CS260624B1 - Method of 2-mercaptoethanesulphonic acid production - Google Patents

Abstract

Process for preparing 2-mercaptoethanesulfonic acid acid is substantially accelerated alkylating the sodium sulfite with 1,2-dichloroethane by adding a small amount sodium bromide to the reaction mixture and use of crude sodium 2-chloroethanesulfonate to react with thiourea with the addition of a catalyst sodium bromide a concentrating the reaction mixture during the reaction the formation of 2-S-thiuronium sulfonate which is formed converted to the guanidinium salt by treatment with ammonia in an inert gas atmosphere is also used in the release of 2-mercaptoethanesulfonic acid acid and its neutralization hydroxide or an organic base.

Description

The invention relates to a process for the preparation of 2-mercaptoethanesulfonic acid and its salts.

2-mercaptoethanesulfonic acid and its salts have been known for many years; they were first tested as an antidote to arsenic and some heavy metals, later as a mucolytic agent. It has been found that mercaptoethanesulfonic acid is part of coenzyme M, which is a growth factor for methanogenic bacteria, which is important for the anaerobic transformation of organic substances into methane. Recently, mercaptoethanesulfonic acid sodium ("Mesna") has been used in the administration of cytostatic drugs as it reduces their urotoxic effects. It has also been possible to incorporate 'Mesna' chemically into a molecule of cyclophosphamide, so that new analogous drugs do not have a toxic side effect, thus increasing their importance especially in the prevention and treatment of tumors of the urinary tract and other organs.

Use of 2-mercaptoethanesulfonic acid, resp. their salts are apparent from the above summary. Its importance and need for the pharmaceutical industry, as well as the interest in a simple and economical way of production, is growing. Other suggestions for the use of this substance are also known, for example as an additive and a stabilizer for copolymers, and in the dyeing industry as dyes for cotton.

The earliest known works on the preparation of 2-mercaptoethanesulfonic acid and its salts are based on the reaction of sodium 2-bromomethanesulfonate with sodium sulfide (Lipov IM: Z. prikl. Chim. 18, 720 [1945]], which was later Schramm Ch. H. and Karlson RH was replaced with thiourea, and the mercapto group was liberated from the resulting thiuronium salt by treatment with ammonia (U.S. Pat. No. 2,695,310). Chem. Abstr. 49, 13 289 [1955]) Reppe W. et al protected the preparation of the compound with hydrogen sulfite on ethylene sulfide (Ger. P. 696 773) 2-mercaptoethanesulfonic acid can be used according to Belgian patent no. 842,665 thus obtained by alkylation of tert-butyl mercaptan with sodium 2-chloroethanesulfonate and acid hydrolysis of the resulting sodium S-tert-butyl mercaptoethanesulfonate. No. 252,564 describes the preparation of said mercaptosulfonate by alkylation of alkaline thioacetate with sodium 2-haloethanesulfonate and hydrolysis of the resulting S-acetyl mercaptoethane sulfonate.

The present invention provides a process for the preparation of 2-mercaptoethanesulfonic acid and its salts by first reacting ethylene dichloride in 1.5 and 3 molar excess with sodium sulfite in an aqueous ethanolic solution in the presence of Vio to Vs mol of sodium bromide per mole of sodium sulfite to form 2- sodium chloroethanesulfonate. This is preferably not isolated, but in admixture with the sodium halides present, after distilling off the excess ethylene dichloride, ethanol and water, the reaction with thiourea again in the presence of sodium bromide, in an amount of Vi5 to V20 moles per mole thiourea accelerates the reaction. by boiling in an aqueous solution for three hours, distilling from 0.1 to 0.2 water content. The isolated thiuronium ethanesulfonate is converted to guanidinium 2-mercaptoethanesulfonate by heating with concentrated ammonia, preferably to 45-55 [deg.] C. under an inert atmosphere from which the 2-mercaptoethanesulfonic acid is liberated using an acidic ion exchanger. The acid solution is neutralized under cooling with an alkaline solution of hydroxide or the corresponding amine under an inert atmosphere. The neutral solution is concentrated under reduced pressure to half volume and diluted with an equal volume of methanol or ethanol under stirring under an inert atmosphere. The precipitated corresponding 2-mercaptoethanesulfonic acid salt is filtered off, washed with a small amount of alcohol and dried under reduced pressure.

An advantage of the present invention is the use of inexpensive chemicals, which allows the use of a small amount of sodium bromide in the preparation of 2-chloroethane sulfonate from ethylene dichloride, while reducing the reaction time from 72 hours to 10-12 hours. By using an inert atmosphere, it maintains the purity of the products by preventing oxidation of the sulfhydryl groups. Filtration of the precipitated mercaptoethanesulfonic acid salt also results in greater purity of the end product. During the entire production process, only inorganic salts are dispensed with, and the recovered solvents can be returned to production without costly purification. In addition to elemental analysis, the purity of 2-chloroethanesulfonate can be monitored rapidly during the reaction by isotachophoresis or by iodometric titration.

The invention is further described in the following examples.

Example 1

Sodium 2-chloroethanesulfonate

In a 2 liter 2-3 neck flask was added 150 g (120 mL) of ethylene dichloride, 400 g (506 mL) of ethanol, and 20.6 g of sodium bromide and heated to boiling. Then 150 ml of water and a solution of 126 g of anhydrous sodium sulphite in 480 ml of water (or 252 g of crystallized sulphite in 360 ml of water) are added, 0.2 g of copper powder or bronze is added and heated to reflux for 10-12 hours. . Then, excess ethylene dichloride and ethanol are distilled off from the mixture on the evaporator (ethylene dichloride can be separated in a separator and used immediately for the next batch, or regenerated by shaking with CaCl 2 and distillation). Ethanol can also be used in another batch. Further dry distillation of the reaction mixture yielded a white crystalline residue which was then extracted with 95% ethanol (4-5 X 800 mL).

Sodium 2-chloroethanesulfonate is obtained from the extracts either by cooling or by faster distillation of ethanol (on a rotary evaporator) to dryness, while ethanol is returned to the extraction. The product yield is 65-83 g (40-50% of theory, calculated on sodium sulfite), and the product can be crystallized from ethanol as needed. The melting point of the uncrystallized product is 285-295 ° C with decomposition.

Example 2

A mixture of 1.2 L (1508 g, 15.24 mol) of ethylenedichloride, 3 L of 95% ethanol and 70 g (0.68 mol) of sodium bromide was heated at reflux for 1 hour and then a freshly prepared solution of 1.3 was added. kg of crystalline sodium sulfite containing 15% of sodium sulfate (i.e. 4.38 moles of sulfite) and 2 g of copper powder. The mixture was then heated at reflux for 10 hours while the pH of the solution dropped from 8 to 6.5 (as measured by indicator paper). Then, excess ethylene dichloride and a portion of the ethanol were distilled off under normal pressure, and the remaining ethanol with water was then distilled off under reduced pressure. The reaction mixture was then concentrated to 2 L, from which crystals, consisting mainly of sulfate, chloride and sodium bromide, precipitated the next day. Filtration of this ballast yielded a solution containing 648 g of sodium 2-chloroethanesulfonate according to isotachophoresis analysis. The yield on the sulphite used was 88.8%.

Example 3

2-S-thiuronium ethanesulfonate

A mixture of 100 g (0.6 mol) of sodium 2-chloroethanesulfonate, 240 ml of water, 45.6 g (0.6 mol) of thiourea and 3.1 g (0.03 mol) of sodium bromide was added in a 0.5 liter flask in the stirring was heated to boiling for 2 hours; then distill 90 ml of water from the mixture. The next day, the precipitated crystals are filtered off, washed with 2 x 50 ml cold water and once with 50 ml ethanol and dried. The yield of 2-S-thiuronium ethanesulfonate is 70-80 g (73-83%), mp 275-285 ° C dec.

Example 4

A solution of 1.83 kg of crude sodium 2-chloroethanesulfonate (90% pure), 500 g (about 7 moles) of thiourea and 50 g (0.5 moles) of sodium bromide in 2.5 L of water was heated to boiling in a 6 liter flask. 5 hours, 260 ml of water were distilled off.

The reaction mixture was transferred to another vessel while warm and allowed to crystallize freely the next day. After filtration, washing 2X with 350 ml of water and once with 200 ml of ethanol, 720 g of thiuronium salt (about 40% of the starting chloro derivative) was isolated after drying, m.p. 270 DEG-280 DEG C. (decomposition).

Example 5

Guanidinium 2-mercaptoethanesulfonate

A mixture of 73.6 g (0.4 mol) of 2-S-thiuronium ethanesulfonate and 150 ml of 20% ammonium hydroxide is slowly heated under stirring to a bath temperature of 60 to 70 ° C under stirring. Around 45 ° C in the flask (thermometer in the reaction mixture), an exothermic reaction occurs at which the temperature of the reaction mixture spontaneously rises to 55 ° C even though heating is discontinued. After 2 hours, the solution was concentrated to dryness on a rotary evaporator under reduced pressure, always evacuated by evacuating nitrogen into the apparatus. After recrystallization from absolute ethanol, about 45 g of the 2-mercaptoethanesulfonic acid guanidinium salt having a melting point of 117-118 ° C was isolated. For C 3 H 10 N 3 S 2 O 3 (m / m 200.13) calculated: 17.91% C; 5.51% M; N, 20.89; Found: 18.06% C; 5.43% 14; 20.30% N.

Example 6

To 800 g of 2-S-thiuronium ethanesulfonate was added 1,700 ml of concentrated ammonia, and the mixture was heated with gentle nitrogen bubbling at a bath temperature of 70 degrees Celsius up to 45 ° C in the reaction mixture. After the start of spontaneous boiling (evolution of ammonia), heating was discontinued and the temperature in the solution rose to 58 ° C. After 3 hours the temperature dropped to 30 ° C, when excess ammonia was removed from the solution under reduced pressure and the solution was concentrated to 1200 ml. This solution can be used to prepare 2-mercaptoethanesulfonic acid (directly to release the acid on the ion exchanger) or evaporated to dryness as described in Example 5. The resulting guanidinium 2-mercaptoethanesulfonate solution contains isotachophoresis analysis, 96-98% pure product.

Example 7

Sodium 2-mercaptoethanesulfonate

A solution of 20 g (0.1 mole) of 2-mercaptoethanesulfonic acid guanidinium salt in 50 ml of distilled boiled water is slowly poured over 100 to 120 ml of acidic ion exchanger (Ostion KS with a capacity of at least 2 mval / ml) and washed with distilled boiled water. (always allowed to cool under nitrogen) until the acidic reaction of the eluate disappears. The free acid solution was collected under a nitrogen atmosphere. The eluate is concentrated under reduced pressure to about 100 ml (vacuum is always disturbed by the addition of nitrogen) and neutralized with 1 N sodium hydroxide solution under a nitrogen atmosphere. When neutralizing larger amounts of acid, it is cooled externally with ice water. The solution of sodium 2-mercaptoethanesulfonic acid is concentrated to 50 ml, 100 ml of ethanol are added and the precipitated sodium salt is filtered off, again preferably under a nitrogen atmosphere. After washing the product with ethanol and drying, up to 14 g of the sodium salt are obtained, the purity of which, when analyzed by isotachophoresis, is between 95 and 98%.

Claims (1)

Process for preparing 2-mercaptoethanesulfonic acid and its salts by treating ethylene dichloride in excess on crystalline or anhydrous sodium sulfite in an aqueous alcoholic solution to form sodium 2-chloroethanesulfonate, which is converted by thiourea to thiuronium salt by boiling with concentrated ammonia to boiling with ammonia. salt from which 2-mercaptoethanesulfonic acid is released by pouring through an acidic ion exchanger, which is then neutralized to the corresponding salt, characterized by treating with a 1.5 to 3 molar excess of ethylenedichloride while boiling in alcohol on Vio to Vis moles of sodium bromide, calculated per mole of sodium sulphite, for 0.5 to 2 hours, and then sodium sulfite / water 1: 5 to 1: 10 is added and the reaction mixture is further heated to boiling for 10 to 12 hours in an isolated reaction. or crude sodium 2-chloroethanesulfonate with thiourea is added Vis to V20 mol of sodium bromide, calculated on 1 mole of thiourea, and the reaction mixture is distilled off under normal or reduced pressure of 0.1 to 0.2 of the original water content for 2 to 3 hours in water and the conversion to guanidinium salt is carried out in water. an inert gas atmosphere, as well as washing the salt through ion exchange and neutralizing the 2-mercaptoethanesulfonic acid to the corresponding salt, and isolating the resulting 2-mercaptoethanesulfonic acid salt from the solution by concentrating the solution to about 20-50% by volume, ethanol is added and the precipitated salt is then filtered off and dried under reduced pressure, the vacuum always being canceled by injecting inert gas.