KR870001166B1 - Process for preparing furan derivatives - Google Patents

Abstract

Ranitidine having formula (I) is produced from methylation of (II). The methylating agents are methyl halide, dimethyl sulfate or methyl sulfonic ester. The rxn. performed in the presence of base i,e, sodium (or potassium)carbonate(or bicarbonate), pyridine or triethylamine. The rxn. temp. is 0-50deg. N-[2-[[[5-[methylamino) methyl -2-furanyl methyl thio ethyl -N'-2-nitro-1,1ethenediamine salt with HCl in MeOH and K2CO3 are treated with iodomethane for 5 hr to give N-[2-[[[5-[dimethylamino)methyl 2ffuranyl -methyl thio ethyl - N'-methyl-2-nitro-1, 1-ethene diamine.

Description

Method for preparing furan derivative

The present invention relates to a novel process for the preparation of furan derivatives.

Furan derivatives of formula (I), known as ranitidine, are described in British Patent Specification 1565966 as a potent and selective H ₂ -antagonist.

The present invention provides a novel and useful method for preparing ranitidine of formula (I), characterized by reacting a compound of formula (II) with a methylating agent.

Wherein R is a hydrogen atom or a methyl group.

Suitable methylating agents include methyl halides such as methyl bromide or methyl iodide, dimethyl sulfate, or methyl sulfonic acid esters such as methyl methane sulfonate or methyl P-toluene-sulfonate.

The reaction may optionally be carried out in the presence of a base, or a salt such as an alkali metal methylsulfinyl methide.

Suitable bases include carbonates such as sodium carbonate or potassium carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, or organic bases such as pyridine or triethylamine.

When the reaction is carried out in the presence of a base, the compound of formula (II) may conveniently be used in the form of an acid addition salt such as hydrochloride salt.

When the reaction is carried out in the presence of alkali metal methylsulfinylmethide salts, for example potassium salt or more particularly sodium salt NaCH ₂ S (O) CH ₃ , they are in situ alkali metal hydrides such as sodium hydride and dimethyl It can be conveniently prepared from sulfoxide.

When the compound of formula (II) is reacted with a methylating agent alone or in the presence of a base, the reaction is carried out with amides (for example dimethylformamide or N-methyl pyrrolidone), or acetonitrile, or alcohol ( For example in methanol or ethanol), or in aprotic solvents such as ketones (eg methylethylketone). On the other hand, when organic bases are used, they can also be used as a solvent of the reaction.

The reaction with the alkali metal methyl sulfinyl meted salt may also be carried out in the presence of a solvent, suitable solvents include dimethylsulfoxide, or ethers such as tetrahydrofuran.

The methylation reaction is conveniently carried out at a temperature of 0 to 50 ° C., preferably at room temperature.

A preferred process according to the invention is the process for the preparation of ranitidine of formula (I) by methylation of a compound of formula (II) wherein R is a methyl group.

If desired, the furan derivative of formula (I) once obtained can be converted to acid addition salts, for example hydrochloride, using conventional methods. That is to say, for example, an appropriate amount of free base of formula (I) and an acid such as hydrochloric acid can be mixed in a suitable solvent, for example in an alcohol such as ethanol or isopropanol, or in an ester such as ethyl acetate.

The process of the present invention is convenient in that the starting material of formula (II) can easily be obtained in pure crystalline form. Moreover, the process of the present invention has the advantage of no thiol release. In other words, this is a significant advantage in that it is necessary to prevent the release of thiols to the surrounding environment and to prevent the release of such thiols requires the use of expensive equipment.

The present invention is specifically described by the following examples and is by no means intended to be limiting, in the examples the temperature is expressed in ° C. and hplc is high performance liquid chromatography.

Example 1

N- [2-[[5-[(dimethylamino) methyl] -2-furanylmethyl] -thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

(a) A mixture of sodium hydride (70% dispersion in oil, 0.15 g) and anhydrous dimethylsulfoxide (30 ml) is heated under a nitrogen atmosphere at 70-75 ° C. for 0.75 h. N- [2-[[5-[(methylamino) methyl] -2-furanylmethyl] thio] ethyl] -N'-methyl-2-nitro- in dimethyl sulfoxide (10 ml), cooling to 20 ° C. A solution of 1,1-ethenediamine (1.2 g) (Compound A) was added dropwise, and then iodomethane (0.27 ml) in dimethyl sulfoxide (10 ml) was added, and the solution was then stirred for 18 hours at 20 ° under a nitrogen atmosphere. Stir while. Water (10 ml) is added and the mixture is evaporated in vacuo. The residue is partitioned between dichloromethane (50 ml) and 2N aqueous sodium carbonate (50 ml). The dichloromethane layer is separated and the aqueous layer is further extracted with dichloromethane (2 x 50 ml). The combined dichloromethane extracts were washed with brine, dried (Na ₂ CO ₃ ) and evaporated, and the residue (1.5 g) was purified by silica [Merck No. 7734, 80 g] was chromatographed using dichloromethane: ethanol: 0.88 ammonia (75: 8: 1) as eluent to afford the title compound (0.17 g). The results of Nmr and Ir spectroscopy on the product indicate that this sample is the same compound as the title compound prepared according to the method of Example 15 of British Patent Specification 1565966.

(b) Similarly, hplc results using sodium hydride (60% dispersion in oil, 0.44 g), dimethyl sulfoxide (60 ml), compound A (1.5 g) and methyl tosylate (1.02 g). Obtained product which is found to contain 157 mg.

(c) Similarly, using sodium hydride (60% dispersion in oil, 0.44 g), dimethyl sulfoxide (80 ml), compound A (1.5 g) and dimethyl sulfate (0.76 ml), approximately 157 mg of the title compound was obtained by hplc. Obtained product which is found to contain.

Example 2

N- [2-[[[5-[(dimethylamino) methyl] -2-furanyl] -methyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine

(a) N- [2-[[[5-[(methylamino) methyl] -2-furanyl] methyl] -thio] ethyl] -N'-methyl-2-nitro-1 in methanol (25 ml), 1-ethenediamine hydrochloride (Compound B) (1.33 g) and potassium carbonate (0.55 g) are treated with iodomethane (0.56 g) at 0-4 ° for 5 hours and then at room temperature for an additional 17 hours. . The reaction mixture was identified by hplc to contain 211 mg of the title compound.

(b) Similarly, using Compound B (0.54 g), triethylamine (0.33 g), methanol (12 ml) and iodomethane (0.1 ml), a mixture found to contain about 50 mg of the title compound by hplc To obtain.

(c) Similarly, using Compound B (0.54 g), pyridine (0.19 g), methanol (12 ml) and iodomethane (0.1 ml) to obtain a mixture which was found to contain about 50 mg of the title compound by hplc. do.

(d) Similarly, using Compound A (0.54 g), methanol (12 ml) and iodomethane (0.1 ml) to give a mixture which was found to contain about 50 mg of the title compound by hplc.

Claims (10)

A process for preparing ranitidine of formula (I), characterized by reacting a compound of formula (II) with a methylating agent

Wherein R is a hydrogen atom or a methyl group. The method of claim 1 wherein the methylating agent is methylhalide, dimethylsulfate or methyl sulfonic acid ester. The method of claim 1 wherein the reaction is carried out in the presence of a base. 4. The process of claim 3 wherein the base is sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine or triethylamine. The process of claim 1 wherein the reaction is carried out in the presence of an alkali metal methylsulfinyl meted salt. The process according to claim 5, wherein the alkali metal methylsulfinylmethide salt is prepared from alkali metal hydride and dimethyl sulfoxide in situ. The process of claim 1 wherein the reaction is carried out at a temperature of from 0 to 50 ° C. The method according to any one of claims 1 and 2 to 7, wherein the furan derivative of structural formula (I) is subsequently converted to an acid addition salt. The method of claim 8, wherein the acid addition salt is hydrochloride. 8. The method of any one of claims 1 and 2-7 wherein R is a methyl group.