IE61492B1 - Cyclobutene compound - Google Patents

Description

The present invention provides a novel compound useful as an intermediate in the preparation of certain histamine H^-antagonists which are useful in the treatment of peptic ulcers and other conditions caused or exacerbated hy gastric acidity.

Our colleagues A. A. Algieri and R.R. Crenshaw disclose histamine H2-receptor antagonists in U.S. Patents 4,390,701 issued June 28, 1983, 4,395,553 issued July 26, 1983, 4,552,943 issued June XI, 1985 and 4,526,973 issued July 2, 1985 which are substantially the same as those mentioned above.

United States Patent 4,521,625 issued June 4, 1985 to T.K. Brown and R.C. Young discloses compounds of the formula wherein R1 is hydrogen or a C,„e alkyl group and X is hydroxy or a group displaceable by hydroxy or the equivalent thereof which are used in a process for the preparation of compounds which are substantially the same as those described in the above-mentioned U.S- patents.

Patent Specification No. 48750 discloses inter alia intermediates of the formula. in which W represents the group -CHO or -((¾) and 3, n, X, m, Rg, R4, Rg, and 2¾ correspond to a large number ©f substituents.

The novel compound' provided in the present invention is useful in an improved process for the preparation of histamine Ε,-antagonists „ A nowl compound 1-amino-2-butoxy-1cyclobutene-3, 4-dione is disclosed as well as a process for preparing this compound including a one pot process for such preparation.

The compound is useful as an intermediate in the preparation of certain histamine H2-antagonists which are used in the treatment of peptic ulcers or other conditions caused or exacerbated by gastric acidity.

The- present invention which is a divisional application of Patent Specification No. 1459/88 relates to a novel compound which is useful in the preparation of certain histamine H2-antagonists which are described herein. Accordingly, the present invention provides' the compound 1 -amino-2-butoxy-1-cyclobutene-3, 4-dione.

In the present invention, as used herein and in the claims, the ter® lower alkyl means straight or branched chain alkyl containing from 1 to 6 carbon atoms. Preferably they contain from 1 to 4 atoms and, most preferably, they contain 1 to 2 carbon atoms. Unless otherwise specified in the particular instance, the terms butyl and butoxy* as used herein and in the claims is intended to mean n-butyl and n-butoxy and other C* alkyl and alkyloxy groups.

The compounds of formula IV nay be prepared from the compound' of formula II by reaction with a compound of formula III. The acetal of formula la thereby produced is hydrolyzed to an aldehyde of formula lb followed by reaction with a secondary amine in the presence of formic acid to produce the desired histamine Ha-antagonist of the formula IV as illustrated in Scheme 1.

Schetnc The compound of formula II may he prepared by the procedures described in Patent Specification No. 48750.

The compounds of formula III say be prepared by the reaction of ammonia or a primary lower alkyl amine with a χ.„ 2-dialkoxy-l-cyc lobutene-3,4-dione which is itself prepared from sguarxc acid according to the general procedures described by G. Maahs, Justus Xiebiqs- Jinn« Chem. 686. 55 (1963) and A. Schmidt, Snvthesjs, 869 (1978).

The compounds of formula III may be prepared in a two-step process from squaric acid, however, in another aspect of the present invention, we have found that the novel compound of formula III wherein B“ is hydrogen and R5 is butyl may be prepared in a stepwise manner in a one pot IS reaction. Furthermore, we have found that the preferred lamino-2-butoxy-l-cyclobutene-3,4-dione as described herein may readily be prepared in high yield and purity on a manufacturing scale in a “one pot reaction from squaric acid which is especially useful for the preparation of the compounds of the present invention and certain histamine H,antagonists thereof.

In reaction Scheme l, R3 Is hydrogen or lower alkyl and, preferably, hydrogen. Preferably Rs is cyclohexy 1 ©r lower alkyl for example, methyl, ethyl, propyl, isopropyl, 2S butyl, sec-butyl, tertiary-butyl, neopentyl, pentyl and the like. Host preferably, Rs Is butyl, sec-butyl or secpentyl. For the compounds of formula IV or a non-toxic pharmaceutically acceptable salt thereof, R2 and R3 are lower alkyl, or R2 and R3, taken together with the nitrogen 3© to which they are attached, may be pyrrolidine, methylpyrrolidxno, piperidino, mefthylpiperidln©, hoaopiperidino, heptamethyleneimino or cctamethyleneimino. Most preferably, R’ and R9 are joined together with the nitrogen atom to form a piperidino group.

The compounds of formula la may be prepared by foe reaction of the compound of formula Π with a compound of formula Hl in a non-reactive solvent such as methanol, ethanol, acetonitrile, tetrahydroforan aad the life at a temperature from about 0°C to the reflux temperature of the solvent. For credence, we prefer so conduct foe reaction at about ambient temperature. The aldehydes of foe formula Ib may be prepared by acid hydrolysis of the acetals of formula la. The hydrolysis reaction may be conducted in a non-reactive solvent such as methanol, ethanol, tetrahydrofuran and aqueous mixtures thereof in the presence of an organic or inorganic acid for example, hydrochloric acid, sulfuric acid, formic add and psoluenesulfonic acid.

The histamine BL-antagonist compounds of formula TV may then be prepared fey foe reaction of a compound of formula Ib with a secondary amine of foe formula R’R’NH in the presence of at least one equivalent of formic acid as reducing agent. The reductive amination may be conducted in an excess of formic add wherein the formic add is also used as solvent. Preferably foe reaction is conducted in a nonreactive solvent such as benzene, toluene, xylene and n-propanol with at least one equivalent of formic add and, preferably, two to three equivalents. It is also preferred to az&otropically remove the water which is thereby produced at about foe reflux temperature ©f foe solvent employed.

The compounds of formula IV may also be prepared from foe compounds of formula Bs as illustrated in Scheme 2. j· la reaction Scheme 2, a compound of formula Ife is reduced co an alcohol of formula Ic which is then converted by conventional techniques to a compound of formula id. The conventional leaving group is then displaced by an amine of the formula R’R’NH co produce the desired histamine H^-antagonist of the formula IV wherein R‘, RJ and R’ are as previously defined.

The compounds of formula Ic may fee prepared from die aldehydes of formula lb fey catalytic hydrogenation or reducing metal hydrides according to methods wellknown im the an. The conversion of the hydroxy radical in formula Ic to a conventional leaving group may be carried out with suitable halogcnadng agents or o sulfonating agents. Suitable halogenadng agents such as thionyl chloride and thionyl bromide may be employed neat or in a non-reactive solvent and, preferably, in the presence of a base such as a tertiary amine (e.g., triethylamine, pyridine and lutidine) or inorganic base (e.g., sodium carbonate and potassium carbonate) at a temperature of 0°C to about the reflux temperature of the solvent. Suitable Ί 5 sulfonating agents such as methanesulfonyl chloride, benzcnesulfonyl chloride, psoluenesulfonyl chloride, p-bromobenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride may be employed in a non-reactive solvent, for example, dichloromethane, acetonitrile, tetrahydrofuran, and dimethylformamide and, preferably, im the presence of a tertiary amine or inorganic base to remove the acid which is produced.

The compounds of formula IV may then be prepared by the reaction of a compound of formula Id with the appropriate amine of formula in a nonreactive solvent and preferably in the presence of a base to remove foe acid which is thereby produced. e Sn the following examples, all temperatures are given in degress Centigrade and melting points and boiling points are uncorrected. All evaporations of solvents were performed under reduced pressure. As used herein, the term Skellysolve B is a petroleum solvent fraction having a bp range of 60-68°C consisting essentially of n-hexane.

ExamsleJ - Amlno-2-hutoxy-1 -cyglokigens:3.4 Preoaration.A: A solution of 1,2-dibutoxy-l -eyclobutene-3,4-dione(6.09,0.027 mole) in 40 mL of tetrahydrofuran was cooled to 5°C in an ice-water bath and treated dropwise over a period of 9 minutes with a solution of 1.8 mL of concentrated ammonium hydroxide in a mixture of 8 mL of tetrahydrofuran and 1 mL of methanol. After stirring at 5®C for 30 minutes and at ambient temperature for 90 minutes the mixture was concentrated under reduced pressure to a slurry, a small amount of Skellysolve B was added and the product was collected by filtration after 16 hours of standing at 0°C to give 3.26 g of the title compound. A sample (8.54 g) was partly dissolved in acetone, filtered and cooled to give 4.51 g of purified tide compound; mp«165.5-168°C (clear melt).

Anal. Calcd. for CJ8..NQ,: C, 36.79; H, 6.56; N, 8.28 Found: C. 36.46; H, 6.19; N„ 8.56.

Preparation Β: Λ solution of l,2-dibutoxy-l-cyclcfeutene-3,4-dione (30.0 g, 0.123 mole, 92.5 area % pure by glc assay) in 300 mL of tetrahydrofuran was cooled to 5°C and treated dropwise, over 30' minuses, with a solution of oonceatrated NH40H (8. IS mL, 0.123 mole) in a mixture ©f 40 mL of tetrahydrofuran and 5 mL of methanol. Tfee resultant solution was stirred in the ice-water hath for 30 minutes follow,ed by 5.5 hours ss ambient temperature.

The hazy solution was filtered through diatomaceous earth io remove a small amount of bright yellow solid and the filtrate was concentrated under reduced pressure io near dryness. The solid residue was rubbed under a small amount of o Skellysolve B and diethyl ether and cooled at OC. The mixture was filtered and dried to give 17.9 g (86%) of the title compound as white solid; mp«165-167.5°C (clear melt).

Pn^aration C: In a 5-Liter flask equipped with stirrer and nitrogen inlet/outlet tubes was placed l,2-dhydraxy-l-cydobutene-3,4-dione ¢400.0 g, 3.506 moles), 11 5 butanol (1.2 L) and toluene ¢800 mL). The mixture was stirred and heated under reflux with a Dean-Stark water trap until water stopped passing over (136 mL water collected, about S.5 bouts). The dear reaction mixture was heated under reflux for a further ©ne hour, then cooled under nitrogen to 0-5<>C. The cooled stirred solution was treated dropwise at such a rate that die reaction remains at or below 10°C (2.5 2o hours required) with a solution containing 14 M ammonium hydroxide (240 mL, 3.37 moles), 1-butanol (960 mL) and methanol (40 mL). Stirring was continued at ambient temperature for 2 hours, then ti» mixture was cooled to 0-5<»C for 1.5 hours and filtered. The product was washed with toluene (800 mL) and dried to give 492.4 g (88.0%) of ss© dfi© compound; mp“165”168°C»

Claims (6)

1. The compound l-ajaino-2 butoxy-l-cyclobutene-3, 4dione.

2. A process for preparing the compound of claim 1 5 comprising fhe steps of reacting squaric acid with butanol, and then the resulting product with one equivalent of ammonia.

3. The process of claim 2 which is a one pot process. 10

4. The conpound as claimed in claim 1 substantially as hereinbefore described with particular reference to the Example.

5. A process as claimed in claim 2 substantially as hereinbefore described with particular reference to the Example. 15

6. The compound of claim 1 whenever prepared by a process as claimed in claim 2 or 5.