FI82239B - FRAMSTAELLNING AV AMINDERIVAT. - Google Patents

Description

1 82239

Preparation of ami im leads - Framstä11 Ning av aminderivat

The present invention relates to the preparation of amine derivatives. N-methyl-1-yl-thio-2-nitroethylamine derivatives are useful intermediates in the preparation of ranitidine and other histamine H2 antagonists having a -NHC (= CHNO2) NHCH3 terminal group, such as nizatidine.

Such intermediates have previously been prepared by directly reacting a single alkylthio group in 2,2-bisylthio-1-nitroethylene derivatives by reaction with methylamine. However, this reaction is not selective and gives 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-1-nitroethylene.

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

R2S NHR

II

c wherein X and Y, which may be the same or different, each represent hydrogen, nitro, cyano or SO 2 Ar (wherein 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

CH2XY -> Sv NHR -> R2S NHR

RN = C = S / R2Ha 1 \ /

X C C

I II

CHXY C.

X * ^ ^ Y

2,82239

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 carried out 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 with methyl iodide to give N-phenyl-1-methylthione troethenamine.

The use of sodium hydride 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 present invention provides a process for the preparation of a compound of formula (I) QS 1 C = CHNO 2 (I) CH 3 NH 4 wherein the methyl isothiocyanate is reacted with a carbanion of nitromethane in the presence of dimethyl sulfoxide as a solvent, optionally with a co-solvent. The carbanion is conveniently formed in situ from nitromethane by reaction with a suitable base. In formula (I), Q is a cation derived from the base used to prepare the carbanion of nitromethane.

3,82239

A compound of formula (I) wherein Q is a hydrogen atom may be prepared from a compound of formula (I) wherein Q is a cation by the addition of one equivalent of a suitable acid.

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 a dialkyl sulphate (e.g. dimethyl sulphate) to form an N-methyl sulphate of formula (I). my alkylthio due to troethylene amine

R1S

C = CHNO 2 (M)

CH3NH

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

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-nitroethanamine derivatives of formula (II) takes place in particularly good yield, provided that the reaction between methyl isothiocyanate and nitromethane carbanion the reaction is performed using dimethyl sulfoxide as a solvent, optionally in the presence of a co-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 to 35 when dimethyl iformamide is used as the solvent to 59 to 35 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 1 solvent medium.

4,82239

In a preferred process of the invention for the preparation of N-methyl-1-alkylthio-2-nitroethyleneamine derivatives of formula (II), methyl isothiocyanate is reacted with a carbanion of nitromethane to give a compound of formula (I) in situ, followed by alkylation as described above. with the indicated suitable alkylating agent by carrying out the reaction in the presence of dimethyl sulfoxide used as a solvent, optionally in the presence of a co-solvent. Suitable co-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 acetate to give N-methyl-1-methylthio-2-nitroethenamine, i. a compound of Formula (II) wherein R 1 is methyl.

The compounds of formula (I) are novel. They may exist in tautomeric forms, and formula (I) encompasses all such forms. Compounds of formula (I) wherein Q is hydrogen or an early metal cation, especially sodium or potassium) are also part of the invention.

The process of the present invention provides, in good yield, N-methyl-1-alkylthio-2-nitroethyleneamines of formula (II) and in a form which can be used without further purification to prepare 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-nitroethenamine.

5,82239

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

Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or sodium hydroxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tert-butoxide. Early metal hydroxides are preferred, and when the base is early metal hydroxide, it can be added as a water 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.

The invention also provides a process for the preparation of compounds, in particular histamine H 2 antagonists, containing an NHC (= CHNO 2) NHCH 3 end group. In this method, an N-methyl-1-alkylthio-2-nitroetheneamine derivative of formula (II) prepared as described above is reacted with a suitable amine. Thus, in accordance with part of this invention, ranitidine can be prepared from 2- [5- (N, N-dimethylaminomethyl) -2-furanmethylthio] ethylamine used as an amine, preferably using N-methyl-1-methylthio-2-nitroethenamine as the compound of formula (II). 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: 6,82239

Example 1 N-methyl-1-methylthio-2-nitroethyleneamine (i) Nitromethane (1.25 g) was added over 1 minute to a suspension of flaky potassium hydroxide (1.15 g) in dimethyl sulfoxide (7.5%). water) (18 ml). A solution of methyl isothiocyanate (1.5 g) in dimethyl oxide (containing 7.5 SS of 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 SS, sp. 113-116,5®C.

(ii) Nitromethane (1.32 g) in dimethyl sulfoxide (containing 7.5 SS of water) (5 ml) was added over 5 minutes at 0-5 ° C to sodium hydride (0.52 g). In 1 f oxide (containing 7.5 SS of water) (20 mL). The mixture was allowed to warm to room temperature and after 30 minutes methyl isothiocyanate (1.58 g) in dimethyl oxide (containing 7.5 SS of water) (5 ml) was added over 5 minutes. The mixture was treated with methyl iodine di 11a (3.07 g) in dimethyl sulfoxide (with 7.5 Ss of 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 SS, 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 7,82239 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 (0.96 g), yield 66.1%, m.p. 113-115,5®C.

(iv) The procedure of Example 1 (iii) was followed, but potassium tert-butoxide was replaced by sodium hydroxide (1a) (1.6 g), using nitromethane (2.44 g) in dimethyl sulfoxide (containing 7.5% water) (35 ml) and methylene chloride. isothiocyanate (2.92 g) in dimethyl sulfoxide (with 7.5% water) (5 ml) followed by alkylation of methyl iodide (6.25 g). There was thus obtained the title compound (2.64 g), yield 44.5 X, m.p. 113-116 ° C.

Example 2 N-methyl-1-methylthio-2-nitroethyleneamine

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 oxide (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).

(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 8,82239 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), yield 45.1 *, m.p. 112.5 to 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-nitroethyleneamine

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 hydride (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 according to the method of Example 1 (i) to give the title compound (1.30 g), yield: 50.8 °, m.p. 113.5 to 115.5 <> C.

Example 4 N-methyl-1-methylthio-2-nitroethyleneamine

Nitromethane (22.7 g) was added over 8 minutes to a stirred suspension of flaky potassium hydroxide (20.86 g) in dimethyloxide (157.5 ml) and water (6.4 ml) maintaining the temperature at 15-20 ° C. A solution of methyl isothiocyanate (27.19 g), dimethyl 1-oxide (27 ml) and water (1 ml) was added dropwise over 20 minutes maintaining the temperature at 15-25 ° C. Stirring was continued for a further 1 hour at room temperature 9 82239 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, then water (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-Γ 2-Γ 5- (dimethylaminomethyl-2-furanylmethylthiol-ethyl-N'-methyl-2-nitro-1,1-ethylenediamine 2- [5- (N, N-dimethylaminomethyl) -2 A solution of -furan-methylthio] ethylamine (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. Methyl isobutyl ketone (150 ml) was added to the solution, and water was removed by azeotropic distillation, and the solution was cooled to 60 [deg.] C. and carbon (1.5 g) was added, the mixture was filtered, the carbon residue was washed with methyl isobutyl ketone (50 ml) and the combined filtrate and washings were cooled to 0. The title compound (39 g), mp 68-70 ° C crystallized and separated by filtration.

Claims (6)

10 82239 A process for the preparation of a compound of formula (I) QS 2 C = CHNO 2 (I) CH 3 NH wherein Q is hydrogen, a cation from a suitable base or C 1 -C 4 alkyl, wherein the methyl isothiocyanate is reacted with a carbanion of nitromethane in a solvent, optionally in the further presence of an additional solvent, the carbanion of nitromethane being formed in situ from nitromethane and a base, and optionally further treating the compound where Q is a cation with a suitable acid to form a compound wherein Q is hydrogen, and optionally alkylating the compound wherein Q is hydrogen or cation To form a compound of formula I wherein Q is C 1 -C 4 alkyl, characterized in that the solvent in the reaction between the methyl isothiocyanate and the carbanion of nitromethane is dimethyl sulfoxide. Process according to Claim 1, characterized in that the base is an alkali metal hydroxide, preferably potassium hydroxide, in particular in the form of an aqueous solution. Process according to Claim 1, characterized in that the base is an alkali metal hydride, in particular sodium hydride, or an alkali metal alkoxide, in particular potassium tert-butoxide. Process according to one of Claims 1 to 3, characterized in that the reaction with the alkylating agent is carried out with a compound of the formula (I) prepared in situ, in which Q is hydrogen or a cation. 11 82239 Process according to one of Claims 1 to 4, characterized in that the alkylating agent is an alkyl halide or a dialkyl sulphate. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, wherein Q is methyl, characterized in that the alkylating agent is methyl iodide or dimethyl sulphate i. 82239