FI80450B - FRAME FOR EXAMINATION OF N- [2 - // 5 - / (DIMETHYLAMINO) METHYL] -2-FURANYLMETHYL / -THIO / EECL / -N'METHYL-2-NITRO-1,1-ETENDIAMINE. - Google Patents

Description

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Process for the preparation of N- [2 - [[5 - [(dimethylamino) methyl] -2-furanylmethyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine - For the preparation of N- [ 2 - [[5 - [(dimethylamino) methyl] -2-furanylmethyl] thio] ethyl] -N'-methyl-2-nitro-1,1-etenediamine The present invention relates to a process for the preparation of a furan derivative.

British Patent Publication 1565966 discloses that a furan derivative of formula (I) X X sm ° 2

Me2NCH2 O CH2SCH2CH2NHCNHMe (I) known as ranitidine is a potent and selective H2 antagonist.

The aforementioned British Patent 1,565,966 describes various processes for the preparation of ranitidine, for example the reaction between furfurylthiol and omega-bromoalkylthalimidine. French Patent 2,413,373 describes a process for the preparation of cimetidine and its analogs, in which the corresponding imidazolylmethylthiol is reacted with a suitably substituted aziridine.

In contrast to cimetidine, ranitidine has a strong reactive ethylenediamine function. Thus, it would have been expected that aziridine suitably substituted for the preparation of ranitidine would be highly unstable or prone to conversion reactions that make such a reaction difficult or impossible.

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Since the appropriately substituted thiol due to the dimethylaminomethyl function for the preparation of ranitidine is substantially more basic than the imidazolylmethylthiol described in the French patent and even more basic than the disubstituted furanmethyl thiol of the di very poor stability and tendency to oxidize, its use in the manufacture of ranitidine in reasonable yields impossible.

Finnish patent publication 72318 describes a process for the preparation of ranitidine in which hydroxymethylfuran and a thiol are reacted with each other. The OH group is removed by protonation under acidic conditions. The reported yield is 14% ranitidine.

It has now surprisingly been found that 5-C (dimethylamino) methyl-O-2-furanmethanethiol is capable of reacting with an alkylating agent of formula III below to form ranitidine in good yield.

The present invention provides a process for the preparation of a furan derivative of formula (I) wherein the thiol of formula (II)

Me2NCH2 O 'CH2SH (II) is reacted with an alkylating agent of formula (III) 3 80450 CH2 ^ CHNO2 1 \ "N-CNHMe (III) CH2 ^

The process of the present invention is a novel and useful process for the preparation of raniditine.

The reaction can be carried out without a solvent or in the presence of a solvent. Suitable solvents are water, alkanol (for example methanol) or dimethylformamide. The reaction is best carried out under heating, for example at 100 ° C, and in an inert atmosphere, for example under nitrogen.

The thiol (II) may be used directly or formed in situ from an acid addition salt such as an oxalate salt.

The thiol of formula (II) can be prepared by introducing the corresponding alcohol of formula (V)

Me2NCH2 O CH2OH (V) to react with thiourea in the presence of a concentrated acid such as concentrated hydrochloric acid to form isothiourea (IV),

IFH

Me2NCH2 O CH2SCNH2 (IV) which is then converted to the thiol of formula (II) by treatment with a base such as sodium carbonate or 5N sodium hydroxide, preferably in the presence of an antioxidant such as sodium 4,80450 dithionite or sodium metabisulphite. The free base thus formed and isolated can be converted into a stable acid addition salt by treatment with a suitable acid, especially oxalic acid, preferably in the presence of a solvent such as tetrahydrofuran.

If it is desired to isolate the isothiourea (IV), it is also best isolated as a stable salt, for example a bis-maleate, by treatment with a suitable acid, preferably in a solvent such as tetrahydrofuran.

A compound of formula (III) may be prepared by reacting an ethyleneimine with a nitroethane amine of formula (VII) CHNO2

II

L "-CNHMe (VII) wherein L" is a leaving group, for example a C 1-4 alkoxy group or a C 1-4 alkylthio group, preferably methylthio. The reaction may be performed in a suitable aprotic solvent such as acetonitrile.

The acid addition salts of the thiol of formula (II), the compound of formula (III), CH 2 -CHNO 2, III N-CNHMe (III) CH 2 and the isothiourea of formula (IV) and its acid addition salts are all novel compounds. The compound of formula (III) is to be considered as part of the present invention.

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The thiol of formula (II) and the isothiourea of formula (IV) are not particularly stable, but it has been found that they can be stabilized by conversion to the acid addition salt. Examples of such stable acid addition salts are hydrochlorides, sulphates, alkyl and aryl sulphonates, acetates, fumarates, maleates and benzoates. One preferred acid addition salt of the thiol of formula (II) is the oxalate. One preferred acid addition salt of isothiourea (IV) is bis-maleate.

The invention is illustrated by the following examples.

Preparation Example 1 1 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methylthio] methanimidamide. maleate (1: 2) 5 - [(dimethylamino) methyl] -2-furanmethanol (3.1 g) was gradually added to thiourea (1.53 g) in concentrated hydrochloric acid (5 ml). The solution was allowed to stand at room temperature for 18 hours, then heated at 98-100 ° C for 30 minutes. The solution was cooled, tetrahydrofuran (100 ml) and excess anhydrous sodium carbonate were added, and after 30 minutes the mixture was filtered. A solution of maleic acid (4.65 g) in dry tetrahydrofuran (40 ml) was added to the filtrate. The separated solid was filtered, washed with tetrahydrofuran 11a and ether to give the title compound (8.1 g), m.p. 144-145 ° C.

Preparation Example 2 5 - [(Dimethylaminomethyl-2-furanmethanethiol. Oxalate (1: 1)] 5 - [(dimethylamino) methyl] -2-furanmethanol (7.76 g) was gradually added to a solution of thiourea (3.81 g) in concentrated hydrochloric acid (12 After 18 hours the solution was heated to 680450 for 30 minutes at 98-100 ° C and evaporated to a small volume, a solution of sodium hydroxide (10 g) in water (50 ml) and sodium dithionite (10 g) were added and after 1 hour the solution was extracted with ether (6 x 50 ml), boric acid (35 g) was added to the aqueous fraction and the suspension was extracted with ether (4 x 50 ml), sodium dithionite (2 g) and excess anhydrous sodium carbonate were added to the combined ether extracts. 6.3 g) in a solution of dry tetrahydrofuran (60 ml) The separated solid was filtered, washed with 1A tetrahydrofuran and dried to give the title compound (5.84 g), m.p.

116.5-118 ° C.

Preparation 3 N-f-methyl-α-nitromethylene-1-aziridine-methanamine

A solution of ethyleneimine (0.47 g) and M-methyl- (1-methylthio) -2-nitroetheneamine (1.48 g) in acetonitrile (5 ml) was stirred for 2 days at room temperature and the residue was extracted with hot ethyl acetate (100 ml). Evaporation of the extract in vacuo gave a residue which was suspended in ethyl acetate (50 ml) and filtered. The filtrate was evaporated to about 5 ml and chromatographed (silica / ethyl acetate). Relevant eluate [TLC (silica ethyl acetate)

Rf 0.28] was evaporated in vacuo to give the title compound (0.33 g), m.p. 118-119 ° C.

Preparation Form 4 5 - ((dimethylamino) methyl) -2-furanmethanethiol, oxalate (1: 1)

Potassium carbonate (83.5 g), sodium metabisulphite (22.9 g) and 1 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] -780450 methanimidamide maleate (1: 2 ) (26.73 g), water (140 ml) and ether (160 ml) were stirred under nitrogen for 24 hours at room temperature. Anhydrous sodium carbonate (10 g) was added and stirred for a further 2 hours, after which the ether fraction was separated and washed with a solution of sodium metasulphite (5 g) and potassium carbonate (88 g) in water (60 ml). The ether extract was dried (Na 2 SO 4) for 1 hour and filtered into a solution of oxalic acid (7.6 g) in tetrahydrofuran (100 ml). The separated solid (13.3 g) was crystallized from tetrahydrofuran to give the title compound (12.20 g), m.p. 116.5-119 ° C.

Example 1 Ν-Γ2-Γ Γ5-Γ (dimethylaminomethyl) -2-furanmethylmethylthioethyl-N1-methyl-2-nitro-1,1-ethylenediamine 5 - [(dimethylamino) methyl] -2-furanmethanethiol, branch (1: 1) (0.156 g), a mixture of sodium dithionite (0.05 g) and anhydrous sodium carbonate (0.15 g) in water (0.4 ml) was added ether (15 ml) and excess anhydrous sodium carbonate. The filtrate was evaporated in vacuo, N-methyl-α- (nitro-methylene) -aziridinemethanamine (0.072 g) and methanol (2 ml) were added to the residue, and the solution was evaporated to dryness, and the residue was heated at 98-100 ° C for 1.25 hours and the product was chromatographed. (silica / methanol - 0.88 ammonia, 79: 1) The eluate was evaporated in vacuo to give the title compound (0.113 g; 72%).

NMR (CDCl 3) δ: 3.43 (1H, s, = εHNO 2), 3.8-3.9 (2H, AB, 2CH furanyl), 6.25 (2H, s, furan CH 2 S), 6.58 (2H, s, NCH 2 furan), 6.68 (2H, m, CH 2 CH 2 N), 7.07 (3H, d, NHCH 2), 7.20 (2H, t, SCH 2 CH 2), 7.72 (6H, s, N (CH3) 2).

TLC (Si-methanol: 0.88 ammonia, 79: 1) Rf 0.3.

Claims (4)

A process for the preparation of N- [2 - [[5 - [(dimethylamino) methyl] -2-furanylmethyl] thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine of formula (I) is y \ X ΐΗΝθ2 Me2NCH2 O CH2SCH2CH2NHCNHMe (I) characterized in that the thiol XX of the formula (II) Me2NCH2 O CH2SH (II) is reacted with an alkylating agent of the formula (III) CH2 chno2 I N-CNHMe (III) CH2 Process according to Claim 1, characterized in that the thiol of the formula (II) is formed in situ from an acid addition salt. N-methyl-α- (nitromethylene) -1-aziridin-methanamine of formula (III) CH2 chno2 I N-CNHMe (III) CH2 9 80450