HU194848B - Process for preparing 2-brackets open /5-(dimethylamino)-methyl/-furyl brackets closed- methyl-thioethane-amine - Google Patents

Abstract

A novel process is described for the preparation of 2 - (((5- (dimethylamino) methyl-2-furanyl) methyl) tio) ethanamine of the formula I in which 2 - (((5- (dimethylamino) methyl-2- furanyl) methyl) thio) ethanol of the formula II to the corresponding halide of the formula III in which Hal is chlorine or bromine, is reacted and the resulting compound is aminated with ammonia to the desired compound. The desired compound is a valuable intermediate in the preparation of the therapeutically important compound ranitidine, which is used to treat ulcer diseases.

Description

The present invention relates to a process for preparing 2 - {5 - [(dimethyl) aminomethyl] furyl} methylthloethaneamine (I). This compound is a valuable intermediate, N- [2- [5- (dimethylamino) methyl-2-furyl] methylthioethyl] -N'-methyl-2-nitro-1,1-ethane diamine can be used to produce.

The latter compound is known as ranitidln, first disclosed in German Patent Publication No. 27,34070. This compound inhibits gastric acid secretion stimulated through histamine H1 receptors. Ranitidine, in the form of its hydrochloric acid salt, is a valuable medicinal substance useful for the treatment of gastric ulcer.

In the prior art (German Patent Publication No. 27,34070), the compound of formula I is prepared in 54% yield from clsteamine hydrochloride and compound of formula II.

The starting material 5 - [(N, N-dimethylamino) methyl] -2- (hydroxy-methyl) furan (II) is a known compound which can be prepared in good yield (70%) from 2-furylmethanol. (from furfuryl alcohol) by the Mannlch reaction (GUI and Ing., J. Chem. Soc., 4278-4731 (1958)).

A disadvantage of the known process is the use of clsteamyl-hydrochloric acid salt, which is a very expensive and toxic compound. In addition, the yield of the reaction is low when the yield of the starting material is taken into account and the reaction time is very unfavorable.

The total yield of the present invention using 2-mercaptoethanol as starting material is 45%. The preparation of 2-mercaptoethanol is described in U.S. Patent 3,349,192. (C.A. 69.95951x), whereby 2-mercaptoethanol is obtained in almost quantitative amounts starting from ethylene oxide (oxlran) and hydrogen sulfide.

The preparation of cysteamyl is described in Ann. 566 210 (1950) and Bull. Soc. Chim. 2493 (1964). The known process involves the reaction of ethylamine (azirldine with hydrogen sulphide; the starting material aziridine is a highly toxic substance, carcinogenic), because of its low boiling point, it is expected to be a violent, exothermic reaction. A further disadvantage of the known process is that an undesirable side reaction occurs with the reaction with azirld: the cysteamine formed in the reaction reacts with the azirldine present in the reaction mixture to form bis-2-aminoethyl sulfide. the hydrogen sulphide should be used in a large excess, the operation should be carried out in a significant amount of solvent and with a large excess of hydrogen sulphide at a low temperature.The cysteamine is of unsatisfactory quality and yields only 60-70% due to by-product formation. .

For these reasons, cysteamine needs to be purified, the product is high in price, while mercaptoethanol 2 can be produced in good quality at low cost. If the yields of the starting materials are also taken into account, the compound of formula (I) can be obtained in a more favorable manner according to the invention. It is true that the process according to the invention involves several steps, but also taking into account In the disclosure, the reaction components must be reacted with cooling for 18 hours, and the reaction time of the present invention, despite the number of steps, is not longer than the known process.

A further advantage of the process according to the invention is that it can be carried out at room temperature or at 50-70 ° C.

The process of the present invention is carried out by treating the 2- {5 - [(N, N-dimethylaminomethyl) methyl] -2-furyl} methylthio-ethanol of formula III with methylene chloride solution at room temperature. halogenated with chlorine, and the resulting halide derivative (IV) or an acid addition salt thereof, wherein Hal is chlorine or bromine, is reacted with gaseous ammonia in methanol, heated to reflux or aqueous ammonia, to convert the compound into an acid addition salt.

The starting compound of formula (HI) may be derived from 5- (N, N-dimethylaminomethyl) methyl-2-hydroxymethyl-furan or 2- [2-furyl] -methyl-t-ethanol.

The following examples illustrate the present invention.

Example 1

2- {5 - [(Dimethylamino) methyl] furyl) methylthioethane chloride hydrochloride (IV)

Dissolve 0.5 g (2.3 mmol) of 2- {5 - [(dimethylamino) methyl] furyl} methylthioethanol in 7 mL of methyl chloride. To the solution is added dropwise 0.5 ml of 3 ml of methylene chloride dissolved in 3 ml of methylene chloride with stirring at room temperature. After half an hour, the reaction mixture was evaporated; 0.42 g of crude product is obtained.

Rt = 0.58 _(CHCl3: MeOH = 5: 1);

MMR Spectrum: Same as Example 3.

Yield: 0.42 g (81%)

Example 2

2- {5 - [(dimethylamino) methyl] -2-furyl} methylthioethane-amine (I)

0.42 g of crude 2- {5 - [(methylmethylamino) methyl] -2-furyl] methylthioethane chloride hydrochloride (

Prepared according to Example 1) is dissolved in 30 ml of methanol. Ammonia gas was bubbled through the solution for 4 to 5 hours using a reflux condenser. The solvent is then distilled off and the oily residue is dissolved in a minimum amount of water; the aqueous solution was neutralized with sodium carbonate and extracted with ether. The ethereal extract was dried over sodium sulfate, filtered and evaporated. 214 mg (46%) of the title compound are obtained, Fp; 104-106 ° C.

-2194848

Example 3

2- (5 - ((N, N-dimethylamino) methyl] -furyl} methyl-tip-ethane chloride (IV)

2.15 g (10 mmol) of 2- {5 - [(N, N-dimethylamino) methyl] -2-furyl} methyl toloethanol are dissolved in 18 ml of methyl chloride and at room temperature, while stirring, a solution of 2.18 mL (30 mmol) of tlonl chloride in 9 mL of methyl chloride was added to this solution. The reaction mixture was stirred for an additional hour at room temperature. The solvent was evaporated and the residual red oil was combined with 25 mL of methanol saturated with ammonia. Activated charcoal (100 mg) was added and the mixture was filtered after 1 hour. The solvent was distilled off, ethyl acetate was added to the crude product, filtered, and the ethyl acetate was evaporated. 1.84 g (79% yield) of the title compound are obtained.

R f = 0.58 (CHCl ₃ : MeOH = 5: 1) 20

MS: m / e = 233 (M +)

1 H-MMR (CDCl ₃ ): δ 7.75 (s, -N (CH ₃ ) ₂ ); 7.05-7.35 and 6.45-6.7 (two t, -CH ₂ -CH ₂ ); 6.6 and 6.25 (two s, -CH ₂ -); 3.9 (s, H ₃ , 4)

JCH 2 CH 2 - 7.5 Hz 25

Example 4

2- {5- (N, N-dimethylamino) methyl] furyl] methylthioethane chloride oxate (IV)

A solution of 540 mg of oxalic acid dlhydrate in 30 ml of ethyl acetate was dissolved in 1 g of 2- {5 - [(N, N -dimethyl-amyl-30-no) methyl] -2-furyl} -methyl-toluene-chlorod. ethyl acetate solution. The precipitated product is filtered off. 0.94 g of the oxalate are obtained; m.p. 87-9ΓΟ.

^1H-NMR (DMSO-d6): ^Ti = 7.35 (s, N (CH3) 2); 7.2 35 oz 6.3 (two t, -CH ₂ -CH ₂ -); Ós 6.15 5.85 (two s, CH _2); 3.7 and 3.5 (d, H ₃₄ ); 1.0 (wide, OH)

Jh ₃ , ₄ = 3 Hz Jch ₂ = 7.5 Hz

Analysis Calcd for C ₂ HieCINOS

Calculated: C, 44.51; H, 5.60; N, 4.33; 40

Found: C, 44.41; H, 5.30; N, 4.76.

Example 5

2- (5 - ((N, N-Dimethylamino) methyl] thurite} methylthloethaneamine (!)

2- {5 - [(N, N-Dimethylamino) methyl] furyl} methylthloethane chloroform (640 mg, 2.7 mmol) was combined with 50 mL of aqueous ammonia the mixture was stirred for 12 hours at room temperature. The aqueous solution was then extracted with ethyl acetate (430 mL). The combined extracts were dried over sodium sulfate (50) and the solvent was evaporated. Yield: 440 mg (75% yield); the resulting compound is MMR,

IR spectroscopic MS spectrum was as expected. Melting point: 104-106'C. 55

Example 6

2- (5 - ((N, N-Dimethylamino) -methyl-furyl} -methyl-ethoxy-amine dioxalate (1)

A solution of 518 mg of oxalic acid in 26 ml of ethyl acetate was dissolved in 440 mg (2.1 mmol) of 2- [5- (N, N-dimethyl-60'-amylno) -methyl-furyl] -methyl-thioethane-amine in ethyl acetate. acetate solution. The precipitated compound was filtered to give the title dloxalate (690 mg, 85% yield).

160-163 ° C. 65

Analysis Ci4H ₂₂ N ₂ C> 9S formula:

Calculated: C, 42.53; H, 5.61; N, 7.08;

Found: C, 42.55; H, 5.76; N, 7.24.

Example 7

2- {5 - [(N, N'-dimethylamino) methyl] -2-furyl] methylthioethanol (III) g (6.45 mmol) 5 - [(N, N-dimethylamino) amino] N-N'-dichlorocyclohexyl) carbamoyl (1.6 g, 7.77 mmol), CuCl ₂ (1.6 g, 7.77 mmol) was stirred at 55-65 ° C for one hour. After adding 10 ml of petroleum ether, a solution of 0.45 ml of 2-mercaptoethanol in 5 ml of petroleum ether is added dropwise with stirring in an ice bath. The solution was stirred at room temperature for 2 hours and then the oily product, which still contained crystalline Ν, Ν-cyclohexyl-urea, was separated with petroleum ether. The residue was suspended in 30 ml of chloroform, the N, N'-cllohexylurea was filtered off. The filtrate was dried over sodium sulfate and then filtered. 1.06 g (76.8%) of the title compound are obtained.

R f = 0.41 (CHCl ₃ : CH ₃ OH = 5: 1) ¹ H-MMR (CDCl 3): 7.75 (s, -N (CH 3) ₂ ); 7.2-7.45 Ós 6.3-6.5 (t, -CH ₂ -CH _2); 6.6 (s, -CFe); 6.2 (s, -CH ₂ -); 3.95 (s, H 34).

MS: m / e = 215 (M +).

Prior to elemental analysis, the resulting compound was converted to the oxalate salt and recrystallized from ethanol. Melting point: 82-85'C.

Analysis calculated for C ₂ HigNO6S calcd

Calculated: C, 47.20; H, 6.27; N, 4.59; Found: C, 47.34; H, 6.34; N, 4.74.

Example 8

2- (5 - ((N, N'-dimethylamine) methyl) -1-furyl) methylthioethanol (III) g (6.45 mmol) 5- (N, N-methylmethyl) -amlno) -methyl-2-hydroxy-methyl-furan ose 0.45 ml of 2-mercaptoethanol in 4 ml cc. Stir in HCl at 0-5'C for 20 hours. The solution was then neutralized with 50% aqueous sodium hydroxide solution and extracted twice with 10 ml of methylene chloride. The extract was dried over sodium sulfate and concentrated. 0.98 g (71%) of the title compound is obtained.

Claims (1)

Patent Claim Point A process for preparing the acid addition salt of 2- {5 - [(methylmethylamino) methyl] furyl) methylthioethaneamine of formula (I): - (5- [N, N-Dimethylamino) methyl] -2-furyl} methylthioethanol is halogenated at room temperature in methylene chloride solution with thionyl chloride and the halide derivative (IV) The acid addition salt of compound (III) wherein Hal is chlorine or bromine is reacted with gaseous ammonia in methanol solution at reflux temperature or aqueous ammonia solution at room temperature, and if desired, converted to the acid addition salt. 1 page drawing with formulas Int. CL, C 07 D 307/52 (CH ₃ ) ₂ NCH 2 _x j _x CH ₂ SCH ₂ CH ₂ NH ₂ (I) (CH ₃ , ₂ NCH ₂ IX (II) (CH ₃ ) ₂ NCH _2x ^ _z O ^ _x CH ₂ SCH ₂ CH ₂ OH (III) (CH ₃ ) ₂ NCH _2x A.CH ₂ SCH ₂ CH 2 - Hal (IV,