IE47605B1 - Process for the preparation of 4-carbalkoxyimidazoles - Google Patents

Description

This invention relates to the preparation of 4-carbalkoxyimidazoles by the desulfurization of a 2-mercapto-4-carbalkoxy-imidazole using Raney Alloy. 4-Carbalkoxyimidazoles are important intermediates for preparing 5 end products which have pharmaceutical utility as Hg-antagonists and in particular cimetidine (our Patent Specifications Nos. '36050 and '38353 and British Patent Applications Nos. 18879/77 and 33932/76) This process is represented by the final step in the following sequence: RCOCHgCOgR^ RCOC — II NOH C02R RCOCH-CO„R I 2 NHg.HCl .οο2κ* -f—τ N NH V SH 'in which R is hydrogen or alkyl of 1-4 carbons, preferably methyl, and ί ‘»5, ’ £ Ί ’ ν'*’ ' ; ' ; R -¾fbranched or straight alkyl of 1-4 carbons preferably ethyl, butyl or isopropyl.

The process of this invention will be illustrated by the commercially important species in which R is methyl and R1 is methyl, isopropyl, butyl and especially ethyl but may be applied to any imidazole carboxylic acid ester.

For example a readily available starting material is ethyl acetoacetate. The first two steps in this sequence outlined above are known to the art.

First, the oxime of the active methylene group of the acetoacetate ester is formed. This oxime is reduced to its 2-amino congener. In practice, we have found it convenient not to isolate the amine but to proceed directly to the subsequent cyclization step. The 2-aminoacetoacetate ester is reacted with thiocyanic acid (HSCN) generated in situ from sodium or potassium thiocyanate and acid. The medium is most conveniently aqueous methanol or ethanol. The cyclization proceeds at from room temperature up to the reflux temperature of the reaction mixture. The overall yields from ester run 60-75%.

The last step of the sequence is the desulfurization of the 2-mercaptoimidazole, which is readily accomplished by the reaction of Raney Alloy in an acid medium, preferably dilute hydrochloric acid, dilute sulfuric acid or especially a formic acid solution (90%). The desulfurization is continued until the evolution of hydrogen sulfide is complete which may be, for example, at room temperature up to the reflux temperature of the mixture. Heating at reflux for up to several hours is often most effective.

We believe to the best of our knowledge that a Raney Alloy desulfurization on an imidazole-2-thiol having a carbalkoxy substituent is new to the art. The action of Raney nickel on organic compounds is reviewed by H. Hauptmann and W. Walter, Chem, Rev. 62 347 (1962). A cyclization similar to that described above but using intermediates without an ester substituent was reported by E. Ochiai et al., Chem.

Ber. 73 28 (1940). The desulfurization step in this reference used nitric acid as the essential ingredient, without the addition of nickel or aluminium.

Raney alloy is well known to the art as a mixture of nickel and aluminium used in the field of catalytic hydrogenation. For that use the aluminium is leached out of the alloy by hot alkali to activate the nickel. In the application described herein, the Raney alloy is employed as such.

Its composition may vary over a wide range of proportions. Most useful is a Raney alloy having about 50% by weight of nickel. This alloy is used at about one molar equivalent of nickel by weight based on the ester reactant. An excess is not detrimental. The scope of permissible alloys, combinations of metals and acid conditions which may be used in this general reaction is discussed by N. Nakamizo et al., Bull. Chem.

Soc. Japan, 44 2192 (1971).

The following example is designed to illustrate the most preferred aspect of this invention. All temperatures are in degrees Centigrade.

EXAMPLE A mixture of 9.54 g (0.138 m) of sodium nitrite in 32 ml of water was added dropwise into a solution of 15.62 g (0.12 m) of ethyl acetoacetate in 48 ml of glacial acetic acid cooled to 5° at a rate to maintain the temperature at about 5-10°. After addition, stirring was continued for 2 hours in the cold. The mixture was then poured into 200 ml of water. The quenched mixture was extracted into ether (3 x 100 ml). The combined ether extracts were washed, dried and evaporated to give 19.1 g (92.1%) of the desired oxide as a light yellow oil.

A mixture of 17.6 g (0.11 m) of ethyl 2-oximoacetoacetate and 1.76 g of 5½ palladium-on-charcoal (0.1 g/l g oxime, 50% water wet), ml of absolute ethanol, 60 ml of water and 9.1 ml of 12.1 N hydrochloric acid was reacted in a hydrogen atmosphere at room temperature and 50 pounds per square inch for 3.5 hours. The catalyst was removed and washed.

This mixture (the amine product may be optionally isolated) in 4.55 ml of cone, hydrochloric acid was added to 10.7 g (0.11 m) of potassium thiocyanate in 15 ml of water. The mixture was heated at reflux with stirring as a white solid separated. The mixture was cooled in ice and the product was isolated by filtration. The white product; 2-mercapto-4-carbethoxy-5-methy1imidazo1e, was washed with water and dried to give 14.67 g.

The 2-thiol ester (14.67 g, 0.079 m) was mixed with 60 ml of 90% formic acid and 9.28 g of Raney alloy (50% nickel by weight) added in one portion. The mixture was heated at reflux until the odour of hydrogen sulfide stopped, about 1.5 hours.

The catalyst was removed and washed with water. All the filtrates were combined and evaporated to give a green oil. The oily product was taken up in 100 ml of water and concentrated ammonium hydroxide added to pH 8. The resulting white solid, 4-carbethoxy-5-methylimidazole, was washed with water and dried to give 11.80 g (97%). Overall yield 64.2%.

Substituting the methyl, butyl or isopropyl ester of acetoacetic acid gives the corresponding 4-methoxy, 4-butoxy or 4-isopropoxycarbonyl-5methylimidazole intermediates.

Claims (6)

1. A process for preparing a compound of Structure 1; C0 2 R* (1) in which R is hydrogen or C^-C^ alkyl and R is straight or branched C^-C^ alkyl, which comprises reacting a compound of Structure 2 (2) (in which R and R^ are as defined above) with a Raney alloy in an acid medium. A process according to Claim 1 in which R is C^-C^ alkyl.

2.

3.

4. ,1 A process according to Claim 2 in which R is methyl. A process according to any one of claims 1 to 3 in which R is ethyl. 4760S 5. A process according to any one of Claims 1 to 3 in which is methyl, isopropyl or butyl. 6. A process according to any one of Claims 1 to 5 in which the acid medium is 90% formic acid. 7. A process according to any one of Claims 1 to 5 in which the acid medium is dilute hydrochloric acid or dilute sulfuric acid. 8. A process according to any one of Claims 1 to 7 in which the Raney alloy contains about 50% by weight of nickel. 9. A process according to Claim 8 in which the amount of Raney alloy used is such that about one molar equivalent of nickel is used for each mole of the compound of Structure 2. 10. A process according to any one of Claims 1 to 9 in which the reaction is carried out at the reflux temperature of the reaction mixture until the evolution of hydrogen sulfide is substantially complete. 11. A process according to any one or Claims 1 to 10 in which the compound of Structure 2 is prepared by the reaction of a C-j-C^ alkyl 2-aminoacetoacetate with thiocyanic acid. 12. A process according to Claim 11 in which the C^-C^ alkyl 2-aminoacetoacetate is prepared from a C-j-C^ alkyl acetoacetate by preparation of the 2-oxime and catalytic reduction of this oxime. 13. A compound of Structure 1 in Claim 1 whenever prepared by a process according to any one of Claims 1 to 12. 14. 4-Carbethoxy-5-methylimidazole whenever prepared by a process according to Claim 4. 15. A compound of Structure 1 in Claim 1 in which R is methyl and R 1 is methyl, ethyl, isopropyl or butyl whenever prepared by a process substantially as described in the Example.

5. 1

6. 4-Carb'ethoxy-5-methylimidazole whenever prepared by a process substantially as described in the Example.