GB2217713A

GB2217713A - Preparation of ranitidine

Info

Publication number: GB2217713A
Application number: GB8909397A
Authority: GB
Inventors: Derek Leslie Crookes
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 1988-04-26
Filing date: 1989-04-25
Publication date: 1989-11-01
Anticipated expiration: 2009-04-25
Also published as: IT8947880A0; JPH0256476A; FI891950A; GB2217713B; DK200589A; DK200589D0; IT1231461B; KR890016033A; FI891950A0; GB8809836D0; GB8909397D0

Abstract

A process for the preparation of ranitidine of formula (I> <IMAGE> comprises reacting 2[[[5-(dimethylamino)met[hyl-2-furanyl]methyl]thio]ethanamine of formula (VI> <IMAGE> with a 1-alkoxy-N-methyl-2-nitroethanamine of formula <IMAGE> in which L represents a C1-4 alkoxy group.

Description

PROCESS FOR THE PREPARATION OF A FURAN DERIVATIVE This invention relates to a process for the preparation of a furan derivative.

The furan derivative N-F2[[[5(dimethylamino)methyl-2-furanyl] methyl]thio]ethyl]-N'-methyl-2-nitro-l,l-ethenediamine, which is known as ranitidine, and has the formula (I)

is disclosed in British Patent Specification No. 1565966 as a potent and selective H2-antagonist.

A variety of methods for the preparation of ranitidine are described in British Patent Specification No. 1565966. According to one method, compounds of the general formula (11)

including ranitidine, may be prepared by reacting an amine of formula (III)

with a compound of formula (IV)

In the above formulae (II), (III) and (IV), R1 and R2, which may be the same or different, each represent hydrogen, lower alkyl, cycloalkyl, lower alkenyl, aralkyl or lower alkyl interrupted by an oxygen atom or a group -N(-R4)- in which R4 represents hydrogen or lower alkyl, or R1 and R2 may, together with the nitrogen atom to which they are attached, form a heterocyclic ring which may contain other heteroatoms selected from 0 and Alk represents a straight or branched alkylene chain of 1 to 6 carbon atoms;; X represents -CH2-, 0 or S; m is an integer from 2 to 4, and n is 1 or 2, or, when X is S or -CH2-, n is zero, 1 or 2; R3 represents hydrogen, lower alkyl, lower alkenyl or alkoxyalkyl; Y represents =NRg or :CHR6; R5 represents hydrogen, nitro, cyano, lower alkyl, aryl, alkylsulphonyl or arylsulphonyl; R6 represents nitro, arylsulphonyl or alkylsulphonyl; and L represents a leaving group.

Examples of leaving groups are halogen, 3,5-dimethylpyrazolyl, alkoxy or methylthio, and the use of a compound of formula (IV) in which L represents methylthio is particularly advantageous.

European Patent Specification No. 230127 discloses the reaction of a compound of formula (IV) (in which R3 represents a methyl group, Y represents CHN02 and L represents a C1,4alkaxy group) with 4-[[(2 aminoethyl ) thio] methyl] -N, N-dimethyl-2-thiazolemethanamine having the formula (V)

to give the anti-ulcer compound nizatidine.

It has now been found that the reaction of an amine of formula (III) (in which R1 and R2 both represent methyl groups, Alk represents a methylene group, X represents S, n represents 1 and m represents 2) with a compound of formula (rv) (in which R3 represents a methyl group, Y represents CHN02 and L represents an alkoxy groups affords a novel and useful method for the preparation of ranitidine and, in particular, has the advantage that the evolution of methanethiol, which occurs when an amine of formula (III) is reacted with a compound of formula (IV) in which L represents a methylthio group, is avoided. This is a significant advantage since it is necessary to prevent the release of thiol into the environment, and this requires the us of specialised equipment which is expensive to run.

Thus the present invention provides a process for the preparation of ranitidine of formula (I) which comprises reacting 2-LE [5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine of formula (VI)

with a l-alkoxy-N-methyl-2nitroethenamine of formula (VII)

in which L represents a C14 alkoxy group.

The alkyl portion of the alkoxy group L may be straight. or branched, and L may be for example a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy or t-butoxy group, more preferably ethoxy.

The reaction according to the invention may be carried out in a solvent such as water or an alcohol (e.g. ethanol) or mixtures thereof, conveniently at room temperature. Alternatively the amine (VI) and the alkoxy compound (VII) may be heated in the absence of a solvent at a temperature of for example 80 to 1000C.

The amine of formula (VI) may be used as the free base, or in the form of a salt with an organic or inorganic acid e.g. as an acetate or hydrochloride salt.

The alkoxy nitroethenamine of formula (VII) may be prepared by reacting the corresponding nitroethenamine of formula (VII) in which L represents an alkylthio (e.g. methylthio) group with an appropriate alkoxide, conveniently generated in situ by dissolving an alkali metal (e.g. sodium) in the appropriate alcohol (e.g. ethanol).

If desired, the furan derivative of formula (I) once obtained may be converted into an acid addition salt, e.g. a hydrochloride, using conventional methods. Thus for example, appropriate quantities of the free base of formula (I) and an acid, e.g. hydrochloric acid, may be mixed in a suitable solvent(s), e.g. an alcohol such as ethanol or isopropanol, or an ester such as ethyl acetate.

The invention is illustrated but not limited by the following examples, in which temperatures are in OC.

Preparation l-Ethoxy-N-methyl-2-nitroethenamine Sodium (1.59) was added with stirring to absolute ethanol (lOOml). When the sodium had completely dissolved, a suspension of N-methyl-l-methylthio-2-nitroethenamine (10 Og) in absolute ethanol (400ml) was added, and the mixture heated under reflux for 3.5hr.

The solution was cooled to room temperature and the precipitated solid was collected, washed with industrial methylated spirit (IMS) (3xlOOml) and dried in vacuo at 600 to give the title compound (75.29). A second crop of solid (11.2g) was obtained by concentrating the reaction mixture to ca. lOOml and again cooling to room temperature.

The combined solids were recrystallised from ethyl acetate to give the title compound (62.9g), m.p. 127.5-129.50. Evaporation of the mother liquors and re-crystallisation of the resulting residue from ethyl acetate gave a second crop (13.19), m.p. 127-129.50.

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

2-E[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (lo. 7g) was added at room temperature to a stirred suspension of l-ethoxy-Nmethyl-2-nitroethenamine (7.39) in water (20ml). The resulting solution was left overnight, before adding sodium chloride (5.859) to give an emulsion which was extracted into methyl isobutyl ketone (MIBK) (2x25ml) at 500. The extracts were combined and evaporated to give an orange oil (18.259) which slowly became a crystalline mass.

A portion of this product (14.69) was triturated with isopropyl acetate (25ml). The resulting precipitate was collected, washed with isopropyl acetate (3xlOml) and dried in vacuo at 350 to give a product (4.249), which was recrystallised from MIBK (15ml) (with filtration of the solution through Hyflo) to yield the title compound (1.099), m.p.

72.5-74.5 .

Example 2 N-[2-[[[5-(Dimethylamino)methyl-2-furanyl]methylathio]ethyl]-N'- methyl-2-nitro-l ,l-ethenediamine.

2-[[[5(Dimethylamino)methyl-2furanyl]methyl]thio]ethanamine (10.79) was added at room temperature to a stirred suspension of l-ethoxy-N-methyl-2-nitroethenamine (7.39) in IMS (20ml), and the mixture was stirred overnight. Thin layer chromatography (carried out using silica gel and eluting with ethanol: isopropanol:water: 0.88 ammonia 25:15:2:2) indicated the presence of the title compound in the reaction mixture.

Example 3 N-[2-[[[dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N '- methyl-2-nitrol ,l-ethenediamine.

2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio] ethanamine (107mg) and l-ethoxy-Nmethyl-2-nitroethenamine (87mg) were heated with stirring at 1000 under nitogen for 30 minutes. The mixture was then chromatographed on silica coated plates, eluting with isopropanol: ethyl acetate: water: 0.88 ammonia (15:25:8:2), to give the title compound (40mg), thin layer chromatography (carried out on silica gel, using the above solvent system) and n.m.r. spectoscopy providing consistency with an authentic sample of ranitidine.

Claims

1. A process for the preparation of ranitidine of formula (I)

which comprises reacting 2- (([5- (dimethylamino) methyi-2- furanyl]ethy1]thio)ethanamine of formula (VI)

with a l-alkoxy-N-methyl-2-nitroethenamine of formula (VII)

in which L represents a C1-4 alkoxy group.

2. A process as claimed in claim 1 in which the ranitidine is subsequently converted into an acid addition salt.

3. A process is claimed in claim 1 in which the ranitidine is subsequently converted into the hydrochloride salt.

4. A process as claimed in any of claims 1 to 3 in which L is ethoxy.

5. A process as claimed in any of claims 1 to 4 in which the reaction is carried out in a solvent.

6. A process as claimed in claim 5 in which the solvent is water, an alcohol or a mixture thereof.

7. A process as claimed in any of Claims 1 to 4 in which the reactants are heated in the absence of a solvent.

8. A process as claimed in any of claims 1 to 7 in which the amine of formula (VI) is used in the form of the free base or in the form of a salt with an organic orinorganic acid.