KR870002019B1 - Process for preparation of amine derivatives - Google Patents

Abstract

Amine derivs. having formula (QS-)(CH3NH-)C=CHNO2 were prepd. by reacting methylisocyanate with carbanion of nitrome thane in the presence of DMS. Q=derived-cation from suitable base is used to generate carbanion of nitromethane in the same rxn.-system. (R'S-) (CH3NH-)C=CHNO2 was prepd. by reacting (QS-)(CH3NH-)C=CHNO2 with alkylating agent i.e. alkyl halide, dialkylsulfonate. Prepg. N- methyl-1-alkylthio-2-nitroetheneamine is useful for the intermediates of lanitidine contg. -NHC(=CHNO2)NHCH3 end gp. and other histamine H2-antagonist.

Description

Method for preparing amine derivative

It relates to a process for preparing the amine derivative of the present invention. N-methyl-1-alkylthio-2-nitroethenamine derivatives are intermediates for the preparation of ranitidine and other histamine H ₂ -antagonists containing -NHC (= CHNO ₂ ) NHCH ₃ end groups, such as nizatinine. useful.

Such intermediates have been prepared in the prior art by reacting a single alkylthio group in a 2,2-bisalkylthio-1-nitroethene derivative with methylamine to directly substitute it. However, this reaction lacks selectivity, resulting in N-methyl-1-alkylthio-2-nitro contaminated with unreacted starting material and 2,2-bismethylamino-1-nitroethene, a bis-amined byproduct. Provide ethene.

British Patent 1414292 describes a process for preparing compounds of Formula (A) according to the following scheme:

In the above scheme,

X and Y are the same or different and each is hydrogen, natro, cyano or SO ₂ Ar (where Ar is optionally substituted phenyl), provided that X and Y cannot both be hydrogen; Is lower alkyl and R ² is lower alkyl or aralkyl.

Substituted methane CH ₂ XY is reacted with isothiocyanate ester after strong base reaction such as sodium hydride or sodium hydroxide. In a particular embodiment of this reaction described, 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, p591 to 604 (1967), describe the reaction of phenyl isothiocyanate with nitromethane, and that the reaction must also be carried out in the presence of sodium hydride in dimethylformamide. The reaction is subsequently methylated with methyl iodide to yield N-phenyl-1-methylthio-2-nitroethenamine.

As taught in the above reference, the use of sodium hydride in dimethylformamide is unsuitable for large scale preparation in view of the known dangerous enzymes involved in mixing these reagents.

The present invention provides a process for preparing a compound of formula (I) wherein methyl isothiocyanate is reacted with carbanion of nitromethane in the presence of dimethyl sulfoxide as a solvent, optionally in the presence of a cosolvent. To provide.

Typically carbanion is generated in situ from nitromethane by reaction with a suitable base. In the compound of general formula (I), Q is a cation derived from the base used to produce the carbanion of nitromethane.

Compounds of formula (I) wherein Q is a hydrogen atom can be prepared from compounds of formula (I) wherein Q is a cation by adding one equivalent of a suitable acid.

Compounds of formula (I) wherein Q is hydrogen or a cation are treated with a suitable alkylating agent such as alkyl halide (e.g., methyl bromide or methyliodide) or dialkyl sulfate (e.g., dimethyl sulfate) N-methyl-1-alkylthio-2-nitroethenamine derivative of formula (II) is produced.

In the above formula,

R ₁ is a C _1-4 alkyl group, preferably methyl.

When the reaction of methyl isothiocyanate and nitromethane with carbanion is carried out in dimethyl sulfoxide as a solvent, optionally in the presence of a cosolvent, formation of a compound of formula (I) and N- of formula (II) The production of methyl-1-alkylthio-2-nitroethenamine derivatives takes place in particularly good yields. Thus, when methyl isothiocyanate is reacted with nitromethane in the presence of sodium hydride as the base, the yield increases from 22% when using dimethylformamide as solvent to 59% when using dimethyl sulfoxide in solvent.

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

A preferred process according to the invention for the preparation of N-methyl-1-alkylthio-2-nitroethene-amine derivatives of general formula (II) is to react methyl isothiocyanate with carbanion of nitromethane in situ. A compound of formula (I) is obtained in the interior, and then alkylated with a suitable alkylating agent as mentioned above, and the reaction is carried out in the presence of dimethyl sulfoxide as a solvent, optionally in the presence of a cosolvent. Suitable cosolvents to be selected depending on the base used are aprotic solvents (eg dimethyl-formamide and N-methyl-pyrrolidone) and water.

Particular embodiments of the process include N-methyl-1-methylthio-2-nitro by methylating a compound of formula (I) prepared in situ using a suitable methylating agent such as methyl iodide or dimethyl sulfate. Etheneamine, ie, obtaining a compound of formula (II) wherein R ₁ is methyl.

The compound of general formula (I) is a novel compound. These compounds may exist in tautomeric forms, and general formula (I) includes all such forms. The present invention further encompasses as compounds of general formula (I) wherein Q is hydrogen or an alkali metal cation (particularly sodium or potassium).

The process of the present invention provides N-methyl-1-alkylthio-2-nitroethenamine of the general formula (II) in a form that can be used to prepare compounds such as ranitidine without further purification and with good yields. To provide. Inexpensive, simple and commercially available starting materials can generally be safely carried out under mild conditions on a large scale. In particular, the method of the present invention is applicable to the production of N-methyl-1-methyl-thio-2-nitroethenamine.

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

If the compound of formula (I) prepared in situ is continuously reacted with an alkylating agent, the same solvent medium will generally be used for the alkylation reaction.

The range of reaction temperature is 0-50 degreeC normally, and it is preferable to carry out reaction at room temperature.

According to another aspect of the invention, the present invention is characterized in that the N-methyl-1-alkylthio-2-nitroethenamine derivative of the general formula (II) prepared as described above is reacted with a suitable amine. Provided is a method for preparing a compound containing -NHC (= CHNO ₂ ) NHCH ₃ endgroup, in particular histamine H ₂ antagonist. Thus, according to this aspect of the present invention from 2- [5- (N, N-dimethylaminomethyl) -2-furanmethylthio] ethylamine as amine, preferably N-methyl as compound of formula (II) Lanitinine can be prepared using -1-methylthio-2-nitroethenamine. The reaction can be carried out in a solvent such as water, optionally by heating.

The following examples illustrate the invention but do not limit the invention.

Example 1

N-methyl-1-methylthio-2-nitroethenamine

(i) Nitromethane (1.25 g) is 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 sulfoxide (containing 7.5% water: 2.5 ml) was added over 2 minutes while maintaining 20 to 26 ° C. After stirring the solution at room temperature for 0.5 hours, methyl iodide (3.19 g) is added dropwise over 2 minutes while maintaining 22-24 ° C. Stirring is continued for 1 hour at room temperature, then the solution is diluted with water (200 ml) and extracted with dichloromethane. The combined extracts are washed with water, evaporated to dryness and the residue is crystallized from 2-propanol to give the title compound (1.5 g) with a melting point of 113 to 116.5 ° C. in a yield of 49.4%.

(ii) Sodium hydride (0.52 g) in dimethyl sulfoxide (7.5% water: 20 ml) and nitromethane (1.32 g) in dimethyl sulfoxide (7.5% water: 5 ml) at 0-5 ° C. over 5 minutes. Add. The mixture is allowed to warm to room temperature and after 30 minutes methyl isothiocyanate (1.58 g) in dimethyl sulfoxide (7.5 ml water: 5 ml) is added over 5 minutes. The mixture is treated with methyl iodide (3.07 g) in dimethyl sulfoxide (5 ml containing 7.5% of water) while maintaining below 30 ° C. and the resulting solution is stirred overnight. The solvent was removed, water (50 ml) was added to the residue, and the mixture was finished following the procedure in Example 1 (i) to give the title compound (1.88 g) having a melting point of 112 to 114 ° C. in a yield of 58.7%. do.

(iii) Nitromethane (0.62 g) was added dropwise over 2 minutes to a suspension of potassium tert-butoxide (1.1 g) in anhydrous dimethyl sulfoxide (9 ml) under a nitrogen atmosphere maintained at 20-25 ° C. The mixture is stirred for 10 minutes, then a solution of methyl isothiocyanate (0.715 g) in dimethyl sulfoxide (7.5% water: 3 ml) is added dropwise over 2 minutes. Stirring is continued at room temperature for 0.5 hours, and then methyl iodide (1.52 g) is added dropwise over 2 minutes while maintaining at 20-25 ° C. Stir the solution at room temperature for 2 hours, dilute with water (100 ml) and finish according to the procedure of Example 1 (i) to give the title compound (0.96 g) with a melting point of 113 to 115.5 ° C. in a yield of 66.1%. To obtain.

(iv) Nitromethane (2.44 g) and dimethyl in dimethyl sulfoxide (7.5% water: 35 ml), following the procedure of Example 1 (iii) but using sodium hydroxide (1.6 g) instead of potassium tert-butoxide Subsequent alkylation with methyl iodide (6.25 g) using methyl isothiocyanate (2.92 g) in sulfoxide (7.5% water: 5 ml) afforded the title compound (2.64 g) having a melting point of 113 to 116 ° C. Obtained in% yield.

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) while maintaining 10 to 15 ° C. do. Stirring is continued at 10-15 ° C. for 60 minutes and then the solution is divided into two equal portions (120 ml each).

(i) The first fraction is stirred at 10 to 15 ° C. while dimethyl sulfate (17.62 ml) is added over 15 minutes. Stirring was continued for 30 minutes, then water (90 mL) was added and finished according to the procedure of Example 1 (i) to give the title compound (12.45 g) with a melting point of 112.5 to 114 ° C. in a yield of 45.1%.

(ii) The second fraction was treated with methyl iodide (11.66 mL) and then finished in the same manner to give the title compound (14.61 g) having a melting point of 112.5 to 114 ° C. in a yield of 52.9%.

Example 3

N-methyl-1-methylthio-2-nitroethenamine

A stirred suspension of sodium hydride (0.41 g) in dimethylformamide (4.3 mL) while maintaining nitromethane (1.05 g) and ethyl isothiocyanate (1.26 g) in anhydrous dimethyl sulfoxide (6.71 g) below 25 ° C. Add in 70 minutes. Stirring is continued for 3 hours, and then methyl iodide (2.45 g) is added over 15 minutes while maintaining below 30 ° C. The resulting solution was stirred for 30 minutes, water (9 mL) was added, and the solution was finished according to the procedure of Example 1 (i) to give 50.8% of the title compound (1.30 g) having a melting point of 113.5 to 115.5 ° C. Obtained in yield.

Example 4

N-methyl-1-methylthio-2-nitroethenamine

Nitromethine (22.7 g) was added to the suspension of flaky potassium hydroxide (20.86 g) in dimethyl sulfoxide (157.5 mL) and water (6.4 mL) over 8 minutes, maintaining 15-20 ° C. A solution of dimethyl sulfoxide (27 mL) and dimethyl isothiocyanate (27.19 g) in water (1 mL) was added dropwise over 20 minutes while maintaining 15-25 ° C. After further stirring at room temperature for 1 hour, methyl iodide (52.78 g) is added over 10 minutes while maintaining 15-20 ° C. The resulting mixture was further stirred for 1 hour at room temperature, followed by addition of water (178 mL), followed by the procedure of Example 1 (i) to give the title compound (25.68 g) having a melting point of 113 to 116 ° C. in a yield of 46.6%. Obtained as

Example 5

N- [2- [5- (dimethylamino) methyl-2-furanylmethylthio] ether] -N'-methyl-2-nitro-1,1-ethenediamine

A solution of 2- [5- (N, N-dimethylaminomethyl) -2-furan-methylthio] ethylamine (32.1 g) in water (25 ml) was added with N-methyl-1-methylthio- in water (40 ml). To a stirred solution of 2-nitroethenamine (23 g) is added dropwise at 50 ° C. over 4 hours. The reaction mixture is further heated at 50 ° C. for 2 hours and then to 90 ° C. Methyl isobutyl ketone (150 ml) is added to the solution, followed by azeotropic distillation to remove the water. The solution is cooled at 60 ° C. and charcoal (1.5 g) is added. The mixture is filtered and the charcoal residue is washed with methyl isobutyl ketone (50 mL), then the mixed filtrate and wash are cooled to 0 ° C. The title compound (39 g) having a melting point of 68 to 70 DEG C is crystallized and filtered.

Claims (18)

A process for preparing a compound of formula (I) characterized by reacting methyl isothiocyanate with carbanion of nitromethane in the presence of dimethyl sulfoxide as a solvent.

In the above general formula, Q represents a cation derived from a suitable base used to generate carbanion of nitromethane in situ. The method of claim 1 wherein dimethylsulfoxide is used in conjunction with a cosolvent. The method of claim 1 or 2, wherein the base is an alkali metal hydroxide. The method according to claim 3, wherein the base is an alkali metal hydroxide used as an aqueous solution. 4. The process of claim 3 wherein the alkali metal hydroxide is potassium hydroxide. The process according to claim 1 or 2, wherein the base is an alkali metal hydride or an alkali metal alkoxide. The method of claim 6, wherein the base is sodium hydride or potassium tert-butoxide. Methyl isothiocyanate is reacted with carbanion of nitromethane in the presence of dimethyl sulfoxide as a solvent to prepare a compound of formula (I), and then the resulting compound of formula (I) is reacted with a suitable alkylating agent to N-methyl-1-alkylthio-2-nitroethenamine derivatives of formula (II), characterized in that the formation of N-methyl-1-alkylthio-2-nitroethenamine derivatives of formula (II) Method of Making Derivatives.

Wherein Q represents a cation derived from a suitable base used to generate carbanion of nitromethane in situ, and R ₁ represents a C _1-4 alkyl group. A process for preparing an N-methyl-1-alkylthio-2-nitroethenamine derivative of formula (II), characterized by reacting a compound of formula (I) with a suitable alkylating agent.

In the formulas above, Q represents hydrogen or a cation derived from a suitable base and R ₁ represents a C _1-4 alkyl group. The process according to claim 8, wherein the reaction with the alkylating agent is carried out on the compound of general formula (I) prepared in situ. The process according to claim 8 or 10, wherein the alkylating agent is an alkyl halide or dialkyl sulfate. 12. The process according to claim 11, wherein R ₁ is methyl, using methyl iodide or dimethyl sulfate as the alkylating agent. In the presence of dimethyl sulfoxide as a solvent, methyl isothiocyanate is reacted with caranion of nitromethane to prepare a compound of formula (I), and the resulting compound of formula (I) is reacted with a suitable alkylating agent (ⅱ) of N- methyl-1-alkylthio-2-one prepared in the ten derivatives nitro, and then continue to characterized the general formula (ⅱ) Sikkim appropriate amine and reacting the derivative of -NHC (= CHNO ₂ ) A process for preparing a compound containing NHCH ₃ endgroups.

In the above general formula, Q represents a cation derived from a suitable base used to generate carbanion of nitromethane in situ, and R ₁ represents a C _1-4 alkyl group. The method of claim 13, The compound containing -NHC (= CHNO ₂ ) NHCH ₃ endgroup is ranitidine and the amine is 2- [5-N, N-dimethylaminomethyl) -2-furanmethylthio] ethylamine. The method of claim 14, wherein the compound of formula (II) is N-methyl-1-methylthio-2-nitro-ethenamine. The method of claim 4 wherein the alkali metal hydroxide is potassium hydroxide. 10. The method of claim 9, wherein the alkylating agent is an alkyl halide or dialkyl sulfate. 18. The process of claim 17, wherein R ₁ is methyl using methyl iodide or dimethyl sulfate as alkylating agent.