JPH0643382B2 - Method for producing amine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to the production of amine derivatives. N-methyl-1
- alkylthio-2-nitro-ethene derivatives are ranitidine and -NHC (= CHNO ₂₎ NHCH ₃ terminus Other histamine containing a group H ₂ - are useful as intermediates in the preparation of antagonists for example nizatidine.

[Problems to be Solved by Prior Art and Invention]

These intermediates are 2,2-by reaction with methylamine.
It has been conventionally prepared by the direct substitution of a single alkylthio group of a bisalkylthio-1-nitroethene derivative. However, this reaction lacks selectivity and the unreacted starting material and the bis-aminated by-product 2,2-bismethylamino-1-
This results in N-methyl-1-alkylthio-2-nitroethene mixed with both nitroethene.

British Patent 1421712 is a formula [In the formula, X and Y may be the same or different and each is hydrogen,
Nitro, cyano or SO ₂ Ar (wherein Ar is optionally substituted phenyl) wherein X and Y are not both hydrogen and R represents lower alkyl and R ² represents lower alkyl or aralkyl ] The compound of It is disclosed to be manufactured by The substituted methane CH ₂ XY is said to be reacted with an isothiocyanate ester after treatment with a strong base such as sodium hydride or sodium hydroxide. In the only specific embodiment of this reaction disclosed, methyl isothiocyanate is reacted with malononitrile in the presence of sodium hydride and dimethylformamide. The second stage of the reaction is carried out by adding dimethylformamide methyl iodide.

Chem, Ber 100 , 591-604 (1967) discloses the reaction of phenylisothiocyanate with nitromethane and also states that the reaction must be carried out in the presence of sodium hydride in dimethylformamide. Disclosure. The reaction involves methylation with methyl iodide to produce N-phenyl-1-methylthio-2-nitroethenamine.

The use of sodium hydride in dimethylformamide taught by the aforementioned references is not suitable for large scale production due to the well known hazards associated with the combination of these reactants.

[Means for solving problems]

The present invention comprises a compound of formula (I) which comprises reacting methylisothiocyanate with a carbanion of nitromethane in the presence of dimethylsulfoxide as a solvent and optionally in the presence of a cosolvent (CO-Solvent). A method of making the compound of claim 1 is provided. The carbanion is conveniently generated in situ from nitromethane by reaction with a suitable base. In formula (I), Q represents a cation derived from the base used to prepare the carbanion of nitromethane.

Compounds of formula (I) where Q is a hydrogen atom may be prepared from compounds of formula (I) where Q is a cation by the addition of one equivalent of a suitable acid.

Compounds of formula (I) where Q is hydrogen or a cation have been treated with a suitable alkylating agent such as an alkyl halide (eg methyl bromide or methyl iodide) or a dialkyl sulphate (eg dimethyl sulphate). Formula (II) Prepare an N-methyl-1-alkylthio-2-nitroethenamine derivative of the formula: wherein R ₁ is a C _1-4 alkyl group, preferably methyl.

Formation of a compound of formula (I) and N-methyl-1 of formula (II) if the reaction of methylisothiocyanate with the carbanion of nitromethane is carried out in dimethylsulfoxide as solvent and optionally in the presence of a cosolvent. It was surprisingly found that the preparation of the -alkylthio-2-nitroethenamine derivatives occurs in particularly good yields. Therefore, when the reaction of methylisothiocyanate and nitromethane is carried out in the presence of sodium hydride as a base, the yield is from 22% when dimethylformamide is used as a solvent to 59% when dimethylsulfoxide is used as a solvent. Increase.

Preferably the compound of formula (I) is reacted in situ with the alkylating agent and in this case the reaction will also generally be carried out in the same solvent medium.

A preferred method according to the invention for preparing N-methyl-1-alkylthio-2-nitroethenamine derivatives of formula (II) is the reaction of methyl isothiocyanate with the carbanion of nitromethane to give compounds of formula (I). The reaction then consists in situ of carrying out an alkylation with a suitable alkylating agent as described above in the presence of dimethylsulfoxide as solvent and optionally in the presence of a cosolvent. The choice depends on the base used but suitable cosolvents are aprotic solvents such as dimethylformamide and N-.
Methylpyrrolidinone) and water.

A particular embodiment of the present invention is the methylation of an in situ prepared compound of formula (I) with a suitable methylating agent such as methyl iodide or dimethylsulfate to give N-methyl-1-methylthio-2. - comprising nitro ethene amine i.e. R ₁ to obtain a compound of formula (II) is methyl.

The compounds of formula (I) are new. They can exist in tautomeric forms and formula (I) is meant to include all these forms. Compounds of formula (I) in which Q represents hydrogen or an alkali metal cation (particularly sodium or potassium) are specific examples of compounds of formula (I).

The process of the invention produces N-methyl-1-alkylthio-2-nitroethenamines of formula (II) in the form used to produce compounds such as ranitidine without further purification and in high yields. This method, which is inexpensive, simple, and uses commercially available raw materials, will generally be safe on large scale and under mild conditions. The method of the present invention is particularly applicable to the production of N-methyl-1-methylthio-2-nitroethenamine.

The carbanion of nitromethane is conveniently prepared in situ by treating nitromethane with a suitable base. Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or alkali metal alkoxides such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tertiary-butoxide. Alkali metal hydroxides are preferred and when the base is an alkali metal hydroxide it will be added as an aqueous solution.

Subsequent reaction with an alkylating agent was made in situ (I)
The same solvent medium will generally be used for the alkylation reaction when carried out for the compounds of.

The temperature of the reaction is conveniently in the range 0-50 ° C. and the reaction is preferably carried out at room temperature.

According to another aspect, the present invention comprises reacting an N-methyl-1-alkylthio-2-nitroetheneamine derivative prepared as described above [Formula (II)] with a suitable amine --NHC (= Provided is a method for preparing a compound, especially a histamine H ₂ antagonist, having a CHNO ₂ ) NHCH ₃ end group. Therefore, according to this aspect of the invention, ranitidine preferably uses N-methyl-1-methylthio-2-nitroethenamine as the compound of formula (II) and 2- [5- (N, N) as the amine.
-Dimethylaminomethyl) -2-furanmethylthio] ethylamine. The reaction will be carried out in a solvent such as water, optionally with heating.

Examples The present invention is illustrated by the following examples, but in no way limited thereby.

Example 1 N-Methyl-1-methylthio-2-nitroethenamine (i) Nitromethane (1.25 g) in dimethylsulfoxide (containing 7.5% water) (18 ml) for 1 minute (18 ml) potassium hydroxide flakes (1.15 g). Was added to the suspension. A solution of methyl isothiocyanate (1.5 g) in dimethyl sulfoxide (containing 7.5% water) (2.5 ml) was added over 2 minutes keeping the temperature at 20-26 °. Add 0.5 more solution at room temperature
Methyl iodide (3.19 g) was added dropwise over 2 minutes with stirring and maintaining the temperature at 22-24 °. 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 (1.5g). Yield 49.4
%, Melting point 113-116.5 °.

(ii) Dimethyl sulfoxide (containing 7.5% water) (5 m
Nitromethane (1.32 g) in 1) was added to sodium hydride (0.52 g) in dimethyl sulfoxide (containing 7.5% water) (20 ml) at 0-5 ° C over 5 minutes. The mixture was allowed to come to room temperature and after another 30 minutes methyl isothiocyanate (1.58 g) in dimethylsulfoxide (containing 7.5% water) (5 ml) was added over 5 minutes.
Mixing the mixture with methyl iodide (3.0 ml) in dimethyl sulfoxide (containing 7.5% water) (5 ml) keeping the temperature below 30 °.
7 g) and the resulting solvent was stirred overnight. The solvent was removed, water (50 ml) was added to the residue and the mixture was treated according to the procedure of Example 1 (i) to give the title compound (1.88 g). Yield 58.7%, melting point 112-114
°.

(iii) Nitromethane (0.62 g) was added to dry dimethyl sulfoxide (9%) under a nitrogen atmosphere while maintaining the temperature at 20 to 25 °.
(3 ml) of potassium tert-butoxide (1.1 g) in 2 ml over 2 minutes. The mixture was stirred for 10 minutes and dimethyl sulfoxide (containing 7.5% water)
A solution of methyl isothiocyanate (0.715g) in (3ml) was added dropwise over 2 minutes. Stirring was continued at room temperature for 0.5 hours and then methyl iodide (1.52g) was added dropwise over 2 minutes, maintaining the temperature at 20-25 °. The solution was stirred for 2 hours at room temperature, diluted with water (100 ml) and treated according to the procedure of Example 1 (i) to give the title compound (0.9
6 g) was obtained. Yield 66.1%, melting point 113-115.5 °.

(iv) Following the procedure of Example 1 (iii) but substituting potassium tertiary-butoxide with sodium hydroxide (1.6 g),
Dimethyl sulfoxide (containing 7.5% water) (35 ml)
The title compound (2.64 g) was obtained by alkylation with methyl iodide (6.25 g) using methyl isothiocyanate (2.92 g) in nitromethane (2.44 g) and dimethyl sulfoxide (containing 7.5% water) (5 ml) in. g) was obtained. Yield 4
4.5%, melting point 113-116 °.

Example 2 N-Methyl-1-methylthio-2-nitroethenamine Potassium hydroxide (20.88 g) in water (12.4 ml) was added to methyl isothiocyanate (27.22 g) and nitromethane (22.75 g) in dimethyl sulfoxide (185 ml). ) Was added to the stirred solution and the temperature was maintained at 10-15 °. Stir 10
It was continued for 60 minutes at -15 ° and the solution was divided into two aliquots (120 ml each).

Part (1) such as (i) was stirred at 10 to 15 °, during which dimethyl sulphate (17.62 ml) was added over 15 minutes.
Stirring was continued for 30 minutes and water (90 ml) was added and the mixture was treated according to the procedure of Example 1 (i) to give the title compound (12.45 g). Yield 45.1%, melting point 112.5-114
°.

(ii) The second portion was treated with methyl iodide (11.66 ml) and treated in a similar manner to give the title compound (14.61 g).
Yield 52.9%, melting point 112.5-114 °.

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 to dimethylformamide while keeping the temperature below 25 °. (Four.
To a stirred suspension of sodium hydride (0.41g) in 3ml) was added over 70 minutes. Stirring was continued for 3 hours, then methyl iodide (2.45 g) was added over 15 minutes, keeping the temperature below 30 °. The resulting solution was stirred for 30 minutes, water (9 ml) was added and the solution treated according to the procedure of Example (i) to give the title compound (1.30 g). Yield 5
0.8%, melting point 113.5-115.5 °.

Example 4 N-Methyl-1-methylthio-2-nitroethenamine Nitromethane (22.7 g) keeping the temperature at 15-25 °.
To a stirred suspension of potassium hydroxide flakes (20.86 g) in dimethylsulfoxide (157.5 ml) and water (6.4 ml).
Added over a minute. Dimethyl sulfoxide (27m
l) and methyl isothiocyanate (27.) in water (1 ml).
The solution of 19 g) was added dropwise over 20 minutes while keeping the temperature at 15 to 25 °. Stirring is continued for another hour at room temperature and methyl iodide (52.7
8 g) was added over 10 minutes. The resulting mixture was stirred at room temperature for a further 1 hour then water (178 ml) was added and the mixture was treated according to the procedure of Example 1 (i) to give the title compound (25.68 g). Yield 46.6%, melting point 113
~ 116 °.

[Reference example]

N- [2- [5- (Dimethylamino) methyl-2-furanylmethylthio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine 2- [5- (in water (25 ml). N, N-Dimethylaminomethyl) -2-furanmethylthio] ethylamine (32.1
g) solution of N-methyl-1 in water (40 ml) at 50 °.
-Methylthio-2-nitroethenamine (23g) was added dropwise over 4 hours to a stirred solution. The reaction mixture was heated to 50 ° for a further 2 hours and then to 90 °. Methyl isobutyl ketone (150 ml) was added to the solution and water was removed by azeotropic distillation. The solution was cooled to 60 ° and charcoal (1.5g) was added. The mixture was passed, the charcoal residue was washed with methyl isobutyl ketone (50 ml) and the combined liquor and washings were cooled to 0 °. The title compound (39 g) mp 68-70 ° crystallized out and was collected.

Claims (12)

[Claims] 1. A general formula (Wherein Q is hydrogen, a cation derived from a suitable base or a C _1-4 alkyl group), wherein methyl isothiocyanate is added in the presence of dimethyl sulfoxide as a solvent. The carbanion of nitromethane (however, the carbanion of nitromethane is generated in situ from nitromethane and the base), and if necessary, a compound in which Q is a cation is added with an appropriate acid. Treating to produce a compound where Q is hydrogen and optionally alkylating a compound where Q is hydrogen or a cation to produce compound (I) wherein Q is C _1-4 alkyl. A process for producing a compound of general formula (I), characterized in that 2. The method according to claim 1, wherein the reaction is carried out in the presence of a cosolvent. 3. The method according to claim 1, wherein the base is an alkali metal hydroxide. 4. The method according to claim 3, wherein the alkali metal hydroxide is potassium hydroxide. 5. The method according to any one of claims 3 to 4, wherein the alkali metal hydroxide is an aqueous solution. 6. The method according to claim 1, wherein the base is an alkali metal hydride. 7. The method of claim 6, wherein the alkali metal hydride is sodium hydride. 8. The base is an alkali metal alkoxide,
The method according to claim 1. 9. The method of claim 8, wherein the alkali metal alkoxide is potassium tertiary butoxide. 10. The process according to claim 1, wherein the reaction with an alkylating agent is carried out on a compound (I) in which Q is an in situ produced cation or hydrogen. 11. The method according to any one of claims 1 to 10, wherein the alkylating agent is an alkyl halide or a dialkyl sulfate. 12. The process according to claim 1, for the preparation of compounds (I) in which Q is methyl, the alkylating agent being methyl iodide or dimethylsulfate.