FI84059C - FORM OF FRAMSTAELLNING AV N- / 2 - // 5 - / (DIMETHYLAMINO) METHYL / -2-FURANYLMETHYL / THIO / EECL / -N'-METHYL-2-NITRO-1,1-ETENDIAMINE. - Google Patents

Description

84059 Process for the preparation of N- [2 - [[5 - [(dimethylamino) methyl] -2-furanylmethyl) thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine - Preparation for the preparation of N- [ The present invention relates to a new process for the preparation of a furan derivative. 2 - [[5 - [(di-methylamino) methyl] -2-furanylmethyl] thio] ethyl] -N'-methyl-2-5 nitro-1,1-etenediamine.

British Patent Publication 1565966 describes a furan derivative of formula (I) I I chno2 15 Me2NCH2 O CH2SCH2CH2NHCNHMe (I) known as ranitidine, which is a potent and selective H2-antagonist.

The present invention provides a novel 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) CHNOo If 1 L CH2CH2HNCNHMe (III) wherein L is a leaving group such as halogen, preferably chlorine.

2,84059

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

The process of the invention may be carried out in a suitable solvent such as water, aqueous tetrahydrofuran, dimethylformamide, alkanol (e.g. methanol) or a ketone solvent such as acetone, optionally with the addition of water. The reaction is best carried out in the presence of a base such as an inorganic base (e.g. alkali or 10 carbonate or hydroxide such as potassium carbonate or potassium or sodium hydroxide), alkoxide (e.g. sodium methoxide) or a tertiary amine (e.g. triethylamine) and at a suitable temperature, e.g. 10 to 80 ° C. . The reaction is carried out in an inert atmosphere, for example under nitrogen. In a variation of this process, the thiol of formula (II) may be reacted with an alkylating agent (III) in a two-phase system using, for example, chloroform and water in the presence of a phase transfer catalyst (e.g. a quaternary ammonium salt such as benzyltitrile ammonium chloride) and a base (e.g. ).

Particularly preferred conditions for carrying out the alkylation reaction are when the thiol of formula (II) is treated with an alkylating agent (III) either in the presence of an alkali metal hydroxide (e.g. potassium hydroxide) in water or in the presence of potassium carbonate under aqueous tetrahydrofuran. .

30

The thiol (II) may be used directly or formed in situ from an acid addition salt such as an oxalate salt. Alternatively, when the reaction is carried out in the presence of a base, the thiol (II) may be formed in situ from isothiourea (IV) or 3,84059 of a salt thereof, for example a bis-maleate salt, under basic reaction conditions.

5 li il A Jk ΪΗ

Me2NCH2 ^ CH2SCNH2 (IV)

The thiol of formula (II) can be prepared by reacting the corresponding alcohol of formula (V) with Me 2 NCH 2 O 2 CH 2 OH (V) in the presence of a concentrated acid, such as concentrated hydrochloric acid, to form the isothiourea (IV) which 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 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 a solvent such as tetrahydrofuran.

A compound of formula (III) wherein L is halogen (e.g. chlorine) may be prepared by reacting a compound of formula (VI) 35 4 84059 CHNO-5 It ά L'CNHMe (VI) 5 (wherein L 'is a leaving group, e.g. methylthio ) to react in the presence of a haloalkylamine such as chloroethylamine, preferably in the form of a salt, for example as the hydrochloride. The reaction is carried out in a suitable solvent such as water in the presence of a base such as triethylamine, and preferably at an elevated temperature, for example about 100 ° C.

The acid addition salts of the thiol of formula (II) are all novel compounds and should be considered as part of the present invention.

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, sulfates, alkyl and aryl sulfonates, 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. 30 Preparation Example 1 1-Γ Γ Γ 5-Γ (dimethylamino) methyl] -2-furanylmethylthiol methanimidamide, maleate (1: 2) 5 84059 5 - [(dimethylamino) methyl] -2-furanmethanol and 3.1 g ) was gradually added to a solution of 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 and ether to give the title compound (8.1 g), m.p. 144-145oC.

Preparation Example 2 5 - [(Dimethylamino) methyl] -2-furanmethanethiol, oxalate (1: 1) 20 5 - [(dimethylamino) methyl] -2-furanmethanol (7.76 g) was gradually added to a solution of thiourea (3.81 g). in concentrated hydrochloric acid (12.5 ml). After 18 hours, the solution was heated at 98-100 ° C for 30 minutes 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). To the combined ether extracts were added sodium dithionite (2 g) and an excess of anhydrous sodium carbonate. After 3 hours, the mixture was filtered into a solution of oxalic acid (6.3 g) in dry tetrahydrofuran (60 ml). The separated solid was filtered, washed with tetrahydrofuran 11a and dried to give the title compound (5.84 g), 35 m.p. 116.5 - 118oC.

6 84059

Preparation Example 3 N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethylenediamine 5 N-methyl- (1-methylthio) -2-nitroethyleneamine (5.93 g) and 2-chloroethanamine To a solution of the hydrochloride (18.56 g) in water (4 ml) at 98-100 ° was added triethylamine (24 ml). The mixture was stirred for 10 minutes at 98-100 ° C and kept under vacuum (12-20 mm) for 50 minutes. 10 water (8 ml) was added and the mixture was heated in vacuo for 20 minutes at 98-100 ° C. Acetone (200 ml) and excess anhydrous magnesium sulfate were added to the residue, and the suspension was refluxed for 45 minutes. The solid was filtered off and washed with hot acetone (3 x 50 mL).

The combined filtrate and washings were cooled and the resulting crystalline precipitate was filtered off. The filtrate was concentrated to 100 ml, the separated solid was filtered off and the filtrate was evaporated to a small volume and chromatographed (silica / acetone). The eluate 20 was evaporated in vacuo, the residue suspended in ethyl acetate: ether (1: 4) and filtered to give the title compound (2.8 g), m.p. 113-115oC. TLC silica; 2-butanone;

Rf 0.4.

25

Preparation Example 4 5 - [(Dimethylamino) methyl] -2-furanmethanethiol, oxa-1ate (1: 1) 30

Potassium carbonate (83.5 g), sodium metabisulphite (22.9 g) and 1 - [[[5 - [(dimethylamino) methyl] -2-furanyl] methyl] thio] methanimidamide maleate (1: 2) (26 , 73 g), a mixture of water (140 ml) and ether (160 ml) was stirred under nitrogen; 35 below 24 hours at room temperature. Anhydrous 84059 7 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 metasulfite (5 g) and potassium carbonate (88 g) in water (60 ml). The ether extract was dried (Na 2 SO 4) for 1 hour 5 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 - 119oC.

Example 10 Ν-Γ2-ΓΓ5-Γ (dimethylamino) methyl-2-furanylmethyl-thiolethyl-N'-methyl-2-nitro-1,1-ethylenediamine N- (2-chloroethyl) -N'-methyl-2- nitro-1,1-ethylenediamine (0.9 g), 5 - [(dimethylamino) methyl] -2-furanmethanethiol oxalate (1: 1) (1.3 g), potassium carbonate (2.7 g), water (10 ml) and tetrahydrofuran (10 ml) were stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo, the residue was taken up in water (40 ml) and the suspension was extracted with ether (2 x 30 ml).

The aqueous fraction was evaporated in vacuo and the residue evaporated with ethanol (2 x 10 ml). Tetrahydrofuran (20 ml), magnesium sulphate and decolorizing carbon were added and after 25 hours the mixture was filtered. Evaporation of the filtrate gave an oil (1 g) which was chromatographed (silica / methanol: 0.88 ammonia, 79: 1). The eluate was evaporated and the oily residue (0.66 g) was extracted with hot isopropyl acetate. The separated solid was filtered to give the title compound (0.4 g), m.p. 65 - 68oc. The melting point did not decrease when mixed with a sample prepared by the method of Example 15 of British Patent Publication No. 1565966.

35 8 84059

Example 2 Ν-Γ2-ΓΓ5-Γ-dimethylamino) methyl-2-furanylmethylthio-1-ethyl-N, -methyl-2-nitro-1,1-ethylenediamine 5 1 - [[[5 - [(dimethylamino) methyl] -2-furanyl ] methyl] thio] -methanimidamide maleate (1: 2) (2.23 g), N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethylenediamine (0.9 g) ), potassium carbonate (3.46 g), water (10 ml) and tetrahydrofuran (10 ml) were stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo; the residue was suspended in water (50 ml) and extracted with ether (2 x 40 ml). The aqueous fraction was evaporated in vacuo and magnesium sulfate and tetrahydrofuran (100 ml) were added. After 15 hours, the mixture was filtered and the filtrate was evaporated to a semi-solid which was chromatographed (silica / methanol). The eluate was evaporated in vacuo to give the title compound (0.3 g), which was NMR identical to the product of Example 1 above.

20

Example 3 Ν-Γ2-ΓΓ5-Γ (dimethylamino) methyl] -2-furanylmethylthiol-ethyl 1-N'-methyl-2-nitro-1,1-ethylenediamine

A solution of potassium hydroxide (1.04 g) in water (3 ml) was added under nitrogen to a stirred mixture of 5 - [(dimethylamino) methyl] -2-furanmethanethiol oxalate (1: 1) (1.31 g) and 45 ° C under nitrogen. (2-chloroethyl-N'-methyl-2-nitro-30,1,1-ethylenediamine α (1.08 g) in water (20 ml) The solution was stirred for 2.5 hours at 45 ° C and room temperature for 15 hours. The solution was evaporated in vacuo, the residue was dissolved in water and a stream of air was bubbled in. The mixture was extracted with ether (2 x 15 ml) and the aqueous fraction was evaporated in vacuo. After 1 h, the mixture was filtered, the filtrate was evaporated in vacuo and the oily residue was dissolved in 4-methyl-pentan-2-one (8 ml).

The separated solid was filtered and washed with 4-methylpentan-2-one to give the title compound (0.72 g), m.p. 63 - 66oC. The melting point did not decrease when mixed with a sample prepared by the method of Example 15 of British Patent Publication No. 1565966.

10

Example 4 Ν-Γ2-ΓΓ5-Γ (dimethylaminolmethyl-2-furanylmethylthiol-ethyl-N1-methyl-2-nitro-1,1-ethylenediamine 15

A solution of potassium hydroxide (1.68 g) in water (3 ml) was added under a nitrogen atmosphere to a stirred solution of 1 - [[5 - [(dimethylamino) methyl] -2-furanylmethyl] thio] methanimidamide maleate (1: 2) under nitrogen. ) (2.23 g) and N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethylenediamine (1.08 g) in water (20 ml). The solution was kept at room temperature for 40 hours, then extracted with ether (2 x 50 ml) and the aqueous phase evaporated in vacuo. To the residue were added tetrahydrofuran (70 ml), decolorizing carbon and excess anhydrous sodium carbonate, and the mixture was refluxed for 30 minutes. After 3 hours the mixture was filtered and the filtrate evaporated in vacuo to give a semi-solid which was dissolved in a mixture of methanol and acetone and chromatographed on silica; methanol: acetone (1: 1). The corresponding eluate was evaporated in vacuo to give the title compound as an oil (0 .37 g), part of which was crystallized from 4-methylpentan-2-one, m.p.

Claims (5)

10 84059 A process for the preparation of N- [2 - [[5 - [(dimethylamino) methyl] -2-furanylmethylthio] ethyl] -N'-methyl-2- (5-nitro-1,1-) of formula (I); for the preparation of ethylenediamine II chno2 Me2NCH2 O CH2SCH2CH2NHCNHMe (I) characterized in that the thiol ii of formula (II) Me2NCH2 CH2SH (II) is reacted with an alkylating agent of formula (III) CHNO2 II 11 L CH2CH2HNCNHMe (III) wherein L is a leaving group such as halogen, preferably chlorine. 25 Process according to Claim 1, characterized in that the thiol of the formula (II) is formed in situ from an acid addition salt. Process according to Claim 1 or 2, characterized in that the thiol of the formula (II) is formed in situ under basic conditions from isothiourea (IV) or a salt thereof '35 Me 8NCH 2 / ^ 0'X ^ CH 2 SCNH 2 (IV) 5 4. 5 - [(Dimethylamino) methyl] -2-furanmethane of the formula (II) as a stable acid addition salt of Me 2 NCH 2 O 2 CH 2 SH (II). 12 84059