CS196377B2 - Method of producing optically active derivatives of nor-pinene - Google Patents

Description

The present invention provides a process for the preparation of optically active 6,6-dimethylInorpineb derivatives by reacting optically active noplnone enolacetate with lead acetate. The novel compounds thus prepared are useful as intermediates for the synthesis of hexahydrodibenzopyranones.

It has been found that certain 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibene, [b, d] pyra, n-9- they are useful because of their effect on the central nervous system of mammals. The dl-mixture of these compounds in which the hydrogen atoms attached at positions 6a and 10a are trans relative to each other is particularly valuable for the treatment of anxiety states, for the treatment of depression and as an analgesic. US Patent Nos. 3,953,603, 3,928,598 and 3,944,673 disclose the use of said compounds, paying particular attention to the use of the dl-racemic mixture 6a, 10-trans-1-hydroxy-3- (1,1-dimethylheptyl). J -6,6-dlmethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyrah-9-one, now known as "Nabilone".

Recently, it has been found that by separating the dl-racemic mixture of both the cis and trans isomers of the above hexahydrodibenzopyranones into the corresponding optically active isomers, compounds with different biological properties are obtained. In particular, 198377 one of the optical isomers of both cis- and trans-hexahydrodibenzopyranones is always more effective in terms of mammalian central nervous system efficacy than the other optical isomer. BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of intermediates for the preparation of optically active isomers of certain cis- and trans-1-hydroxy-3-subst.-6,66-dimethyl-6,6a, 7,8,10,10a-hexaihydro-9H. -dibenzo [b, d] pyram-9-ones.

The present invention relates to a process for the preparation of optically active norpinene derivatives of the general formula I

wherein R 1 represents an acetoxy group or together with R 5 forms a double bond, R 2 represents acetoxy or together with R 3 forms a double bond and R 3 forms the same bond either together with R 1 or together with R 2, characterized in that optically active nopinone enolacetate of formula II F

198377

is reacted with lead acetate in a non-reactive organic solvent.

It will be appreciated that only one of R 1 and R 2 in formula I is acetoxy, the other of R 1 and R 2 being taken together with R 5 to form a double bond.

In accordance with the invention, the novel optically active norpinine starting materials of formula I are prepared by reacting an optically active nopinone enolacetate of formula II with di-acetate. The optically active nopinone enolacetates of formula II can be readily prepared by the method of Coxon et al. in Aust. J. Chem. 23, 1069 (1970). These compounds are derived from the corresponding optically active d- and 1-isomers (3-pinene).

Norpinene derivatives of formula I are prepared by reacting nopinone enolacetate of formula II with an excess of lead acetate in a non-reactive organic solvent, preferably benzene. Lead acetate is usually used in a two to ten disimolar excess, but if desired, a larger excess can also be used. The reaction is normally carried out at a temperature of 50 to 100 ° C, the duration of the reaction determining the nature of the resulting product.

The reaction is complete after 1 to 3 hours and isolated as the reaction. the product of the optically active isomer of 6,6-dimethyl-2,2'-acetyl-3-norpineh wherein R 1 is acetoxy and R 2 and R 5 together form a double bond. If the reaction is allowed to proceed for 16 to 20 hours, the product is an optical isomer of 6,6-dimethyl-2,4-diacetoxy-2-norpinine a, wherein R 1 together with R 1 forms a double bond and R 2 represents an acetoxysuppline. In each of these cases, the reaction product is isolated by filtration of the reaction mixture and distillation of the filtrate.

The (-) - nopinone-eraolacetate (II) is converted to (-) - 2,4-aciacetoxy-2-noripine or (+) -2,2-diacethoxyxy-3-norpinene (I) as described above. The (II) derivative is converted to the (+) - 2,4-acetoxy compound of formula I.

The optically pure isomers of 6,6-dimethyl-2,4-diacetoxy-2-norpinene and 6,6-diimethyl-2,2-diacetoxy-3-norpinene of formula I give optically pure 4- (4) by reaction with 5-substituted resorcinol. (2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinasnon. Treatment of both the aforementioned 2,2-diacetoxynorpine derivative and the 2,4-diacethoxynorpine derivative, in the form of an optically pure d- or 1-isomer, with a 5-substituted resorcinol in the presence of an acid yields an optically pure

4- (4-Substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinsainone. . ¹

The condensation reaction between the 2,2-diacetoxynorpine derivative or the 2,4-dlacetoxynorpine derivative of the formula I and the resorcinol is carried out by mixing approximately equimolar amounts of these reactants in the presence of approximately equimolar amounts of acid. Protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid and p-bromotoluenesulfonic acid, as well as Lewis acids, including boron trifluorides, tin tetrachloride and boron bromide can be used. The preferred acid is p-toluenesulonic acid.

The reaction is preferably carried out in a non-reactive organic solvent. Any of a wide variety of solvents such as halogenated hydrocarbons such as chloroform, dichloromethane, chloroethane, 1,2-dichloroethane and 1,1-dibromo methane, aromatic hydrocarbons such as benzene, toluene, chlorobenz, m- xylene and p-xylene, ethers such as diethyl ether and aliphatic solvents such as hexane.

A typical example is the following:

Roughly equimolar amounts of optically pure norpinene derivative of formula I, such as (+) -6,6-dimethyl-2,2-diacetoxy-3-norpinene, and 5-substituted resorciinol, such as 5-n-pentylresorcinol, are mixed in a conventional, non-reactive organic solvent, such as benzene, and the solution is stirred at 25 ° C for 4 hours in the presence of an equimolar amount of a protonic acid such as sulfuric acid. The product of this reaction is optically pure. (+} -4 + 4-n-Pentyl-2,6-dihydroxyphenyl} -6,6-diethyl-2-inorpinanone Such compounds are readily isolated by simply washing the reaction mixture with a mild base such as sodium bicarbonate and evaporating the reaction mixture. solvents.

The 4- (4-subst.-2,6-dihydroxyphenyl) -6,6-dimethylthiyl-2-norpinanones thus obtained are further converted to the optically active isomers of either 6a, 10a-cis-1-hydroxy-3-subst.-6. 6,6-dimethyl-6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ans or 6a, 10a-trans-1-hydroxy-3-substituted-6,6- dimethyl-6,6a, 7, 8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones Solvents commonly used include halogenated hydrocarbons such as chloroform, dichloromethane, 1; 2-dibromoethane and chloropropane, aromatic solvents such as benzene, toluene, chlorobenzene and xylene, and alcohols such as ethanol.

Both protonic acids and Lewis acids are used in the preparation of these compounds. When using protonic acid, the product is predominantly optically pure isomer of the cis-form, with Lewis acid the predominant product is the trans-form.

The temperature at which these compounds are prepared ranges from 0 to 80 ° C. Generally, the preferred temperature range for proton, ava / acid is from 30 to 8 ° C and for Lewis acid is from about Q to 3 ° C.

Conversion of the norpinanone derivative to the corresponding hexahydrodibenzopyranone is generally accomplished by reacting norpinanone with about one to about ten molar excess of acid, preferably about one to about three molar excess.

The 6α, 10α-cis-hexahydrodibenzopyranones, in addition to being pharmacologically active themselves, also serve as intermediates to produce the somewhat more potent 6α, 10α-trans-isomers. The (? -Isomers) of these 6a, 10a-trans derivatives are particularly important as agents for the treatment of depression and anxiety (+? -Isomers of these 6a, 10a-derivatives are particularly valuable as intermediates. For example (+) -Fans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyrain-9- it can be reduced at the 9-keto group to give a (+) -trans-1,9R-dihydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7, 8.10 ₁ 10-hexahydro-9 H -dibenzo [b, d] pyran, which compound is valuable due to its central nervous system efficacy in mammals, as shown by standard mouse efficacy assays.

As stated above, certain hexahydrodibenzopyanonones have been found to be useful as analgesics in mammals and for the treatment of anxiety, depression and similar conditions associated with the central nervous system. Although ois-1-hydroxy-3-substituted-6,6-dimethyl-B.Ba.Ta10.10a-hexahydro-1H-dibenzo [b, d] pyran-9-ols in the form of racé-trans-isomers normally the somewhat homologous mixtures of d- and 1-isomers are themselves pharmacologically active, the corresponding ones being more effective. The separated d- and 1-opioid isomers of these 6α, 10α-cis- and 6α, 10α-trans-hexahydrodibenzopyranones, prepared by the method of the invention, are useful in the treatment of anxiety and depression as well as intermediates. The separated pharmacologically active optical isomers of these cis- and trans-hexahydrodibine-pyranones prepared according to the process of the invention are accordingly used in the same manner as the corresponding racemic mixtures described in the above references.

The invention is illustrated by the following non-limiting examples.

EXAMPLE 1 (-J-E, -Dimethyl-N-diiacetoxy-2-norenone)

To a solution of 18.0 g of (.beta.-nopinone enolacetate) in 250 ml of dry benzene is added under a single atmosphere of nitrogen to 48.8 g of lead acetate dried under vacuum over phosphorus pentoxide and potassium hydroxide in a single portion. The mixture was heated to reflux, stirred for 18 hours, the lever was cooled to room temperature, filtered, washed with 10% aqueous sodium bicarbonate solution and water, dried and the solvent was evaporated under reduced pressure. 1.5 g of the crude product in the form of a clear liquid

9.3 g of (-) - 6,6-dimethyl-2,4-diacetoxy-2-norpinene, boiling in the range of 115-118 ^° C / 667 Pa; [.Alpha.] D @ ²⁰ = -89.7 DEG (c = 1.0 in chloroform);

@ ¹ H NMR (CDCl3 ⁾ .delta.

5.25 (m, 2H),

2.4 (m, 4HJ); 2.1 (s, 3H);

2.0 (s, 3 HJ,

1.35 (3H),

1.0 (s, 3H).

IR (chloroform:

1730, 17 & 3 cm @ ¹ , carbanyl; mass spectrum: m / e:

196 (M ^{+ -} CH 2 = C - O).

Example 1 and d 2;

(+) -6,6-dimethyl-2,2-dlacetoxy-3-norenone

To a solution of 18.0 g of (-. Beta.-nopinane enolacetate in 250 ml dry benzene) was added in one portion with stirring under nitrogen atmosphere.

48.8 g of vacuum acetate dried over phosphorus pentoxide and potassium hydroxide. The reaction mixture was heated to reflux and stirred for 2 hours, then cooled to room temperature, washed with aqueous, sodium bicarbonate solution and water, dried and the solvent was evaporated under reduced pressure. The oily residue is distilled to give 9-8 g of (+ 1-ee-dimethyl-4-diacetoxy-5-norpinene, b.p.

[.alpha.] D @ ²⁰ = + 33.2 DEG, (c = 1.0 in chloroform). For C 13 H 18 O 1: calculated: 66.53% C, 7.61% H, 36.12% COCH 3, found:.

66.77% C, 7.32 O / o H, 36.56% COCH 3.

¹ H NMR (CDCl 3):

6.4 (m, 2H),

3.15 (m, 1H),

2.3 (m, 3H); 2.1 (s, 6H);

1.4 (s, 3 HJ,.

1.1 (s, 3HJ).

Mass Spectrum ·: m / e:

196 (M ⁺ -42); .

IR (chloroform):

175Q cm ^-1, carbonyl.

198377

The following examples illustrate the use of compounds of formula (I) for the preparation of optically active hexahydrodibenzopyranones.

Example 3 (+) -4- (4- (1,1-dimethyilheptyl) -2,0-dihydroxyphenyl) -6,6-dimethyl-2-norphananone

A solution of 1.19 g (-) - 6,6-diimethyl-2,4-diacethoxy-5-nitpinene, and 1.18 g of 5- (1,1-dimethylheptyl) resorcinol in 50 ml of chloroform containing 0.95 g of p-toluenesulfonic acid monohydrate is allowed to stand at 25 ^° C for 4 hours. The reaction mixture is diluted with 100 ml of diethyl ether, the resulting solution is washed with 101% aqueous sodium hydrogen carbonate solution and water, dried and evaporated. under reduced pressure. The remaining semi-crystalline solid was triturated with 25 mL of n-hexane and then filtered to give 1.30 g of (+) - 4 - ((1,1-dimethylheptyl) -2,6-dihydroxyphenyl) -6,6 - dimethyl-2-norpinanone, m.p. 171-174 ° C;

[.alpha.] D @ ²⁰ = + 55.8 DEG (c = 1.0 in chloroform).

H, 9.74; Found: C, 77.59; H, 9.83.

¹ H NMR (CDCl 3, δ-dimethylsulfoxide pet, <5):

8.05 (s, 2 Ή, phenol hydroxyl),

6.35 (s, 2H), ^4.05 (t, 1H)

3.65 (m, 1H),

2.45 (m, H);

1.35 (s, 3H);

1.15 (m, 19H),

0.95 (s, 3H).

IR (KBr):

1068 cm ^-1 , carbonyl; mass spectrum: m / e:

372 (M +).

In an analogous manner, 1.18 g of (+) -6,6-dimethyl-2,1-diacethoxy-3-norlenen is converted to (+) -4- [4i (1,1-dimethyilheptyl) -2,6-dihydroxyphenyl). 8,6-Dimethyl-2-norpinpinanone having the same physical constants as the product obtained as described above. Example 4 (-) - cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a ₎ 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

Solution 372 img (+) -4- (4- (1,1-Dimethylheptyl-2,6-dihydropyloxyphenyl) -6,6-dimethyl-2-norpinanone in 25 ml of chloroform containing 190 mg of monohydrate p The reaction mixture was cooled to room temperature, diluted with 2 (5 ml of water) and extracted several times with 25 ml of diethyl ether. The ether extracts were combined, washed with 10% aqueous sodium carbonate solution and water, dried, and the solvent was evaporated under reduced pressure to give 380 mg of the product as a white foam The crude product thus obtained was chromatographed on a silica gel column (Woelm, activity II) eluting. Evaporation of the solvent from the appropriate fractions gave 228 mg of (-) - cis-1-hydroxy-3- (1,1-dimethylethyl) -6,6-dimethyl-6,6a, 7,6. , 10,10-hexahydro-9H-dibenzo [b, d] pyran-9-one _pulse, • ture mp 139.5 DEG-141 DEG;

[ _.alpha. ] _D @ ²⁰ = -50.0 DEG (c = 1.0 in chloroform).

Mass spectrum m / e: Calcd. For C 24 H 36 O 3 372.2664, found ¹ 372.2665. '.. ··

Example 5 (-) - tr-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9'H-dibenzo [b , d] pyran-9-one

To a solution of 372 mg of (+) -4- [4- (1,1-dimethylheptyl-2,6-dihydroxyphenyl) -6,6-dimethyl-2-niorpinianone in 25 ml of chloroform is added in a single portion 1. 0 ml cínlčltého chloride. the reaction mixture was stirred for 16 hours at 25 ^Q C and then poured into 50 g of ice. the aqueous reaction with, mon extracted with several ml of diethyl ether was '25 ethereal extracts were combined, washed with 2 N hydrochloric acid hydrochloric acid and then 5% aqueous sodium bicarbonate solution, the organic layer was washed with water, dried and the solvent was evaporated under reduced pressure ^1. 378 mg of a crude foamed product was chromatographed on a silica gel column (Woelm, activity II). Use of benzene as eluent Evaporation of the solvent from the fractions containing only one component according to thin layer chromatography gave 305 mg of (- β-trans-1-hydroxy-3- (1,1-dimetylheptyl) -6,6). -dimethyl-6,6a, 7,8,10,10a-hexahydro-9'H-dibenzo [b, d] py ran-9-one o [α] _D ²⁰ = -52.3 ^L (c = 1.0 in chloroform).

Mass Spectrum m / e: Calcd. For C24H3O3, 372.2664, found · 372.2667.

Evaporation of the solvent from the eluates which contained another component according to thin layer chromatography gave 55 mg of (1-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a), 7,8,10,10a-hexahydro-9H-dibehizo [b, d] pyran-9-O'n α (d) d ²⁰ = -50 * (c = 1.0 in chloroform).

Claims (9)

1. Z, land ^; for the preparation of optically active norpinene derivatives of the general formula I in which R1 represents an acetoxy group or together with R3 forms a double bond, R2 represents an acetoxy group or together with R1 forms a double bond and R3 forms a double bond either together with R1 or together with R2, characterized in that optically active nopinone enolacetate of formula (II) OF THE INVENTION is reacted with lead acetate in a non-reactive organic solvent. 2. Process according to claim 1, characterized in that the reaction is carried out for 1 to 3 hours. 3. The process according to claim 1, wherein the reaction is carried out for a period of from 16 to 20 hours. 4. A process according to claim 2 wherein the solvent is benzene. 5. The process of claim 3 wherein the solvent is benzene. 6. Process according to claim 4, characterized in that the reaction mixture is refluxed. 7. Process according to claim 5, characterized in that the reaction mixture is refluxed. 8. A process according to any one of Claims 1 to 7, wherein the starting material is the β-isomer of the compound of formula II. 9. A method according to any one of claims 1 to 7, wherein the (. + -.) Isomer of the compound of formula II is used as starting material.