IE52876B1 - Preparation of amexinium metilsulfate - Google Patents

Abstract

1. A process for the preparation of amezinium metilsulfate by reacting 1-phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium metilsulfate by crystallization, wherein unreacted dimethyl sulfate, before crystallization of the amezinium metilsulfate, is bonded to an amide of the formula R**1 -(NH)n -CO-NR**2 R**3 , where R**1 is hydrogen, C1 -C8 -alkyl, C1 -C6 -alkoxy or C1 -C8 -alkylamino, R**2 and R**3 are each hydrogen or C1 -C8 -alkyl, or R**1 and R**2 together are a C3 -C5 -alkylene radical, and n is 0 or 1, at least one of the radicals R**1 , R**2 and R**3 , however, denoting hydrogen, or to the corresponding thioamide.

Description

The present invention relates to a process for the preparation of amezinium metilsulfate (l-phenyl-4amino-6-methoxypyridazinium methosulfate).

The anti-depressant amezinium metilsulfate has been disclosed in German Published Application DAS 1,912,941 (cf. Exanple 1). It is obtained by reacting l-phenyl-4-aminopyridaz'6-one with dimethyl sulfate and filtering off the product under suction from the reaction mixture. The resulting amezinium compound is dark brown, contains residues of dimethyl sulfate, and cannot be purified without substantial loss.

We have found a route for obtaining the amezinium compound in good yield and quality.

The present invention provides a process for the preparation of amezinium metilsulfate by reacting 1phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium metilsulfate by crystallization, wherein unreacted dimethyl sulfate is bonded, before crystallization of the amezinium metilsul1 2 3 fate, to an amide of the formula R -(NH)n-CO-NR R , where r! is hydrogen, C^-Cg-alkyl, C^-Cg-alkoxy or C^-Cg2 3 alkylamino, R and R are hydrogen or C^-Cg-alkyl, or 1 2 R and R together are Cg-C^-alkylene, and n is 0 or 12 ? 1, provided that at least one of R , R and RJ is hydrogen, or to a corresponding thioamide.

The reaction of l-phenyl-4-aminopyridaz-6-one with dimethyl sulfate (DMS) may be carried out in a conventional manner. The DMS is advantageously used in excess, but it is also possible to combine it with other solvents (cf. German Published Application DAS 1,912,941 - 3 column 3, lines 4-10). However, if these solvents are used at all, only a limited amount should be added, so that the concentration of DMS is not too low, in particular towards the end of the reaction.

The reaction can be carried out at from 0 to 200°C, in particular at from 30 to 110°C, preferably, however, at from about 60 to 90°C. The reaction time is chosen such that the decomposition to give brownish black crystal slurries, which, for example, occurs In the course of one hour at 120°C, is substantially suppressed, for example 2 hours at 70"C being suitable. The reaction can be carried out continuously or batchwise, or semicontinuously, for example in cascades.

In accordance with the invention, an amide is added to the resulting reaction mixture, in .an amount sufficient to destroy the excess dimethyl sulfate.

Specific examples of amides that can be used are: formamide, N-methylformamide, N-methylacetamide, propionamide, isobutyric acid N-methylamide, 2-ethylhexanoic acid isopropylamide, phenylacetic acid cyclohexylamide, pyrrolidone, piperidone, caprolactam, C-methylcaprolactam, caprylolactam, oenantholactam, laurolactam, urea, N-methylurea, N,N-dimethylurea, Ν,Ν,Ν’-trimethylurea, N-methyl-N'-ethylurea, N,Ν'-dimethylurea, Ν,Ν'-diisopropylurea, N-methyl-N'-(2-ethylhexyl)-urea, ethyleneurea, propylene —--:52876 - 4 urea, N-methylpropylene urea, O-methylurethane, N,0dimethylurethane and N,O-diethylurethane.

The amide is added to the reaction mixture in a liquid or solid state or dissolved or suspended in a solvent. The reaction of the amide with DMS is carried out in a temperature range which depends on the concentration, the residence time and the reactivity of the amide, but which leaves the resulting amezinium compound unchanged. The temperature range is from 0 to 10 200°C, preferably from 20 to 120°C, and very particularly in the presence of the amide from 60 to 100°C.

The reaction parameters should be chosen such that the batchwise reaction of the DMS with the amide takes from 5 minutes to 5 hours, preferably from 0.5 to 2 hours.

The amezinium metilsulfate is isolated as a solid from the reaction mixture, if appropriate after dilution of the latter with solvents, for example the alcohols mentioned in German Published Application DAS 1,912,941, preferably methanol.

In contrast to the process described in German Published Application DAS 1,912,941, the amezinium metilsulfate obtained by the novel process is free from DMS. This is a great advantage, since the amezinium compound is unstable to bases and other nucleophilic compounds and the DMS therefore cannot be removed with the aid of the latter.

By the novel process, the amezinium metilsulfate is obtained directly, without further purification, in 5287b - 5 an almost colorless form and in good yields.

The Examples which follow illustrate the invention.

EXAMPLE 1 5 66.35 g of dimethyl sulfate are heated to 80°C, and 40 g of l-phenyl-4-aminopyridaz-6-one are added in the course of 40 minutes. The resulting slurry is stirred for a further 1.5 hours at from 78 to 82°C, and 40.36 g of caprolactam, dissolved in 27 ml of warm 1° methanol, are then added at 80°C, in the course of 15 minutes. Stirring is continued for a further hour at 90°C, 25 ml of methanol are added, and the mixture is cooled to 0°C. The slurry is stirred for 2 hours at from 0 to 5°C, and the crystals are filtered off under suction, washed with methanol and dried. 50.70 g (75.7%) of beige amezinium metilsulfate, melting point 173-175°C (decomposition), are obtained. 30.00 g of the resulting product are recrystallized from methanol and 25.50 g (85.0%) of colorless crystals, melting point 176-177’C (decompc20 sition), are obtained. The yield over both stages is 64.3%.

EXAMPLES 2 TO 10 Example 1 was repeated with the amides given in the Table, and the yields and melting points indicated « were obtained. The crude products were slightly colored, whilst the end products were almost colorless.

COMPARATIVE EXAMPLE If the amounts, given in Example 1, of 1-phenyl4-aminopyridaz-6-one are reacted as described in Example 53876 - 5 1 of German Published Application DAS 1,912,941, a 91% yield of a dark brown crude product of melting point 148-157°C is obtained. Recrystallization of the crude product gives 21% (based on l-phenyl-4-aminopyridaz5 6-one) of a brown product of melting point 162-164’C 16.6% of a pure product of melting point 174.5-175.5°C are obtained only after the recrystallization is repeated once again.

Claims (4)

1. A process for the preparation of amezinium metilsulfate by reacting l-phenyl-4-aminopyridaz-6-one with dimethyl sulfate and subsequently isolating the amezinium 5 metilsulfate by crystallization, wherein unreacted dimethyl sulfate, before crystallization of the amezinium metilsulfate, is bonded to an amide of the formula R 1 -(NH) n -CX-NR 2 R 3 where R 1 is hydrogen, C^-Cg-alkyl, C^-Cg-alkoxy or C^-Οθ

2. 2 10 alkylamino or together with R is C^-C^-alkylene, R 1 is hydrogen or Cj-Cg-alkyl or together with R is Cg-Cg-alkylene, R^ is hydrogen or C^-Cg-alkyl, X is oxygen or sulfur and n is zero or 1, provided that at 12 3 least one of R , R and R is hydrogen. 15 2. A process as claimed in claim 1, wherein the bonding of excess dimethyl sulfate to the amide is carried out at from 60 to 100°C, sufficient amide to react with all the excess dimethyl sulfate being added to the reaction mixture in a liquid or solid state or 20 dissolved or suspended in a solvent.

3. A process for the preparation of amezinium metilsulfate carried out substantially as described in any of the foregoing Examples 1 to 10.

4. Amezinium metilsulfate when prepared by a process 25 as claimed in any of claims 1 to 3.