KR820000850B1 - Process for preparing 6.6-dimethylinorpynene compounds - Google Patents

Abstract

Title compds. (I; R1 forms double bond with acetoxy or R3; R2 forms with acetoxy or R3; R3 forms with R1 or R2 respectively) were prepd. by reactions of norpinone enol-acetate (II) with lead tetraacetate in the presence of inert org. solvent. Thus, (-)-norpinoneenolacetate 18.0g reacted with lead tetraacetate 48.8g to give (-)-6,6-dimethyl-2,4-diacetoxy -2-norpinene 9.3g. I had antidepressant and antianxiety activity.

Description

Method for preparing 6,6-dimethylnorpinene compound

The present invention relates to a process for preparing the 6,6-dimethylnorpinene compound of the following general formula (I), which is optically active as an effective intermediate in the synthesis of a compound called hexahydro dibenpyri.

In the above general formula, R ₁ is bonded to acetoxy or R ₃ to form a double bond, R ₂ is bonded to acetoxy or R ₃ to form a double bond, and R ₃ is bonded to R ₁ or R ₂ to form a double bond. Form.

Some 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is used in mammals. Has an effect on the central nervous system. DL mixtures in which the hydrogen atoms attached at positions 6a and 10a have a trans position at other hydrogen atoms are particularly effective for treating anxiety and depression and are used for anesthesia.

US Pat. Nos. 953,603, 3,928,598 and 3,944,673 describe the use of such compounds, and 6a, 10a-trans-1-hydroxy-3- (1,1-, currently called Nabilone). Large methylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, particularly the use of dL-racemic mixtures of It is attracting attention.

It has been found that the dL-racemic mixture of cis and trans isomers of hexahydrodibenzopyranone mentioned above is separated into the corresponding isomers which are optically active and have biological properties. In particular, one of the optical isomers of cis and trans-hexahydrodibenzopyranone was found to have a greater effect on the central nervous system of mammals than the other isomers. The present invention provides optically active cis and trans-3-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexedo-6H-dibenzo [b, d An isomer of pyran-9-one and an optically active hexahydrodibenzopyra are intended to provide a process for preparing novel compounds that are effective as intermediates for the preparation.

The general formula (I) compound of the present invention is prepared by reacting the optically active nopinone enol acetate of the following general formula (II) with lead tetraacetate in an inert organic solvent.

It can be seen that in Formula (I), only _one of R ₁ and R ₂ is acetoxy and the other one of R ₁ and R ₂ is connected to R ₃ to form a double bond.

According to the present invention, the optically active new nophi of general formula (I) is prepared by reacting enol acetate with lead tetraacetate. Optically active nopineone enol acetate of the general formula (II) can be obtained according to the method described in the following document.

〔Reference; Coxon et al., Aust, J. Chem 23, 1069, (1970)],

-이성체에 기인된다.These compounds are each of optically active d-pinene d,

It is due to isomers.

The norpinene derivative of the general formula (I) is obtained by reacting the nopienol acetate of the general formula (II) with an excess lead tetraacetate in an inert organic solvent, preferably benzyl.

Generally, lead tetraacetate can be used in excess if desired, but it is advantageous to use an excess of 2-10 moles. Usually the reaction is carried out at 50-100 ° C. and the reaction time depends on the product obtained.

When the reaction is carried out for 1-3 hours, the product to be separated is optically active 6,6-dimethyl-2,2-diacetoxy-3 in which R is acetoxy and R ₂ and R ₃ form a double bond -Norpinene isomer.

When the reaction is continued for 16-20 hours, the product formed is 6,6-dimethyl-2,4-diacetoxy- ₂ , in which R ₁ is linked to R ₃ to form a double bond, and R ₂ is acetoxy It is an optical isomer of noropinene. The reaction product is also separated by filtration of the reaction mixture and distillation of the filtrate.

The (-)-nopi of the general formula (II), the enon acetate is (-)-3,4-diacetoxy-2-norpinene of the general formula (I), or (+) And -2,2-diacetoxy-3-norpinene.

Optically pure 6,6-dimethyl-2,4-diacetoxy-2-norpinene and 6,6-dimethyl-2,2-diacetoxy-3-norpinene of formula (I) are 5- The substituted tezorsin is reacted with to give optically pure 4- (4-substituted 2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone. The optically pure substituted 4- (2) -dimethoxynopinene derivatives or the 2,4-dioxynopinepinene derivatives mentioned above, which are optically pure isomers, and 5-substituted resorcinol are reacted in the presence of acid. 4-2,6-dihydroxyphenyl) -6,6--dimethyl-2-norpinanone is obtained. The condensation reaction of the 2,2-dimethoxynopinepinene derivative or the 2,2-dimethoxynopinepinene derivative of the general formula (I) with resorcinol is carried out by mixing equimolar amounts of reactants in the presence of equimolar amounts of acid. Acids capable of producing protons, such as hydrochloric acid, sulfuric acid, phosphoric acid, P-toluenesulfone, and P-bromotoluenesulfonic acid and bromotoluenesulfonic acid can be used. Preferred acids are P-toluenesulfonic acid.

The reaction is best carried out in an inert organic solvent. Such solvents include halogenated hydrocarbons such as chloroform, dichloromethane, chloroethane, 1,2-dichloroethane and 1,1-diboromoethane and aromatics such as benzene, toluene, globenzene, m-xylene P-xylene And ethers such as diethyl ether and aliphatic materials such as hexane.

In a typical embodiment, equimolar amounts of optically pure norpinene derivatives of the general formula (I) such as (+)-6,6, -dimethyl-2,2-diacetoxy-3-norpinene and 5-n- The 5-substituted resorcines such as pentyl-resorcinol are mixed in a common inert organic solvent such as benzene, and the solution is stirred at 25 ° C for 4 hours using an equimolar amount of an acid capable of producing a proton such as sulfuric acid . This reaction product is optically pure (+)-4- (4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone.

This is separated by washing the reaction mixture with a mild base such as sodium bicarbonate and removing the reaction solvent.

4- (4-substituted-2,6-dihydroxyphenyl-6,6--dimethyl-2-norpinanoneone is the optically active isomer of the above 6a-10a-cis-1-hydroxy-3-substituted 6,6-dimethyl-6,6a, 7,8,10,10a-hexedo-9H-dibenzo [b, d] pyran-9-one or 6a-10a-trans-1-hydroxy-3 -Substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexedro-9H-dibenzo [b, d] pyran-9-one.

Commonly used solvents include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dibromoethane, chlorophorophane and aromatic solvents such as benzene, toluene, chlorobenzene, xylene and alcohols such as ethanol.

Both proponic acid and Lewis acid. It is used to prepare the above general formula (I) compound. When using proponic acid, the product is predominantly sus optically pure isomer. When Lewis acids are used, the product is predominant in the trans form.

The temperature at which the general formula (I) compound is prepared is 0 ° to 80 ° C. In general, the preferred temperature range in which protonic acid is used is 30 ° C to 80 ° C. The preferred temperature range in which Lewis acid is used is 0 ° to 80 ° C.

The nornanon derivatives are reacted with about 1-10 molar excess of acid, preferably about 1-3 molar excess, to convert the nornanon derivatives to the corresponding hexahydrodibenzopyranones of the general formula (I).

A pharmaceutically active substance is added to 6a, 10a-cis-hexahydrodibenzopyranone to convert it to an intermediate derived from the more active 6a, 10a-trans isomer.

Such (-)-isomers of the 6a, 10a-trans isomers are particularly important for the treatment of bathing and anxiety.

The (+) isomer of the 6a-10a-trans isomer is particularly valuable as an intermediate. For example, trans-1-hydroxy-3- (1,1-dimethylmethyl) -6,6-dimethyl-6,6a, 7,8,10a-hexahydro-9-dibenzo [b, d] pyran The (+) isomer of -9-one is reduced at the 9-based tones and the corresponding (+)-trans-1,9R-dihydroxy-3- (1,1-dimethyl) -6,6-dimethyl-6 , 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran, which was subjected to standard activity assays using mice, showing significant effects on mammalian central nervous system. Appeared.

As noted above, certain hexahydrodibenzopyranones are useful for anesthetizing mammals and are used to treat anxiety, depression and similar reactions related to central nervous system.

cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran- which is a d, 1 racemate The 9-one itself is pharmaceutically useful, and the corresponding d, 1-trans isomer is somewhat more potent biologically.

Each of the d, 1 optical isomers of such 6a-10a-cis and 6a, 10a-trans-hexahydrodibenzopyranones prepared according to the preparation method of the present invention is effective as an anxiety and depression treatment, or intermediate.

Each of the pharmaceutically active optical isomers of the cis and trans-hexahydrodibenzopyranones prepared according to the process of the invention is used in the same manner as the corresponding racemates described in the literature.

The following preparations and examples are given to further illustrate aspects of the present invention. Such embodiments do not limit the invention.

Example 1

(-)-6,6-dimethyl-2,4-diacetoxy-2-norofene

18.0 g of (-)-nopinone-enol acetate was dissolved in 250 ml of anhydrous benzene under a nitrogen stream, and 48.8 g of lead tetraacetate dried in vacuo over phosphorus pentoxide and potassium hydroxide was dissolved in a stirred solution. The reaction mixture is heated, refluxed and plated for 18 hours. The reaction mixture is then cooled to room temperature and filtered, the filtrate is washed with 10% aqueous sodium bicarbonate solution and water, dried and the solvent is evaporated under reduced pressure to give 23.5 g of a clear liquid crude product.

The product thus obtained is distilled off to obtain 9.3 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene.

Boiling Point: 115-118 ° C (at 5 Torr)

-89.7°(C=1.0, 클로로포름)[α]

-89.7 ° (C = 1.0, chloroform)

H′nmr (CDC1 ₃ ) δ5.25 (m, 2H), δ2.4 (m, 4H), δ2.1 (s, 3H), δ2.0 (s, 3H), δ1.35 (s, 3H ), δ 1.0 (s, 3H).

IR (chloroform): 1730,1763 cm ^-1 , carbonyl mass spectrum m / e: 196 (M ⁺ -CH ₂ = C = O).

Example 2

(-)-6,6-dimethyl-2,2-diacetoxy-3-norropinene

18.0 g of (-)-nopinone-enol acetate was added to 250 ml of anhydrous benzene under a nitrogen stream, and 48.8 g of lead tetraacetate dried under vacuum over phosphorus pentoxide and potassium hydroxide was added to the stirred solution. The reaction mixture is heated to reflux and stirred for 2 hours. The mixture was then cooled to room temperature, washed with aqueous sodium bicarbonate solution and water, dehydrated, and evaporated under reduced pressure to give 9.8 g of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene. Get

Boiling Point: 102-103 ° C (at 5 Torr)

＋33.2°(c=1.0, 클로롤포름)[α]

+ 33.2 ° (c = 1.0, chloroform)

Elemental Analysis (C ₁₃ H ₁₈ O ₄ )

Theoretic value: C 65,53; H 7.61; COCH ₃ 36.12

Found: C 65.77; H 7.32; COCH ₃ 36.56

H′nmr (CDC1 ₃ ) δ6.4 (m, 2H), δ3.15 (m, 4H), δ2.3 (m, 3H), δ2.1 (s, 6H), δ1.4 (s, 3H ), δ1.1 (s, 3H).

Mass spectrum m / e: 196 (M ⁺ -42)

IR (chloroform): 1750 cm ^-1 , carbonyl

[Production Example 1]

(+)-4-4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl-6,6-dimethyl-2-norpinanone

1.19 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene and 1.18 g of 5- (1,1-dimethylheptyl) -resorcinol were converted to 9-toluenesulfonic acid monohydrate. To 50 ml of chloroform containing 0.95 g was added and stopped at about 25 ° C. for 4 hours. Thereafter, the reaction mixture is diluted with 100 ml of diethyl ether, and the solution is washed with 10% aqueous sodium bicarbonate solution and water and dehydrated. The solvent is evaporated and removed under reduced pressure to give a semicrystalline solid material. The product was treated with 25 ml of n-hexane and filtered to give (+)-4- [4- (1,1 dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpina Get 1.30 g of paddy. Melting Point: 171-174 ℃

＋55.8°(C=1.0, 클로로포름)[α]

+ 55.8 ° (C = 1.0, chloroform)

Elemental Analysis (C ₂₄ H ₃₆ O ₃ )

Theoretic value: C 77.381; H 9,74

Found: C 77.59; H 9.83

H ′ nmr (CDC1 ₃ + DMSO _d6 ) δ8.05 (s, 2H, phenolic OH), δ6.35 (s, 2H), δ4.05 (t, 1H), δ3.65 (m, 1H), δ 2.45 (m, 5H), δ 1.35 (s, 3H). δ 1.15 (m, 19H), δ 0.95 (s, 3H).

IR (KBr): 1668 cm ^-1 , carbonyl

Mass spectrum m / e: 372 (M ⁺ ).

According to the preparation method as described above, 1.18 g of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene had (+)-having the same physical buck properties as those obtained by the method described above. 4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone.

[Production Example 2]

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

From Preparation Example 1, (+)-4- [4- (1,1 dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone was dissolved in 25 ml of chloroform, 190 mg of p-toluenesulfonic acid monohydrate is added, heated to reflux and stirred for 24 hours. Thereafter, the reaction mixture was cooled to room temperature, diluted with 25 ml of mole, diluted with 25 ml of diethyl ether, and extracted several times with 25 ml of diethyl ether.

The ethereal extracts are combined, washed with 10% aqueous sodium bicarbonate solution and water, dried, and the solvent is evaporated and removed under reduced pressure to give 380 mg of white, crude product. The resulting crude product is chromatographed on a column layered with Woelm activity silica gel and eluted with 5% dimethyl ether in benzene.

Remove the solvent from the appropriate fractions to remove (-)-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro 228 mg of -9H-dibenzo [b, d] pyran-9-one is obtained. Melting Point: 139.5141 ℃

－50.0°(C=1.0, 클로로포름)[α]

-50.0 degrees (C = 1.0, chloroform)

Mass spectrum '1 column m / e: Theoretical value for C ₂₄ H ₃₆ O ₃ , 372,26,64; Found 372,2665

[Manufacture example 3]

(-)-Trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one.

(+)-4- [4- (1,1 dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone 372 mg in 25 ml of chloroform 1.01 ml of tin is added. The reaction mixture is stirred at 25 ° C. for 16 hours and then added to 50 g of ice. The aqueous reaction mixture was extracted several times with 25 ml of diethyl ether, and then the ethereal extracts were collected, washed with 2N hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The oil layer was then washed with water, dried and the solvent was evaporated and removed under reduced pressure. To give 378 mg of foamy product. The product is then chromatographed, eluting with benzene on film activity II silica gel knife. In the fraction containing one composition, the solvent was evaporated and removed to remove (-)-trans-1-hydroxy-3- (1,1, -dimethylheptyl) -6,6-dimethyl-6,6a, 7, 305 mg of 8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

－52.3°(C=1.0, 클로로포름)[α]

-52.3 degrees (C = 1.0, chloroform)

Mass spectrum m / e: Calcd for C ₂₄ H ₃₆ O ₃ : 372,2664,: 372,2667 (Measured paper)

In the eluate containing the other composition, the solvent was evaporated and removed to remove (-)-cis-1-hydroxy-3- (1,1, -dimethylheptyl) -6,6-dimethyl-6,6a, 7,8, 55 mg of 10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

－50°(C=1.0, 클로로포름)[α]

-50 degrees (C = 1.0, chloroform)

Claims (1)

The optically active 6,6-dimethyl nod of the following general formula (I) is characterized by reacting the optically active nopinone enol-acetate of formula (II) with lead tetraacetate in the presence of a ball active organic solvent. Process for preparing pinene compound.

In the above general formula, R ₁ is bonded to acetoxy or R ₃ to form a double bond, R ₂ is bonded to acetoxy or R ₃ to form a double bond, and R ₃ is bonded to R 1 or R ₂ to form a double bond. To form.