CS235040B2 - Method of 2-(l(5-(dimethylamini) -methyl-2-furanyl)-methyl (thi)ethamin production - Google Patents

Description

The resulting product can be used as an intermediate in the production of ranitidine, which is used as a medicament for ulcer disease.

a solution of hydrogen bromide in acetic acid to give the corresponding halide of formula III '

The present invention relates to a novel process for the preparation of 2 - {[(5- / dimethylamino) methyl-2-furanyl) methyl] thioJethanamine of the formula I

(AND)

This compound is a valuable intermediate in the synthesis of N- {2 - [([5- (dimethylamino) methyl-2-furanyl / methylthio] ethyl} -N'-methyl-2-nitro-1,1-ethylenediamine. This substance is known under the international name ranitidine and was first described in DOS 27 34 070 as a selective Ha-antagonist, which means that it inhibits gastric juice secretion caused by irritated histamine H 2 -receptors. medicament for the treatment of ulcer disease.

Also described in the above-mentioned NSR is a process for the preparation of the intermediate 2 - [[(5- / dimethylamino / methyl-2-furanyl) methyl] thio; ethamin so that the starting 5- (N, N-liiiiethylamino] methyl'2-hydroxymethylfuran of the formula X tCHJ ₉ HCH ^ ™ l n ^OH

- LX (X) reacts with cystamine hydrochloride. [Example A above] in 54% yield. The starting material 5- [N, N-dimethylamino) methyl-2-hydroxymethylfuran is known and can be obtained in good yield of _70/0 2-F uranmethanolu [furfuryl) a Mannich reaction in a manner which has been described by Gill and Ing . J. Chem. Soc. 4,728-4731 (1958).

A disadvantage of this process is the use of cystamine hydrochloride, which is very expensive, and the yield of this reaction is also low. Moreover, the reaction takes a very long time.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel process for the preparation of 2 - {[(5- (dimethylamino) methyl-2-furanyl) methyl] thiojethamine in good yield without the use of expensive and difficult to obtain cystamine hydrochloride.

This object is achieved by the process according to the invention by converting 2 - [[(57-dimethylamino / methyl-2-furanyl) methyl] thiojethanol of formula II

cw ₂ sch ₂ ch ₂ oh (II) by treatment with SOCl 2 in methylene chloride or where

Hal represents a chlorine or bromine atom, and the obtained compound is subjected to amination with ammonia to give 2 - {[(5- / dimethylamino / methyl-2-furanyl) methyl] thiojethanolamine of formula (II)? N CH (1)

4 ·. ··. «

The starting 2 - {[(4-dimethylamino) methyl-4-furanyl] ethyl] thioethanol can be obtained in a known manner from 5- (N, N-dimethylamino) methyl-2-hydroxymethylfuran or 2 - {[(2-uranyl) (methyl) thiojethanol.

The invention will be illustrated by the following examples.

Example 1

2 - [(methyl) thio] ethane chloride hydrochloride

0.5 g (2.3 mmol) of 2 - {[(5-dimethylamino / methyl-2-furanyl) methyl] thio-ethanol is dissolved in 7 ml of methylene chloride. While stirring at room temperature, the solution is treated with 0.5 ml of SOCl 2 which is added dropwise in solution in 3 ml of methylene chloride. After half an hour, the reaction mixture was evaporated. 0.42 g of crude product is obtained.

Example 2

2 - {[(57-Dimethylamino / methyl-2-furanyl) methyl] thio} ethanamine

0.42 g of the crude 2 - {[(57-dimethylamino / methyl-2-furanyl) methyl] iodoethane chloride hydrochloride obtained in Example 1 was dissolved in 30 ml of methanol. Ammonia gas was bubbled through the solution for 4 to 5 hours at reflux. The solvent is evaporated, the oily residue is dissolved in as little water as possible, the solution is neutralized with sodium carbonate and extracted with ether. The ether extracts were dried over sodium sulfate, filtered and evaporated. 214 mg of the title compound are obtained. The yield is 46% based on 2 - {[(5- (dimethylamino) methyl-2-furanyl) methyl] thio] ethanol.

Example 3 —N / CH3 / 2), 7.2 and 6.3 (2t, —CF2 — CH2-),

6.15 and 5.85 (2s, -CH 2), 3.7 and 3.5 (d, H34), 1.0 (broad, OH) J mass = 3 Hz, J mass = 7.5 Hz .

2 - ([:( 57N, N-Dimethylamino / methyl-2-furanyl) methyl] thioacetate

A solution of 2.15 g (10 mmol) of 2 - ([(5- (N, N-dif-methylamino) -methyl-2-uranyl) -methyl] -thio-ethanol in 18 ml of methylene chloride is added dropwise at room temperature with stirring. to a solution of thionyl chloride (2.18 ml, 30 mmol) in methylene chloride (9 ml) The reaction mixture was stirred at room temperature for an hour, then the solvent was evaporated and the remaining red oily liquid was overlaid with ammonia saturated methanol (25 ml). The mixture was allowed to stand for an hour and then filtered, the solvent was evaporated, the crude product was treated with ethyl acetate, the solution was filtered and the ethyl acetate was evaporated, yielding 1.84 g (79%) of the desired product.

Rf = 0.58 with 5: 1 chloroform: methanol.

Mass spectrum: m / e = 233 (M < + >).

1 H NMR Spectrum (CDCl 3): τ = 7.75 (s, NN / CH 3/2), 7.05-7.35 and 6.45-7.7 (2 ₍ , —CH 2 -CH 2), δ) , 6 and 6.25 (2s, —CH2 -), 3.9 (s, H34) J CH2CH2 - = 7.5 Hz.

Example 4

2 - ([(5- / Dimethyhylamino) methyl-2-furanyl) methyl] thiojethane chloride oxalate

A solution of 540 mg of oxalic acid dihydrate in 30 ml of ethyl acetate was added dropwise to a solution of 1 g of 2 - ([(5- / N, N-dimethylamino / methyl-2-furanyl) methyl] thiojoethane chloride in ethyl acetate. This gives 0.94 g of the corresponding oxalate, m.p. 87-91 ° C.

1 H NMR Spectrum (DMSO-d 6): τ = 7.35 (s,

Analysis of C12H18CINOS:

calculated:

H, 5.60; N, 4.33.

found:

45.41% / o G, 5.30% H, 4.76% N.

Example 5

2 - ([(5- / Diin / thylaImno / methyl12-uranyl) methyl] thiojethanamine

640 mg (2.7 mmol) of 2 - ([(5- [N, N-dimethylamino / methyl-2-furanyl) methyl] thio] ethane chloride was overlaid with 50 ml of aqueous ammonia solution and stirred at room temperature for 12 hours. The solution was then extracted with ethyl acetate (4.times.30 ml), the extracts were combined, dried (Na2 SO4) and the solvent evaporated to give 440 mg (75%) of the title compound, NMR, IR, and mass spectrum were consistent with the proposed structure. .

Example 6

2 - ([(5- / N, N-IDm / thylamino / methyl-2-furanyl) methyl] thiojethanamine dioxalate

A solution of 518 mg of oxalic acid in 26 mL of ethyl acetate was added dropwise to a solution of 440 mg (2.1 mmol) of 2 - (((5- / N, N-dimethylamino / methyl-2-furanyl) methyl) thiojethanamine in ethyl acetate. The precipitated product was collected by suction filtration to give 690 mg of the corresponding dioxalate (85% yield), m.p. 160-163 ° C.

Analysis of C 14 H 22 N 2 O 9 S calculated:

42.53 Ό / _ο C, 5.61% H, 7.08% N; found:

H, 5.76; N, 7.24.

Claims (3)

object of the invention A process for the preparation of 2 - {[(5- (dimethylamino) methyl-2-furanyl) methyl] thiolethanamine of formula I CH SCH _{Í Í Í} CH NH _I wherein CH ₂ SCH ₂ CW ₂ -H 2 V (III) (I) characterized in that in 2j [[S-dimethylamino / methyl-2'-uranyl] methyl] thiojethanol of formula (II): ум ^ ^а 1г ^сн г ^т II (II) halogenates the primary alcohol hydroxy to form a compound of formula III Hal represents a chlorine or bromine atom, and the obtained compound is aminated to give the title compound with ammonia. 2. A process according to claim 1, wherein the halogenation of the primary alcohol hydroxy group is carried out by treatment with SOCl2 in methylene chloride at room temperature or with a solution of hydrogen bromide in acetic acid. 3. The process of claim 1 wherein the amination is carried out with ammonia at reflux temperature.