IE48755B1 - Derivatives of tetrahydropyran-2,3,5-trione useful as intermediates and a process for preparing them - Google Patents

Description

This invention relates to tetrahydropyran-2,3,5trione derivatives useful as intermediates.

Patent Specification No. 4&1S4 i, relates to novel derivatives of 4,5-dihydro-4-oxofuran-25 carboxylic acid having two substituents at position 5 and in addition being optionally further substituted at position 3 with a lower alkyl group as well as esters thereof. These derivatives are useful as hypolipidemic agents in a mammal at dosages which do not elicit undesirable side effects and have the formula (I) 2 in which R and R each is lower alkyl, lower cycloalkyl, lower alkoxy(lower)alkylene, phenyl or phenyl mono- or disubstituted with lower alkyl, lower alkoxy, halo, nitro or trifluoromethyl; or R and R together form a -(CH.) -X-(CH.) - chain wherein m and n each is an m 2 n integer from orie to four and X is methylene, oxa or thia; •12 ' .. or R and- R -together with the carbon atom to which they are joined form a spiro[l,2,3,4-tetrahydronaphthalene] 1 or spiro(indan]-1 radical; R3 is hydrogen or lower alkyl; and R4 is hydrogen, lower alkyl, lower cycloalkyl, phenyl(lower)alkylene, amino(lower)alkylene, lower alkylamino (lower) alkylene, di(lower alkyllamino(lower )alkylene or 3-pyridinyl(lower)alkylene, or a therapeutically acceptable addition salt thereof.

A preferred group of compounds of formula 1 are those in which R1 is lower alkyl, phenyl or phenyl 1 monosubstituted with halo; R is lower alkyl; or R and R2 together with the carbon atom to which they are joined form a spiro[l,2,3,4-tetrahydronaphthalene]-l radical; R3 is hydrogen; and R4 is hydrogen, lower - 3 alkyl or 3-pyridinyl(lower)alkylene, or a therapeutically acceptable addition salt thereof.

A most preferred group of compounds of formula I are those in which R1 is lower alkyl, phenyl or 4-chloro2 12 phenyl; R is lower alkyl; or R and R together with the carbon atom to which they are joined form a spiro o [l,2,3,4-tetrahydronaphthalene]-l radical; R is hydrogen; and R is hydrogen, lower alkyl or 3-pyridinylmethyl, or a therapeutically acceptable addition salt thereof.

The present invention provides novel intermediates useful for preparing certain compounds of formula I wherein R is hydrogen, said intermediates having the formula II: 0 3 wherein R , R and R are as defined above with the proviso that when R3 is hydrogen then R3 is lower alkoxy(lower)alkylene, or mono- or di-substituted phenyl 1 2 as defined herein or R and R form a spiro[l,2,3,4tetrahydronaphthalene]-l or spiro(indan]-1 radical.

Compounds of formula II may be hydrolysed under aqueous alkaline conditions at pH 10 to 12, e.g. using KOH or NaOH, and then acidifying to pH 0.5 to 3 to give corresponding compounds of formula I wherein R is hydrogen.

The term lower alkyl as used herein means straight chain alkyl radicals containing from one to six carbon atoms and branched chain alkyl radicals containing three or four carbon atoms and includes methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl and n-hexyl.

The term lower alkoxy as used herein means straight chain alkoxy radicals containing from one to six carbon atoms and branched chain alkoxy radicals containing three or four carbon atoms and includes methoxy, ethoxy, isopropoxy, n-butoxy and n-hexyloxy.

The term lower alkylene as used herein means a divalent organic radical derived from either straight or branched chain aliphatic hydrocarbons containing from one to six carbon atoms by removal of two hydrogen atoms and includes methylene, ethylene, 1-methylpropylene, 2-methylpropylene, 2-ethylpropylene and 2-butylethylene.

The term lower cycloalkyl as used herein means saturated cyclic hydrocarbon radicals containing from three to six carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term strong inorganic proton acceptor as used herein means the inorganic bases or corresponding alkoxides, preferably the alkali metals, the alkali metal hydrides, amides, hydroxides and alkoxides, for example, sodium, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide and sodium hydride.

Also included in this invention are the stereochemical isomers of the compounds of formula II which result from asymmetric centres, contained therein.

It is to be understood that all isomers and mixtures thereof arising from such asymmetry are included within the scope of this invention. When two asymmetric centres are present diastereomers are obtainable in substantially - 5 pure form by classical separation techniques and by sterically controlled synthesis.

Individual enantiomers are included. These can be separated by fractional crystallization of the diastereo5 meric salts thereof.

This invention provides a process for preparing a compound of formula (II) as defined hereinabove which comprises reacting a compound of formula III R1 -C - CO - CH2r3 OH (III) 3 wherein R , R and R are as defined hereinabove with a di(lower alkyl)oxalate in the presence of a strong inorganic proton acceptor under anhydrous conditions in an anhydrous inert organic solvent and then reacting the product with water at a pH from 8 to 9; the term strong inorganic proton acceptor denoting an inorganic base or a corresponding alkoxide.

The process can be carried out by condensing the α-hydroxyketone of formula II with a di(lower alkyl) oxalate in the presence of one to four molar equivalents of a strong inorganic proton acceptor, preferably sodium hydride, in an anhydrous inert organic solvent. Preferred inert organic solvents can be selected from the di(lower alkyl)-ethers or cyclic ethers, for example, diethyl ether, dioxane and tetrahydrofuran. The reaction mixture is mixed with about an equal volume of water and if necessary the resulting aqueous solution is adjusted to pH 8 to 9, for example, with dilute hydrochloric acid or sodium hydroxide. The resulting aqueous solution- is preferably maintained at pH 8 to 9 and at 15 to 30°C for one to five hours and washed with a water immiscible organic solvent, preferably diethyl ether. The mixture is acidified, maintained at 10 to 50°C, preferably 20 to 30°C, for one to thirty minutes and extracted, with a water immiscible solvent, to obtain the corresponding intermediate of formula II.

The following Example 1 illustrates the preparation of compounds of formula III. Example 2 is a reference example which illustrates the general procedure for the process of preparing compounds of formula II.

EXAMPLE 1 1 3-Hydroxy-3-phenyl-2-butanone (III:R = Me, R = Ph and R3 = H).

The title compound is prepared by using a modified method of G.F.Hennion and B.R.Fleck, J.Amer.Chem.Soc., 77, 3258(1955). To a mixture of methanol (5 ml), water (0.2 ml), sulfuric acid (100 mg), and mercuric sulfate (100 mg) is added at 55°C a solution of 3-hydroxy-3phenyl-l-butyne (2 g) in 90% aqueous methanol (5 ml) over a period of 90 min. The reaction is slightly exothermic, and the inside temperature is maintained at 55-57°C. During the reaction time, 50 mg of mercuric sulfate is added. When addition of the acetylenic component is complete, another portion (50 mg) of mercuric sulfate is added, and the mixture is stirred at 55C° for 1 hour. During this time 1 ml of water is added. After cooling, the reaction mixture is poured into ice-water and extracted with diethyl ether. The combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The • 48755 - 7 resultant oil is chromatographed on silica gel using benzene. The appropriate eluates are evaporated to give 0.5g of the title compound, ir(CHCl3)3450 and 1751 cm1 and nmr(CDCl3)ζ 1.75(s), 2.08(e), 4.50(s) and 7.40(m).

EXAMPLE 2 6-Methyl-6-phenyltetrahydropyran-2,3,5-trione (IXsR = Me, R1 = Ph and R3 = H) To a stirred suspension of sodium hydride (10.5g 54% in mineral oil) in dry tetrahydrofuran (400 ml) is added dropwise a sclution of diethyl oxalate (16 g) and 3-hydroxy-3-phenyl-2-butanone (16.4 g described in Example 1) in tetrahydrofuran (50 ml). The solution temperature is maintained at 55-60°C, and the solution is maintained at this temperature for 18 hr after the addition is completed. The cold reaction mixture is poured into water and the mixture is adjusted to pH 8 to 9 with sodium hydroxide or hydrochloric acid. This mixture at pH 8 to 9 is allowed to stand for 24 hours and extracted with diethyl ether. The ether extract is dried, evaporated and crystallised from diethyl ether to obtain the title compounds mp 142-144°C; ir(Nujol) 3130, 1718 and 1640 cm 1; uv (MeOH)X IuaX 268nm(£ = 8830) and nmr (MeOH-d3) 1.89 (s), 5.92 (s, and 7.34 (s).

Anal. Calculated for C^2H9°4: C' 66.05; H, 4.62% Pound: Cr 66.14; H, 4:83%.

Claims (6)

1. A compound of formula II (II) in which R and R each is lower alkyl, lower cycloalkyl,lower alkoxy(lower) alkylene, phenyl or phenyl mono- or disubstituted with lower alkyl, lower alkoxy, halo, nitro or trifluoromethyl; or R 3- and R 2 together form a (CHj^-X-fCHj^chain wherein m and n each is an integer from one to four and X is methylene, oxa or thia; or R 2 and R together with the carbon atom to which they are joined form a spiro[l,

2. ,

3. ,

4. -tetrahydronaphthalene]-l or spiro!indan]-1 radical; and R 3 is hydrogen or lower alkyl; with the proviso that when R 3 is hydrogen, then is lower alkoxy(lower)-alkylene or mono or di-substituted phenyl as defined herein, or R and R form a spiro(l,2,3,4-tetrahydronaph“ thalene]-l or spiro[indan]-1 radical, the term lower used in relation to an alkyl or alkoxy group denoting that such a group contains 1 to 6 carbon atoms when a straight chain and 3 or 4 carbon atoms when a branched chain; the term lower alkylene denoting a straight or branched chain divalent organic radical derived from aliphatic hydrocarbons containing from 1 to 6 carbon atoms, and the term lower cycloalkyl denoting a saturated cyclic hydrocarbon radical of 3 to 6 carbon atoms. - 9 2. A process for preparing a compound of formula II as defined in Claim 1 which comprises reacting a compound of formula III OH CO CH 2 R (III) 12 3

5. Wherein R , R and R are as defined m Claim 1, with a di(lower alkyl)oxalate in the presence of a strong inorganic proton acceptor under anhydrous conditions in an anhydrous inert organic solvent and then reacting the product with water at a pH

6. 10 from 8 to 9; the term strong inorganic proton acceptor” denoting an inorganic base or a corresponding alkoxide.