NO162461B - PROCEDURE TE FOR THE PREPARATION OF AMINE DERIVATIVES. - Google Patents

Description

The present invention relates to a method for the production of ranitidine, that is N-[2-[5-(dimethylamino)methyl-2-furanylmethylthio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine.

The production takes place according to the invention by

a) methyl isothiocyanate is reacted with the carbanion of nitromethane in the presence of dimethyl sulfoxide as solvent, optionally

in the presence of a cosolvent, the carbanion of nitromethane being formed in situ from nitromethane and a suitable base,

to form a compound of formula (I)

where Q' is a cation derived from the base, and

the compound where Q' is a cation is optionally treated with a suitable acid to form the compound of formula I where Q' is hydrogen, b) the prepared compound where Q' is hydrogen or a cation, C^ is alkylated to form an N- methyl-1-alkylthio-2-nitroethenamine derivative, and c) said N-methyl-1-alkylthio-2-nitroethenamine derivative of formula I where Q' is a C 1. i( alkyl group, is reacted with 2-[5 -(N,N-dimethylaminomethyl)-2-furanmethylthio]ethylamine.

In step b) it is produced and in step c) it is used

preferably N-methyl-1-methylthio-2-nitroethenamine is used as the compound of formula (I). The reaction can be carried out in a solvent such as water, optionally with heating.

The following example shall serve to further illustrate the invention.

EXAMPLE

1) N-methyl-1-methylthio-2-nitroethenamine

(i) Nitromethane (1.25 g) was added over 1 minute to a suspension of flaky potassium hydroxide (1.15 g) in dimethyl sulfoxide (containing 7.5% water) (18 ml). A solution of methyl isothiocyanate (1.5 g) in dimethyl sulfoxide (containing 7.5% water) (2.5 mL) was added over 2 minutes while maintaining the temperature at 20-26°C. The solution was stirred for an additional 0.5 hour at room temperature, and methyl iodide (3.19 g) was added dropwise over 2 minutes, while maintaining the temperature at 22-24°C. Stirring was continued for 1 hour at room temperature, and the solution was then diluted with water (200 mL) and extracted with dichloromethane. The combined extracts were washed with water, evaporated to dryness, and the residue crystallized from 2-propanol to give the title compound (1.5 g), yield 49.4% m.p. 113 - 116°C. (ii) Nitromethane (1.32 g) in dimethyl sulfoxide (containing 7.5% water) (5 ml) was added to sodium hydride (0.52 g) in dimethyl sulfoxide (containing 7 .5% water) (20 ml). The mixture was allowed to warm to room temperature, and after a further 30 minutes, methyl isothiocyanate (1.58 g) in dimethyl sulfoxide (containing 7.5% water) (5 ml) was added over 5 minutes.

The mixture was treated with methyl iodide (3.07 g) in dimethyl sulfoxide (containing 7.5% water) (5 mL) while maintaining the temperature below 30°C, and the resulting solution was stirred overnight. The solvent was removed, water (50 ml) was added to the residue and the mixture was worked up according to the procedure of option (i) to give the title compound (1.88 g), yield 58.7%, m.p. 112 - 114 °C.

(iii) Nitromethane (0.62 g) was added dropwise over 2 min to a suspension of potassium tert-butoxide (1.1 g) in dry dimethyl sulfoxide (9 mL) under an atmosphere of nitrogen while maintaining the temperature at 20 - 25°C. The mixture was stirred for 10 minutes, and a solution of methyl isothiocyanate (0.715 g) in dimethyl sulfoxide (containing 7.5% water) (3 ml) was added dropwise over 2 minutes. Stirring was continued

0.5 hour at room temperature, and then methyl iodide (1.52

g) added dropwise over 2 minutes while the temperature was maintained at 20 - 25"C. The solution was stirred at room temperature

for 2 hours, diluted with water (100 ml) and worked up according to the procedure of Example 1(i) to give the title compound (0.96 g), yield 66.1%, m.p. 113 - 115.5°C.

(iv) According to the method according to alternative (iii), but by replacing potassium tert-butoxide with sodium hydroxide (1.6

g) gave nitromethane (2.44 g) in dimethyl sulfoxide (containing 7.5% water) (35 mL) and methyl isothiocyanate (2.92 g) in

dimethyl sulfoxide (containing 7.5% water) (5 mL) followed by alkylation with methyl iodide (6.25 g), the title compound (2.64

g), yield 44.5%, m.p. 113 - 116°C.

2) N-r2-r5-(dimethylamino)methyl-2-furanylmethylthiolethyl 1-N'-

methyl-2-nitro-1,1-ethenediamine

A solution of 2-[5-(N,N-dimethylaminomethyl)-2-furan-methyl-thio]ethylamine (32.1 g) in water (25 ml) was added dropwise over 4 hours to a stirred solution of N- methyl-1-methylthio-2-nitroethenamine (23 g) in water (40 ml) at 50°C. The reaction mixtures were heated at 50°C for an additional 2 hours and then heated to 90°C. Methyl isobutyl ketone (150 mL) was added to the solution and the water was removed by azeotropic distillation. The solution was cooled to 60°C and charcoal (1.5 g) was added. The mixture was filtered, the charcoal residue was washed with methyl isobutyl ketone (50 mL), and the combined filtrates and washings were cooled to 0°C. The title compound (39 g), m.p. 60-70°C, crystallized and was filtered off.

Claims (2)

1. Process for the production of N-[2-[5-(dimethylamino)methyl-2-furanylmethylthio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, characterized in that a) methyl isothiocyanate is reacted with the carbanion of nitromethane in the presence of dimethylsulfoxide as solvent, possibly in the presence of a co-solvent, the carbanion of nitromethane being formed in situ from nitromethane and a suitable base, to form a compound of formula (I) where Q' is a cation derived from the base, and the compound where Q' is a cation is optionally treated with a suitable acid to form the compound of formula I where Q' is hydrogen, b) the prepared compound where Q' is hydrogen or a cation, C^ is alkylated to form an N- methyl-1-alkylthio-2-nitroethenamine derivative, and c) said N-methyl-1-alkylthio-2-nitroethenamine derivative of formula I where Q' is a C 1 -alkyl group, is reacted with 2-[5-(N ,N-dimethylaminomethyl)-2-furanmethylthio]ethylamine. 2. Method according to claim 1, characterized in that in step a) a compound of formula (I) is prepared where Q' is methyl.