KR820000784B1 - Stereo selective preparation of hexahydro dibenzo pryanones - Google Patents

Abstract

Dibenzopyranones (I; R4 = C5-10 alkyl, C5-10 alkenyl, C5-8 cycloalkyl or C5-8 cycloalkenyl) useful as analgesics, antidepressants, and entianxiety agents (no data) were prepd. Thus, 1.6g (+)-apoverbenone was treated with 2.8g 3,5-(HO)2-C6H3CMe2(CH2)5Me to give 720 mg I[R4 = CMe2(CH2)5Me .

Description

Method for preparing optical isomer of hexahydro-dibenzopyranone compound

The present invention relates to a method for preparing optical isomers of the hexahydro dibenzopyranone compound of the general formula (I), which is effective as an antidepressant.

In the above general formula

Hydrogen at positions 6a and 10a may have a cis or trans configuration

R ₄ is alkyl having 5 to 10 carbons, alkenyl having 5 to 10 carbon atoms, cycloalkyl having 5 to 8 carbon atoms or cycloalkenyl having 5 to 8 carbon atoms.

The present invention reacts an optically active 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone with an acid so that the hydrogen atoms at positions 6a and 10a are either cis or trans. 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one having a coordination structure It is characterized by producing an optical isomer of. Optically norpinanone is the optically active 6,6-dimethyl-2,4-diacetoxy-2-norpinene or 5,6-dimethyl-2,4 optically substituted 5-substituted resorcinol. Prepared by reaction with diacetoxy-3-norpinene, these compounds are derived from β-pinene, a known optical activity.

Any 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8-10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one of the mammal It has an effect on the central nervous system. The dl mixture, in which the hydrogen atom attached at positions 6a and 10a has a trans position at another hydrogen atom, is particularly effective in the treatment of anxiety and depression and is used for anesthesia. US Patent Nos. 3,953,603, 3,928,598 and 3,944,673 describe the use of such compounds, and are currently referred to as Nabilone 6a, 10a-trans-1-hydroxy-3- (1,1- Of particular note is the temperature of the dl-racemic mixture of dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one Is dragging.

It has been found that the dl-racemic compounds of cis and trans isomers of hexahydrodibenzopyranone mentioned above are separated into 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 in mammals than the other isomers. The present invention provides optically active cis and trans-1-hydroxy-3-substituted 6,6-dimethyl-6,6s, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] Provided are methods for preparing the isomers of pyran-9-one and these novel compounds are effective as intermediates in the preparation of optically active hexahydro dibenzopyranone.

The optical isomer of hexahydrodibenzopyranone of the general formula (I) is prepared by reacting the optically active norpyranone of the following general formula (II) with an acid.

R ₄ in the general formula is as described above.

The optically active intermediate of formula (II) is prepared by reacting the optically active norpinene compound of formula (III) with resorcinol of formula (IV) in the presence of an acid in an inert organic solvent: do.

In the above general formula

R ₁ together with acetoxy or R ₃ form a double bond,

R ₂ together with acetoxy or R ₃ form a double bond,

R ₃ forms a double bond with R ₁ or a double bond with R ₂ ,

R ₄ is as mentioned above.

The optically active intermediate of formula (III) is prepared by reacting the optically active-nopinone enol acetate of formula (V) with lead tetraacetate in an inert organic solvent.

Preferred preparations according to the invention inactivate the optically activated 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of formula (II). By reacting with protonic acid in an organic solvent, the optical isomer 6a, 10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H- To obtain dibenzo [b, d] pyran-9-one.

In addition, a preferred preparation method included in the present invention is optically active 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of the general formula (II). Was reacted with Lewis acid in an inert organic solvent to give the optical isomer 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8-10,10a-hexahydro-9H -Dibenzo [b, d] pyran-9-one. Particularly preferred groups of Lewis acids are ditin, boron trifluoride and aluminum chloride. Particularly preferred production methods are (+)-4- (4- (C ₅ -C ₁₀ alkyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone and ditin chloride. By reaction to the corresponding (-)-6a, 10a-trans-2-hydroxy-3- (C ₅ -C ₁₀ alkyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexide -9H-dibenzo [b, d] pyran-9-one is obtained.

In Formula (III), 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.

In the present specification, R ₄ is C ₅ -C ₁₀ alkyl, C ₅ -C ₁₀ alkenyl, C ₅ -C ₈ cycloalkyl and C ₅ -C ₁₀ cycloalkenyl. The term “C ₅ -C ₁₀ alkyl” is straight chain. And branched carbon chains, including n-pentyl, n-hexyl, n-octyl, n-heptyl, n-decyl, 1-methylpentyl, 1-methylhexyl, 1,2-dimethylhexyl, 1,1 -Dimethylheptyl, 1,1-diefilpentyl, 1,2,3-trimethylheptyl, 2-ethylhexyl, 3-propylpentyl, 1,3-dimethyloctic, 2,2-dimethyloctyl and 2,3-dimethyl There is a pen pill.

“C ₅ -C ₁₀ alkenyl” groups include 2-pentenyl, 3-hexenyl, 4-octenyl, 5-decenyl, 1,2-dimethel-1-heptenyl, 1,1-dimethyl-2 -Heptenyl, 1-ethyl-3-hexenyl, 3,4-dimethyl-3-4heptenyl.

Groups of “C ₅ -C ₈ cycloalkyl” include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In addition, “C ₅ -C ₈ cycloalkenyl” includes 1-cyclopentenyl, 2-cyclohexenyl, 2-cycloheptenyl and 3-cyclooctenyl.

Optically inert norpinene, the starting material of general formula (III), is prepared by reacting optically active nopinone enol acetate of general formula (V) with lead tetraacetate. Optically active nopinone enol acetate of general formula (V) can be obtained according to the method recorded in the literature. Coxon et.al., Aust J. Chem 23,1069 (1070).

Such compounds are each derived from the dl isomer of optically active β-pinene.

The norpinene derivative of the general formula (III) is obtained by reacting the nopineone enol acetate of the general formula (V) with an excess lead tetraacetate in an inert organic solvent, preferably benzene. Generally, lead tetraacetate can be used in excess if necessary, but it is advantageous to use an excess of 2 to 10 moles. Usually the reaction is carried out at 50 to 100 ° C. and the reaction time depends on the product obtained.

When the reaction is stopped at 1 to 3 hours, the product to be separated is optically active 6,6-dimethyl-2,2-diacetoxy- wherein R is acetoxy and R ₂ and R ₃ together form a double bond. 3-norpinene isomer. When the reaction is allowed to proceed for 16 to 20 hours, the product formed is 6,6-dimethyl-2,4-diacetoxy2-, wherein R ₁ is connected to R ₃ to form a double bond, and R ₂ -acetoxy. It is an optical isomer of norpinene. In either case, the reaction is separated by filtration of the reaction mixture and distillation of the filtrate.

(-)-Ninofinone acetate of general formula (V) is (1) -2,4 diacetoxy-2-norpinene or (+)-2 of general formula (III) by the said manufacturing method. Is converted to, 2-diacetoxy-3-norpinene.

Optically pure 6,6-dimethyl-2,4-diacetoxy-2-norpinene and 6,6-dimethyl-2,2-diacetoxy-3-norpinene of the general formula (III) 4- (4-substituted 2,6-dihydroxyphenyl) -6,6-dimethyl-2- of formula (II), which is optically pure by reaction with 5-substituted resorcinol of formula (IV) Norpinanone is obtained. The optically pure general is obtained by reacting the above-mentioned 2,2-diacetoxynorpinene derivative or 2,4-diacetoxy norpinene derivative which is an optically pure dl isomer with 5-substituted tezorsinol in the presence of an acid. 4- (4-substituted 2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of formula (II) is obtained.

When optically pure compounds of the general formula are obtained herein, this relates to the stereochemistry of the norpinanone portion of the molecule and does not represent the stereochemistry of the group defined by R ₄ . Thus, when R ₄ is a group containing an asymmetric center, the separation of possible stereoisomers contributing to it is not included in the present invention.

In (-)-2,4-diacetoxy-2-norpinene or (+)-2,2-diacetoxy-3-norpinene of formula (III)

The (+) compound of the general formula (II) is prepared. Conversely, in the formula (III) of (+)-2,4-diacetoxy-2-norpinene or (-)-2,2-diacetoxy-3-norpinene of the general formula (II) A negative compound is prepared.

The condensation reaction of the 2,2-diacetoxynorpinene derivative of the general formula (III) or the 2,4-diacetoxynorpinene derivative with the resorcinol of the general formula (IV) is carried out in the presence of an equimolar amount of acid. By mixing equimolar amounts of reactants. Acids capable of producing protons such as hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and p-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-dibromoethane and aromatics such as benzene, toluene, chlorobenzene, m-xylene and p-xylene Substances and ethers such as diethyl ether and aliphatic materials such as nucleic acids.

The compound of formula (II) is prepared at a temperature of -50 to 80 ° C, preferably 0 ° to 30 ° C. The optimum temperature is 20 ° to 30 ° C. The reaction can be used in the range of 1 hour to 72 hours, in which case the reaction time is special, but is usually completed within 2 to 4 hours. The reaction time, of course, depends on the temperature.

In a typical embodiment, 5- optically pure norpinene derivatives of the above general formula (III) such as equimolar amounts of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 5- After mixing 5-substituted resorcinol of the general formula (IV) such as n-pentyl-tesorcinol in a common inert organic solvent such as benzene, the solution is used in an equimolar amount of an acid capable of producing a proton such as sulfuric acid. And stirred at 25 ° C. for 4 hours.

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 weak base such as sodium bicarbonate and removing the reaction solvent. The 4- (4-substituted-pentyl-2,6-dihydroxy-phenyl) -6,6-dimethyl-2-norpinanone of the general formula (II) prepared as described above is conventionally manufactured By the process, i.e., recrystallized with a solvent such as benzene, hexane, octane and related solvents to further refine in advance to obtain a highly crystalline solid material.

Typical examples of the optically active 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone prepared are as follows.

(+)-4- (4-n-octyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone;

(-)-4- [4- (1-methylhexyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone;

(-)-4- [4- (1,2-dimethylbutyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone;

(+)-4-[(4- (3-hexenyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone;

(+)-4- [4- (4-nonenyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone;

(-)-4- (4-cyclohexyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone;

(-)-4- (4-cyclooctyl-2,6-dihydroxyphenyl) -6,6-2-dimethylnorpinanone;

(+)-4- [4- (3-cyclohexenyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone;

(+)-4- [4- (1-cycloheptenyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone; And related compounds.

Prepared 4- (4-substituted-2,6-dihydroxyphenyl-6,6-dimethyl-2-norpinanone of Formula (II) is then an optically active isomer of Formula (I) 6a, 10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9- On or 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9- It turns on.

(+)-Norfinanone is reacted to obtain (-)-hexahydrodibenzopyranone, and (-)-norfinanone is reacted to obtain (+)-hexahydrodibenzopinanone. The reaction simply takes place in an inert organic solvent in the presence of an acid.

Commonly used solvents include chloroform, dichloromethane, 1,2-dibromoethane, hydrogen halides such as chloropropane and aromatic solvents such as benzene, toluene, chlorobenzene, xylene and alcohols such as ethanol.

Both protonic acid and Lewis acid are used to prepare the above general formula (I) compound. When protonic acid is used, the product is predominantly the cis type optically pure isomer. If Lewis acids are used, the product is dominant in the trans form.

The temperature at which the general formula (I) compound is prepared is 0 ° to 80 ° C. Generally, the preferred temperature range in which protonic acid is used is from 30 ° to 80 ° C, and the preferred temperature range in which Lewis acid is used is from 0 ° to 30 ° C. However, the temperature range used may depend on the acid dml form. 8 to 36 hours is enough to complete the reaction. Shorter and longer times are often used but depend on the reaction temperature used.

The reaction product of formula (I) is separated by washing only the reaction solution without the remaining acid. For example, an organic solution containing a base such as water-soluble sodium bicarbonate is washed and then separated by removing the reaction solvent.

The product thus formed is purified by standard chromatographic methods to separate 6a, 10a-cis-hexahydrodibenzopyranone from 6a, 10a-trans derivatives.

Norpinanone is reacted with about 1 to 10 molar excess of acid, preferably about 1 to 3 molar excess to convert the norpinanone derivative to the corresponding hexahydrodibenzopyranone of formula (I).

If desired, 6a-10a-hexahydrodibenzopyranone can be converted to the corresponding 6a-10a-trans isomer by reaction with aluminum chloride.

A pharmaceutically active substance is added to 6a-10a-cis-hexahydrodibenzopyranone to act as an intermediate leading to the more active 6a-10a-trans isomer. Such (-)-isomers of the 6a-10a-trans isomers are particularly important for the treatment of depression and anxiety. The (+) isomer of the 6a-10a-trans isomer is particularly valuable as an intermediate. For example trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d The (+) isomer of pyran-9-one is reduced at the 9-ketone site to yield the corresponding (+)-trans-1,9R-dihydroxy-3- (1,1-dimethylheptyl) -6,6- Dimethyl-6,6a7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran was obtained, and this compound was subjected to a standard activity assay using a mouse. Noticeably.

Separation of 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of the general formula (III) is not absolutely necessary. Because 6,6-dimethyl-2,4-diacetoxy-2-norpinene and 6,6-dimethyl-2,2-diacetoxy-3-norpinene of the general formula (III) Optically active cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] in one step process Because it can be converted to pyran-9-one or optically active 6a, 10a-trans-hexahydrodibenzopyranone. In particular, the 2,4-diacetoxy-2-norpinene derivative or the 2,2-diacetoxy-3-norpinene derivative is about 12 to 36 hours in a protonic acid such as p -toluenesulfonic acid and an inert organic solvent such as chloroform. And reacted with an optically active cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a7,8,10 at an elevated temperature of about 30 to 80 ° C. Predominantly, 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained. Optically active 2,4-diacetoxy-2-norpinene or 2,2-diacetoxy-2-norpinene or 2,2-diacetoxy-3-norpinene to Lewis such as borontrifluoride Optically active trans-1-hydroxy-3-substituted-6 by reacting similarly with 5-substituted resorcinol at temperatures between about 0 to 30 ° C. for 8 to 16 hours in organic solvents such as acids and chloroform , 6-Dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained predominantly.

The above mentioned norpinene derivatives of the general formula (III) can be converted into optically active 6a, 10a-cis and 6a, 10a-trans-hexahydrodibenzopyranone in one step by selecting appropriate reaction conditions. In this case, it can be converted to 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of the above-mentioned optically active formula (II). According to the present invention, it is preferable to carry out the reaction so that the diacetoxy norpinene derivative and the 5-substituted resorcinol are reacted to separate the norpinanone intermediate, and purified to be converted into hexahydrodibenzopyranone. Do. Such a preferred method of preparation eliminates the need for a more expensive purification step for hexahydrodibenzopyranone, which is prepared from diacetoxy norpinene in one step. This is because a small amount of terpene impurity is present when converted directly, and it is rather difficult to remove it from the desired product.

As noted above, certain hexahydro dibenzopyranones are useful for anesthetizing mammals and are used to treat anxiety, depression, and similar reactions related to the central nervous system. ciL-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-benzo [b, d] pyran-9-one Themselves are pharmaceutically useful, and the corresponding d-trans isomers are usually somewhat more potent biologically. The d and l optical isomers of such 6a, 10a-cis and 6a, 10a-trans-hexahydrodibenzopyranones prepared according to the preparation method of the present invention are effective as therapeutic agents for anxiety and depression or as intermediates. Each pharmaceutically active optical isomer of cis and trans-hexahydrodibenzopyranone 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.

[Production Example 1]

[(-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene]

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 under vacuum on phosphorus pentoxide and potassium hydroxide was dissolved in a stirred solution. The reaction mixture was heated to reflux and stirred for 18 hours. The reaction mixture is then cooled to room temperature and filtered to afford 23.5 g of a 10% aqueous solution. The product thus obtained is distilled off to obtain 9.3 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene. Boiling Point: 115 to 118 ° C (at 5 Torr)

-89.7°(C=1.0, 클로로포름.

-89.7 ° (C = 1.0, chloroform.

H ¹ nmr (CDCI ₃ ): δ 5.25 (m, 2H), δ 2.4 (m, 4H), δ 2.1 (s, 3H), δ 2.0 (s, 3H), δ 1.35 (s, 3H), δ 1.0 (s, 3H)

1R (chloroform): 1730,1763cm ^-1 , carbonyl

mass spectrum m / e: 196 (M ⁺ -CH ₂ = C = 0).

[Production Example 2]

[(+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene]

18.0 g of (-)-nopinone enol acetate was added to 250 ml of anhydrous benzene under a stream of nitrogen, and 48.8 g of leaded teracetate 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 is then cooled to room temperature, the aqueous sodium bicarbonate is washed with solution and water, dehydrated and the solvent is evaporated under reduced pressure to afford (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene- 9.8 g is obtained. Boiling Point: 102-103 ° C (at 5 Torr)

-33.2°(C=1.0, 클로로포름)

-33.2 ° (C = 1.0, chloroform)

Elemental Analysis (C ₁₃ H ₁₈ O ₄ )

This launch: C 65.53, H 7,61, COCH ₃ 36.12

Found: C 65.77, H 7,32, COCH ₃ 36.56

H ¹ nmr (CDCI ₃ ): δ 6.4 (m, 2H), δ 3.15 (m, 1H), δ 2.3 (ш, 3H), δ 2.1 (s, 6H), δ 1.4 (s, 3H), δ 1.1 (s, 3H)

mass spectrum m / e: 196 (M ⁺ -42)

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

[Manufacture example 3]

[(+)-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 added to P-toluenesulfonic acid monohydrate 0.95. It is added to 50 ml of chloroform containing g and it is left to stand at about 25 degreeC for 4 hours. The reaction mixture is then diluted with 100 mL of diethyl ether, and this solution is washed with 10% aqueous sodium bicarbonate solution and water and dehydrated. The solvent was 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-di 1.30 g of hydroxyphenyl] -6,6-dimethyl-2-norpinanone is obtained. Melting Point: 171 ~ 174 ℃

=＋55.8°(C=1.0, 클로로포름)

= + 55.8 ° (C = 1.0, chloroform)

Elemental Analysis (C ₂₄ H ₃₅ O ₃ )

This launch: C 77.38, H 9,74

Found: C 77.59, H 9.53

H ¹ nmr (CDCI ₃ + DMOd ₆ : δ 8.05 (s, 2H, pulmonary OH), δ 6.35 (s, 2H), δ 4.05 (t, 1H), δ 3.65 (m, 1H), δ 2.45 (m, 5H), δ 1.35 (s, 3H), δ 1.15 (m, 19H), δ 0.95 (s, 3H)

1R (KBr) 1668 cm ^-1 , Carbonyl

mass spectrum m / e: 372 (M ⁺ )

According to the preparation method described above, 1.18 g of (+)-6,6-dimethyl-2.2-diacetoxy-3-norpinene had (+)-having the same physical properties as those obtained by the method described in Preparation Example 3. 4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone.

[Production Example 4]

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

238 mg of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 236 mg of 5- (1,1-dimethylheptyl) -resorcinol were diluted to 12.5 in dichloromethane in a flask equipped with a dry tube. Dissolve in ml. Cool the mixture to −10 ° C. and add about 15 mg of borontrifluoride diethyl etherate. The mixture is then stirred at −10 ° C. for 1.5 hours and then warmed to 0 ° C. During stirring, the solid falls into the crystals. The reaction mixture is then poured into water and the oil layer is washed with 5% sodium bicarbonate solution. The oil layer is then dehydrated and evaporated in vacuo to yield a pale yellow oil that is soluble in hot nucleic acid. Cool and filter to obtain 135 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpina. The product is the same as the product of Preparation Example 3 above.

Production Example 5

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

1 g of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 1 g of 5- (1,1-dimethylheptyl) resorcinol are dissolved in 50 ml of 3: 1 hexane: diethyl ether. The mixture is cooled to −40 ° C. in a flask with a dry tube. Then 0.65 ml of borontrifluoride diethyl etherate is added and the mixture is stirred at -40 ° C for 1 hour. It is then warmed to 0 ° C. with stirring for an additional 11 hours. The mixture is then poured on ice and extracted with diethyl ether. The oil layer is washed twice with 5% sodium bicarbonate solution and dehydrated with sodium sulfate. The dehydrated organic liquid was evaporated to give a yellow oily substance, which was dissolved in 3: 1 hexane / cyclohexane and cooled to obtain the same (+)-4- [4- (1,1-dimethyl) as the product of Preparation Example 3. Heptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpinanone.

[Manufacture example 6]

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

9.5 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene and 18.9 g of 5- (1,1-dimethylheptyl) resorcinol were dissolved in 250 ml of chloroform and the solution was dried. Cool to -20 ° C in the attached flask. 0.5 ml of boron trifluoride diethyl etherate is then added, and the mixture is stirred at a constant temperature for 2 hours. The mixture is then warmed to 0 ° C. and poured into 100 ml of 5% sodium bicarbonate. The water-soluble mixture is then extracted with diethyl ether, and the sediment is washed with 5% sodium carbonate solution, dried over sodium sulfate and evaporated in vacuo to give an oily substance. The oil is chromatographed on silica gel and eluted with chloroform, then eluted with chloroform containing 1 to 2% methanol and finally eluted with diethyl ether. The product containing fractions were evaporated to dryness, collected and recrystallized from cyclohexane / hexanes to give (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl 3.5 g of 2-norfinanone are obtained. The product is the same as the product of Preparation Example 3 above.

[Manufacture example 7]

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

238 mg (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene and 236 mg of 5- (1,1-dimethylheptyl) -resorcinol are dissolved in 12.5 ml of benzene. To this was added 198 mg of P-toluene sulfonic acid monohydrate. The mixture was stirred at reflux for 2 hours, cooled and diluted with diethyl etherate. The mixture is then washed three times with 10% sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo to give 439 mg of yellow oil. The oil was extracted with hexane and evaporated to dryness to give (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6 which was analytically identical to the product of Preparation Example 3. 20 mg of dimethyl-2-norpinanone is obtained.

[Manufacture example 8]

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

340 mg of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 330 mg of 5- (1,1-dimethylheptyl) -resorcinol were dissolved in 12.5 ml of dichloromethane at 0 ° C., 50 mg of borontrifluoride diethyl etherate is added. The mixture is stirred for 1.5 hours and warmed to room temperature with a further 1 hour of stirring. The mixture is then poured into water and extracted with diethyl ether.

The oil layer is washed with 5% sodium bicarbonate and dried. Evaporation in vacuo gave a slightly yellow oil which was treated with 15 ml of hexane and left to stand (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6- 98 mg of dimethyl-2-norpinanone is obtained. The liquid is chromatographed on silica gel to give the product again. The product is the same as the property of Preparation Example 3.

[Manufacture example 9]

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

119 mg of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 118 mg of 5- (1,1-dimethylheptyl) -resorcinol were dissolved in 12.5 ml of dichloromethane at room temperature, and boron. 0.05 mg of tripololide diethyl etherate is added.

The mixture is stirred for 4 hours, poured into ice and sodium bicarbonate, and extracted with diethyl ether. The oil layer is dried over sodium sulfate and evaporated in vacuo to give 250 mg of oil. The oil was treated with 10 ml of hexane and filtered to give 60 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl] -6,6-dimethyl-2-norpina. Get The product is identical in properties to the above for the preparation.

[Production Example 10]

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

119 mg of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene and 118 mg of 5- (1,1-dimethylheptyl) -resorcinol were dissolved in 12.5 ml of benzene at room temperature and boron tree 0.5 ml of fluoride diethyl etherate is added. The mixture was stirred at room temperature for 4 hours, reacted and purified as described above to give (+)-4- [4- (1,1-dimethylheptyl) -2,6- the same properties as in Example 3 above. Dihydroxyphenyl] -6,6-dimethyl-2-norpinanone is obtained.

[Production Example 11]

[(+)-4- (4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone]

1.19 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene and 0.9 g of 5-n-pentyl resorcinol are dissolved in 50 ml of chloroform at room temperature and P-toluenesulfonic acid monohydrate 0.95 g is added. The mixture was stirred at room temperature for 3 hours, poured into 100 ml of diethyl ether, and washed twice with sodium bicarbonate solution and once with saturated sodium chloride solution. The oil layer is then dried over sodium sulfate and evaporated to dryness. The oil of the residue is chromatographed on silica gel and eluted with chloroform, then eluted with chloroform with increasing amounts up to 2% methanol. The product containing the fractions are collected to give 1.08 g of (+)-4- (4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone.

＋41.6°(C=1.0, 메탄올).

+ 41.6 ° (C = 1.0, methanol).

[Manufacture example 12]

[(+)-4- (4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone]

Using (19) (19) (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene as starting material, iteratively repeated according to the preparation method of Preparation Example 11, and the properties of Preparation Example 11 810 mg of the same (+)-6,6-dimethyl-2-norpinanone is obtained.

Example 1

[(-)-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 Example 3, (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norfinanone was dissolved in 25 ml of chloroform. , 190 mg of P-toluenesulfonic acid hydrate is added, heated to reflux and stirred for 24 hours. The reaction mixture is then cooled to room temperature, diluted with 25 ml of water, 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 a white foamy product. The resulting crude is chromatographed on a column packed with Woelm activity II silica gel and eluted with 5% diethyl 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: 139.5 ~ 141 ℃

-50.0°(C=1.0, 클로로포름)

-50.0 ° (C = 1.0, chloroform)

mass spectrum m / e: Theoretical for C ₂₄ H ₃₆ O ₃ , 372.2664; Found, 372.2665

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]

The foamy residue obtained by evaporation of the extraction solvent was carried out according to the preparation method of Example 1, except that the residue was chromatographed on silica gel with benzene and benzene containing a small amount of diethyl ether.

The product containing fractions were evaporated to yield the same (-)-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7 as the product of Example 1 above. 200 mg of 8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, and also have the same corresponding (-)-trans-hexahydrodibenzopyra as the product of Example 18 below Get 100 mg of paddy.

Example 3

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

The solvent is carried out according to the preparation method of Example 1, except that the reaction mixture is refluxed for only 4 hours using 25 ml of benzene. The solvent was evaporated off to yield 455 mg of cis and trans isomers, a mixture of about 1: 1, and the composition was chromatographed on silica gel using benzene containing 3% ethyl acetate, the products of Examples 6 and 1, respectively. Equivalent to 140 mg of pure trans isomer and 154 mg of cis isomer are obtained.

Example 4

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

25 ml of ethanol containing 300 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone and 25 ml of 6N hydrochloric acid And the mixture is stirred at reflux for 16 hours. The mixture is then cooled and purified according to the preparation method of Example 1 to obtain an oil residue. This was crystallized with hexane to give 20 mg of product, which was confirmed by TLC to give cis and trans isomers which are approximately the same 1: 1 mixture as the products of Examples 1 and 6, respectively.

Example 5

[(-)-Cis and trans-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] Pyran-9-On]

632 mg of (+)-4- [4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norfinanone of Example 4 was dissolved in 25 ml of chloroform, and P-toluic acid was dissolved. 380 mg of phonic acid monohydrate is added and refluxed for 24 hours. Confirm that the reaction mixture has been completely changed to cis and trans-hexahydrobenzo [b, d] pyranone named above. The reaction mixture is then carried out according to the method of Example 1 to obtain a foamy product.

Example 6

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

Chlorine chloride in a solution of 372 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone in 25 ml of chloroform 1.0 ml of tin is added. The reaction mixture was 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 is then washed with water and dried, the solvent is evaporated and removed under reduced pressure to give 375 mg of foamy product. The product is then chromatographed on a film activity II silica gel column, eluting with benzene. In the fraction containing one composition, the solvent is evaporated and removed to remove (-)-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8 305 mg of, 10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

-52.3°(C=1.0, 클로로포름)

-52.3 ° (C = 1.0, chloroform)

mass spectrum: C ₂₄ H ₃₆ O ₃ calcd, 372.2664, m / e: 372.2667 (observed)

The solvent was evaporated off in the eluate containing the other composition to give (-)-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10, 55 mg of 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one are obtained.

-50°(C=1.0, 클로로포름)

-50 ° (C = 1.0, chloroform)

Example 7

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

10 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norfinanone at reflux for 1 hour at boron tripolo Treatment with 1 ml of lide diethyl etherate. The reaction mixture is then poured into ice and extracted with diethyl ether. The organic layer is washed with 5% sodium bicarbonate solution. The organic layer is then dried, evaporated and analyzed by TLC.

This compound is a trans, cis isomer of the same 3: 1 mixture as the products of Examples 6 and 1, respectively.

Example 8

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

50 mg of the same norpinanone used in the above example is added to 5 ml of dichloromethane and stirred, and 0.2 ml of ditin chloride is added. The mixture is stirred at room temperature for 20 hours and then analyzed by TLC.

This compound is a trans, cis isomer, which is the same 9: 1 mixture as the products of Examples 6 and 1, respectively.

Example 9

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

The reaction solvent is benzene, and the mixed solution is first stirred at room temperature for 2 hours, then stirred at reflux for 4 hours, and then stirred at room temperature for 16 hours, according to the method of Example 20. TLC analysis confirmed that 100% conversion of the trans and cis isomers, which are the same 9: 1 mixture as the products of Examples 6 and 1, respectively.

Example 10

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

Dissolve 50 mg of (+)-4- [4- (1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone in 5 ml of dichloromethane and boron triple fluoride. 0.2 ml of diethyl etheride is added. The mixture is stirred for 1 hour at room temperature and 0.2 ml of another boron fluoride diethyl etherate is added. The mixture is stirred for another 4 hours and analyzed by TLC.

This compound constitutes the same trans isomer as the product of Example 6, and has a small amount of the cis isomer as the product of Example 1.

Example 11

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

632 mg of (+)-4- (4-n-pentyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norfinanone are treated with 780 mg of ditin chloride for 6 hours at room temperature. Analysis by TLC confirms that the starting material norpinanone is converted to a mixture of cis- and trans-hexahydrodibenzo [b, d] pyranone of the name and the predominant product is the trans isomer. The reaction mixture was continued and purified according to the method of Example 1 to obtain 622 mg of foamy product.

Example 12

[(-)-Trans-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran- 9-on]

Each of the products obtained in Examples 5 and 11 was dissolved in 25 ml of dichloromethane, respectively, and 2 g of anhydrous aluminum chloride was added to each solution. The mixture is stirred for 16 hours at room temperature. It is then poured into ice and diluted with diethyl ether. The organic layer is first washed with water, then with 10% aqueous sodium bicarbonate solution, dried and evaporated in vacuo to give about 560 mg of each oily product. The product was collected and chromatographed on silica gel, eluting with 1: 1 hexane: diethyl ether.

The product containing fractions were combined and evaporated to dryness to give 333 mg of product. This product is taken up in diethyl ether and washed with 1N sodium hydroxide solution for 1 hour. The oil layer is then dehydrated with sodium sulfate and evaporated in vacuo to give essentially pure (-)-trans-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexa 297 mg of hydro-9H-dibenzo [b, d] pyran-9-one are obtained.

-37.3°(C=1.0, 클로로포름)

-37.3 ° (C = 1.0, chloroform)

The following example illustrates the preparation of hexahydrodibenzopyranone in norpinene of the general formula (III) in a one step process. These examples do not describe preferred embodiments of the present invention but rather describe possible methods that can be applied to the present invention.

Example 13

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

2.38 g of (-)-6,6-dimethyl-2,4-diacetoxy-2-norpinene and 2.76 g of 5- (1,1-dimethylheptyl) -resorcinol were treated with borontrifluoride diethyl ether. Dissolve in 50 ml of dichloromethane containing 10.2 g of rate, cool to 0 C in an ice bath and stir for 1 hour. The reaction mixture is then warmed to 25 ° C. and stirred for another 12 hours. Thereafter, the reaction mixture was poured into 25 g of ice, and the resulting aqueous solution mixture was extracted with diethyl ether. The organic layer is separated, washed with 10% aqueous sodium bicarbonate solution, dried, and the solvent is evaporated and removed under reduced pressure to yield 4.1 g of a brown oil. The oil obtained is purified by chromatography on a column packed with film activity II silica gel, eluting with benzene. The appropriate fractions containing the desired product are combined and the solvent is evaporated and removed to afford (-)-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6, 1.06 g of 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one are obtained.

-47.5°(C=1.0, 클로로포름)

-47.5 ° (C = 1.0, chloroform)

According to the method detailed above, (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene was substituted with 5- (1,1-dimethylheptyl) in the presence of boron tripololide diethyl etherate. Reaction with resorcinol (-)-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -Dibenzo [b, d] pyran-9-one is obtained.

The following preparation example illustrates the method for converting the cis compound of formula (I) to a trans compound.

Example 13

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

(-)-Cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] To 5 ml of dichloromethane containing 77 mg of pyran-9-one and stir at 25 ° C. for 4 hours.

The reaction mixture is then diluted with 20 g of ice and the resulting aqueous mixture is extracted with diethyl ether. The ethereal extracts are combined, washed with 2N hydrochloric acid, washed with 10% aqueous sodium bicarbonate solution, washed with water, dried and the solvent is evaporated and removed under reduced pressure to give 75 mg of oily product. The oil formed is chromatographed on a plate coated with silica gel. Elution with a solution containing 20% ethyl acetate solution in benzene and evaporation and removal of the solvent gave (-)-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6, 54 mg of 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

-53.8°(C=1.0, 클로로포름)

-53.8 ° (C = 1.0, chloroform)

Claims (1)

A process for preparing the optical isomer of the hexahydro dibenzopyranone compound of the following general formula (I) characterized by reacting an optically active norpinanone compound of the following general formula (II) with an acid.

In the general formula, hydrogen at positions 6a and 10a may have a cis or trans coordination structure and R ₄ is alkyl having 5 to 10 carbon atoms, alkenyl having 5 to 10 carbon atoms, cycloalkyl having 5 to 8 carbon atoms or cyclo having 5 to 8 carbon atoms. Alkenyl.