CS272922B1 - Method of 2-(benzyl-substituted) amino-nitrobenzene preparation - Google Patents

Abstract

The invention concerns the method of preparation of 2-(benzyl-substituted)-amino-nitrobenzene of general formula I, where R represents an atom of hydrogen, halogen, the nitro group, one methoxyl group or two methoxyl groups, whereas these compounds are important intermediate products, for example in the synthesis of benzimidazole derivatives blocking periphery H1-receptors and used for the therapy of allergy illnesses, as shown by the case of astemizole (Hismanal<R> Janssen).The new method of preparing substances of formula I is based on the fact that 2-nitraniline is allowed to react with benzylhalogenide of general formula VI, where Hal represents the atom of chlorine or bromine and R has the same meaning as in formula I. The reaction occurs in the heterogeneous environment of the solution system, whose first phase is formed by benzene, toluene or xylene and the second by free aqueous 45 to 50 % sodium or potassium hydroxide; whereas for 1 mol of 2-nitraniline 4.5 to 5.0 mol sodium or potassium hydroxide is used, quaternary ammonium salt is added as a catalyst of the phase transformation. The reaction mixture is heated while mixing for 10 - 12 hours to the temperature of backflow and, after the reaction stops, the solvent is distilled from the separated organic part and the substance is thus isolated. Triethylbenzyl ammonium chloride can be used as a catalyst. Yields fluctuate above 70 % of the required product of general formula I.<IMAGE>

Description

(57) The invention relates to a process for the preparation of 2- (substituted-benzyl) -amino-nitrobenzanes of the general formula I, wherein R represents a hydrogen atom; halogen, nitro, 'methoxy group or two methoxy groups, with the ^one that these compounds are important intermediates e.g. in the synthesis of benzimidazole derivatives blocking peripheral Hi-receptors, and used for the therapy of allergic diseases, as evidenced by Example aste MIZOLA (Hismanal ^R Danssen).

A novel preparation of the compounds of formula I consists in reacting 2-nitraniline with a benzyl halide of formula VI; wherein Hal represents a chlorine or bromine atom and R has the same meaning as in formula I; the reaction is carried out in a heterogeneous environment of a solvent system, one of which consists of benzene / toluene or xylene and the other aqueous 45 to 50% ni sodium or potassium hydroxide, with 4/5 to 5/0 mol of sodium hydroxide per mole of 2-nitraniline or potassium, quaternary ammonium salt is added as a phase transfer catalyst to the reaction mixture, and the reaction mixture is heated to a temperature of 10-12 hours with efficient stirring.

- reflux and after the reaction, or from the separated organic solvents in a proportion _w poorly soluble in water is distilled off and the product thus Isola "is. As a catalyst, e.g.

«Trlethylbenzylammonium chloride. The yields are above 70% of the desired product of formula (I).

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CS 272 922 Bl

The invention 3e relates to a process for the preparation of 2- (subst, benzyl) amino nitrobenzenes of the formula I

wherein R represents a hydrogen atom; halogen? nitrogroup? methoxy or two methoxy groups. These compounds are important intermediates, inter alia, in the synthesis of various benzimidazole derivatives; blocking peripheral H 2 -receptors and used to treat allergic diseases? as evidenced by the example of 1- (4-fluorobenzyl) -2- [1- (4-methoxyphenyl) -4-piperidyl] amino] benzimidazole of formula XI

O (F.AN33ens was asleep; O.Msd.Chera. 28; 1934 (1985) 7 Hismanal preparation from Oanssen)? in which one variant of ss synthesis is based on 2- (4-fluorobenzylamino) nitrobenzene (I; R a b 4-F).

The compounds of formula (I) have so far been largely prepared by two steps: The first method (method A) consisted of long-term heating at 80 to 100 ° C or heating at 150 to 160 ° C of a mixture of 1 mole of 2-chloronitrobenzzene III with 2-2.5 moles of the appropriately substituted benzylamine IV are either directly? or in the high boiling point of the organic reagent? in terms of reaction

According to the second method (method B), 2-nitraniline V? whose 2 to 2.5 moles were heated for a long time either directly; or with the addition of organic bases (e.g. pyridine) of its alkali carbonates with 1 mol of substituted benzyl halide VX

in formula VI, Hal represents a chlorine atom or a bromine atom. In both methods, the desired products of formula (I) were mostly isolated by diluting the reaction mixture with water and then removing the precipitated substances with suction? or shaken into an organic solvent and this was then evaporated.

In both cases, raw products were heavily contaminated with the starting component? which was in molar excess and therefore had to be purified by multiple crystallizations. These methods have been described several times in the literature (see, for example, FEKingf RMAchason? O.Chem.Soc. 1946; 681; MSGibson? O.Chem.Soc * 1956; 1076 / BWAshton? H.Suschitzky? O.Chem.Soc. 1957;

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CS 272 922 Bl

4559: O.jerkosch? Mh.Chem. 92; 1107 (1261); H.Greengreen, 'G.Zollner? Helv.cbim.Acta 49, ’

913 (1956); O.Machin et al? 0.Chem.Soc.Perkin i; 1975 (394) and others) have various disadvantages. With the A ee method, wheel yields reach 60%? but does it have to be based on the corresponding benzylamines IV? whose preparation usually requires multistage synthesis. For this more valuable reactant, 2 to 25 mol per 1 mol of 2-chloronitrobenzene III is used; on a technical scale, therefore, it is necessary for economic reasons to introduce its regeneration from the hydrochloride (IV) ^7, which however requires further operations, - The disadvantage of method Θ is, inter alia, repeated crystallization of crude products I to separate them from excess 2-nitraniline? which greatly reduces yields ⁷ which is typically only around 30 to 50%.

Now we find out? that the compounds of the formula I can be relatively easily and in high yields (70 to 80%) obtained by N-alkylation of 2-nitraniline with the corresponding benzyl halides of the formula VI? using a heterogeneous solvent system in the presence of concentrated alkaline lyes and addition of quaternary ammonium salt phase transfer catalysts. Similar procedures have been previously described and successfully applied for N-alkylations of indole derivatives (e.g., A. Barco S.Benetti G. G. Pollini Syntheses 1976; 124). N-acylanilines (e.g. R.Brehme® Syntheses 1975-114) and the like.

A new approach to the preparation of the compounds of Formula I is that? 1 mol

2-nitraniline in a non-polar solvent such as benzene, toluene or xylene; add a 45-50% aqueous solution of 4.5-5 moles of sodium or potassium hydroxide? 0.1 to 15 mol of a suitable quaternary aramonium salt and only a small excess (10 to 10 mol) of the corresponding benzyl halide VI and reaction reaction are heated to reflux for 10 to 12 hours with efficient stirring. a given boiling point of an azeotropic mixture of water with an appropriate solvent. After cooling and suepensa diluted with water to dissolve the mineral salts? the organic portion was separated and the solvent was distilled off. The residue is mixed with a suitable solvent? preferably with ethanol or isopropanol? optionally mixed with petroleum ether or hexane, depending on the solubility of the resulting material, and the precipitated product is suctioned off after cooling,

Oako phase transfer catalysts can be used in various commercial preparations of suitable quaternary ammonium salts such as N-methylpyridinium chloride? N-acatyl-N; N? N-trimethylammonium bromide? triethylbenzylammonium chloride, etc. The highest yields are generally obtained when triethylbenzylammonium chloride (TEBA) is used.

Methods of carrying out the reaction? described in the examples below? I am just examining the invention and cannot exhaust all of its possibilities.

Example 1

13.8 g of 2-nitraniline are dissolved in 65 ml of benzene. is a solution of 33 g of potassium hydroxide in 25 ml of water added? 2-5 g of cetyltrimethylammonium bromide (CTA8) is added and, after stirring, then 22 g of 4-chlorobenzyl bromide and the mixture is stirred and heated to reflux for 5.5 h. Thereafter, 1.3 g of CTAB are added and stirring and heating is continued for 6 h. The cooled suspension is diluted with 60 ml of water. the upper organic fraction is separated? It is filtered and the solvent is distilled off in vacuo. The residue is stirred with a mixture of 20 ml of ethanol and 50 ml of petroleum ether; after cooling to 0-5 ° C, the product is filtered off with suction and washed with 30 ml of the same mixture. After drying, 18.9 g (72%) of 2- (4-chlorobenzylamino) -nitrobenzene (1H-R-4-01) are obtained. at 105 to 108 ° C;

Example 2

35.0 g of 2-nitraniline are dissolved in 150 ml of toluene. a solution of 51 g of sodium hydroxide in 51 ml of water and 5 - 4 g of benzyltributylammonium bromide (BTB) is added and, after stirring, 42 - 5 g of 4-methoxybenzyl chloride are added and then the mixture is refluxed for 12 h; after which 3 hours of STB is added after heating for 3 hours, 120 ml of water are added to the cooled 3Θ mixture? the separated toluene layer was filtered and the solvent was evaporated in vacuo. To the solution in hot isopropanol was added hexane to turbidity and the mixture was allowed to stand at 0-5 ° C for 10 h. The precipitated product is suction / washed with ethanol-hexane 1: 2 and dried. There was thus obtained 50/0 g (76/3%) of 2- (4-methoxybenzylamino) nitroanzane / melting at 92-95 ° C (1/1 R 4 -OCH 8).

Example 3 ’

To a solution of 35.0 g of 2-nitraniline in 150 ml of toluene is added a solution of 51 g of sodium hydroxide in 51 ml of water / 4 g of triethylbenzylammonium chloride (TEBa) is added and 33/5 ml of 4-fluorobenzyl bromide is added. exothermic reaction. The mixture is heated to reflux with vigorous stirring and maintained at this temperature for 6 h. Thereafter, 2 g of TEBA are added and heating and stirring is continued for a further 6 h. After cooling below 50 ° C, 100 ml of water is added / stirred 10 min. The upper toluene fraction was separated / filtered and the toluene was evaporated in vacuo. A mixture of 22 ml of ethanol and 50 ml of hexane was added to the oily residue and cooled to 0-5 ° C for 10 hours. ml of a mixture of 10 ml of ethanol and 35 ml of hexane and dried. 48/6 g (78%) of 2- (4-fluorobenzylamino) -nitrobansane (if R-4-F) / melting at 74 to T7 ° C are obtained.

Example 4

A solution of 27/5 g of 2-nitraniline in 135 ml of xylene is mixed with a solution of 40 g of sodium hydroxide in 40 ml of water / 3β 5/2 g of catylpyridinium chloride monohydrate (CPC) is added / after stirring 25/0 ml of benzyl chloride are added. with good stirring, heated to reflux for 12 h by adding 2/6 g of PCC after 6 h. After heating, the mixture was cooled; diluted with stirring with 130 ml of water / the organic layer was separated and filtered. The xylene is distilled off from the filtrate in vacuo; the residue was dissolved in 60 ml of ethanol while hot, and petroleum ether was added until turbid. After standing at 0 to 5 ° C for 10 hours, the product is filtered off with suction / washing with a 1: 2 mixture of ethanol and hexane and evaporated. There was thus obtained 34/7 g (78%) of 2-benzylamino-nitro-benzene; m.p. at 70-73 ° C (if R and H).

Example 5.

To a solution of 13/8 g of 2-nitraniline in 65 ml of toluene is added a solution of 20 g of sodium hydroxide in 20 ml of water / 1/6 g of TEBA is added and after stirring, 19/2 g of 3,4-dimethoxybenzyl chloride are added. to 5 [deg.] to the reflux temperature / an additional 0.8 g of TEEA is added and the reaction is completed by heating for 3 h. 70 ml of water are added to cool the suspension / after stirring the toluene is separated / filtered and the solvent is distilled from the filtrate in vacuo. The residue was crystallized from ethanol with the addition of petroleum ether. Yield 23/0 g (80%) of 2- (3/4-dimethoxy-benzylamino) nitrobenzene (I; R »3 / 4- (0CH _{3) 2)} J melting from 111 to 114 ° C.

Example 6

To a solution of 27.6 g of 2-nitraniline in 125 ml of toluene is added 80 g of 50% aqueous sodium hydroxide solution / 3/2 g of TENA is added, after stirring 47 g of 4-nitrobenzyl bromide and the reaction mixture is refluxed for 12 h. with that; after 6 h, an additional 1 / sg of TEBA was added. The mixture was then cooled / diluted with 120 ml of water; The toluene was collected by filtration and the toluene was evaporated in vacuo. Crystallization of the residue from isopropanol with addition of hexane gave e. 43; 1 g of (2- (4-nitrobenzylamino) nitrobenzene (1; R, 4-NO2 ₎ ) (m.p. 132-134 ° C).

CS 272 922 B1 reiterates the invention

Claims (2)

A process for the preparation of 2- (substituted-benzyl) amino-nitrobenzenes of the general formula I HO R wherein R is hydrogen, ^- halogen, nitroskuplnu, methoxy group or two methoxy groups, the reaction of 2-nltranllinu with a benzyl halide of formula VI, VI in which Hal denotes a chlorine or bromine atom and R has the same meaning as in formula 1 (characterized in that the reaction is carried out in a heterogeneous medium of a solvent system whose one phase consists of benzene, toluene or xylene and the other aqueous 45 to 50% sodium or potassium hydroxide (with 4.5 to 5.0 mol of sodium or potassium hydroxide per 1 mol of 2-nitraniline), quaternary ammonium salt is added to the reaction mixture as phase transfer catalyst, and the reaction mixture is heated with efficient stirring 10-12 h at reflux temperature and after the reaction has been completed, the solvent is distilled off from the separated organic fraction * 2. The method of item 1; characterized in that triethylbenzylammonium chloride is used as the catalyst.