PROCEDURE TO PREPARE N,N-DIMETHYLAMINOETHANOL 2-CHLOR-4-DIMETHYL-AMIDOSULFONYL-FENOXYACETATE HYDROCHLORIDE

Abstract: This invention relates to a procedure to prepare N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride of formula (1). This compound is the active principle of ROMENERG drug (Meclosulfonat) having a psychoenergizing and anticonvulsive action. Procedure to prepare N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride, wherein the transesterification of 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate ester with N,N-dimethylaminoethanol is performed at 100 DEG C for four hours, in the presence of sodium N,N-dimethylaminoethoxide as catalyst, followed by separation of oleos ester from the reaction medium, its extraction and drying in benzene at temperature below 10 DEG C, treatment of anhydrous benzene solution with gaseous hydrochloric acid in cold conditions, and purification of the final product by recrystallization from a mixture of ethanol and dimethylformamide.

Description: Procedure to prepare N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl- fenoxyacetate hydrochloride This invention relates to a procedure to prepare N,N-dimethylaminoethanol 2-chlor-4- dimethyl-amidosulfonyl-fenoxyacetate hydrochloride of the formula: This compound is the active principle of ROMENERG drug (Meclosulfonat) having a psychoenergizing and anticonvulsive action. Romanian patents RO 61526, RO 78977, and RO 110060 give some procedures to prepare amidosulfonylfenoxyacetic dimethylaminoethyl esters. These procedures to obtain such type of compounds are achieved by condensation of the of amidosulfonylfenoxyacetic acids in benzene with diethylaminoethanol in a molar ratio of 1 :2 or 1 : 1 , in the presence or in the absence of sodium acid carbonate, starting from 40-45°C, then 80-82°C for an hour, maximum reaction yield being of 64-65 %. Procedure according to this invention ensures the increase of the yield to get N,N- dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride by providing the transesterification at 100°C for four hours of 2-chlor-4-dimethyl-amidosulfonyl- fenoxyacetate ester with N,N-dimethylaminoethanol in the presence of sodium N,N- dimethylaminoethoxide as catalyst prepared in situ, separation of oleos ester from the reaction medium, its extraction and drying in benzene at temperature below 10°C, and the treatment of anhydrous benzene solution with gaseous hydrochloric acid in cold conditions, and purification of the final product by recrystallization from a mixture of ethanol and dimethylformamide. Procedure advantages according to this patent: - the increase of the yield to get N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl- fenoxyacetate hydrochloride to at least 75 %; - the product obtained according to this procedure has an active compound content of 99-102 % referring to dry substance and high purity that is identified by the presence of a single spot of Rf = 0.4 in the thin layer chromatography separation according to Xth edition of Romanian Pharmacopoeia; - the advanced purity degree of the product obtained according to this invention allows, together with an anticonvulsive and psychoenergizant activity, a significant antidepressant action, acting by diminution of the anxiety and depressant charge, with good results in the treatment of asthenodepressant syndrome, depressant-melancholic hyperthimic syndrome, as well as depressant syndrome on preinvolutive base; - the product obtained according to this invention has moderate analgesic as well as antiemetic extra actions, that are therapeutically useful, as single medication or in associations. The following example for the procedure according to this invention is given below. The achievement of the procedure according to this invention requires a well-known vessel, provided with mechanical stirrer, heating/cooling and temperature controlling system for the reaction medium, fractionating column attached to the vessel and a system to recycle the distillate from the fractionating column to the reaction medium. 7 liter (6.23 kg) dimethylaminoethanol are introduced in the vessel. Then 2 kg metallic sodium are added stepwise, under mechanical stirring, at 50°C. When all the amount of sodium has been consumed, 3.07 kg 2-chlor-4-dimethyl-amidosulfonyl-methylfenoxyacetate are introduced in the vessel under stirring. The mixture is heated at 100°C, and maintained at this temperature, for 4 hours, under stirring and by removing the fraction of 80°C on the top of the fractionating column (this temperature will be read on the top of the fractionating column). After 4 hours of reaction, the reaction medium temperature is increased at 135-136°C and 5-5,5 liter aminoethanol is distilled, that is recycled to the reaction medium. The reaction is considered accomplished when this volume of distilled aminoethanol will be reached. The vessel content is cooled till 10°C, and 10 liter of water, cooled at 8-10°C, are introduced in the medium under stirring. The aqueous phase is separated by removing from the vessel. Then the oleos medium is washed two times with 5-6 liter water each, at 8-10°C. Finally, the oleos phase is extracted in benzene, and the benzene solution of dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate is dried on anhydrous sodium sulfate. In the anhydrous benzene solution gaseous hydrochloric acid is bubbled, under stirring, in cold conditions, when N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl- fenoxyacetate hydrochloride precipitates as final product. The product is purified by recrystallization from a mixture of ethanol/dimethylformamide. 3 kg N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl-fenoxyacetate hydrochloride are obtained with a minimum yield of 75 %. The product obtained according to this invention has a content of active substance of 98- 102 % (referring to dry substance). It is a white, bitter crystalline powder, without any smell. The product is very soluble in water (the solution obtained by dissolving 2.5 g compound in 50 mL water is clean and colorless). The product has a low solubility in ethanol, chloroform, acetone, and benzene. The melting point (under the microscope) of the product is between 188-192°C. The UV spectrum of aqueous solution of the product containing 0.001 g % shows an absorption maximum at 242 nm (± 2 nm), El %/l cm = 0.35 (+0.02). The product obtained according to this procedure has a high purity, that is identified by the presence of a single spot of Rf = 0.4 in the thin layer chromatography separation according to Xth edition of Romanian Pharmacopoeia. The calcination residue is < 0.1 %, and the heavy metals content is < 0.001 %. The pharmaco-toxicological preclinic studies concerning this product, in comparison with the product Meclofenoxat, have pointed the following: ■ the product is of low toxicity group (two times weaker than Meclofenoxat) having lethal dose LD50 at the administration of 1578 mg/kg in mouse and 1691 mg/kg in rat; ■ the product does not exhibit either mutagene action or teratogene action in rat; ■ in vitro the product does not induce neoplazia transformations of the cells of the human embrion. Pharmacodynamic studies carried out showed that the product exhibit a neurotonic action superior to Meclofenoxat. It exhibited also other effects on tested animals, that can be useful in therapeutical practice, like an anticonvulsive effect similar to that of trimetadione, a moderate analgesic effect, an emetic effect, and an antidepressant effect. Radio-pharmacodynamic studies reveal that the product has a good gastrointestinal absorption, the maximum blood concentration being attained after one hour of administration. The biological half-time of the product in blood is of about 22 hours. The maximum concentrations in the therapeutically interesting organs are attained after 12 hours of administration. The elimination of the product is achieved by urine and fecals. Clinical studies on the product obtained according to this invention have shown a significant increase of the intellectual performance, simultaneously with a diminution of both depressant charge and anxiety. The drug obtained according to this invention has shown good results especially in the cases of neurasthenic syndrome, astheno-depressant syndrome, depressant-melancholic hyperthymic syndrome, and depressant syndrome on preinvolutive base. The lack of toxicity insures a good tolerance of the product, the absence of secondary effects and counter-indications. The good maniability of the product makes possible the ambulatory treatment. Clinical study in infantile sequels and microsequels encephalopathies, in some psychical disturbances as well as in infantile epilepsy have demonstrated that , by difference of all the other Nervous Central System roborantes products , the product obtained according to this invention has psychoenergisant effect together with anticonvulsive and antipsychotic effects. It is known that in infantile cerebral diseases, where the symptomathology contains most of the times neurological as well as psychical disturbances, the irritative phenomena intricate with the lackability phenomena. Consequently, in many cases of infantile perinative encephalopathy, the motive deficiencies ( halfpareses, tetrapareses) coexist with epileptic manifestations, or behavior disturbances are the end of cerebral harms that are established especially antenative or intranative. The results of the clinic experiment with the product obtained according to this invention are given below. Table 1. Infantile sequel and microsequel encephalopathies (ISME) Table 2. Epileptic paroxysmal manifestations resistant to classical treatment. Epileptic manifestations Table 3. Psychical disturbances Clinical studies demonstrate that the product obtained according to this invention is effective in the therapy of infantile sequel encephalopathia, with deficiencies in the neuroflexomotive and/or psychical development. The therapeutical value of the product is important because it can be administrated in encephalopathies with paroxysmal epileptic manifestations, too. The most remarkable and consistent results were obtained in the cases in which an acute pathogen ( traumatic, toxic, infectious) factor has determined immediate and hard neuropsychical modifications. It is also efficient in cognitive disturbances, especially in oligophrenia forms with mental debility and/or liminar intellect, in monotherapy. Consequently, the product obtained according to this invention is a drug with administration doses of: -10 mg/kg/day, without exceeding 500 mg/day, for children; -200-600 mg/day, for adults. The doses can be administrated in unique administration, in the morning (in the case of small doses), or 2-3 doses daily (in the case of medium and great doses).

Claims: What is claimed is: 1. Procedure to prepare N,N-dimethylaminoethanol 2-chlor-4-dimethyl-amidosulfonyl- fenoxyacetate hydrochloride, wherein the transesterification of 2-chlor-4-dimethyl- amidosulfonyl-fenoxyacetate ester with N,N-dimethylaminoethanol is performed at 100°C for four hours, in the presence of sodium N,N-dimethylaminoethoxide as catalyst, followed by separation of oleos ester from the reaction medium, its extraction and drying in benzene at temperature below 10°C, treatment of anhydrous benzene solution with gaseous hydrochloric acid in cold conditions, and purification of the final product by recrystallization from a mixture of ethanol and dimethylformamide. 2. Procedure according to claim 1, wherein sodium N,N-dimethylaminoethoxide is prepared in situ from dimethylaminoethanol and metallic sodium in weight ratio of 62.3:2 and at 50°C. 3. Procedure according to claim 1, wherein during the transesterification reaction the fraction that distills under 80°C is removed from the reaction medium. 4. Procedure according to claim 1, wherein at the end of the transesterification reaction the temperature of the reaction medium is increased to 135-136°C.

Inventors: CARSTEA ALEXANDRU, CILIANU BIBIAN STEFAN PAUL, DICU IOANA VIRGINIA, DOBRESCU DUMITRU, FUNIERU GABRIELA, HARLES LUCIAN SERGIU, ONISCU CORNELIU, CARSTEA, ALEXANDRU, CILIANU BIBIAN, STEFAN, PAUL, DICU, IOANA, VIRGINIA, DOBRESCU, DUMITRU, FUNIERU, GABRIELA, HARLES, LUCIAN, SERGIU, ONISCU, CORNELIU
Applicants: SOCIETATEA COMERCIALA SINTOFAR, SOCIETATEA COMERCIALA SINTOFARM S.A.
Application year: 1998
Main classification: C07C311
IPC codes: C07C69, C07C303, C07C311