RU2792890C2 - Method for production of 2-chlor-4-nitrophenol - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, specifically to a method for the production of 2-chlor-4-nitrophenol used for the treatment of fungal skin lesions. According to the proposed method, 2-chlor-4-nitrophenol is obtained by chlorination of 4-nitrophenol, while t-BuOCl is used as a chlorinating agent, the reaction is carried out in the presence of catalysts selected from FeBr₂, Fe(C₅H₅)₂, FeCl₂⋅4H₂O, FeCl₃⋅6H₂O, at 20°C for 0.5-5 h, at a molar ratio of [catalyst] : [4-nitrophenol] : [t-BuOCl] = 0.1-1:100:100-120.

EFFECT: proposed method allows for simplification of a technology and reduction in cost price of the production of 2-chlor-4-nitrophenol, as well as reduction in amount of waste.

1 cl, 1 tbl, 10 ex

Description

The present invention relates to the field of organic chemistry, in particular, to a method for producing 2-chloro-4-nitrophenol (1) used as the active ingredient of antifungal drugs "Nitrofungin" [Directory of medicines. Mashkovsky M.D. Medicines. M., 1996, - T. 2, - S. 435]. Nitrofungin is effective for the treatment of skin diseases caused by fungi and yeasts, as well as fungal diseases of the external auditory canal. [Medications approved for use in the USSR. M." Medicine, 1979, p. 162; Chervyakov et al. Medicines in veterinary science. M. Kolos, 1980, p. 347].

The drug "Nitrofungin" is produced in the Czech Republic (TEVA Czech Industries, s.r.o. (Czech Republic)). There is no production of 2-chloro-4-nitrophenol (1) in Russia.

A known method for producing 2-chloro-4-nitrophenol (1) from 2-chlorophenol. The method is essentially two-stage. In the first stage, an alkaline solution of 2-chlorophenol and sodium nitrite is treated with acid. The resulting 4-nitroso-2-chlorophenol is oxidized with nitric acid [UK patent No. 2011386, publ. July 11, 1979]. The yield of 2-chloro-4-nitrophenol by this method is low and amounts to ~50%.

Disadvantages of the method

1. Nitrosation of 2-chlorophenol in an alkaline medium promotes the formation of highly toxic dioxins;

2. Fire and explosion hazard of the method, because the oxidation of 4-nitroso-2-chlorophenol is carried out under pressure;

3. Two-stage process;

4. Low yield of the target product;

5. The use of 2-chlorophenol as the starting compound, the synthesis of which and purification are associated with a number of experimental difficulties.

In [US patent No. 539524, publ. April 16, 1957] a method for obtaining 2-chloro-4-nitrophenol (1) by chlorination of 4-nitrophenol with gaseous chlorine in the presence of an aqueous solution of hydrochloric acid at a temperature at which 4-nitrophenol melts, but below the temperature at which significant decomposition occurs (70-90°C).

A known method for producing 2-chloro-4-nitrophenol (1) (72.5%) by chlorination of 4-nitrophenol with gaseous chlorine in the presence of acetic acid [Czechoslovakia patent No. 181644, publ. March 31, 1978].

In [US patent No. 2629645, publ. February 24, 1953] 2-chloro-4-nitrophenol (1) is prepared by passing chlorine into a mixture of dilute hydrochloric acid and 4-nitrophenol at a temperature above the melting point of 4-nitrophenol, but below its decomposition. The secondary product of the reactions is hydrogen chloride, so by the end of the reaction the concentration of hydrochloric acid is higher than at the beginning.

Disadvantages of Methods

1; The use of gaseous chlorine, which requires special (corrosion-resistant) equipment due to the high aggressiveness of chlorine;

2. The need to use acetic acid as a medium;

2. Low (up to 72.5%) yield of the target product;

3. The reaction is carried out under conditions of strict control over the amount and rate of transmission of gaseous chlorine, since there is a high probability of occurrence of side processes that reduce the yield of the target product;

4. Formation of a large amount of acid waste (HCl + CH ₃ COOH).

In a known method [German patent No. 184241, publ. August 31, 1978] 2-chloro-4-nitrophenol (1) is prepared by chlorination of 4-nitrophenol with chlorine in acetic acid (chlorine is generated in situ by treatment with conc. HCl with 32% H ₂ O ₂ solution). In the patent, the yield is given in the following form (60-1 g of 2-chloro-4-nitrophenol from 60 g of 4-nitrophenol).

In the RF patent [RF patent No. 2046794, publ. October 27, 1995] a new version of the oxidative chlorination of 4-nitrophenol is presented. Chlorination of 4-nitrophenol is carried out in a hydrochloric acid solution at 25-30°C by adding 20-30% nitric acid ΗΝO ₃ or 19-30% hydrogen peroxide H ₂ O ₂ to the hydrochloric acid solution of 4-nitrophenol. The process is carried out at a molar ratio of 4-nitrophenol: oxidizing agent 1:1. After recrystallization from water, the yield of 2-chloro-4-nitrophenol (1) is 83%.

In a known method [RF patent No. 2269511, publ. February 10, 2006] 2-chloro-4-nitrophenol (1) was synthesized by oxidative chlorination of 4-nitrophenol with a mixture of hydrochloric acid and hydrogen peroxide (19-33%) in a sulfuric acid medium with a concentration of 30-60%. The molar ratio of 4-nitrophenolic acid is 1:1. A precipitate of 2-chloro-4-nitrophenol (1) is obtained, which is filtered off and washed with cold water.

Disadvantages of Methods

1. Use of strong aggressive mineral acids HCl and ΗΝO ₃ ;

2. Low product yield 83-85%;

3. Equipment corrosion;

4. Formation of a large amount of inorganic waste.

2-Chloro-4-nitrophenol (1) was synthesized by chlorination of 4-nitrophenol with sodium hypochlorite under stirring in a hydrochloric acid medium at a temperature of 0°C. The precipitated 2-Chloro-4-nitrophenol (1) is filtered off and dried. Output (1) by this method is 98%. [RF patent No. 2268877, publ. January 27, 2006].

Disadvantages of the method

1. Large consumption of hydrochloric acid;

25 g (0.18 mol) of 4-nitrophenol is mixed with 200 ml of hydrochloric acid (concentration 35-38% of the mass);

2. The reaction is carried out at a temperature of 0°C;

3. The need to use special corrosion-resistant equipment;

4. Formation of a large amount of waste containing HCl and NaCl.

The authors propose a method for obtaining 2-chloro-4-nitrophenol (1), which does not have the disadvantages of known methods.

The objective of the invention is to simplify the technology and reduce the cost of 2-chloro-4-nitrophenol (1) by using tert-butyl hypochlorite as a chlorinating agent, as well as reducing the amount of waste.

The essence of the method lies in the interaction of 4-nitrophenol with tert-butyl hypochlorite in the presence of iron-containing catalysts FeBr ₂ , or Fe(C ₅ H ₅ ) ₂ , or FeCl ₂ ⋅4H ₂ O, or FeCl ₃ ⋅6H ₂ O ₂ , at 20°C in an open system for 0.5-5 hours, at a molar ratio of [catalyst]:[4-nitrophenol]:[t-BuOCl]=0.1-1:100:100-120, preferably [FeBr ₂ ]:[4-nitrophenol] :[t-BuOCl]=l:100:100. The reaction is carried out in a reactor in an environment of CH ₂ C1 ₂ . The yield of 2-chloro-4-nitrophenol (1) is 100%.

Significant differences between the proposed method and the prototype.

The chlorinating agent of 4-nitrophenol to obtain 2-chloro-4-nitrophenol (1) is tert-butyl hypochlorite, and the reaction takes place in the presence of catalytic amounts of FeBr ₂ .

Advantages of the proposed method.

1. Cost reduction and technology simplification due to mild reaction conditions (~20°С, 0.5–5 h);

2. The yield of 2-chloro-4-nitrophenol (1) is 100%;

3. Absence of side products except for tert-butanol, which facilitates the isolation and purification of the target 2-chloro-4-nitrophenol (1). tert-Butanol can be isolated by distillation and used for the synthesis of t-BuOCl;

4. The process can be carried out in conventional equipment.

The proposed method is illustrated with examples:

EXAMPLE 1. In a glass reactor (V=100 ml) were placed 0.02 g (0.000072 mol) FeBr ₂ , 1 g (0.0072 mol) 4-nitrophenol, 2 ml (0.0022 mol) CH ₂ Cl ₂ . Then, 0.82 ml (0.0072 mol) of freshly prepared t-BuOCl was added to the reaction mixture. The reaction mass was stirred at room temperature (~20°C) for 1.5 hours on a magnetic stirrer under reflux. After the completion of the reaction, the reaction mass was neutralized with a 10% aqueous solution of Na ₂ CO ₃ (stirring on a magnetic stirrer for 0.5-1 hour), the organic layer was extracted with CH ₂ Cl ₂ and filtered. The solvent was distilled off, the solid residue was washed 3-5 times with water (4-6 ml) and distilled under vacuum. Yield of 2-chloro-4-nitrophenol (1) 100%. T _PL =110-111°C.

EXAMPLES 2-10. Similar to example 1. The results are shown in the table.

Claims (1)

A method for obtaining 2-chloro-4-nitrophenol by chlorination of 4-nitrophenol, characterized in that t-BuOCl is used as a chlorinating agent, the reaction is carried out in the presence of catalysts selected from the series FeBr ₂ , Fe(C ₅ H ₅ ) ₂ , FeCl ₂ ⋅4H ₂ O, FeCl ₃ ⋅6H ₂ O, at 20°C for 0.5-5 h at a molar ratio of [catalyst] : [4-nitrophenol] : [t-BuOCl] = 0.1-1:100:100-120 .