HU222238B1 - 6,7-dihydro-3-(2-nitrophenyl)-1,2-benzisoxazol -4(5h)-one and process for producing the same - Google Patents

Abstract

The present invention relates to a compound of formula (3) and a process for producing a compound of formula (4), wherein a compound of formula (4) is compounded with a compound of formula (5) wherein R8 and R9 are lower alkyl or a nitrogen atom with a nitrogen atom. ŕ

Description

The present invention relates to dihydrobenzisoxazoline of formula (3) and to processes for its preparation.

Synthesis 1978, 1, p 43 describes a one-step synthesis for the preparation of tetrahydrobenzisoxazoles. The compounds are useful organic chemical intermediates. The process involves the 1,3-cycloaddition of nitrile oxides to cyclohexane-1,3-dions.

The compound of formula (3) is a useful intermediate of the 9-amino-1,2,3,4-tetrahydroacridine derivatives of formula (I) wherein

Y is or CHOH,

R ¹ is hydrogen or lower alkyl,

R ² is hydrogen, lower alkyl or phenyl (lower alkyl);

R ³ is hydrogen or -OR ⁴ -

R ⁴ is hydrogen or -COR ⁵ - wherein

^R5 is lower alkyl preparation. These compounds are useful in the treatment of memory loss, such as Alzheimer's disease.

Preferred 9-amino-1,2,3,4-tetrahydroacridine derivatives are those wherein Y is

C = O or CHOH and R ³ is R ⁴ where R ⁴ is hydrogen.

In the specification and claims, the term lower alkyl refers to a straight or branched C1-C8 hydrocarbon group which does not contain a double bond. Examples of lower alkyl include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 1-pentyl, 3-hexyl, 4-heptyl, 2-octyl. The term alkoxy refers to a monovalent substituent, which is an alkyl group attached via an ether bonded oxygen atom and has a free valence on the ethereal oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy, 1-butoxy, 1-pentoxy, 3-hexoxy, 4-heptoxy, 2-octoxy. Halogen may be fluorine, chlorine, bromine or iodine. The term "lower" refers to the groups listed above and refers to groups having up to 6 carbon atoms.

The novel dihydrobenzisoxazoline derivative of the invention may be prepared according to Scheme a). Accordingly, 2-nitrobenzhydroxamic acid chloride (4) is condensed with cyclohexane-1,3-dione enamine (5).

The hydroxamic acid chloride (4) [YH Chang, J. Org. Chem., 36, 2146 (1971)] with the enamine (5) [M. Forchiassin et al., Gazz. Chim. Drink. 112 (7/8), 335-338 (1982)] (for example, an enamine where ^R8 and ^R9 form is an alkyl group or together form a heterocycle such as morpholine) condensation with dihidrobenzizoxazolinszármazékká formula (3) in an ethereal solvent such as 1 2-dimethoxyethane, 2-methoxyethyl ether, dioxane, tetrahydrofuran, preferably tetrahydrofuran. The condensation temperature is not critical and the reaction is preferably conducted at the reflux temperature of the reaction mixture.

The 6,7-dihydro-3- (2-nitrophenyl) -benzisoxazol-4 (5H) -one of formula (3) can be converted to the 9-amino-1,2,3,4- tetrahydroacridine derivatives for reductive cyclization of the compound to 9-amino-3,4-dihydroacridin-1 (2H) -one N-oxide of formula (7), which is reacted with 4- (alkanoyloxy) -9-amino of formula (8) The compound is rearranged to -3,4-dihydroacridin-1 (2H) -one, and this compound is reduced and cleaved to the diol 9. The reaction is illustrated in Scheme b.

Reductive cyclization of the dihydrobenzisoxazole derivative (3) to the amino acridinone N-oxide (7) is carried out by hydrogenation of the benzisoxazoline derivative (3) under ether conditions in an ethereal solvent. The catalyst may be, for example, platinum, palladium, rhodium and ruthenium, in a supported state or without a support, such as carbon, alumina or calcium carbonate. Palladium on carbon is preferably used as the catalyst. The ethereal solvent is, for example, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane or tetrahydrofuran. Tetrahydrofyran is preferred. The acidic reaction conditions are provided with dilute mineral acids such as dilute hydrochloric acid, hydrobromic acid, nitric acid or phosphoric acid. Preferably, a 5% solution of hydrogen chloride is used. Under these conditions, hydrogenation is carried out at a suitable rate, the hydrogen pressure being used being between about atmospheric pressure and about 100 psi. The hydrogen pressure is preferably about 50 psi.

The rearrangement of the acridinone N-oxide of formula (7) to the 4-alkanoyloxyacridinone of formula (8) is carried out with the alkanoic anhydride of formula (R ⁵ CO) 2 O, wherein R ⁵ is alkyl. ^(R5 CO) 2 O anhydride is employed as reactant and solvent as well. Acetic anhydride is preferably used. The rearrangement process can be easily carried out at the reflux temperature of the reaction mixture, but can also be carried out at room temperature.

The reduction! and performing the cleavage step by treating the 4- (alkanoyloxy) -9-aminoacridinone derivative of formula (8) with an alkali metal hydride such as lithium, sodium or potassium aluminum hydride in an ethereal solvent such as diethyl ether. ether, 1,2-dimethoxyethane, 2-methoxyethyl ether, dioxane or tetrahydrofuran. Lithium aluminum hydride is preferably used as the alkali metal hydride and tetrahydrofuran is preferably used as the ethereal solvent. The reaction temperature of the reduction and cleavage step is not critical, but preferably at about room temperature. Under the given conditions, the cis and trans-acridine diols of formulas 9a and 9b are formed and can be separated by flash chromatography. The reaction is illustrated in Scheme c).

The following example illustrates the invention without limiting it.

HU 222 238 Bl

Example 1

6,7-Dihydro-3- (2-nitro-chloro-phenyl) -l, 2-benzisoxazol-4 (5H) -one

To a solution of 1,3-cyclohexadione-morpholine-enamine (20.8 g), tetrahydrofuran (150 mL) and triethylamine (2 mL) was added 2-nitrobenzhydroxamic acid chloride (17.7 g) in tetrahydrofuran (100 mL) under reflux. ml) dropwise over 2 hours. The reaction mixture was refluxed for 1 hour and then concentrated. The residue was partitioned between 3N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with 3N hydrochloric acid, 10% sodium carbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate. The appropriate fractions were collected and evaporated. The residue was recrystallized from dichloromethane / hexane to give 15.0 g (66%) of product, mp 125-127 ° C.

Elemental analysis based on C ₁₃ H ₁₀ N ₂ O ₄ :

Found: C, 60.47; H, 3.90; N, 10.85;

Found: C, 60.81; H, 4.13; N, 10.88.

Claims (2)

PATENT CLAIMS A compound of formula (3). 2. A process for preparing a compound of formula (3), characterized in that a compound of formula (4) (5) a compound of the formula: - wherein ^R8 and ^R9 je15 Lentes lower alkyl or form a morpholine ring together with the nitrogen - condensed.