DD121927B1 - PROCESS FOR THE TECHNICAL PREPARATION OF 2,4'-DICHLOR-4-NITRO-DIPHENYLAETHERE - Google Patents

Abstract

The invention relates to a process for the preparation of 2,4'-dichloro-4-nitrodiphenyl ether (I), an H H

Description

Vl

30 area%

50 area%

4 area%

VII- 20 Area%

VI (mp 73-74 ° C) and VII (mp 71-72 ° C) were available as reference substances. An over-chlorination does not occur, but it can in principle still isolate the valuable compounds I and III from the mother liquor.

Especially at the end of the reaction, the methanol is oxidized by the excess of chlorine. This is proved by the above-mentioned gas chromatographic results as well as the HCI content of the mother liquor, which is sometimes significantly above the theory. In the directly excreted in the chlorination I can be gas chromatography, characteristically no VII (as in the mother liquor) detect, but only about 5 to 10% III. This is largely removed by washing with methanol. The washing methanol can then be used again in the chlorination. Further purification can be carried out by recrystallization from benzene or chlorobenzene and methanol. I is thus obtained with a residual content of about 1.5% of III. If the diphenyl ether I contaminated with III is used in the rafoxanide (II) synthesis, the resulting II active compound may contain some VIII. By a special purification on the dimethylformamide adduct VIII can be easily separated from II with little loss.

Execution example

A solution of 99 g of phenol in 300 ml of dimethylformamide is added under stirring with 42 g of NaOH as a 40 to 50% aqueous solution so that the temperature does not exceed 40 ⁰ C. To complete the phenolate formation is stirred for a further 30min, the mixture can slowly assume room temperature. Then, with further stirring, a solution of 192 g of 3,4-dichloronitrobenzeri (pure and isomer-free according to gas chromatogram) in 400 ml of dimethylformamide added. The mixture is heated slowly to 150 to 152X, wherein from 120 ⁰ C, the reaction water formed is azeotropically overdriven with DMF (about 100 to 120 ml). The mixture is then stirred for 1 to 2 h at 150 to 152 ° C. The mixture is filtered off at 80 to 100 ⁰ C of precipitated NaCl and this washed with a little dimethylformamide (amount of NaCl about 60g). The filtrate is concentrated in vacuo until almost all the solvent is removed. The residue is stirred with 0.5% sodium hydroxide solution, whereby the 2-chloro-4-nitrophenylether deposits as a brownish, relatively light oil. The aqueous layer is separated, taken up in a water-immiscible solvent, dried and distilled the latter again.

Yield: 230 to 240 g (92 to 96% of theory of a pale, brownish-yellow oil which slowly, not completely solidifies at room temperature.) It is only in the literature (US-PS 1881074, C. 1933.1.126) as an oil described. crude mp. after the pressing on clay 40 to 41 ⁰ C. In a mixture of 250 g of this product with 11 methanol is passed, first without cooling, a rapid stream of chlorine in. If about 50 ⁰ C is reached by the exothermic reaction After cooling for 15 to 20 minutes, I precipitates in the form of almost white crystals, then the chlorine stream is switched off at intervals of about 10 minutes, stirred for 2 minutes and then maintained in the quiescent time (3 to 4 minutes) until There is enough clear liquid on the mixture to be pipetted from there to a sample of 1 ml and it is immediately poured with shaking into a solution of 0.3 to 0.5 g KJ in 25 ml of water and then added with 0.1 η Sodium thiosulfate solution against starch t The titration is complete when 2.0 to 3.0 ml of thiosulphate solution are consumed. In the same liquid hydrochloric acid can be titrated by titration with 0.1 η lye against phenolphthalein or methyl red. The consumption must be at least the theoretical amount of HCl at the end of chlorination, but it can also be significantly higher. Of course, in small batches, the control of the chlorine uptake can be done by weighing.

If the chlorine uptake is complete, it is stirred for another 40 to 60 min at 50 ⁰ C after. The said thiosulphate consumption drops to about 0.3 ml. Thereafter, another acidimetric control is performed. At high chlorine content of the solution, the acidimetric titration is virtually impracticable because the indicator is always bleached.

It is then cooled to room temperature, allowed to stand for a few hours and filtered off with suction. After thorough squeezing is suspended in 375 ml of methanol, filtered off with suction and washed on the filter with 125 ml of methanol. The wash methanol, made up with pure methanol, is used instead of the fresh methanol for the next batch. The product is dried in air.

Yield: 190 to 200 g (when using the washing methanol) almost white, crystalline I. Mp. 103 to 107 ° C. The substance contains according to gas chromatogram about 5 area% III. For further purification, 200 g of the product are dissolved hot in 100 ml benzene or chlorobenzene. Then add 240 ml of methanol boiling and slowly cooled to room temperature. It is then filtered off, washed on the suction filter twice with 80 ml of methanol and dried again in air. Yield: 175 g of white crystals of I, mp 108 to 109 ⁰ C. The substance according to gas chromatogram still 1.5 area% III. In the further processing of the more or less III containing inventive products (I) to the rafoxanide active ingredient (II), a content of the crude II to VIII (mp 162 to 163 ° C) can not be completely excluded. However, as Table 1 shows, VIII of II is relatively smooth to separate in the following purification over the dimethylformamide adduct. 10 g of the respective Il / VIII mixture is dissolved in 10 ml of dimethylformamide with shaking. It slowly adds 30 ml of methanol, the temperature is maintained at 50 to 60 ⁰ C, then cooled to 10 to 2O ⁰ C, allowed to stand overnight at this temperature and aspirated off sharply. The moist adduct (mp in dry state about 90 ⁰ C) is well suspended in 30 ml of methanol. While shaking, 3 ml of concentrated hydrochloric acid are added dropwise, the mixture is heated to boiling with further shaking and finally boiled for 5 minutes (conversion of the crystals into blocks). Now it is cooled to room temperature, filtered off with suction after 1 to 2 hours, washed with 3 ml of methanol and then three times with 20 ml of water and dried in air. The results with different defined Il / VIII mixtures are listed in Table 1.

Table 1:

Purification of defined Il / VIII mixtures via the dimethylformamide adduct

Yield in the purification of lOgdesll / VIII mixture

mixture

In the sulfuric acid apparatus after cleaning *

0.0 0.5 2.5 5.0 10.0

9.40 g 9.40 g 9.20 g 9.05 g 8.80 g 175 to 177 ⁰ C * 175 to 177 ⁰ C 175 to 176.5 ⁰ C 174bis176 ° C from 173 to 175 ⁰ C

Melting of the used Il before cleaning 175 to 177 ° C

11131} ψ

^ -Ν \ - ο

Cl

I: X = Cl, Y = H III: X = Y = H VI: X = Y = Cl VII: X = H, Y = Cl

(A)

(A) (A) (A)

/ Лео - _Ш - / ~ \ -о

Cl

II: X = Cl VIII: X = H

Claims (1)

Process for the technical preparation of 2,4'-dichloro-4-nitrodiphenyl ether by halogenating a crude 2-chloro-4-nitrodiphenyl ether prepared from 3,4-dichloronitrobenzene, alkali phenolate and a polar solvent, preferably dimethylformamide, characterized in that in the 2 ' Chloro-4-nitrodiphenylether after dilution with methanol at 40 to 6O ⁰ C chlorine is introduced, the control of the reaction by the incoming crystallization of the 2,4'-dichloro-4-nitrodiphenylethers, the iodometric determination of the excess chlorine and the acidimetric titration of the hydrochloric acid formed takes place. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of 2,4'-dichloro-4-nitrodiphenyl ether (I), which is used as an intermediate for the production of the control of liver flukes in veterinary medicine rafoxanide active ingredient (II) and for the synthesis of dyes and Pesticides is significant. Characteristic of the known technical solutions It is known that is obtained from 3,4-dichloronitrobenzene (IV) and the potassium salt of malodorous p-chlorophenol at temperatures up to 170 ⁰ CI (VCBarry, JCBeiton, MLConalty, LO.'Rourke and D.Twomey, Proc. Roy. Irish Acad. Sect. B.53, 61-83 [1960]; C. 1951,1,1437; AA Patsche, "DR Hoff and H. Mrozik, South African Patent 6,703,354, December 12, 1968; CA. 72, 31468z [1968]. ), whereby the use of polar solvents is advantageous (eg DD-PS 111069). However, p-chlorophenol is not present in sufficient quantity, and in-house recovery necessitates the technically relatively difficult distillative separation of the mixture of o- and p-chlorophenol resulting from the monochlorination of phenol (HE Fierz-David and L. Blangey, Basic Operations of Color Chemistry, Vienna, p. 140). Object of the invention The invention is intended to eliminate the abovementioned deficiencies in the industrial recovery of 2,4'-dichloro-4-nitrodiphenyl ether by the use of readily available and less odor-inhibiting starting material. Explanation of the essence of the invention task The invention has for its object to provide a technical method for the production of 2,4'-dichloro-4-nitrodiphenyl ether, which does not require p-chlorophenol as the starting material, odor nuisance largely avoids and requires no elaborate distillations. Features of the invention According to the invention, this object is achieved in that the known methods (eg DD-PS 111069) by means of 3,4-dichloronitrobenzene (IV) and alkali phenolate (V) in a polar solvent, preferably dimethylformamide, accessible 2-chloro-4-nitrodiphenylether ( III) in methanol by introducing chlorine to 40 to 6O ⁰ C crystalline, relatively pure 2,4'-dichloro-4-nitrodiphenylether (I) in good yield. The control of the reaction is possible even with large technical batches by the time of crystallization, the iodometric determination of the excess chlorine and the acidimetric titration of the HCI formed. The well-known use of polar solvents in the preparation of 2-chloro-4-nitrodiphenylethers (III) is essential, since the other melt processes give a dark, tar-containing III, which only after extensive vacuum distillation for use in the Ill chlorination (I. Extraction) is sufficiently pure. If this purification is omitted, the yields of crystalline I in the chlorination decrease sharply. It has proved to be particularly favorable if the alkali metal phenolate is produced before addition in the solvent from alkali metal carbonate, such as sodium or potassium carbonate, and phenol. The partial decomposition of about the preferred dimethylformamide when using alkali metal hydroxide to formate and dimethylamine, associated with the formation of 2-chloro-4-mitrodimethylanilin, can thus be almost completely avoided. The gas chromatographic examination of the mother liquors after completion of the elimination of I during the chlorination gave the following average result (total content of diphenyl ethers in area% equal to 100):