KR810000429B1 - Preparation of trans-hexahydrodibenzo pyranones - Google Patents

Abstract

6a,10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d pyrane-9-on ( I; R =C5-10 alkyl, alkenyl, C5-8cycloalkyl, cycloalkenyl ), useful as analgesics, antidesuppressant agents, antianxiety agents(no data) were prepd. by reaction of apoverbenone(II) and 5-substituted resorcinon(III) in the presence of inactive organic solvent contg. aluminium chloride. Thus, 1.6 g (+)-apoverbenone was treated with 2.8 g 3,5-(HO)2C6H3CMe2(CH2)5Me to give 720 mg I(R = CMe2(CH2)5Me).

Description

Method for preparing trans-hexahydrodibenzopyranone

The present invention provides the following structural formula (I) 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-, which are effective as anesthetics, antidepressants and anti-anxiety agents. Hexahydro-9H-dibenzo [b, d] pyran-9one.

R in the above formula is C ₅ -C ₁₀ alkyl, C ₅ -C ₁₀ alkenyl, C ₅ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl.

The present invention reacts 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a by reacting 5-substituted resorcinol with optically active apobenbenone in the presence of aluminum chloride. And 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one.

Preparation of 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is first followed by It is described in the reference. [See: fahrenholz, Lurie and Kierstead, J. Am. Chem. Soc., 88, 2079 (1966); 89, 5934 (1967). The synthesis described in this reference is a method of separating the corresponding dl-6a, 10a-cisomers and obtaining more dl-6a, 10a-trans compounds. It is reported that the compound is used only as an intermediate by Farenholtz and is not pharmaceutically active. In recent years, such hexahydrodibenzopyranone has various biologically useful properties, and thus has been reported to be effective in the antagonism of various mammals. U.S. Patent Nos. 3, 953, 603, 3, 944, 673 and 3, 928, 598 describe that hexahydrodibenzopyranone causes anxiety, depression, and anesthesia. Dl-6a, 10a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6a, 7,8,10,10a-hexa, a potent drug commonly named Nabilone Hydro-9H-dibenzo [b, d] pyran-9-one is of particular interest.

dl-6a, 10a-trans-hexahydrodibenzopyranone is pharmacologically more active than the corresponding dl-6a, 10a-cis-isomer. Further analysis of these dl-trans racemates revealed that all biological activities by dl-trans-hexahydrodibenzopyranone were possessed by optically active isomers having 6a and 10a hydrogen atoms as R absolute stereostructures. ought. Optically active trans isomers of 6a and 10a hydrogen atoms with S absolute stereostructures are particularly useful as synthetic intermediates for compounds having central nervous system activity. Therefore, it is desirable to selectively synthesize optically active trans-hexahydro dibenzopyranone.

The optically active isomers covered herein are identified by the following reference, which is a definite way to describe the coordination structure of asymmetric carbon atoms. [Cahn-Ingold-Prelog Convention]. The above references are described in the following documents. eg, Cahn, Ingold and Prelog, Angew, Chem. Intern. Ed. Engl. 5, 385 415 (1966); Experientia 12, 81 (1956): J. Chem. Educ. 41, 116 (1964).

Stereoselective synthesis of (-)-'' tetrahydrocannabinol is described in the following references. [Reference ; Mechoulam, Braum and Gaoni, J. Am. Chem. Soc. 89, 4552 (1967). The compounds are synthesized by condensing optically active (-)-verbenol with 5-substituted resorcinol. The above method cannot be applied to synthesize hexahydrodibenzopyranone derivatives. This is because the latter compound is a 9-keto group rather than a methyl substituent.

The present invention is characterized by reacting the optical isomer of apoberbenone of formula (II) and 5-substituted resorcinol of formula (III) in the presence of aluminum chloride in an inert organic solvent. The optically active substance is 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] A method for stereoselectively preparing pyran-9-ones.

R is C ₅ -C ₁₀ alkyl, C ₅ -C ₁₀ alkenyl, C ₅ -C ₈ cyclo alkyl or C ₅ -C ₈ cycloalkenyl.

The preparation method preferably uses resorcinol wherein R is C ₅ -C ₁₀ alkyl. Preferred inert organic solvents are halogenated hydrocarbons.

According to the preparation method according to the present invention, the 5-substituted resorcinol is reacted with (+)-aporebenone, where 6a, 10a-trans is 6a, 10a-trans, wherein the 6a, 10a hydrogen atom has R absolute particle structure. Obtain hexahydrodibenzo [b, d] pyran-9-one. 5-substituted resorcinol is reacted with (-)-apoberbenone to give 6a, 10a-trans-hexahydrodibenzo, wherein the 6a, 10a hydrogen atom has R absolute stereostructure [b, d] Obtain pyran-9-one.

C ₅ -C ₁₀ alkyl groups include n-pentyl, n-hexyl, n-heptyl, n-decyl, 1-methylpentyl, 1,1-dimethylhexyl, 2-ethylheptyl, 1,2,3-trimethylhexyl, Linear and branched alkyl groups such as 1,2-diethylbutyl, isooctyl, 1-methylnonyl and 3-isopropylhexyl. Typical C ₅ -C ₁₀ alkenyl groups include 2-pentenyl, 4-hexenyl, 1,2-dimethyl-1-heptenyl, 2-isooctanyl, 3-ethyl-2-heptenyl and 1,1-dimethyl Linear and branched alkenyl groups such as 2-heptenyl.

C ₅ -C ₈ cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; typical C ₅ -C ₈ cycloalkenyl groups include 1-cyclopentenyl, 2-cyclohexenyl, 4-cyclohep Tenyl and 1-cyclooctenyl.

According to the preparation method of the present invention, the optically active apoberbenone of the structural formula (II) is reacted with the 5-substituted resorcinol of the structural formula (III). The 5-substituted resorcinol of formula (III) is readily prepared according to the method of the following reference, including 5-n-pentyl resorcinol, 5-n-octyl resorcinol, 5- (1,2 -Dimethylheptyl) resorcinol, 5- (1-propylbutyl) resorcinol, 5- (2-methyl-2-hexenyl) resorcinol, 5- (1,2-dimethyl-1-heptenyl) Resorcinol, 5- (2-hexenyl) resorcinol, 5- (1-ethyl-1-heptenyl) resorcinol, 5- (2-decenyl) resorcinol, 5-cyclopentylresorcy Nol, 5-cycloheptyl resorcinol, 5-cyclooctylesorcinol, 5- (1-cyclooctenyl) resorcinol, 5- (1-cycloheptenyl) resorcinol and 5- (2-cyclo Pentenyl) resorcinol. [See Adams et. al., J. Am. Chem. Soc. 70, 664 (1948).

As mentioned above, the production process according to the present invention uses (+) and (-)-apoberbenone as starting materials, which can be prepared according to the following reference method. That is, (+) and (−)-β-pinene are brominated to form bromo pinene, and debromination reaction gives optically active apoberbenone of the above formula (II).

[See Grimshaw et. al., J. Chem. Soc. Perkin I, 50 (1972)].

(+)-Apoberbenone or (-)-apoberbenone and 5-substituted resorcinol can be used in excess, if desired, but generally use approximately animal. The reaction is carried out using approximately equimolar aluminum chloride. It is also best to carry out in the presence of an inert organic solvent. Typical solvents generally used include dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, bromoethane, 1,2-dibromoethane, 1-bromo-2-chloroethane, 1- Halogenated hydrocarbons such as bromopropane, 1,1-dibromomethane, 2-chloropropane, 1-dodopropane, 1-bromo-2-chloroethane, chlorobenzene, bromobenzene and 1,2-dichlorobenzene And aromatic solvents such as benzene, nitrobenzene, toluene, and xylene. Preferred solvents include halogenated hydrocarbons such as dichloroethane, dichloromethane, bromoethane and 1,2-dibromoethane.

The reaction is typically carried out at a temperature of -20 ° C to 50 ° C, preferably at a temperature of -10 ° C to 30 ° C.

When carried out at these temperatures, the reaction may be longer, if desired, but is usually completed within 24-120 hours. The reaction is most typically completed within 48-96 hours.

Optically active 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] Pyran-9-one can be separated in advance by only diluting the reaction mixture with water or ice and extracting the water insoluble product with an organic solvent that is incompatible with water such as benzene, diethyl ether or chloroform. If desired, the organic layer can be washed with a water-soluble acid and a water-soluble base according to conventional methods. Such products can be further purified, if desired, according to conventional methods such as chromatography and crystallization.

Optically active 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro- prepared according to the process of the invention. 9H-dibenzo [b, d] pyran-9-one is described next.

1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9-one; 1-hydroxy-3-n-octyl-6,6-dimethyl-6,6aS, 7,8,10,10aS-hydroxy-9H-dibenzo [b, d] pyran-9-one; 1-hydroxy-3- (1,2-dimethylhexyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-diben [b, d] pyran-9-one ; 1-hydroxy-3- (2-hexenyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9-one; 1-hydroxy-3- (1,2-dimethyl-1-heptenyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [b, d] Pyran-9-one; 1-hydroxy-3-cyclopentyl-6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9-one; 1-hydroxy-3- (2-cycloheptenyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [b, d] pyran-9-one ; 1-hydroxy-3- (1-cyclooctenyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9-one

The 6aR, 10aR-hexahydrodibenzopyranone compounds of formula (I) are used as anesthetics, antidepressants and anti-anxiety agents. Compounds determine their useful activity according to a variety of standard laboratory tests described in the following references.

[Reference ; United States Patent Nos. 3, 928, 598, 3, 944, 673 and 3, 953, 603.

Pharmaceutically active hexahydro dibenzopyranones prepared according to the process of the invention are formulated in a manner similar to that described in the above-mentioned US patent. For example, 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] Pyran-9-one can be mixed with pharmaceutically toxic carriers, diluents and excipients such as starch, sucrose, polyvinylpyrrolidone and the like. It may be formulated into tablets or capsules to facilitate oral administration. For the treatment, about 0.1-100 mg of active ingredient may be used per patient.

Trans-hexahydrodibenzopyranones having 6a, 10a hydrogen atoms with an S absolute conformation can be reduced to 9-ketone positions to the corresponding trans-hexahydrodibenzopyranols. The latter compound is effective in the central nervous system of warm-blooded animals. For example, 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [b, d] Pyran-9-one is reduced to in particular 3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [ b, d] pyran-1,9-diol.

The following examples show optically active 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b according to the present invention. , d] a method of preparing pyran-9-one.

Example 1

1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9- On

A solution of 1.6 g of (+)-aphoberbenone dissolved in 50 ml of dichloromethane containing 2.8 g of 5- (1-, 1-tylheptyl) resorcinol was cooled to 0 ° C. in an ice bath and 1.6 g of aluminum chloride was reacted. Stir while adding partly to the mixture. The reaction mixture is then warmed to about 25 ° C. and stirring is continued at the same temperature for 72 hours. After that, the reaction mixture is poured into 50 g of ice, and the aqueous mixture is extracted several times with diethyl ether. The ethereal extracts are combined, washed with 2N hydrochloric acid solution, washed with water, and finally with 5% aqueous sodium bicarbonate solution. The organic layer was separated, dried and the solvent was evaporated and removed under reduced pressure to yield 4.5 g of the title compound as crude oil. The oil material obtained is chromatographed by eluting with benzene on a film silica gel activity II column. Fractions containing the desired product are combined and the solvent removed to remove 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-. 720 mg of 9H-dibenzo [b, d] pyran-9-one are obtained.

-40.2℃(C=1, 클로로포름)

-40.2 ° C (C = 1, chloroform)

m / e: Calcd for C ₂₄ H ₃₆ O ₃ , 372.2664

Found, 372.2663

Example 2

1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [b, d] pyran-9- On

According to the preparation method of Example 1, (-)-apoberbenone was reacted with 5- (1,1-dimethylheptyl) resorcinol in the presence of aluminum chloride to give 1-hydroxy-3- (1,1- Dimethylheptyl) -6,6-dimethyl-6,6aS, 7,8,10,10aS-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

Example 3

1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9- On

10.2 g of (+)-apoberbenone and 18 g of 5- (1,1-dimethylheptyl) resorcinol are dissolved in 250 ml of dichloromethane, and 10 g of aluminum chloride is added to this mixture while stirring. The mixture is then stirred for 72 hours at room temperature. The chromatography is separated on a silica gel column, eluting the product with chloroform containing 1% methanol. The product containing fractions were collected, evaporated to dryness and 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6 found to be the same as the product of Example 1 by optical analysis. , 6aR, 7,8,10,10aR-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

Claims (1)

The optically active following structural formula is characterized by reacting the apoberbenone, the optical isomer of the following formula (II), and the 5-substituted resorcinol of the following formula (III), in an inert organic solvent containing aluminum chloride. 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran of I) Method for preparing -9-one.

R in the above formula is C ₅ -C ₁₀ alkyl, C ₅ -C ₁₀ alkenyl, C ₅ -C ₈ cyclo alkyl or C ₅ -C ₈ cycloalkenyl.