after adding two drops of dimethylformamide, it was processed in analogy to example 1/b. Crystallisation of the residue (16.7 g) from cyclohexane yielded 13.9 g (93%) of 2-(3,4-difluorophenylthio) benzoyl chloride with the melting point 73-74°C.
A solution of 13.8 g of 2-(3,4-difluorophenylthio)benzoylchloride in 96 ml of benzene was added dropwise at temperature not exceeding 8ºC and under intensive stirring to 22 ml of 40% aqueous solution of dimethylamine. Then it was pro cessed in analogy to example 1/c, which yielded 13.9 g of (98%) crude N,N-dimethyl-2-(3,4-difluorophenylthio)benzamide. 3.4 g of sodium borohydride was added to a solution of
13.8 g of crude N,N-dimethyl-2-(3,4-difluorophenylthio)benzamide (0.047 mol) in 90 ml of tetrahydrofuran and then
13.9 g of boron trifluoride etherate was added dropwise under stirring at 27ºC. The mixture was processed in analogy to example 1/d. The residue (15.0 g) of the crude base was dissolved in ether, the solution was filtered and the filtrate was neutralised with a solution of hydrogen chloride in ethanol. 13.3 g of N,N-dimethyl-2-(3,4-difluorophenylthio) benzylamine hydrochloride was obtained as a result of crystallisation, which after recrystallisat ion from a mixture of ethanol and ether melted at 153-154°C.
Example 3:
N,N-Dimethyl-4-fluoro-2-(4-fluorophenylthio)benzylamine.
A reaction of 8.6 g of 4-fluoro-2-(4-fluorophenylthio)benzoic acid (Ger. Offen.2, 545, 841) in 70 ml of benzene with 12.5 g of thionylchloride and dimethylformamide in analogy to example 1/b, yielded 9.2 g (100%) of 4-fluoro-2-(4-fluorophenylthio)benzoylchloride, which after crystallisation and recrystallisation from a mixture of benzene and petroleum ether melted at 105-106 °C.
A reaction of 9.0 g of 4-fluoro-2-(4-fluorophenylthio)benzoyl chloride in 60 ml benzene and 14.5 ml of 40% aqueous solution of dimethylamine, in analogy to example 1/c, yielded 9.26 g (100%) of crude oily N,N-dimethyl-4-fluoro-2-(4-fluorophenylthio)benzamide.
A reaction of crude N,N-dimethyl-4-fluoro-2-(4-fluorophenylthio)benzamide in 60 ml of tetrahydrofuran with 2.3 g of sodium borohydride and 9.3 g of boron trifluoride etherate, in analogy to example 1/d, yielded 8.7 g of oily base, which provided 8.7 g N ,N-dimethyl-4-fluoro-2-(4-fluorophenylthio) benzylamine hydrogen maleate with the melting point 183-184°C (95% ethanol).
Example 4:
N,N-Dimethyl-5-fluoro-2-(3-fluorophenylthio)benzylamine.
9.0 g of potassium hydroxide in 80 ml of water, 10.6 g of 5-fluoro-2-iodobenzoic acid (Rajsner et al. Collect. Czech. Chem. Commun. 40, 719 (1975)), 6.3 g 3-fluorothiophenol (Rajsner M. and Protiva M.: Collect. Czech. Chem. Commun. 32, 2021 (1967)) and 1.0 g of copper were refluxed under stirring for 6.5 h and then the mixture was processed in analogy to example 1/a, which after crystallisation from aqueous ethanol yielded 8.9 g of 5-fluoro-2-(3-fluorophenylthio)benzoic acid, melted at 157.5-159°C.
A reaction of 8.75 g of 5-fluoro-2-(3-fluorophenylthio)benzoic acid with 9.6 g of thiony lchl or ide in 80 ml of benzene, in analogy to example 1/b, yielded 8.2 g of oily 5-fluoro-2-(3-fluorophenylthio)benzoyl chloride.
A solution of 8.0 g of 5-fluoro-2-(3-fluorophenylthio)benzoyl chloride in 60 ml of benzene and 30 g of 40% aqueous solution of dimethylamine was processed in analogy to example 1/c, which yielded 8.6 g of oily N,N-dimethyl-5-fluoro-2-(3-fluorophenylthio)benzamide.
A reaction of 8.6 g of N,N-dimethyl-5-fluoro-2-(3-fluorophenylthio)benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 12 g of boron trifluoride etherate and then through neutralisation with a solution of maleic acid in ether, in analogy to example 1/d, yielded 5.3 g of N,N-dimethyl-5-fluoro-2-(3-fluorophenyIthio)benzylamine hydrogen maleate, which after crystallisation from a mixture of acetone and ether melted at 117.5-118.5ºC. Example 5 N,N-Dimethyl-5-fluoro-2-(4-fluorophenylthio)benzylamine.
9.0 g of potassium hydroxide in 80 ml of water, 10.6 g of 5-fluoro-2- iodobenzoic acid, 5.5 g of 4- fluorothiophenol (Rajsner et. al: Cesk. Farm. 11, 451 (1962)), and 1.0 g of copper were refluxed for 7 h and proccesed in analogy to example 1/a. After crystallisation from ethanol, 9.3 g of 5-fluoro-2-(4-fluorophenylthio)benzoic acid was obtained, which melted at 206-207.5°C.
A reaction of 9.15 g of 5-fluoro-2-(4-fluorophenylthio)benzoic acid with 11.7 g of thiony lch l or i de i n 100 m l of benzene and dimethylf ormami de, in analogy to example 1/b and crystallisation from cyclohexane yielded 9.85 g of 5-fluoro2- (4-fluorophenylthio) benzoyl chloride, m.p. 90-91.0ºC.
A reaction of 9.7 g of 5-fluoro-2-(4-fluorophenylthio)benzoyl chloride in 50 ml of benzene with 31 g of 40% aqueous dimethylamine, in analogy to example 1/c, yielded 10.1 g of oily N,N-dimethyl-5-fluoro-2-(4-fluorophenylthio)benzamide.
A reaction of 10.1 g of oily N,N-dimethyl-5-fluoro-2-(4-fluorophenylthio)benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 10.0 g of boron trifluoride etherate, in analogy to example 1/d, yielded 6.6 g of crystalline N,N-dimethyl-5-fluoro-2-(4-fluorophenylthio)benzylamine hydrogen maleate, which after recrystallisation from a mixture of acetone and ether melted at 135.5-136.5ºC.
Example 6:
N,N-Dimethyl-5-fluoro-2-(3,4-difluorophenylthio)benzylamine. a) A reaction of 5.7 g of potassium hydroxide in 62 ml of water with 4.50 g of 3.4-difluorothiophenol, 7.98 g of 5-fluoro-2-iodobenzoic acid, 0.45 g of copper, in analogy to example 1/a, yielded 7.22 g of 5-fluoro-2-(3,4-difluorophenylthio) benzoic acid with melting point 181-182 C.
b) A reaction of 7.0 g of 5 -fluoro-2-(3,4-difluorophenylthio)benzoic acid with 7.4 g of thionylchloride in 60 ml of benzene, in analogy to the example 1/b, yielded 7.2 g (97%) of crystalline 5-fluoro-2-(3,4-difluorophenylthio)benzoyl chloride, melting at 77-78°C.
c) A reaction of 7.0 g of 5-fluoro-2-(3,4-difluorophenylthio)benzoyl chloride in 50 ml of benzene with 12 ml of 40% aqueous dimethylamine, in analogy to example 1/c, yielded 6.9 g (96%) of oily N,N-dimethyl-5-fluoro-2-(3,4-difluorophenylthio) benzamide.
d) 6.8 g of oily N,N-dimethyl-5-fluoro-2-(3,4-difluorophenylthio) benzamide in 42 ml of tetrahydrofuran with 1.56 g of sodium borohydride and 6.45 g of boron trifluoride etherate were brought into reaction in analogy to example 1/d. The obtained crude base was extracted from an aqueous solution of 3x25 ml of benzene. Neutralisation with a solution of hydrogen chloride in ethanol yielded 6.4 g of crystalline N,N-dimethyl-5-fluoro-2-(3,4-difluorophenylthio)benzylamine hydrochloride, which after crystallisation from ethanol melted at 148-150°C.
Example 7:
N,N-Dimethyl-2-(2,4-dichlorophenylthio)benzylamine. a) 20 ml of thionylchloride was added to a solution of 13.6 g of 2-(2,4-dichlorophenylthio) benzoic acid (Sindelaf K. et al.: Collect. Czech. Chem. Commun. 38, 3321 (1973)) in 100 ml of toluene and the mixture was refluxed for 3 h. The volatile constituents evaporated off i n vacuo , which yielded 14.3 g of crystalline crude 2-(2,4-dichlorophenylthio)benzoyl chloride, which after crystallisation from petroleum ether melted at 91-93°C. b) A solution of 14.3 g of 2-(2,4-dichlorophenylthio)benzoyl chloride in 200 ml of dioxane was saturated with gaseous dimethylamine over a period of 2 h under occasional external cooling with icy water. After 16 h of standing, the volatile constituents evaporated off i n vacuo and the residue was extracted between water and benzene. The benzene phase was dried with magnesium sulfate and evaporated i n vacuo , to obtain 13.7 g of N,N-dimethyl-2-(2,4-dichlorophenylthio) benzamide, which after crystallisation from a mixture of benzene and petroleum ether melted at 120-122ºC.
c) 3.0 g of sodium borohydride was added to a solution of 11.83 g of N,N-dimethyl-2-(2,4-dichlorophenylthio)benzamide in 60 ml of tetrahydrofuran and then 10 ml of boron trifluoride etherate was added dropwise over a period of 40 min. The reaction mixture was processed in analogy to example pie 1/d. The crude base was dissolved in chloroform and purified by filtration on a 150 g silica gel column. After evaporating the chloroform, the obtained crude base was neutralised using 5.0 g of oxalic acid dihydrate in 50 ml of ethanol, which yielded 10.6 g of crystalline N,N-dimethyl-2-(2,4-dichlorophenylthio)benzylamine hydrogen oxalate, melting at 208-211°C.
Example 8:
N,N-Dimethyl-2-(2,5-dichlorophenylthio)benzylamine.
A reaction of 11.0 g of 2-(2,5-dichlorophenylthio)benzoic acid (Sindelaf K. et. al: Collect. Czech. Chem. Commun. 38, 3321 (1973)) in a mixture of 100 ml of toluene and 20 ml of thionylchloride was carried out in analogy to example 1/b, which yielded 12.0 g of 2-(2,5-dichlorophenylthio)benzoyl chloride, which after crystallisation from cyclohexane melted at 104-105.5°C.
A reaction of 12.0 g of 2-(2,5-dichlorophenylthio)benzoyl chloride in 200 ml of dioxane with gaseous dimethylamine carried out in analogy to example 7/b, yielded 11.2 g (93%) of crystalline N,N-dimethyl-2-(2,5-dichlorophenylthio)benzamide, which after crystallisation from a mixture of benzene and petroleum ether melted at 124-126ºC.
2.6 g of sodium borohydride was added to a solution of 10.2 g of N,N-dimethyl-2-(2,5-dichlorophenylthio)benzamide in 60 ml of tetrahydrofuran and then 8.6 ml of boron trifluoride etherate was added dropwise at room temperature under nitrogen over a period of 30 min The reaction mixture was processed in analogical procedure to example 1/d to obtain the crude oily base (9.7 g). The base was neutralised using 4.7 g of oxalic acid dihydrate in ethanol. The subsequent crystallisation yielded 9.0 g (73 %) N,N-dimethyl-2-(2,5-dichlorophenylthio) benzylamine hydrogen oxalate which melted at 180-182.5°C.
Example 9:
N,N-Dimethyl-2-(3,4-dichlorophenylthio)benzylamine.
A reaction of 14.2 g of 2-(3,4-dichlorophenylthio)benzoic acid (Cervena I. and others: Collect. Czech. Chem. Commun. 41, 881 (1976)) in 180 ml of benzene with 15.2 g of thionylchloride, carried out in analogy to example 1/b, yielded 15.5 g of crude crystalline 2-(3,4-dichlorophenylthio)benzoyl chloride, which after crystallisation from cyclohexane melted at 104.5-105.5°C.
15.3 g of 2-(3,4-dichlorophenylthio)benzoyl chloride in 100 ml of benzene was mixed with 32 g of 40% aqueous solution of dimethylamine under mild cooling over a period of 10 min. The mixture was stirred for 4 h at room temperature and evaporated i n vacuo . The residue contained 15.3 g of oily N,N-dimethyl-2-(3,4-dichlorophenylthio)benzamide.
A reaction of 15.3 g of oily N,N-dimethyl-2-(3,4-dichloro phenylthio)benzamide in 100 ml of tetrahydrofuran with 4.5 g of sodium borohydride and 15.0 g of boron trifluoride etherate under nitrogen and the procedure carried out in analogy to example 1/d yielded crystalline N,N-dimethyl-2-(3,4-dichlorophenylthio)benzylamine hydrogen maleate, which after crystallisation from a mixture of acetone and ether melted at 127.5-128.5°C.
Example 10:
N,N-Dimethyl-2-(3,5-dichlorophenylthio)benzylamine.
A suspension of 3,5-dichloroaniline hydrochloride obtained from 29.0 g of 3,5-dichloroaniline and 75 ml of diluted hydrochloric acid (1:1) was diazotized under stirring at 0-5ºC with a solution of 13.7 g of sodium nitrite in 30 ml of water. 0.2 g of nickel sulfate was added to a solution of the diazonium salt and the cooled mixture was added in small amounts to a solution of 35 g of potassium xanthate in 45 ml of water kept between 40-45ºC. After having added everything, this temperature was kept for a further 1 h. After cooling, the mixture was extracted with ether, the ethereal extract was washed with 50 ml of 10% solution of sodium hydroxide, dried with calcium chloride and ether evaporated off. The residue was dissolved in 115 ml of ethanol and 45 g of potassium hydroxide was slowly added to the boiling solution. The mixture was refluxed for 8 h, the ethanol was distilled off and 160 ml of 3M sulfuric acid was added to the residue at a temperature of 25ºC maximum. The oily product was extracted with the ether and the extract was evaporated, which yielded 16.1 g of semicrystalline crude 3,5-dichlorothiophenol.
A reaction of 16.1 g of crude 3,5-dichlorothiophenol, 24 g of 2-iodobenzoic acid and 1.65 g of copper with 20.8 g of potassium hydroxide in 225 ml of water at 50-60ºC, refluxing under stirring for 9 h and then processing in analogy to example 1/a, yielded 24 g (90%) of 2-(3,5-dichlorophenylthio)benzoic acid, which after crystallisation from ethanol melted at 198-200°C.
22 ml of thionylchloride was added under stirring over a period of 1.5 h to a suspension of 24.0 g of 2-(3,5-dichlorophenylthio) benzoic acid in 220 ml of benzene heated up to 70ºC. The mixture was then processed in analogy to example 1/b. Crystallisation from cyclohexane yielded 23.2 g of 2-(3,5-dichlorophenylthio) benzoyl chloride with melting point 104-107°C.
A solution of 23.2 g of 2-(3,5-dichlorophenylthio)benzoyl chloride in 160 ml of toluene was added under intensive stirring at 4-6ºC over a period of 1 h to 80 ml of 40% aqueous solution of dimethylamine. The filtrate was stirred a further 2 h at room temperature. The toluene phase was separated, washed with water and dried with potassium carbonate which was filtered off. The mixture was evaporated i n vacuo , which yielded 17.5 g of oily N,N-dimethyl-2-(3,5-dichlorophenylthio) benzamide, which crystallised on standing and after recrystallisation from a mixture of benzene and petroleum ether melted at 120-122°C.
3.6 g of sodium borohydride was added to a solution of 18.0 g N,N-dimethyl-2-(3,5-dichlorophenylthio)benzamide in 125 ml of tetrahydrofuran and then 18.3 g of boron trifluoride etherate was added dropwise under nitrogen at 20-27ºC over a period of 1 h. The mixture was then processed in analogy to example 1/d. The residue of the crude base was dissolved in ether, the solution was filtered and the filtrate was neutralised with a solution of hydrogen chloride in ether. The precipitated crystalline N,N-dimethyl-2-(3,5-dichlorophenylthio)benzylamine hydrochloride after recrystallisation from a mixture of ethanol and ether melted at 185-189°C. Example 11: N,N-Dimethyl-5-chloro-2-(2,4-dichlorophenylthio)benzylamine.
8.95 g of 2, 4-dichlorothiophenol (Sparke M.B. et. al: J. Am. Chem. Soc. 75, 4907 (1953)), 14.1 g of 5-chloro-2-iodobenzoic acid (Pelz K. et. al: Collect. Czech. Chem. Commun. 33, 1852 (1968)) and 2.5 g of copper were step by step added to a solution of 9.1 g of potassium hydroxide in 100 ml of water and the mixture was refluxed under stirring for 7.5 h. Then the mixture was diluted with 150 ml of hot water, filtered and further processed in analogy to example 1/a. Crystallisation from ethanol yielded 14.9 g (89%) of 5-chloro-2-(2,4-dichlorophenylthio)benzoic acid, m.p 188-191ºC.
A mixture of 14.8 g of 5-chloro-2-(2,4-dichlorophenylthio)benzoic acid in 100 ml of toluene and 20 ml of thionylchloride was heated up to 80ºC under stirring under reflux condenser and then was processed in analogy to example 1/b, which yielded 12.4 g (80%) of crude crystalline 5-chloro-2-(2,4-dichlorophenylthio)benzoylchloride, which after crystallisation from cyclohexane melted at 129-132ºC.
A reaction of 12.0 g of crude 5-chloro-2-(2,4-dichlorophenylthio)benzoyl chloride in 200 ml of dioxane with gaseous dimethylamine in analogy to example 7/b yielded the crude amide, which was dissolved in 60 ml of chloroform and filtered on a 130 g silica gel column. The column was eluted with chloroform, the solvent evaporated off to obtain 10.3 g (84%) of crystalline N,N-dimethyl-5-chloro-2-(2,4-dichlorophenylthio)benzamide, which after crystallisation from a mixture of benzene and petroleum ether melted at 96-97ºC.
8.6 g of N,N-dimethyl-5-chloro-2-(2,4-dichlorophenylthio)benzamide in 50 ml of tetrahydrofuran, 2.0 g of sodium borohydride and 6.6 ml of boron trifluoride etherate was processed in analogy to example 1/d, which yielded 7.4 g of oily N,N-dimethyl-5-chloro-2-(2,4-dichlorophenylthio)benzylamine. This was dissolved in ethanol and neutralised with a solution of hydrogen chloride in ether, which yielded 6.86 g of the crystalline hydrochloride. This, after crystallisation from a mixture of methanol and ethanol, melted at 258-261ºC.
Example 12:
N,N-Dimethyl-5-chloro-2-(2,5-dichlorophenylthio)benzylamine. a) 2.95 g of 2,5-dichlorothiophenol (Sindelaf K. et al. Collect. Czech. Chem. Commun. 38, 3321 (1973)), 14.12 g of 5-chloro-2-iodobenzoic acid and 2.5 g of copper were step by step added to a solution of 9.1 g of potassium hydroxide in 100 ml of water and the mixture was refluxed for 9 h. Vhile still hot, it was diluted with 50 ml of hot water and filtered. After cooling, the filtrate was acidified with 18 ml of diluted hydrochloric acid (1:1) and left standing for 16 h at 0ºC. The precipitated crude 5-chloro-2-(2,5-dichlorophenylthio) benzoic acid was filtered by suction and dissolved in 100 ml of dimethylformamide at 80ºC. The solution was filtered, and the pure acid precipitated by diluting of the cold filtrate with 500 ml of water. This was filtered by suction and its recrystallisation from ethanol yielded 10.90 g (65%) of 5-chloro-2-(2,5-dichlorophenylthio)benzoic acid, m.p. 216-218°C.
b) A reaction of 10.9 g of 5-chloro-2-(2,5-dichlorophenylthio)benzoic acid in 100 ml of toluene with 20 ml of thionylchloride carried out in analogy to example 1/b and after crystallisation yielded 11.0 g of 5-chloro-2-(2,5-dichlorophenylthio) benzoyl chloride, which melted at 105-106ºC.
c) A reaction of 11.0 g of 5-chloro-2-(2,5-dichlorophenylthio) benzoyl chloride in 200 ml of dioxane with gaseous dimethylamine, carried out in analogy to example 7/b, yielded 10.7 g (90%) of crystalline N,N-dimethyl-5-chloro-2-(2,5-dichlorophenylthio)benzamide, which after crystallisation from a mixture of cyclohexane and petroleum ether melted at 92-93°C.
d) A reaction of 10.2 g of N,N-dimethyl-5-chloro-2-(2,5-dichlorophenylthio)benzamide in 60 ml of tetrahydrofuran with 2.58 g of sodium borohydride and 8.6 ml of boron trifluoride etherate, carried out in analogy to example 1/d, yielded the oily base, which was dissolved in 12 ml of ethanol and neutralised by the addition of 10 ml of hydrogen chloride in ether. Crystallisation from ethanol yielded 8.1 g (75%) of N,N-dimethyl-5-chloro-2-(2,5-dichlorophenylthio) benzylamine hydrochloride, m.p. 252-255ºC (in sealed capillary).
Example 13:
N,N-Dimethyl-5-chloro-2-(3,4-dichlorophenylthio)benzylamine.
A reaction of 5.6 g of potassium hydroxide in 100 ml of water with 5.37 g of 3,4-dichlorothiophenol (Cervena I. et al.: Collect. Czech. Chem. Commun. 41, 881 (1976)), 8.48 g of 5-chloro-2-iodobenzoic acid and 2.5 g of copper, carried out in analogy to example 1/a, yielded 9.1 g (91%) of 5-chloro-2-(3,4-dichlorophenylthio) benzoic acid (m.p. 223-227ºC), which after crystallisation from ethanol melted at 225-227° C.
A reaction of 8.6 g of 5-chloro-2-(3,4-dichlorophenylthio)benzoic acid with 20 ml of thionylchloride, carried out in analogy to example 1/b, yielded crystalline 5-chloro-2-(3,4-dichlorophenylthio)benzoyl chloride (100% yield), which after crystallisation from cyclohexane melted at 98-101 .
A solution of 9.0 g of 5-chloro-2-(3,4-dichlorophenylthio)benzoyl chloride in 150 ml of dioxane was saturated with gaseous dimethylamine over a period 1.5 h and processed in analogy to example 7/b. The benzene phase was washed with diluted solution of sodium carbonate and with water, dried with magnesium sulfate, then filtered and evaporated i n vacuo . The residue was dissolved in chloroform and the solution was filtered on a 75 g silica gel column. Evaporating of the filtrate yielded 7.43 g (80%) of oily N,N-dimethyl-5-chloro-2-(3,4-dichlorophenylthio)benzamide.
1.6 g of sodium borohydride was added to a solution of 6.8 g of oily N,N-dimethyl-5-chloro-2-(3,4-dichlorophenylthio)benzamide in 60 ml of tetrahydrofuran and then 8 ml of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 1 h . The mixture was processed in analogy to example 1/d. Neutralisation with a solution of hydrogen chloride in ether yielded 5.25 g (74%) of crystalline N,N-dimethyl-5-chloro-2-(3,4-dichlorophenylthio) benzylamine hydrochloride, which after recrystallisation from a mixture of ethanol and ether melted at 203-207°C.
Example 14: N,N-Dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzylamine. a) A reaction of 5.7 g of potassium hydroxide in 65 ml of water with 5.52 g of 2,4-dichlorothiophenol, 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper, carried out in analogy to example 1 /a , yielded 2- ( 2 , 4 - dichlorophenyl thio)-5-fluorobenzoic acid, which was filtered by suction and recrystallised from ethanol, which yielded 8.32 g of the acid, m.p. 198.5-199.5°C.
b) 9.92 g of thionylchloride was added dropwise under stirring at 60ºC to a suspension of 8.15 g of 2-(2,4-dichlorophenylthio)-5-fluorobenzoic acid in 55 ml of benzene, and the resulting solution was processed in analogy to example 1/b. Crystallisation from cyclohexane yielded 8.3 g of 2-(2,4-dichlorophenylthio)-5-fluorobenzoyl chloride, m.p. 85-86°C.
c) A solution of 8.1 g of 2-(2,4-dichlorophenylthio)-5- fluorobenzoyl chloride in 50 ml of benzene was added dropwise under intensive stirring at 8°C to 11 ml of 40% aqueous solution of dimethylamine. The mixture was stirred for a further 2 h at 15ºC and then was processed in analogy to example 1/c, which yielded 8.3 g (100%) of oily N,N-dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzamide.
d) 7.6 g of oily N,N-dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzamide in 45 ml of tetrahydrofuran, 1.6 g of sodium borohydride and 6.51 g of boron trifluoride etherate reacted in analogy to example 1/d, the gained residue of the crude base was dissolved in ether, the solution was filtered and the filtrate neutralised with a solution of hydrogen chloride in ether. Crystallisation from ethanol yielded 7.05 g of N,N-dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzamine hydrochloride, which after crystallisation from ethanol melted at 209-212°C.
Example 15:
N,N-Dimethyl-2-(2,5-dichlorophenylthio)-5-fluorobenzamine.
A reaction of 5.7 g of potassium hydroxide in 65 ml of water with 5.52 g of 2,5-dichlorothiophenol, 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper, carried out in analogy to example la, yielded 9.05 g (95%) of 2-(2,5-dichlorophenylthio)-5-fluorobenzoic acid, m. p. 224-227ºC.
In analogy to example 1/b, a reaction of 8.9 g of 2-(2,5-dichlorophenylthio)-5-fluorobenzoic acid with 10.8 g of thionylchloride in 60 ml of benzene and dimethylformamide provided 8.45 g (90%) of crystalline 2-(2,5-dichlorophenylthio)-5-fluorobenzoyl chloride, which after recrystallisation from cyclohexane melted at 110-111ºC.
In analogy to example 1/c, a reaction of a solution of 8.2 g of 2-(2,5-dichlorophenylthio)-5-fluorobenzoyl chloride with 11 ml of 40% aqueous dimethylamine and crystallisation from methanol yielded 7.87 g (94%) of crystalline N,N-dimethyl-2-(2,5-dichlorophenylthio)-5-fluorobenzamide, m. p. 98-99°C.
A reaction of 7.6 g of N,N-dimethyl-2-(2,5-dichlorophenylthio)-5-fluorobenzamide in 45 ml of tetrahydrofuran with 1.6 g of sodium borohydride and 6.51 g of boron trifluoride etherate, carried out in analogy to example 14/d, yielded 7.05 g of N,N-dimethyl-2-(2,5-dichlorophenylthio)-5-fluorobenzylamine hydrochloride, which after crystallisation from ethanol melted at 198-201 °C.
Example 16:
N,N-Ddimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzylamine.
In analogy to example la, a reaction of 5.7 g of potassium hydroxide in 70 ml of water with 5.52 g of 3,4-trichlorothiophenol, 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper yielded 8.2 g (86%) of crystalline 2-(3,4-dichlorophenylthio)-5-fluorobenzoic acid, which after crystallisation from ethanol melted at 196-197°C.
In analogy to example 1/b, a reaction of a suspension of 8.0 g of 2-(3,4-dichlorophenylthio)-5-fluorobenzoic acid in 60 ml of benzene with 9.7 g of thionylchloride and dimethylformamide yielded 8.3 g (98%) of crystalline 2-(3,4-dichlorophenylthio)-5-fluorobenzoyl chloride, which after crystallisation from cyclohexane melted at 72-73ºC.
A reaction of 8.1 g of 2-(3,4-dichlorophenylthio)-5-fluorobenzoyl chloride in 50 ml of benzene wi th 1 3 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded 7.6 g (92%) of oily N,N-dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzamide.
A reaction of 7.6 g of oily N,N-dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzamide in 50 ml of tetrahydrogenfuran, 1.57 g of sodium borohydride and 6.5 g of boron tri fluoride etherate was carried out in analogy to example 14/d and after 16 h of standing, the precipitated crude hydrochloride was filtered by suction and crystallised from ethanol, which yielded 5.5 g of N,N-dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzylamine, m.p. 178-180ºC.
Example 17:
N,N-Dimethyl-2-(3-methylphenylthio)-5-fluorobenzylamine.
60 g of thionylchloride was added dropwise under stirring over a period of 20 min to a solution of 42.6 g of 2-(3-methylphenylthio)benzoic acid (Protiva M. et. al: Collect. Czech. Chem. Commun. 47, 3134 (1982)) in 300 ml of benzene and was processed in analogy to example 1/b. Crystallisation from cyclohexane yielded 45.9 g of 2-(3-methylphenylthio)benzoyl chloride, m.p. 78-79°C.
A solution of 13.5 g of 2-(3-methylphenylthio)benzoyl chloride was mixed with 50 ml of 40% aqueous dimethylamine under intensive stirring at 10 C over a period of 20 min. The solution was stirred for 3 h at room temperature and was processed in analogy to example 1/c, which yielded 13.9 g of crude N,N-dimethyl-2-(3-methylphenylthio)benzamide.
4.3 g of 90% sodium borohydride was added to a solution of 13.90 g of crude N,N-dimethyl-2-(3-methylphenylthio)benzamide in 90 ml of tetrahydrofuran, then 15 g of boron trifluoride etherate was added dropwise at room temperature over a period 20 min and the mixture was processed in analogy to example 1/d. The crude base was dissolved in ether and neutralised with a solution of maleic acid in acetone. On standing there crystallised 9.83 g of N,N-dimethyl-2-(3-methylphenylthio) benzylamine hydrogen maleate, m.p. 109-111ºC.
Example 18:
N,N-Dimethyl-4-fluoro-2-(4-isopropylphenylthio)benzylamine. One drop of dimethylformamide was added to a suspension of 22.0 g of 4-fluoro-2-(4-isopropylphenylthio)benzoic acid (Protiva M. et al.: Collect. Czech. Chem. Commun. 51, 698 (1986)) in 200 ml of benzene, then 30 g of thionylchloride was added dropwise under stirring over a period of 5 min and the mixture was processed in analogy to example 1b, which yielded 21.4 g (91%) of crude oily 4-fluoro-2-(4-isopropylphenylthio)benzoyl chloride.
A solution of 20.0 g of crude 4-fluoro-2-(4-isopropylphenylthio)benzoyl chloride in 160 ml of benzene was saturated with gaseous dimethylamine at 12-16 C until its weight addition was 22.5 g (1h). The mixture was stirred for a further 1 h at 12-16ºC and then washed with water, dried with calcium chloride and filtered. The filtrate was evaporated i n vacuo . The oily residue was left standing to crystallise (14 days). After addition of petroleum ether it was filtered by suction, which yielded 13.2 g (64%) of N,N-dimethyl-4-fluoro-2-(4-isopropylphenylthio)benzamide, which after recrystallisation from n-hexane melted at 54-55ºC.
2.25 g of sodium borohydride was added to a solution of 12.2 g of N,N-dimethyl -4 - f luoro- 2 - ( 4- i sopropy l pheny l thio) benzamide , then 11.2 g of boron trifluoride etherate was added dropwise under nitrogen at 20-25ºC over a period of 30 min and the mixture was processed in analogy to example 1/d, which yielded 12.0 g (100%) of oily base. This was dissolved in 20 ml of ether and the solution was mixed with a solution of 4.5 g of maleic acid in 10 ml of ethanol. By cooling 13.8 g of N,N-dimethyl-4-fluoro-2-(4-isopropylphenylthio)benzylamine hydrogen maleate crystallised, which after recrystallisation from a mixture of ethanol and ether melted at 117-118°C.
Example 19:
N,N-Dimethyl-2-(2-(trifluoromethyl)phenylthio)benzylamine. 7.0 g of 2-(trifluoromethyl)thiophenol (Sharghi N. and Lalezari I.: J. Chem. Eng. Data 11, 612 (1966), Chem. Abstr. 66, 10690 (1967)), 9.75 g of 2-iodobenzoic acid and 2.2 g of copper were step by step added to a solution of 7.3 g of potassium hydroxide in 80 ml of water, the mixture was refluxed under stirring for 10 h and then was processed in analogy to example 12/a. 11.4 g of 2-(2-(trifluoromethyl)phenylthio) benzoic acid was obtained, which after recrystallisation from benzene melted at 170-174ºC.
A reaction of 10.5 g of 2-(2-(trifluoromethyl)phenylthio)benzoic acid in 100 ml of benzene with 10 ml of thionylchloride, carried out in analogy to example 1/b, yielded 10.0 g crude 2-(2-(trifluoromethyl)phenylthio)benzyol chloride, which after crystallisation from cyclohexane melted at 70-73°C.
A solution of 10.0 g of 2-(2-(trifluoromethyl)phenylthio)benzoyl chloride in 100 ml of dioxane was saturated with gaseous dimethylamine under external cooling over a period of 1 h. After 16 h of standing, the solvent evaporated i n vacuo and the oily residue was crude N,N-dimethyl-2-(2-(trifluoromethyl)ph nylthio)benzamide.
A reaction of 9.5 g of oily N,N-dimethyl-2-(2-(trifluoromethyl)phenylthio)benzamide in 50 ml of tetrahydrofuran with 2.42 g of sodium borohydride and 9.0 g of boron trifluoride etherate, carried out in analogy to example 1/d, yielded the crude base, which was purified by filtration on a 200 g silica gel column - for eluting a mixture of toluene, chloroform and chloroform saturated with ammonia was used. Evaporating the filtrate yielded 8.7 g (96%) of the chromatographically homogeneous base. Its neutralisation with oxalic acid dihydrate in ethanol yielded 8.5 g of crystalline N,N-dimethyl-2-(2-(trifluoromethyl)phenylthio)benzylamine, which after crystallisation from ethanol melted at 145-147ºC. Example 20: N,N-Dimethyl-2-(3-(trifluoromethyl)phenylthio)benzylamine.
82 . 4 g of thionylchloride was added at 60ºC to a suspension of 63.4 g of 2-(3-(trifluoromethyl)phenylthio)benzoic acid (Peltz K. et al.: Collect. Czech. Chem. Commun. 34, 3936 (1969)) in 470 ml of benzene. The mixture was refluxed for 2 h and processed in analogy to example 1/b. The product was crystallised from cyclohexane, which yielded 63.2 g (94%) of crystalline 2-(3-(trifluoromethyl)phenylthio)benzoyl chloride, m. p. 85-86°C.
A solution of 63.2 g of 2-(3-(trifluoromethyl)phenylthio)benzoyl chloride in 400 ml of benzene was mixed together with 90 g of 40% aqueous dimethylamine under intensive stirring at 5°C. The mixture was stirred for 1 h and after standing for 1 h at room temperature, it was processed in analogy to example 1/c, which yielded 64.6 g (100%) of oily N,N-dimethyl-2-(3-(trifluoromethyl)phenylthio)benzamide.
A reaction of 64.6 g of oily N,N-dimethyl-2-(3-(trifluoromethyl) phenylthio) benzamide in 400 ml of tetrahydrofuran with 11.2 g of sodium borohydride and 58.6 g of boron trifluoride etherate, carried out in analogy to example 1/d, yielded the crude base, which was dissolved in ether, filtered and neutralised with a solution of hydrogen chloride in ether. 62.6 g (90%) of N,N-dimethyl-2-(3-(trifluoromethyl)phenylthio) benzylamine hydrochloride precipitated, which after crystallisation from a mixture of ethanol and ether melted at 165-167°C.
Example 21 :
N,N-Dimethyl-2-(4-(trifluoromethyl)phenylthio)benzylamine.
A reaction of 7.6 g of crude 2-(4-(trifluoromethyl)phenyl thio)benzoic acid (GB 925,539) in 50 ml of toluene with 20 ml of thionylchloride, carried out in analogy to example 7/a, yielded 8.1 g of crude 2-(4-(trifluoromethyl)phenylthio)benzoyl chloride, which after crystallisation from cyclohexane melted at 66-68ºC.
A reaction of 8.1 g of crude 2-(4-(trifluoromethyl)phenylthio) benzoyl chloride in 75 ml of dioxane with gaseous dimethylamine, carried out in analogy to example 7/b, yielded 7.52 g of oily N,N-dimethyl-2-(4-(trifluoromethyl)phenylthio)benzamide.
A solution of 7.5 g of N,N-dimethyl-2-(4-(trifluoromethyl)phenylthio)benzamide in 45 ml of tetrahydrofuran was reduced by 1.3 g of sodium borohydride and 6.8 ml of boron trifluoride etherate. The reaction mixture was processed in analogy to example 1/d to obtain the oily base. The base was neutralised with a solution of 4.1 g of oxalic acid dihydrate in 30 ml of ethanol. By addition of 50 ml of ether, crystalline N,N-dimethyl-2-(4-(trifluoromethyl)phenylthio)benzylamine hydrogenoxalate was obtained, which crystallised in two crystalline modifications: the lower melting one - m.p. 166-170°C, and the higher melting one - m.p. 178-182°C.
Example 22:
N,N-Dimethyl-5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzylamine.
A reaction of 11.2 g of potassium hydroxide in 120 g of water with 14.4 g of crude 4-(trifluoromethyl)-2-nitrothiophenol [obtained by reduction of bis(4-(trifluoromethyl)-2-nitrophenyl)disulfide (Sindelaf K. et. al: Collect. Czech. Chem. Commun. 46, 118 (1981)) by glucose when using described procedure (DRP 204,450)], 17.1 g of 5-fluoro-2-iodobenzoic acid and 1.5 g cooper, carried out in analogy to example 1/a, and crystallisation from a mixture of benzene and cyclohexane yielded 10.5 g (45%) of 5-fluoro-2-(4-(trifluoromethyl)-2-nitrophenylthio)benzoic acid with melting point 156-159°C.
A mixture of 10.1 g of 5-fluoro-2-(4-(trifluoromethyl)-2-nitrophenylthio)benzoic acid, 60 ml of ethanol, 5.1 g of hydrazine hydrate, 0.6 g of filtration charcoal and 0.2 g of ferric chloride hexahydrate was refluxed for 11 h and filtered. Ethanol contained in the filtrate evaporated off i n vacuo . The residue was dissolved in a diluted solution of sodium hydroxide and acidified with acetic acid to obtain 8.4 g of 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzoic acid, which after crystallisation from a mixture of benzene, ethanol and petroleum ether melted at 191-193ºC.
A solution of 2.2 g of sodium nitrite in 5 ml of water was slowly added dropwise under stirring at 0ºC to a solution of 8.0 g of 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzoic acid and 4.2 ml of sulfuric acid in 70 ml of ethanol. The mixture was stirred at the given temperature for a further 15 min, then 4.5 g of sodium hypophosphite monohydrate in 5 ml of water, 0.2 g of copper and 30 ml of ethanol were added and the mixture was refluxed for 1.5 h. After filtration, the filtrate was evaporated i n vacuo , the residue was combined with water and filtered by suction. The solid phase was extracted with boiling ethanol, the insoluble fraction was filtered off and the filtrate was evaporated again. The residue was extracted with boiling benzene and the insoluble fraction was again filtered off. The filtrate was evaporated and crystallisation of the residue from petroleum ether yielded 4.4 g of 5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzoic acid with melting point 127-129.5ºC .
A mixture of 4.2 g of 5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzoic acid, 40 ml of benzene and 4.8 g of thionylchloride was refluxed for 1.5 h and processed in analogy to example 1/b, which yielded 3.9 g of oily 5-fluoro-2- (4-(trifluoromethyl)phenylthio) benzoyl chloride. A solution of 3.9 g of 5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzoylchloride was dissolved in 30 ml of benzene and was mixed under intensive stirring over a period of 15 min with 10 ml of 40% aqueous dimethylamine and processed in analogy to example 1/c, which yielded 4.0 g of oily N,N-di-methyl-5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzamide.
1.0 g of sodium borohydride was added to a solution of 4.0 g of oily N,N-dimethyl-5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzamide in 30 ml of tetrahydrofuran and then 4.5 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 10 min. The mixture was processed in analogy to example 1/d to obtain the crude base (3.5 g). This was dissolved in ether and the solution was neutralised with a solution of 1.5 g of oxalic acid dihydrate in acetone. The precipitated crude N,N-dimethyl-5-fluoro-2-(4-(trifluoromethyl)phenylthio)benzylamine hydrogen oxalate recrystallised from ethanol to obtain 3.25 g of the pure salt with melting point 177.5-179.5°C.
Example 23:
N,N-Dimethyl-2-(4-(methylthio)phenylthio)benzylamine. a) A reaction of 12.4 g of 2-(4-(methylthio)phenylthio)benzoic acid (Pelz K. et. al: Collect. Czech. Chem. Commun. 33, 1895 (1968)) in 100 ml of benzene with 11 ml of thionylchloride, carried out in analogy to example 1/b, yielded 13.0 g of crude 2-(4-(methylthio)phenylthio)benzoyl chloride as a yellowish oil.
b) A reaction of 13.0 g of crude 2- (4- (methylthio) phenylthio)benzoyl chloride in 80 ml of benzene with 40 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded 13.2 g of oily N,N-dimethyl-2-(4-(methylthio)phenylthio)benzamide. c) 3.0 g of sodium borohydride was added to a solution of 13.6 g of oily N,N-dimethyl-2-(4-(methylthio)phenylthio)benzamide in 80 ml of tetrahydrofuran and then 12.0 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 30 min. The mixture was processed in analogy to example 1/d, which provided 14 g of the crude base. This was neutralised with a solution of hydrogen chloride in ether, and after crystallisation from a mixture of acetone and ethanol 8.3 g of N,N-dimethyl-2-(4-(methylthio)phenylthio)benzylamine hydrochloride was yielded, with melting point 141-144°C.
Example 24:
N,N-Dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzylamine.
A reaction of 12.4 g of 5-fluoro-2-(4-(methylthio)phenylthio)benzoic acid (Kopicova Z. et. al: Collect. Czech. Chem. Commun. 40. 3519 (1975)), 90 ml of benzene and 16 g of thionylchloride, carried out in analogy to example 1/b and crystallisation from cyclohexane yielded 11.1 g of 5-fluoro2-(4-(methylthio)phenylthio)benzoyl chloride with melting point 77-78°C.
A reaction of 11.1 g of 5-fluoro-2-(4-(methylthio)phenylthio) benzoyl chloride in 60 ml of benzene with 20 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded oily N,N-dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzamide.
A reaction of 12.2 g of oily N,N-dimethyl-5-fluoro-2-(4- (methylthio)phenylthio)benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 12.5 g of boron trifluoride etherate, carried out in analogy to example 1/d, yielded 12.0 g of crude base. This was neutralised with a solution of hydrogen chloride in ether, which yielded 11.6 g of N,N-dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzylamine hydrochloride, which after crystallisation from a mixture of ethanol and ether melted at 160.5-162.5ºC.
Example 25:
N,N-Dimethyl-5-fluoro-2-(4-(methylsulfinyl)phenylthio)benzylamine.
5 ml of 15% hydrogenperoxide was added to a solution of 2.6 g of N,N-dimethyl-5-fluoro-2-(4-(methylthio)phenylthio)benzylamine hydrochloride (see example 24) in 12 ml of acetic acid and the mixture was left standing at room temperature for 4 days. After diluting with water, it was made alkaline by aqueous ammonium and extracted with ether. The extract was dried with potassium carbonate, filtered and the filtrate was evaporated, which yielded 2.3 g of the base of N,N-dimethyl-5-fluoro-2-(4-(methylsulfinyl)phenylthio)benzylamine base, which after crystallisation from a mixture of benzene and petroleum ether melted at 94-97ºC. Neutralisation of this base with a solution of hydrogen chloride in ether yielded the hydrochloride, which after crystallisation from a mixture of acetone, ethanol and ether melted at 221-223°C.
Example 26:
N,N-Dimethyl-5-chloro-2-(4-(methylthio)phenylthio)benzylamine.
5.0 g of 4-(methylthio)thiophenol, (Pelz K. et. al: Collect. Czech. Chem. Commun. 33, 1895 (1968)), 11.3 g of 5-chloro-2-iodobenzoic acid and 3.0 g of copper were step by step added to a solution of 6.8 g of potassium hydroxide in 120 ml of water and the mixture was refluxed for 8.5 h and processed in analogy to example 1/a. The product was recrystallised from 400 ml of mixture of benzene and petroleum ether (1:1), filtered by suction and dried, yielding 8.9 g of 5-chloro-2-(4-(methylthio)phenylthiobenzoic acid (72%), which melted at 193-195°C.
A reaction of 10.1 g of 5-chloro-2-(4-(methylthio)phenylthiobenzoic acid in 100 ml of toluene with 20 ml of thionylchloride (1 h under stirring at 80ºC) and processing in analogy to example 7/a yielded 9.8 g (95%) of 5-chloro-2-(4-(methylthio)phenylthiobenzoylchloride, which after crystallisation from a mixture of cyclohexane and petroleum ether melted at 78-81°C.
9.4 g of 5-chloro-2-(4-(methylthio)phenylthionbenzoyl chloride in 50 ml of toluene reacted under intensive stirring and cooling with cold water with 30 ml of 40% aqueous dimethylamine. The mixture was stirred at room temperature for a further 2 h, the toluene phase was separated, washed with water and evaporated i n vacuo . The residue was dissolved in chloroform and was purified by filtration on a silica gel column, which was eluted with chloroform. The filtrate evaporated i n vacuo again, which yielded 7.55 g of oily N,N-dimethyl- 5-chloro- 2- (4- (methylthio) phenylthio) benzamide.
A reaction of 7.41 g of oily N,N-dimethyl-5-chloro-2-(4- (methylthio)phenylthio)benzamide in 60 ml of tetrahydrofuran with 3.0 g of sodium borohydride and 10 ml of boron trifluoride etherate, carried out in analogy to example 1/d, yielded the crude base, which was neutralised with a solution of 3.0 g of oxalic acid dihydrate in 80 ml of ethanol. After 16 h of standing, the precipitated product was filtered by suction, washed with ethanol and dried, which yielded 5.05 g (53%) of N,N-dimethyl-5-chloro-2-(4-(methylthio)phenylthio)benzylamine hydrogen oxalate, m.p. 131-134ºC.
Example 27:
N,N-Dimethyl-2-(4-(fluoro-3-methoxyphenylthio)benzylamine. A mixture of 18.5 g of thiosalicylic acid, 150 ml of dimethylformamide, 33.15 g of potassium carbonate, 24.6 g of 5-bromo-2-fluoroanisole (EP 175,452; JP 61/27,768; Chem. Abstr. 105, 42658 (1986)) and 2.2 g of copper was refluxed for 12 h. After cooling, the reaction mixture was diluted with 1.1 1 of water, filtered and washed with benzene. The water phase was acidified with hydrochloric acid, the precipitated crude 2-(4-(fluoro-3-methoxyphenylthio)benzoic acid (20.6 g) was filtered by suction and after crystallisation from ethanol melted at 222-224°C.
A reaction of 8.82 g of 2-(4-(fluoro-3-methoxyphenylthio)benzoic acid in 70 ml of benzene with 12.3 g of thionylchloride, carried out in analogy to example 1/b, yielded 8.6 g (91%) of 2-(4-(fluoro-3-methoxyphenylthio)benzoylchloride, which after crystallisation from a mixture of benzene and cyclohexane melted at 113-114.5ºC.
A reaction of 8.45 g of 2-(4-(fluoro-3-methoxyphenylthio)benzoyl chloride in 60 ml of benzene with 13 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded 7.3 g of crystalline N,N-dimethyl-2-(4-fluoro-3-methoxyphenylthio)benzamide, which after recrystallisation from methanol melted at 97-98, 5°C.
1.75 g of sodium borohydride was added to a solution of 7.0 g of N,N-dimethyl-2-(4-(fluoro-3-methoxyphenylthio)benzamide in 45 ml of tetrahydrofuran and then 6.8 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring. The mixture was processed in analogy to example 6/d, except for the use of a solution of hydrogen chloride in ether for neutralisation. The procedure yielded 6.52 g of N,N-dimethyl-2-(4-(fluoro-3-methoxyphenylthio)benzylamine hydrochloride, which after recrystallisation from a mixture of acetone and ether melted at 146-148ºC.
Example 28:
N,N-Dimethyl-2-(4-fluoro-3-hydroxyphenylthio)benzylamine. A solution of 7.0 g of N,N-dimethyl-2-(4-fluoro-3-methoxyphenylthio)benzylamine hydrochloride (see example 27) in 50 ml of 46% hydrobromic acid was heated up to 120ºC under stirring for 8 h. After cooling, the mixture was diluted with 100 ml of water, its pH was adjusted up to 8 using 20% solution of sodium hydroxide, and the mixture was extracted with chloroform. The extract was filtered over a 100 g silica gel column, which was eluted with chloroform. The filtrate was evaporated, which yielded 4.71 g of the base of oily N,N-dimethyl-2-(4-(fluoro-3-hydroxyphenylthio)benzylamine. Its neutralisation with the corresponding acids and crystallisation from benzene, or a mixture of ethanol and ether, respectively, yielded the hydrochloride with melting point 172-175ºC, and hydrogen maleate with melting point 148-150°C.
Example 29:
N,N-Dimethyl-2-(4-chloro-3-methoxyphenylthio)benzylamine.
A reaction of 4.7 g of 2-(4-chloro-3-methoxyphenylthio)benzoic acid (Cervena I. et. al: Collect Czech. Chem. Commun. 42, 1705 (1977)) in 35 ml of benzene and 3.8 ml of thionylchloride, carried out in analogy to example 1/b, yielded 4.1 g (82%) of crystalline 2-(4-chloro-3-methoxyphenylthio) benzoylchloride, which after recrystallisation from cyclohexane melted at 117-118.5ºC.
A solution of 3.6 g of 2-(4-chloro-3-methoxyphenylthio)benzoyl chloride in 45 ml of toluene was under stirring and external cooling by water and ice saturated with gaseous dimethylamine for 1 h. The mixture was stirred for a further 2 h and evaporated i n vacuo . The oily residue was mixed with a small amount of a mixture of cyclohexane and hexane (1:1) and crystallised. The product's filtration by suction yielded 3.0 g of N,N-dimethyl-2-(4-chloro-3-methoxyphenylthio) benzamide, which after recrystallisation from a mixture of hexane and cyclohexane melted at 84-86ºC.
0.7 g of sodium borohydride was added to a solution of 2.65 g of N,N-dimethyl-2-(4-chloro-3-methoxyphenylthio)benzamide in 20 ml of tetrahydrofuran and then 2.26 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring. The mixture was processed in analogy to example 1/d, which yielded 2.35 g (92%) of the oily crude base. Using hydrogen chloride in ether yielded N,N-dimethyl-2-(4-chloro-3-methoxyphenylthio)benzylamine hydrochloride, which after crystallisation from 2-propanol melted at 162-164°C.
Example 30:
N,N-Dimethyl-2-(4-trifluoromethyl)-2-nitrophenylthio)benzylamine.
22.8 g of 2-methylthiophenol, 41.4 g of 2-chloro-5-(trifluoromethyl)nitrobenzene and 2.0 g of copper were added to a solution of 30.6 g of potassium hydroxide in 325 ml of water. The mixture was refluxed under stirring for 9 h, and after cooling extracted with toluene. The extract was dried with magnesium sulfate, filtered and evaporated, which yielded 50 g of the oily crude 2-(4-trifluoromethyl)-2-nitrophenylthio) toluene of orange colour. After cooling to 0ºC, the product crystallised and after recrystallisation from hexane melted at 55-56ºC.
37 g of N-bromosuccinimide and 0.5 g of 2,2 -azobis(2-methylpropionitrile) were added to a solution of 54.2 g of 2-(4-trifluoromethyl)-2-nitrophenylthio)toluene in 400 ml of tetrachloromethane and the mixture was refluxed under stirring for 4 h. After cooling the precipitated solid compound was filtered off and washed with tetrachloromethane, which yielded 470 ml of filtrate containing 2-(4-trifluoro methyl)-2-nitrophenylthio)benzylbromide. For its characterisation this was isolated from a part of the filtrate as follows: 45 ml of the filtrate was evaporated i n vacuo , then chromatographed on a 100 g silica gel column and the column was eluted by petroleum ether, then cyclohexane and 5% toluene in cyclohexane. After isolation and crystallisation from a mixture of petroleum ether and cyclohexane, the product melted at 77-79°C.
The filtrate (302 ml) containing 2-(4-trifluoromethyl)-2-nitrophenylthio)benzylbromide was cooled to -10ºC and a solution of excess dimethylamine in tetrachloromethane was added little by little under stirring. The mixture was stirred at room temperature for 3 h and the precipitated dimethylamine hydrobromide was filtered off. The filtrate was washed with water, dried with magnesium sulfate and evaporated, which yielded 40 g of the crude oily base of N,N-dimethyl-2-(4-trifluoromethyl)-2-nitrophenylthio)benzylamine, which crystallised on standing and after recrystallisation from hexane melted at 59-60ºC. Its neutralisation and crystallisation from a mixture of ethanol and ether, or aqueous ethanol, respectively, yielded the following salts: the hydrobromide melting at 193-195ºC and hydrogen oxalate melting at 218-219°C.
Example 31:
N,N-Dimethyl-2-(2-aminophenylthio)benzylamine. a) A solution of 4.9 g of 2-(2-aminophenylthio)benzoic acid (Mayer F.: Ber. Dtsch. Chem. Ges. 42, 3046 (1909)) in 50 ml of tetrahydrofuran was added dropwise under stirring over a period of 30 min to a solution of 1.7 g of lithium aluminium hydride in 70 ml of tetrahydrofuran and after an exothermic reaction the mixture was refluxed for 5 h. After 16 h of standing, the mixture was decomposed under stirring by adding dropwise 6.7 ml of 4% solution of sodium hydroxide. The precipitated solid was filtered off and the filtrate was dried with magnesium sulfate and evaporated i n vacuo , which yielded 4.3 g (93%) of 2-(2-aminophenylthio)benzyl alcohol. This crystallised on standing and after recrystallisation from cyclohexane melted at 107-108.5ºC. It provides hydrochloride, which after recrystallisation from a mixture of 2-propanol and ethanol melted at 143-147ºC.
b) 2.6 g of 2-(2-aminophenylthio)benzyl alcohol was slowly mixed at room temperature with 2.7 g of thionylchloride and the mixture was left standing at room temperature for 1 h. Then it was diluted with 20 ml of benzene and all volatile constituents absolutely evaporated off i n vacuo . The residue was 2.7 g of oily crude 2-(2-aminophenylthio)benzyl chloride.
c) A solution of 1.4 g of dimethylamine in 3 ml of toluene was added to a solution of 1.15 g of 2-(2-aminophenylthio)benzyl chloride in 8 ml of toluene and the mixture was under external cooling by water and ice stirred for 1.5 h. After 16 h of standing, the precipitated dimethylamine hydrochloride was filtered off and the filtrate was evaporated, which yielded 1.1 g (92%) of the base as a brown oil. Neutralisation of 1.0 g of this base with 0.7 g oxalic acid dihydrate in 5 ml of heated ethanol yielded crystalline N,N-dimethyl-2-(2-aminophenylthio)benzylamine hydrogen oxalate, which after crystallisation from aqueous methanol melted at 182-186°C.
Example 32:
N,N-Dimethyl-2-(3-aminophenylthio)benzylamine.
7.15 g of crude 3-aminothiophenol (Zincke T., Müller J.: Ber. Dtsch. Chem. Ges. 46, 775 (1913)) was added to a solution of 8.9 g of potassium hydroxide in 80 ml of water and after 20 min of stirring at 50ºC also 14.1 g of 2-iodobenzoic acid and 0.2 g of copper as catalyst were added. The mixture was refluxed for 12 h. After adding of filtration charcoal, the mixture was filtered hot, and the partially cooled filtrate was acidified with diluted hydrochloric acid (1:1). The product was filtered by suction and crystallised from aqueous 2-propanol, which yielded 7.7 g of 2-(3-aminophenylthio)benzoic acid with melting point 160-163ºC.
3.66 g of absolutely dry 2-(3-aminophenylthio)benzoic acid was slowly added to a solution of 3.0 g of lithium aluminium hydride in 100 ml of tetrahydrofuran. The mixture was stirred at room temperature for 30 min, then refluxed for 3.5 h and processed in analogy to example 31/a, which yielded 3.1 g (89%) of crystalline 2-(3-aminophenylthio)benzyl alcohol, which after crystallisation from cyclohexane melted at 69-71°C.
Under cooling by ice and water 3.0 g of 2-(3-aminophenylthio)benzyl alcohol and 2.5 ml of thionylchloride were slowly mixed and the mixture was left standing at room temperature for 1 h. The excess thionylchloride evaporated off i n vacuo and the gained crude 2-(3-aminophenylthio)benzyl chloride hydrochloride was suspended in 20 ml of toluene. 4.5 ml of dimethylamine in 10 ml of toluene was added dropwise under stirring and under external cooling by ice and water. The mixture was left standing at room temperature for 2 h, and was then stirred for a further 2 h. The precipitated dimethylamine hydrochloride was filtered off by suction and the filtrate was evaporated i n vacuo . The residue was 3.0 g of the oily crude base, which was dissolved in a small amount of ethanol and neutralised with a solution of 2.8 g of the oxalic acid dihydrate in ethanol. On standing there precipitated 3.4 g of N,N-dimethyl-2-(3-aminophenylthio)benzylamine bis (hydrogen oxalate), which after crystallisation from methanol melted at 161-162ºC. Examp l e 33 :
N,N-Dimethyl-2-(4-aminophenylthio)benzylamine.
A mixture of 3.7 g of 2-(4-aminophenylthio)benzyl alcohol (Adlerova E. et. al: Collect. Czech. Chem. Commun. 33, 2666 (1968)) and 3.8 g of thionylchloride was processed in analogy to example 31/b. The procedure yielded 3.8 g of crude 2-(4-aminophenylthio)benzyl chloride hydrochloride.
A solution of 4.6 ml of dimethylamine in 10 ml of toluene was added dropwise under stirring to a suspension of 3.8 g of crude 2-(4-aminophenylthio)benzylchloride hydrochloride in 25 ml of toluene and the mixture was processed in analogy to example 31/c, which yielded 3.8 g of the oily base. This was dissolved in 10 ml of ethanol and neutralised with a solution of 3.7 g of oxalic acid dihydrate in 15 ml of ethanol. After 16 h of standing in cold, 3.2 g of N , N-dimethyl-2(4-aminophenylthio) benzylamine bis (hydrogen oxalate) crystallised, which after subsequent crystallisation from methanol melted at 164-166°C.
Example 34:
N,N-Dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)benzylamine.
9.4 g of hydrazinehydrate, 1.3 g of filtration charcoal and a solution of 9.4 g of ferric chloride hexahydrate in
15 ml of ethanol were added under stirring to a suspension of 26.0 g of 2-(4-(trifluoromethyl)-2-nitrophenylthio)benzoic acid (GB 925,539). The mixture was refluxed for 8.5 h. After
16 h of standing, ethanol evaporated off i n vacuo . A solution of 8.6 g of sodium hydroxide in 45 ml of water was added to the residue, the mixture was diluted with 115 ml of water and 1.3 g of filtration charcoal was added. After hea ting up to 90ºC, the mixture was filtered, the filtrate was cooled to 15ºC and under stirring was acidified with 22 g of acetic acid added dropwise. The precipitated product was filtered by suction, washed with water and dried, which yielded 19.9 g (81%) of 2-(2-amino(-4-(trifluoromethyl)phenylthio)benzoic acid, which after crystallisation from benzene melted at 188-190°C.
A solution of 37.6 g of 2-(2-amino(-4-(trifluoromethyl)phenylthio)benzoic acid in 350 ml of tetrahydrofuran was under stirring slowly added dropwise to a solution of 11.6 g of lithium aluminium hydride in 400 ml of tetrahydrofuran and the mixture was refluxed for 5 h. After cooling, the mixture was decomposed by slow adding dropwise of 4% solution of sodium hydroxide (47 ml) under external cooling. Then the mixture was stirred at room temperature for 1.5 h and the precipitated compound was filtered by suction and washed with ether. The filtrate was dried with magnesium sulfate and evaporated i n vacuo . The oily residue crystallised on standing and recrystallisation from cyclohexane yielded 21.8 g (61%) of 2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl alcohol with melting point 88-89ºC.
Vhen working with bigger charges, the reduction of the acid into alcohol is more suitably carried out in the following way: 323 g of 70% solution (toluen) of sodium dihydridobis(2-methoxyethoxo)aluminate (NaAlH2(OCH2CH2OCH3)2 in 300 ml of toluene was under stirring over a period of 75 min added dropwise to a solution of 125 g of 2-(2-amino-4- (trifluoromethyl)phenylthio)benzoic acid in 2 l of toluene and the mixture was stirred at room temperature for 4 h. Under external cooling and under stirring then it was decomposed by adding 2000 ml of 10% solution of sodium hydroxide. The toluene phase was separated, the aqueous phase was extracted with toluene and the toluene solutions were put together, dried with magnesium sulfate and after filtration the toluene evaporated off i n vacuo . The residue was 101 g (92%) of crude 2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl alcohol, which after crystallisation from cyclohexane melted at 88-89ºC and was identical to the product of the previous reduction.
59.8 g of 2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl alcohol was added under stirring at 5-8ºC over a period of 1 h to 29.2 ml of thionylchloride and the mixture was then stirred at room temperature for 2 h. The excess thionylchloride was absolutely evaporated off i n vacuo and the solid product was stirred up with cyclohexane and filtered by suction, which yielded 70.8 g (100%) of 2-(2-amino-4-(trifluoromethyl)phenylthio)benzyl chloride hydrochloride, which melted at 89-93°C.
A solution of 40 ml of dimethylamine in 40 ml of toluene was added dropwise under stirring and under external cooling to a suspension of 70.8 g of 2-(2-amino-4-(trifluoromethyl)phenylthio)b nzyl chloride in 100 ml of toluene. The mixture was stirred at room temperature for a further 1 h and was processed in analogy to example 31/c, which yielded 57.4 g (88%) of the oily crude base of N,N-dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)benzylamine, which after crystallisation melted at 58-59ºC. Its neutralisation with hydrogenchloride in a mixture of ethanol and ether yielded dihydrochloride, which crystallised from a mixture of ethanol and ethylacetate as monohydrate with melting point 180-183 . Neutralisation of the base with oxalic acid dihydrate in hot ethanol and its subsequent cooling yielded the oxalate, which after crystallisation from aqueous ethanol melted at 213-216°C.
Example 35:
N,N-Dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzylamine.
A solution of 40.0 g of 2-(2-amino-4-(trifluoromethyl) phenylthio)-5-fluorobenzoic acid (see example 22) in 200 ml of tetrahydrofuran was added dropwise under stirring over a period of 15 min to a solution of 13.2 g of lithium aluminium hydride in 100 ml of tetrahydrofuran and the mixture was refluxed under stirring for 4 h After 16 h of standing, the mixture decomposed by adding dropwise of 10% solution of sodium hydroxide (40 ml) under stirring. After 2.5 h of stirring, the precipitated compound was filtered off by suction, the filtrate was dried with potassium carbonate and was evaporated. The residue was 41 g of crude 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzylalcohol to which 40 ml of thionylchloride was added dropwise under cooling with ice and under stirring. The mixture was stirred at room temperature for 2 h and left standing for 16 h The excess thionylchloride evaporated off i n vacuo The residue was crude 2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzyl chloride hydrochloride. This was dissolved in 50 ml of benzene and a solution of 40 g of dimethylamine in 50 ml of benzene was added dropwise under stirring and under cooling. The mixture was stirred for 6 h and after 48 h of standing the precipitated dimethylamine hydrochloride was filtered off by suction. The filtrate was evaporated i n vacuo and the residue was chromatographed on a 150 g silica gel column. Elution with chloroform yielded 23.5 g of the oily base, which with hydrogen chloride in ether provided N,N-dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)-5-fluorobenzylamine hydrochloride hemihydrate This crystallised from a mixture of ethanol and ether as a crystalline modification melting at 181-184ºC, and from a mixture of 2-propanol and ethylacetate as another crystalline modification melting at 124-128°C.
Example 36:
N,N-Dimethyl-2-(4-amino-2-(trifluoromethyl)phenylthio)benzylamine 0.93 g of thiosalicylic acid and 1.6 g of 2-bromo-5-nitrobenzotrifluoride (Filler R., Novar H.: J. Org. Chem. 26, 2707 (1961)) were added to a solution of 0.48 g of sodium hydroxide in 25 ml of ethanol and the mixture was refluxed under stirring for 2.5 h. The ethanol evaporated off i n vacuo and the residue was dissolved in 25 ml of hot water. After cooling, the mixture was acidified under stirring with 2.5 ml of 3M hydrochloric acid. Filtration, washing with water and drying yielded 1.85 g (92%) of crude 2-(2-(trifluoromethyl)-4-nitrophenylthio)benzoic acid, which after crystallisation from aqueous methanol melted at 150-152ºC.
0.2 g of filtration charcoal and a solution of 0.1 g of ferric chloride hexahydrate in 5 ml of ethanol were added to a solution of 2.92 g 2-(2-(trifluoromethyl)-4-nitrophenylthio)benzoic acid in 15 ml of 96% ethanol. The mixture was refluxed for 7.5 h, the ethanol evaporated off i n vacuo and the residue was dissolved at 60ºC in 1M solution of sodium hydroxide. The solution was filtered using filtration charcoal, cooled and made slightly acid with acetic acid. The precipitate was filtered by suction, washed with water and dried, which yielded 1.26 g (47%) of 2-(4-amino-2-(trifluoromethyl)phenylthio)benzoic acid, which after crystallisation from a mixture of benzene and petroleum ether melted at 210-214°C.
A solution of 3.13 g of 2-(4-amino-2-(trifluoromethyl)phenylthio)benzoic acid in 30 ml of ether was under stirring slowly added dropwise to a solution of 1.52 g of lithium aluminium hydride in a mixture of 15 ml of ether and 15 ml of tetrahydrofuran and was refluxed for 1.5 h. After 16 h of standing, it decomposed by adding dropwise of 5% sodium hydroxide (6 ml) under stirring. The precipitated compound was filtered off by suction and the filtrate was evaporated i n vacuo . The residue was chromatographed on a 25 g silica gel column, which was eluted with benzene. The procedure yielded 2.7 g of 2-(4-amino-2-(trifluoromethyl)phenylthio) benzyl alcohol, which provided crystalline hydrochloride. This after crystallisation from a mixture of ethanol and ether melted at 160-162°C.
A solution of hydrogen chloride in ether (2 ml containing 5.5 mmol of hydrogen chloride) was added to a solution of 1.61 g of 2-(4-amino-2-(trifluoromethyl)phenylthio)benzyl alcohol in 5.5 ml of benzene and then 5.2 ml of thionylchloride was added dropwise under stirring over a period of 20 min. The reaction mixture was stirred at 24ºC for 1.5 h and the volatile constituents absolutely evaporated off i n vacuo . The residue was 1.7 g (100%) of 2-(4-amino-2-trifluoromethyl)phenylthio)benzyl chloride hydrochloride. which was dissolved in 15 ml of toluene and then a solution of dimethylamine (5x in excess) in 10 ml of toluene was added. The mixture was stirred at room temperature for 1 h and after 16 h of standing it was washed with water. The toluene solution was dried with potassium carbonate and was evaporated i n vacuo . The residue was 1.65 g of the base as an oily liquid. Neutralisation with oxalic acid dihydrate in ethanol hot followed by cooling yielded 1.53 g (88%) of N,N-dimethyl-2-(4-amino-2-(trifluoromethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from 2-propanol melted at 161-163.5°C.
Example 37:
N,N-Dimethyl-2-(3-(hydroxymethyl)phenylthio)benzylamine.
A mixture of 200 ml of dimethylformamide, 24 g of N,N-dimethyl-2-iodobenzamide (Cohen T. et. al: Tetrahedron Lett. 40, 3555 (1974)), 13.7 g of 3-mercaptobenzoic acid, 25 g of potassium carbonate and 1 g of copper was refluxed in the bath heated up to 150 C under stirring for 9 h. Dimethylformamide was distilled off i n vacuo , the residue was diluted with 200 ml of water, the resulting liquid was filtered and the filtrate was acidified with diluted hydrochloric acid (1:1). After 30 min of standing, the precipitate was filtered by suction, dissolved in hot ethanol, the insoluble fraction was filtered off and the filtrate was evaporated. The residue was chromatographed on a 150 g silica gel column, which was gradually eluted with benzene, chloroform, ethylacetate and ethanol. The ethylacetate eluates were evaporated, which yielded 12.4 g of homogenous oily N,N-dimethyl-2-(3-(carboxy phenylthio)benzamide.
12.4 g of oily N,N-dimethyl-2-(3-(carboxyphenylthio)benzamide in 100 ml of tetrahydrofuran, 4.8 g of sodium borohydride and 18.8 g of boron trifluoride etherate were processed in analogy to example 23/c, which yielded 9.8 g of oily base. Its neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2-(3-(hydroxymethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 111.5-113°C.
Example 38:
N,N-Dimethyl-2-(4-(hydroxymethyl)phenylthio)benzylamine.
3.98 g of crude N,N-dimethyl-2-mercaptobenzamide (Schindlbauer H.: Monatsh. Chem. 99, 1799 (1968)), 3.04 g potassium carbonate and 2.63 g of 4-chlorobenzaldehyde were added under stirring to 40 ml of dimethylformamide and the mixture was refluxed for 8 h up to the boiling point. It was diluted with 200 ml of water and extracted with a mixture of ether and ethylacetate. After filtration with filtration charcoal, the extract was dried with potassium carbonate and evaporated i n vacuo . 5.06 g (95%) of oily crude N,N-dimethyl-2-(4-formylphenylthio)benzamide was obtained, which was purified by chromatography on a silica gel column eluted with a mixture of ethylacetate and benzene. 2.27 g of sodium borohydride was added to a solution of 5.14 g of N,N-dimethyl-2-(4-formylphenylthio)benzamide in 30 ml of tetrahydrofuran and after 16 h of standing, 7.67 g of boron trifluoride etherate was added dropwise under stirring in nitrogen atmosphere at 17-24ºC over a period of 0.5 h. After 1 h of stirring at room temperature, the mixture was refluxed for 8 h. After 16 h of standing at room temperature, the mixture was diluted with 10 ml of tetrahydrofuran and then was acidified under stirring at 20-30ºC by adding dropwise of 60 ml of 6M HCl. The mixture was refluxed for a further 3.5 h. After cooling it was made alkaline with 10M solution of sodium hydroxide and extracted with chloroform. The extract was dried with potassium carbonate and evaporated i n vacuo . The residue was 4.42 g (90%) of the crude base, which was purified by crystallisation on a silica gel column gradually eluted with a mixture of chloroform and ethylacetate, chloroform and a mixture of methanol and chloroform saturated with ammonium at last. The residue of the chloroform eluate was an oily base whose neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2-(4-(hydroxymethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 96-98ºC.
Example 39:
N,N-Dimethyl-2-(4-(hydroxymethyl)phenylthio)benzylamine.
This is an alternative method of preparation of the compound according to example 38.
A mixture of 25 ml of dimethylformamide, 4.15 g of 4-mercaptobenzyl alcohol (Pelz et al.: Collect. Czech. Chem. Commun. 33, 1895 (1968)), 3.73 g 2-chlorobenzaldehyde, 3.95 g of potassium carbonate and 0.16 g of copper, as a catalyst, was refluxed under stirring at 98-109ºC for 8 h. After 16 h of standing, the insoluble fractions were filtered off and still on the filter were washed with ethanol. The filtrate was filtered with 1 g of filtration charcoal and evaporated i n vacuo . The residue was divided into 10 ml of water and 3 × 3 ml of ether. The ether phases were put together and were evaporated. The residue reacted with a solution of 10.4 g of potassium pyrosulfite in 26 ml of water. The precipitated "bisulfite adduct" was filtered off by suction, decomposed by 10 ml of 3M sulfuric acid and the free aldehyde was extracted with ether and chloroform. 4.42 g of oily 2-(4-(hydroxymethyl)phenylthio)benzaldehyde was obtained from the extract .
For its characterisation this aldehyde can be converted to crystalline 2,4-dinitrophenylhydrazon in a familiar way, which after crystallisation from a mixture of ethylacetate and ethanol melted at 216-222°C.
A mixture of 3.82 g of 2-(4-(hydroxymethyl)phenylthio)benzaldehyde, 8 ml of dimethyformamide (7.5 g) and 4.6 g of formic acid was refluxed under stirring for 7.5 h (bath temperature was 160-170ºC). After cooling, the mixture was acidified with an addition of 30 ml of 5% hydrochloric acid and the fractions which were not basic were removed by washing with ether. The aqueous solution was filtered with filtration charcoal, the filtrate was made alkaline with 15 ml of 5M solution of sodium hydroxide and the product was extracted with dichloroethane. The extract was dried with potassium carbonate and evaporated i n vacuo . The residue was 3.96 g (93%) of the oily base, whose neutralisation with oxalic acid dihydrate in ethanol yielded crystalline N,N-dimethyl-2-(4-(hydroxymethyl)phenylthio) benzylamine hydrogen oxalate, which after crystallisation from ethanol melted at 96-98ºC and was identical to the compound prepared as described in example 38. Example 40 :
N,N-Dimethyl-2-(2-(dimethylaminomethyl)phenylthio)benzylamine. a) 12.2 ml of thionylchloride in 20 ml of benzene was added dropwise under stirring to a solution of 4.11 g of diphenylsulfido-2-2 -dicarboxylic acid (Mayer F.: Ber. Dtsch. Chem. Ges. 43, 588 (1910)) in 40 ml of benzene and the mixture was refluxed for 4 h. After evaporating and cooling, the solid residue was mixed with a small amount of cyclohexane and isolated by filtration, which yielded 4.28 g (92%) of crystalline diphenylsulfide-2-2 -dicarboxylic acid dichloride, which after crystallisation from cyclohexane melted at 80-83°C.
b) A solution of 3.60 g of diphenylsulfide-2-2 -dicarboxylic acid dichloride in 40 ml of benzene was mixed with 17 ml of 40% aqueous dimethylamine over a period of 1 h under intensive stirring and external cooling with ice and water. The mixture was stirred at room temperature for 3 h and then was processed in analogy to example 1/c. The procedure yielded 3.52 g (93%) of oily N,N-dimethyl-2-(2-(dimethylaminocarbonyl) phenylthio) benzamide, which crystallised on standing (m.p. 95-102°C).
c) A reaction of oily N,N-dimethyl-2-(2-(dimethylaminocarbonyl) phenylthio) benzamide in 40 ml of tetrahydrofuran, 1.84 g of sodium borohydride and 6.4 g of boron trifluoride etherate, in analogy to example 1/d, yielded 3.08 g (96%) of the oily base. This was dissolved in 50 ml of ether and the solution was acidified with 8 ml of ether containing 1.0 g of hydrogen chloride. The precipitated crude N,N-dimethyl-2- (2-(dimethylaminomethyl)phenylthio)benzylamine dihydrochloride crystallised from 2-propanol containing a small amount of water as hemihydrate (m.p. 205-206°C). Example 41 :
N,N-Dimethyl-2-(3-(dimethylaminomethyl)phenylthio)benzylamine. a) 6.16 g of thiosalicylic acid, 9.92 g of 3-iodobenzoic acid and 0.66 g of copper were gradually added to a solution of 9.0 g of potassium hydroxide in 90 ml of water. The mixture was refluxed for 6 h under stirring. After cooling, pH of the mixture was adjusted up to 9 by addition of 5 ml of diluted hydrochloric acid (1:1). Filtration charcoal was added and the mixture was stirred at 80ºC for 10 min, then filtered hot and after cooling the filtrate was acidified with hydrochloric acid up to pH=1. After dilution with 200 ml of water, the fine precipitate was filtered off by suction, washed with water and dried to obtain 10.62 g (97%) of crude diphenylsulfide-2,3 -dicarboxylic acid, which after crystallisation from aqueous ethanol melted at 308-310ºC. b) A reaction of 9.68 g of crude diphenylsulfide-2,3 -dicarboxylic acid in 110 ml of benzene with 46 g of thionylchloride (4 h of refluxing) in analogy to example 40/a, yielded 9.83 g (90%) of crude diphenylsulfide-2,3 -dicarboxylic acid dichloride, which after crystallisation from cyclohexane melted at 112-113°C.
c) A reaction of 8.8 g of diphenylsulfide-2,3 -dicarboxylic acid dichloride in 160 ml of benzene with 36.6 g of 40% aqueous dimethylamine in analogy to example 40/b, yielded 9.28 g (100%) of oily N,N-dimethyl-2-(3-(dimethylaminocarbonyl) phenylthio) benzamide, which crystallised on standing and after recrystallisation from ethanol melted at 129-130ºC. d) In analogy to example 40/c, a reaction of 9.28 g of N,N-dimethyl-2-(3-(dimethylaminocarbonyl)phenylthio)benzamide with 4.88 g of sodium borohydride and 15.5 ml of boron trifluoride etherate in 80 ml of tetrahydrofuran yielded 6.33 g (75%) of the oily base. This was converted into N,N-dimethyl- 2-(3-(dimethylaminomethyl)-phenylthio)benzylamine dihydrochloride, which crystallised from 2-propanol as the solvate containing 1/2 of molecule of this solvent (m.p. 138-141 ).
Example 42:
N,N-Dimethyl-2-(4-(dimethylaminomethyl)phenylthio)benzylamine.
In analogy to example 41/a, a reaction of 4.5 g of potassium hydroxide in 45 ml of water, 3.08 g of thiosalicylic acid, 4.96 g of 4-iodobenzoic acid and 0.35 g of copper yielded 4.61 g (84%) of diphenylsulfide-2,4 -dicarboxylic acid, which after crystallisation from 50% aqueous ethanol melted at 234-236°C.
A reaction of 4.11 g of diphenylsulfide-2,4 -dicarboxylic acid in 50 ml of benzene with 13.2 g of thionylchloride (2.5 h of refluxing) in analogy to example 40/a, yielded 4.31 g (92%) of solid diphenylsulfide-2,4 -dicarboxylic acid dichloride, which after crystallisation from cyclohexane melted at 104-106°C.
A reaction of 4.3 g of diphenylsulfide-2,4 -dicarboxylic acid dichloride in 25 ml of benzene with 12.5 g of 40% aqueous dimethylamine in analogy to example 40/b, yielded 3.6 g (79%) of oily N,N-dimethyl-2-(4-(dimethylaminocarbonyl)phenylthio)benzamide.
In analogy to example 40/c, a reaction of 3.6 g of N,N-dimethyl-2-(4-(dimethylaminocarbonyl)phenylthio)benzamide with 1.8 g of sodium borohydride and 6.4 g of boron trifluoride etherate in 40 ml of tetrahydrofuran yielded 3.3 g (100%) of the oily base. This was converted to crystalline N,N-dimethyl-2-(4-(dimethylaminomethyl)phenylthio)benzylamine dihydrochloride, which crystallised from 2-propanol (m.p. 233-235°C). Example 43: N,N-Dimethyl-2-(2-carboxyphenylthio)benzylamine. a) A mixture of 30 ml of dimethylformamide, 7.7 g of thiosalicylic acid, 7.0 g of 2-chlorobenzaldehyde, 14 g of potassium carbonate and 1.2 g of copper (I) chloride was heated up to 100ºC under stirring in 5 min and then stirred at 110-120ºC for 6 h. After 16 h of standing, the mixture was diluted with 220 ml of water at 60ºC and the resulting cloudy liquid was filtered with 1 g of filtration charcoal. After cooling, the filtrate was acidified with 5M HCl under stirring. The precipitate was filtered off by suction, washed with water and dried, which yielded 9.11 g of crude 2-(2-carboxyphenylthio)benzaldehyde with melting point 167-169°C.
b) A mixture of 5.1 g of 2-(2-carboxyphenylthio)benzaldehyde, 7.3 g of dimethylformamide and 4.5 g of formic acid was refluxed under stirring up to 110-120ºC for 15 h. After cooling, the mixture was acidified with a solution of 6 ml of hydrochloric acid in 60 ml of water and the resulting liquid was washed with toluene. After filtration, the aqueous solution was evaporated to dryness i n vacuo . The residue was crystallised from a mixture of 2-propanol and ethylacetate, which yielded 6.0 g of crystalline N,N-dimethyl-2-(2-carboxyphenylthio)benzylamine hydrochloride monohydrate with melting point 96-99ºC.
Example 44:
N,N-Dimethyl-2-(4-carboxyphenylthio)benzylamine.
In analogy to example 43/a - except for the use of 4-mercaptobenzoic acid instead of thiosalicylic acid (the same amount), 10.6 g (82%) of 2-(4-carboxyphenylthio)benz aldehyde with melting point 178-181ºC, which crystallised from 80% aqueous ethanol or toluene.
In analogy to example 43/b, a reaction of 5.5 g of dimethylformamide, 3.88 g of 2-(4-carboxyphenylthio)benzaldehyde and 3.5 g of formic acid yielded 3.7 g (76%) of N,N-dimethyl-2-(4-carboxyphenylthio)benzylamine hydrochloride, which after crystallisation from a mixture of ethanol and ether melted at 209-211°C.
Example 45:
N,N-Dimethyl-2-(2-(ethoxycarbonyl)phenylthio)benzylamine.
6.4 g of N,N-dimethyl-2-(2-carboxyphenylthio)benzylamine hydrochloride monohydrate (see example 43) was dried at 80ºC i n vacuo . The anhydrous compound was dissolved in 160 ml of ethanol and the solution was saturated with anhydrous gaseous hydrogenchloride at room temperature for 6 h. After 2 h of refluxing, the solution was evaporated to dryness i n vacuo . The residue was added 50 ml of water and 15 ml of aqueous ammonium and the free base was extracted with chloroform. After drying with magnesium sulfate. the extract was evaporated i n vacuo , which yielded 5.0 g of the oily base. Its neutralisation with oxalic acid dihydrate in 2-propanol yielded N,N-dimethyl-2-(2-(ethoxycarbonyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from 2-propanol melted at 151-154°C.
Example 46:
N,N-Dimethyl-2-(3-(ethoxycarbonyl)phenylthio)benzylamine
A solution of 5.0 g of N,N-dimethyl-2-(3-carboxyphenylthio)benzylamine hydrochloride (Kmonicek V. et al.: Collect. Czech. Chem. Commun. 56, 2468 (1991)) in 200 ml of ethanol was saturated with anhydrous gaseous hydrogenchloride for 8 h. The mixture was refluxed for 4 h and processed in analogy to example 45, which yielded 4.35 g (69%) of N,N-dimethyl-2-(3-(ethoxycarbonyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from 2-propanol melted at 145-148°C.
Example 47:
N,N-Dimethyl-2-(4-(ethoxycarbonyl)phenylthio)benzylamine.
A solution of 3.24 g of N,N-dimethyl-2-(4-carboxyphenylthio)benzylamine hydrochloride (see example 44 ) was saturated with anhydrous gaseous hydrogen chloride at 70-75 C and under stirring for 3.5 h. The mixture was evaporated i n vacuo , the oily residue was added 12 ml of 1.2M NaHCO3 and the free base was extracted with ether. Drying and evaporating yielded 3.17 g of the oily base, which was neutralised with 1.26 g of oxalic acid dihydrate in 20 ml of ethanol at 60°C. After cooling and adding of 2 ml of ether, 3.48 g (86%) of N,N-dimethyl-2-(4-(ethoxycarbonyl)phenylthio)benzylamine hydrogen oxalate crystallised, which after recrystallisation from 98% ethanol melted at 172-173.5°C.
Example 48:
N,N-Dimethyl-2-(2-amino-4-(methoxycarbonyl)phenylthio)benzylamine.
A suspension of 5.0 g of N,N-dimethyl-2-(2-(amino-4-(trifluoromethyl)phenylthio)benzylamine oxalate (see example 34) was made alkaline with aqueous ammonium and the free base was extracted with chloroform. The extract was dried with magnesium sulfate and evaporated. The residue base was heated with 8 ml sulfuric acid for 3 h up to 100°C. After 16 h of standing, 40 ml of methanol was added and the mixture was refluxed for 9 h. After pouring on the ice, it was made alkaline with aqueous ammonium and the free base was extracted with ether. From the extract 3.5 g of the oily base of N,N-dimethyl-2-(2-amino-4-(methoxycarbonyl)phenylthio)benzylamine was obtained. Its reaction with a solution of hydrogen chloride in ether provided the monohydrochloride, which after crystallisation from a mixture of ethanol and 2-propanol melted at 200-205°C.
The following Table contains the values of serotonin re-uptake inhibition (5HT), noradrenaline re-uptake inhibition (NA) and paroxetine binding inhibition (PA) for some compounds prepared via the methods described in Examples hereinbefore in relation to the known compounds mentioned in the Background of the Invention hereinbefore.
Figure imgf000058_0001
Figure imgf000059_0001
It is apparent that e.g. in case of the compound prepared via procedure according to example 34, that, in regard to the data concerning paroxetine binding inhibition in membrane fraction of rat brain, the corresponding compound according to the invention shows a good penetration through the blood-brain barrier.
Further, it is apparent that this compound does not show the affinity towards alpha-adrenergic muskarine and benzodiazepine receptors, so that it does not inhibit binding of [3H] preparatives (prazosin, quinuclidinnyl benzilate and flunitrazepam) onto the receptors in the corresponding brain structures. This suggests a low probability of occurrence of some cardiovascular anticholinergic and central neurotropic effects of the benzodiazepine type compounds.
Derivatives of general formula (I) and their pharmaceutically acceptable salts are suitable for the production of pharmaceutical medicaments designed primarily for treatment and prophylaxis of depression, anxious states, migraine and other diseases of the central nervous system, in which the brain serotonin plays an important role.

Claims

C L A I M S
1. Derivatives of N,N-dimethyl-2-(arylthio)benzylamine of general formula (1)
Figure imgf000060_0001
or their salts with inorganic or organic acids which are pharmacodynamically harmless, wherein at least one of the substituents R 1 and R2 in the
A ring in the 4 and 5 positions is a hydrogen atom, while the other substituent R1 or R2 in the A ring is either a fluorine or chlorine atom, and wherein two to three of the substituents R3 to R6 in the B ring in the 2 to 5 positions are hydrogen atoms, while if the both substituents in the A ring are hydrogen atoms, the substituents in the B ring are either three hydrogen atoms and one of the substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms, one fluorine or chlorine atom and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylmethylthio, or nitro, or amino, or methoxy, or hydroxyl group or are two hydrogen atoms and each of the remaining two substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl
- except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms and two fluorine or chlorine atoms; or in case that one substituent in the A ring is either a fluorine or chlorine atom, the substituents in the B ring are either two hydrogen atoms and two fluorine or chlorine atoms. or two hydrogen atoms and one fluorine or chlorine atom and one of the subsituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or three hydrogen atoms and one fluorine or chlorine atom, or one of the substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl
- except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group.
2. N,N-Dimethyl-2-(2-amino-4-(trifluoromethyl)phenylthio)benzylamine and its salts with pharmacodynamically harmless inorganic or organic acids.
3. N,N-Dimethyl-5-chloro-2-(4-methylthio)phenylthio)benzylamine and its salts with pharmacodynamically harmless inorganic or organic acids.
4. N,N-Dimethyl-5-fluoro-2-(4-methylthio)phenylthio)benzylamine and its salts with pharmacodynamically harmless inorganic or organic acids.
5. N,N-Dimethyl-2-(2,4-dichlorophenylthio)-5-fluorobenzylamine and its salts with pharmacodynamically harmless inorganic or organic acids.
6. N,N-Dimethyl-2-(3,4-dichlorophenylthio)-5-fluorobenzylamine and its salts with pharmacodynamically harmless inorganic or organic acids.
7. N,N-Dimethyl-2-(2-amino-4-(trifluoromethyl)-5-fluoro¬phenylthio)benzylamine and its salts with pharmacodynami cally harmless inorganic or organic acids.
8. Pharmaceutical medicament, designed primarily for treatment or prophylaxis of depressive states, characterized in that, that as an effective component contains a derivative of the compound of formula (I) according to claim 1, in the mixture with additives for pharmaceutical medicaments.
9. Methods of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is characteristic, that N,N-dimethylbenzamides of formula (II)
Figure imgf000063_0001
wherein the substituents R1 to R6 are identical to those in the formula (I), and besides that, in the B ring there can also be formyl or dimethylaminocarbonyl, are reduced by diborane generated in situ by the reaction of sodium borohydride with boron trifluoride etherate.
10. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the substituents R3 to R6 is an hydroxymethyl or dimethylaminomethyl group, by reduction of the compounds with formula (II) according to claim 9, wherein one of the substituents R3 to R6 in the B ring is an formyl, dimethylaminocarbonyl or carboxyl group, for which it is characteristic that an formyl, dimethylaminocarbonyl or carboxyl group is reduced at the same time.
11. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is characteristic that benzylhalogenides of formula (III)
Figure imgf000063_0002
wherein the substituents R1 to R6 are identical to those in formula (I) and Hal is a chlorine or bromine atom, react with dimethylamine in an organic solvent at room temperature
12. Method according to claim 11, characterized by that that the reaction is carried out in toluene.
13. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is characteristic that benzaldehydes of formula (IV) ,
Figure imgf000064_0001
wherein the substituents R1 to R6 are identical to those in formula (I), react with dimethylformamide and formic acid at 110 to 120°C.
14. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the substituents R3 to R6 in the B ring is an methylsulfinyl group, for which it is characteristic that the corresponding methylthioderivative is oxidised by hydrogen peroxide in acetic acid at room temperature.
15. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the substituents R3 to R6 is ethoxycarbonyl, for which it is characteristic that the corresponding carboxyderivative is esterified by ethanol.
16. Method according to claim 15, for which it is characteristic that esterification is carried out in the presence of hydrogen chloride.
17. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the substituents R3 to R6 is an methoxycarbonyl group, for which it is characteristic that the corresponding trifluoro methylderivative is hydrolyse with sulfuric acid at 90 to 110ºC and subsequently esterified by methanol.
18. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the substituents R3 to R6 is an hydroxyl group, for which it is characteristic that the derivative of the compound of formula I, wherein one of the substituents R3 to R6 is an methoxyl group, demethylates.
19. Method according to claim 18, for which demethylation by heating with hydrobromic acid is characteristic.
20. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is characteristic that the bases of derivatives of the compound of formula (I) are neutralised with pharmacodynamically harmless inorganic or organic acids.
21. Use of derivatives of the compound of formula (I) according to claim 1, in production of pharmaceutical medicaments designed particularly for treatment and prophylaxis of depressions, anxious states, migraine and other diseases of the central nervous system, in which brain serotonin plays an important role.
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