FI90061C - Process for the preparation of amine derivatives - Google Patents

Description

1 90061

Method for the preparation of amine derivatives - Förfarande för framställning av aminderivat

The present invention relates to the preparation of amine derivatives. N-methyl-1-alkylthio-2-nitroethenamine derivatives are useful intermediates in the preparation of ranitidine and other histamine I 1 antagonists having a -NHC (= CHNC> 2) NHCH 3 end group, such as nizatidine.

Such intermediates have previously been prepared by directly replacing a single alkylthio group in 2,2-bisalkylthio-1-nitroethylene derivatives by reaction with methylamine. However, this reaction is not selective and yields N-methyl-1-alkylthio-2-nitroethylenes which are contaminated with both the unreacted starting material and the bis-aminated by-product, i.e. 2,2-bismethylamino-2-nitroethylene.

British Patent 1,421,792 discloses compounds of the formula

R2S. NHR

II

- wherein X and Y, which may be the same or different, each represent hydrogen, nitro, cyano or the group SC 1 Ar (where Ar is optionally substituted phenyl) except that X and Y cannot both represent hydrogen, R is lower alkyl and R 2 is lower alkyl or aralkyl, preparation by the following reaction sequence 2 90061

CH2XY -> s NHR -> R2S NHR

RN = C = S, / R2Hal \

C C

I II

CHXY C

/ \

X Y

The substituted methane CH2XY is said to be reacted with the isothiocyanate ester after treatment with a strong base such as sodium hydride or sodium hydroxide. In the only specific example of this reaction shown, methyl isothiocyanate is reacted with malononitrile in the presence of sodium hydride and dimethylformamide. The second step of the reaction is performed by adding methyl iodide in dimethylformamide.

Chem. Ber. 100 591-604 (1967) discloses the reaction of phenyl isothiocyanate with nitromethane and also discloses that the reaction should be carried out in the presence of sodium hydride in dimethylformamide. The reaction is followed by methylation of methyl iodide 11a to give N-phenyl-1-methylthione tr oethene amine a.

The use of sodium hybrid in dimethylformamide taught in the documents referred to above is not suitable for large-scale preparations due to the known hazards associated with the combination of these reagents.

The process according to the present invention is characterized in that the process consists of a combination of the following process steps:

- methyl isothiocyanate is reacted with a carbanion of nitromethane in dimethyl sulphoxide, optionally in the presence of an additional solvent, the carbanion of nitromethane being formed in situ from nitromethane and a suitable base, to form a compound of formula I

3 90061 QS \ c = chno2 (I) ch3nh ^ where Q is hydrogen or a base-derived cation, wherein the compound of formula I wherein Q is a cation is optionally treated with a suitable acid to form a compound wherein Q is hydrogen, - the compound of formula I thus obtained wherein Q is hydrogen or a cation is reacted in a manner known per se with a suitable alkylating agent, and - the N-methyl-1-alkylthio-2-nitroethyleneamine derivative of the formula II thus obtained is

Risx c = chno2 (II) ch3nh ^ where

R 1 is a C 1-4 alkyl group, is reacted with a suitable amine in a known manner.

A compound of formula (I) wherein Q is hydrogen or a cation may be treated with a suitable alkylating agent such as an alkyl halide (e.g. methyl bromide or methyl iodide) or dialkyl sulphate (e.g. dimethyl sulphate) to form an N-methyl-1-alkylthio of formula (II). -2-nitro-eteeniamiinijohdannainen

Rls \ c = chno2 (II) ch3nh ^ where

R 1 is a C 1-4 alkyl group, preferably methyl.

4 90061

It has now surprisingly been found that the formation of a compound of formula (I) and thus the preparation of N-methyl-1-alkylthio-2-nitroethylamine derivatives of formula (II) takes place in particularly good yield, provided that the reaction between methyl isothiocyanate and nitromethane carbanion the reaction is carried out using dimethyl sulfoxide as a solvent, optionally in the presence of a solvent. When the reaction of methyl isothiocyanate with nitromethane is carried out in the presence of sodium hydride as a base, the yield increases from 22% when dimethylformamide is used as the solvent to 59% when dimethyl sulfoxide is used as the solvent.

The compound of formula (I) is best reacted in situ with an alkylating agent. In this case, the reaction is also generally carried out in the same solvent medium.

In a preferred process of the invention for the preparation of N-methyl-1-alkylthio-2-nitroethyleneamine derivatives of formula (II), the methyl isothiocyanate is reacted with a carbanion of nitromethane to give a compound of formula (I) in situ, followed by alkylation. with the appropriate alkylating agent referred to above by carrying out the reaction in the presence of dimethyl sulfoxide used as a solvent, optionally in the presence of a solvent. Suitable solvents, the choice of which depends on the base used, include aprotic solvents (such as dimethylformamide and N-methylpyrrolidinone) and water.

In a particular embodiment of this process, a compound of formula (I) prepared in situ is methylated using a suitable methylating agent such as methyl iodide or dimethyl sulphate to give N-methyl-1-methylthio-2-nitroethenamine, i. a compound of formula (II) having methyl.

The compounds of formula (I) may exist in tautomeric forms, and formula (I) encompasses all such forms.

5 90061

The process of the present invention provides, in good yield, the N-methyl-1-alkylthio-2-nitroethylenamines of formula (II) and in a form which can be used without further purification for the preparation of compounds such as ranitidine. Thus, a process using inexpensive, simple, and commercially available starting materials can generally be performed safely on a large scale and under mild conditions. The process according to the invention can be applied in particular to the preparation of N-methyl-1-methylthio-2-nitroethyleneamine.

The carbanion of nitromethane is conveniently prepared in situ by treating the nitromethane with a suitable base.

Particularly suitable bases include alkali metal hydrides, time metal hydroxides or time metal alkoxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium propoxide and potassium tert-butoxide. Alkali metal hydroxides are preferred and when the base is an alkali metal hydroxide, it may be added as an aqueous solution.

When a compound of formula (I) prepared in situ is subsequently reacted with an alkylating agent, the same solvent medium can generally be used in the alkylation reaction.

The reaction temperature is suitably between 0 and 50 ° C. The reaction is best performed at room temperature.

To prepare compounds, especially histamine N 1 antagonists containing -NHC (= CHNO 2) NHCH 3 end groups, the N-methyl-1-alkylthio-2-nitroethyleneamine derivative of formula (II) prepared as described above is reacted with a suitable amine. Thus, in accordance with the present invention, ranitidine can be prepared from 2- [5- (N, N, -dimethylaminomethyl) -2-furanmethylthio] ethylamine used as an amine, preferably using N-methyl-1-methylthio as the compound of formula (II). -2-nitroethenamine. The reaction may be carried out in a solvent such as water, optionally with heating.

The invention is illustrated by the following non-limiting examples:

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 (with 7.5% water) (2.5 ml) was added over 2 minutes maintaining the temperature at 20-26 ° C. The solution was stirred for a further 0.5 hours at room temperature and methyl iodide (3.19 g) was added dropwise over 2 minutes keeping the temperature at 22-24 ° C. Stirring was continued for 1 hour at room temperature and then the solution was 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 to 116.5 ° C.

(ii) Nitromethane (1.32 g) in dimethyl sulfoxide (containing 7.5%) (5 ml) was added over 5 minutes at 0-5 ° C 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 30 minutes methyl isothiocyanate (1.58 g) in dimethyl sulfoxide (with 7.5% water) (5 ml) was added over 5 minutes. The mixture was treated with methyl iodide (3.07 g) in dimethyl sulfoxide (with 7.5% water) (5 ml) keeping the temperature below 30 ° C, after which the resulting solution was stirred overnight. The solvent was removed, water (50 ml) was added to the residue, and the mixture was worked up by the method of Example 1 (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 minutes to a suspension of potassium tert-butoxide (1.1 g) in dry dimethyl sulfoxide (9 ml) under a nitrogen atmosphere 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 at room temperature for 0.5 hours and then methyl iodide (1.52 g) was added dropwise over 2 minutes keeping the temperature at 20-25 ° C. The solution was stirred at room temperature for 2 hours, diluted with water (100 ml) and worked up by the method of Example 1 (i) to give the title compound (0.196 g), yield: 66.1%, m.p. 113-115 ° C.

(iv) Supplied by the method of Example 1 (iii), but potassium tert. butoxide was replaced by sodium hydroxide11a (1.6 g) using nitromethane (2.44 g) in dimethyl sulfoxide (with 7.5% water) (35 ml) and methyl isothiocyanate (2.92 g) in dimethyl sulfoxide (with 7.5% water) (5 ml) followed by alkylation of methyl iodide11a (6.25 g).

There was thus obtained the title compound (2.64 g), yield: 44.5%, m.p. 113-116 ° C.

Example 2 N-methyl-1-methylthio-2-nitroethenamine

Potassium hydroxide (20.88 g) in water (12.4 ml) was added to a stirred solution of methyl isothiocyanate (27.22 g) and nitromethane (22.75 g) in dimethyl sulfoxide (185 ml) maintaining the temperature at 10-15 ° C. Stirring was continued for 60 minutes at 10-15 ° C, after which the solution was divided into two equal portions (120 ml each).

8,90061 (i) The first portion was stirred at 10-15 ° C while dimethyl sulfate (17.62 mL) was added over 15 minutes. Stirring was continued for 30 minutes, after which time water (90 ml) was added and the mixture was treated according to the method of Example 1 (i) to give the title compound (12.45 g) in yield: 45.1%, m.p. 112.5-114 ° C.

(ii) A second portion was treated with methyl iodide (11.66 ml) and worked up in the same manner to give the title compound (14.61 g), yield: 52.9%, m.p. 112.5-114 ° C.

Example 3 N-methyl-1-methylthio-2-nitroethenamine

Nitromethane (1.05 g) and methyl isothiocyanate (1.26 g) in dry dimethyl sulfoxide (6.71 g) were added over 70 minutes to a stirred suspension of sodium hydroxide (0.41 g) in dimethylformamide (4.3 L) keeping the temperature below 25 ° C. Stirring was continued for 3 hours, after which methyl iodide (2.45 g) was added over 15 minutes keeping the temperature below 30 ° C. The resulting solution was stirred for 30 minutes, water (9 ml) was added and the solution was treated by the method of Example 1 (i) 1 to give the title compound (1.30 g), yield: 50.8%, m.p. 113.5-115.5 ° C.

"'· Example 4 N-methyl-1-methylthio-2-nitroethylene amine

Nitromethane (22.7 g) was added over 8 minutes to a stirred suspension of flaky potassium hydroxide (20.86 g) in dimethyl sulfoxide (157.5 ml) and water (6.4 ml) maintaining the temperature at 15-20 ° C. A solution of methyl isothiocyanate (27.19 g), dimethyl sulfoxide (27 ml) and water (1 ml) was added dropwise over 20 minutes maintaining the temperature at 15-20 ° C. Stirring was continued for a further 1 hour at room temperature 99061 and methyl iodide (52.78 g) was added over 10 minutes keeping the temperature at 15-20 ° C. The resulting mixture was stirred for a further 1 hour at room temperature, after which further (178 ml) was added and the mixture was treated by the method of Example 1 (i) to give the title compound (25, 86 g), yield 46.6%, m.p. 113-116 ° C.

Example 5 N- [2- [5- (Dimethylamino) methyl] -2-furanylmethylthiolethyl] -N'-methyl-2-nitro-1,1-ethylenediamine 2- [5- (Ν, Ν-dimethylaminomethyl) -2-furanmethylthio] ethyl A solution of the amine (32.1 g) in water (25 ml) was added dropwise over 4 hours to a stirred solution of N-methyl-1-methylthio-2-nitroethyleneamine (23 g) in water (40 ml) at 50 ° C. The reaction mixture was heated. for a further 2 hours at 50 [deg.] C. and then heated to 90 [deg.] C. To the solution was added methyl isobutyl ketone (150 ml) and the water was removed by azeotropic distillation. ) and the combined filtrate and washings were cooled to 0. The title compound (39 g), mp 68-70, crystallized and was separated by filtration.

Claims (3)

10 90061 A process for preparing a compound containing an -NHC (= CHNO 2) NHCH 3 end group, characterized in that the process consists of a combination of the following process steps: - methyl isothiocyanate is reacted with nitromethane carbanion in dimethyl sulfoxide, optionally in the presence of in situ from nitromethane and a suitable base to form a compound of formula I QS ^ C = CHNO 2 (I) CH 3 NH 4 wherein Q is hydrogen or a cation derived from a base, wherein the compound of formula I wherein Q is a cation is optionally treated with a suitable acid to form a compound wherein Q is hydrogen, - the compound of formula I thus obtained, in which Q is hydrogen or a cation, is reacted in a manner known per se with a suitable alkylating agent, and - the N-methyl-1-alkylthio-2-nitroethyleneamine derivative of formula II thus obtained is R1S \ c = chno2 (II) ch3nh ^ where R! is a C 1-4 alkyl group, is reacted with a suitable amine in a known manner. 11 90061 Process according to Claim 1, characterized in that the compound containing the NHC (= CHNC> 2) NHCH 3 end group is ranitidine and the amine is 2- [5- (N, N-dimethylaminomethyl) -2 -furaanimetyylitiö] -ethylamine. Process according to Claim 2, characterized in that the compound of the formula II is N-methyl-1-methylthio-2-nitroethenamine. 12 90 061