IE45248B1 - A norpinene compound and its use in the preparation of opttically active norpinanones - Google Patents

Description

This invention provides a process for preparing optically active norpinanones by reaction of a 5-substituted resorcinol with an optically active 6,6-dimethyl-2,4-diacetoxy-2-norpinene or an optically active 6,6-dimethyl-2,2-diacetoxy-3-norpinene, which compounds are derived from known optically active 0-pinenes.

Certain l-hydroxy-3-substituted-6,6-dimethyl6,6 a,7,8,10,lOa-hexahydro-SH-dibenzo/b,d7pyran-9-ones have been found to be useful as a result of their effect on the central nervous system of mammals. A dl mixture of such compounds wherein the hydrogen atoms attached at the 6a- and lOa-positions are oriented trans to one another is particularly valuable in the treatment of anxiety, depression, and for providing analgesia.

United States Patent Nos. 3,953,603, 3,928,598 and 3,944,673 describe the use of such compounds, and draw particular attention to the use of the dl-racemic mixture of 6a,lOa-trans-l-hydroxy-3-(1,1-dimethy1heptyl)-6,6-dimethyl-6,6a,7,8,10,lOa-hexahydro-9Hdibenzo/b,d7pyran-9-one, now generically referred to as Nabilone.

It recently has been discovered that separation of the dl-racemic mixture of both cis- and trans-isomers of the aforementioned hexahydrodibenzopyranones into the corresponding optically active isomers provides compounds with varying biological properties. In particular, one of the optical isomers of both cis and trans-hexahydrodibenzopyranones appears to be more active than the other optical isomer in its effect on the central nervous system of mammals. This invention provides a process for preparing intermediates for use in the preparation of optically active isomers of certain cis- and traRs-l-hydroxy-3-3ubstituted-6,610 dimethyl-6,6a,7,8,10,IQa-hexahydro-SH-dibenzo/b ,c£7pyran9-ones. The preparation of the pyranones from these intermediates is described and claimed in Patent Specification No. 45247.

The invention also provides a process for preparing optically active intermediates of Formula CH OH z\.

HO II wherein R^ is Cg-C1Q alkyl, Cg-C10 alkenyl, Cg-Cg cyeloalkyl, or Cg-Οθ cycloalkenyl: vzhich process comprises preparing them by reacting an optically active norpinene compound of the formula - 4 ·> III wherein is acetoxy, or taken vzith Rg, forms a double bond; Rig· is acetoxy or, taken with Rg, forms a double bond; and Rg, taken with R^ forms a double bond, or taken with Rg forms a double bond, vzith a resorcinol of the formula OH HO IV 4SSH8 wherein R^ is as defined above, in the presence of an acid in an unreactive organic solvent.

The present invention further provides the novel optically active intermediates of Formula III, and a process for preparing them by reacting an optically active norpinooe enol acetate of the formula il h i* Cn-jC-O ii with lead tetraacetate in an unreactive organic solvent.

It will be understood that one of R^ and Rj in Formula III is acetoxy, and that the other of R^ and R_ combines with Rn to form a double bond.

Z ΰ» As used throughout this document, R4 is defined as Cg-C-,θ alkyl, Cg-C^0 alkenyl, Cg-Cg cycloalkyl, and Cg-Cg cycloalkenyl. The term ^-^θ alkyl refers to both straight and branched carbon chains, examples of which includes n-pentyl, n-hexyl, n-octyl, n-heptyl, n-decyl, 1-methylpentyl, 1-methyIhexyl, 1,2dimethyIhexyl, 1,1-dimethylheptyl, 1,1-diethylpentyl, 1,2,3-trimethylheptyl, 2-ethyIhexyl, 3-propylpentyl, 1,3-dimethyloctyl, 2,2-dimethyloctyl and 2,3-dimethylp&atyl.

Examples of Cg-C-^θ alkenyl groups include 2- pentenyl, 3-hexenyl, 4-octenyl, 5-decenyl, 1,2dimethyl-l-heptenyl, l,l-dimethyl-2-heptenyl, 1-ethyl3- hexenyl, 3,4-dimethyl-3-hexenyl and 3-ethyl-4heptenyl.

Typical examples of groups designated by the term Cg-Cg cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl, and cyclocctyl. Similarly, typical Cg-Cg cycloalkenyl groups include 1-cyclopentenyl, 2-cyclohexenyl, 2-cycloheptenyl, and 3-cyclooctenyl.

In accordance with this invention, the novel optically active norpinenes of Formula III are produced by reacting an optically active norpinone enol acetate of Formula V with lead tetraacetate in the presence of an unreactive organic solvent. The optically active norpinone enol acetates of Formula V are readily available by the method of Coxon et al., Aust, J. Chem. 23, 1069 (1970). Such compounds are derived from the respective optically active d and 1 isomers of S-pinene.

The norpinene derivatives of Formula III are prepared by reacting the norpinone enol acetate of Formula V with lead tetraacetate preferably in excess, in an unreactive organic solvent, preferably benzene.

The lead tetraacetate generally is utilized in 2 to 10 molar excess, although larger excesses can be used if desired. The reaction normally is carried out at 50 to 100°C., and the length of reaction determines which product is obtained.

When the reaction is terminated after 1 to 3 hours, the product isolated is an optically active isomer of 6,6-dimethyl-2,2-diacetoxy-3-norpinene, v/herein is acetoxy and R2 and Rg together form a double bond. When the reaction is allowed to continue for 16 to 20 hours, the product formed is an optical isomer of 6,6-dimethyl-2,4-diacetoxy-2-norpinene, 2 4 3 wherein together with is a double bond, and Hg is acetoxy. In either case, the product of the reaction is isolated ty filtering the reaction mixture and distilling the filtrate.

A ( - ) zuorpincoe auol acetate of Formula V is converted by the above process to a (- )-2,4diacetoxy-2-norpinenef or to a (+ )~2,2-diacetoxy-3noxpinena of Formula III. Conversely, a ( + 5 compound of Formula V -.-. converts.*? to a ( ·. .1-2,4-diacetoxy compound, cr -co a ( - )-2,2-diacetoxy compound of Formula III.

The optically ours isomers of 6,6-dimethyl2,4-diacetoxy“2-norpinene ana 6,6-dimethyl-2,2diacetoxy-3-ncrpinene of Formula III are reacted with a 5-substituted resorcinol of Formula IV in the presence of an acid in an unreacuive organic solvent to provide an optically pure 4“(4'oubstituted-2,6-aihydroxyphenyl)~ 6,6-dimethyl-2-norpinanone of Formula II. More particularly, reaction of either the aforementioned 2,2-diaaetoxynox-pl!iaae derivative or the 2,4-diacetoxynorpinene dexivatj.:,e, as the optically pure d or 1 isomers, with a 5-substituted resorcinol, in the presence of an acid produces an optically pure 4-(4substituted-2,6-dihydroxyphenyl)-6,6-dimethyl-2norpinanone of Formula II, When reference is made herein to optical purity, regarding compounds of the above formula, it is only intended to refer to the stereochemistry af the norpinanone portion of the molecule, and no designation of stereochemistry of the group defined by H^ is intended. Accordingly, when Rj is a group possessing asymmetric centers, no resolution of the possible stereoisomers attributable thereto is comprehended herein.

A ( + ) compound of Formula II is prepared from a ( - )-2,4-diacetoxy-2-norpinene, or from a ( + )-2,2-diacetoxy-3-norpinene of Formula III. Conversely, a ( - ) compound of Formula II is prepared from a ( + )-2,4-d±acetoxy~2-norpinene, or from a ( - )5 2,2-diacetoxy-3-norpinene of Formula III.

The condensation reaction between a 2,2diacetoxy-norpinene derivative or a 2,4-diacetoxynorpinene derivative of Formula III and a resorcinol of Formula IV is accomplished by commingling preferably approximately equimolar quantities of such reactants in the presence of approximately an equimolar quantity of an acid. Protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, para-toluenesulfonic acid and para-bromotoluenesulfonic acid may be used, as can Lewis acids including boron trifluoride, stannic chloride and boron tribromide. The preferred acid is para-toluenesulfonic acid.

. The reaction is carried out in an unreactive organic solvent. Any of a number of such solvents can be utilized, including halogenated hydrocarbons such as chloroform, dichloromethane, chloroethane, 1,2dichloroethane and 1,1-dibromoethane; aromatics such as benzene, toluene, chlorobenzene, m-xylene and £xylene; ethers such as diethyl ether; and aliphatics such as hexane.

The preparation of compounds of Formula II may be carried out at temperatures from -50°C. to 80°C., and preferably at temperatures from 0°C. to 30°C. The optimum temperature is usually the ambient temperature of 20°c. to 30°C. The reaction is usually substantially complete within 2 to 4 hours, although reaction times from 1 hour, or even less to as much as 72 hours may be used in particular instances. The reaction time needed depends in part on the temperature, of course.

As a typical example, about equimolar quantities 45343 of an optically pure norpinene derivative of Formula III such as ( + )-6,6-6imathyl-2,2-d.iacetoxy-3norpinene, and 5-substiuuted resorcinol of Formula IV such as S-n-pentyl-rasorcinol are commingled in a common unreactive organic sc-lvant such as benzene, and the solution is stirred at 25°C. for 4 hours in the presence of an equimolar quantity of a protonic acid such as sulfuric acid, The product of such reaction is optically pzre ( + ,. »i(<-np:nfcyi-2,6”dihydroxyphenyl)“6i6“f.bafcthyi-2“norpinanone. Such compounds are readily isolated by simply washing the reaction mixture with a mild base, such as sodium bicarbonate, and removing the reaction solvent. The 4-(4-substituted2,6-dihydroxyphenyl) -6,6-dir?.ethyl“2-norpiaanones of Formula II so produced typically exist as highly crystalline solids wh.',o’. are readily purified further if needed by routine procedures, such as recrystallization from solvents sue:·! as benzene, hexane, cyclohexane, octane, and related solvents.

Examples of typically prepared optically active 4-(4-sub+t?. tuted-2,6-dihydroxyphenyl)-6,6dimethyl-2-nc.·-cinanones includes: 4· }-4-(4-n-octyl-2,6-dihydroxyphenyl)-6,6dimethyl-2-norpinanone; ( - )-4 -£j- ί1-methylhexyl)-2,6-dihydroxyphenyl/-6,S-dimefchyl-2-norpinanone; ( - )-4-/3-Cl,2-dimethyIbutyl)-2,6-dihydroxyphenv.v6.· 5-dimethyl-2-norpinaaone> { + }-4-/3-i3-hexenyl)-2,6-dihydroxyphenyl^3.5- dimethyl-2-norpinanone; ( + )-4-/3-(4-nonenyl)-2,S-dihydroxyphenyf?6.6- dimethyl-2-norpinanone; 45s10 ( - )-4-{4-cyclohexyl-2,6-dihydroxyphenyl)6,6-dimethyl-2-norpinanone; ( - )-4-(4-cyclooctyl-2,6-dihydroxyphenyl)6,6-dimethyl-2-norpinanone; ( + )-4-/3-(3-cyclohexenyl)-2,6-dihydroxyphenyl7~6,6-dimethyl-2-norpinanone; ( + )-4-/3-(1-cycloheptenyl)-2,6-dihyaroxyphenyl7~6,6-dimethyl-2-norpinanone; and related compounds.

The 4-(4-substituted-2,6-dihydroxyphenyl)-6,6dimethyl-2-norpinanones of Formula II so produced are next converted to optically active isomers of either 6a 10a-cis-l-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8, 10,l0a-hexahydro-9H-dibsnzo2b,d7pyran-9-ones or 6a,10atrans-l-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10, 10a-hexahydro-9H-dibenzo/B,d7pyran-9-ones of Formula I, by the process of patent Specification Mo. 45247.

Isolation of the 4-(4-substituted-2,6dihydroxyphenyl)-6,6-dimethy1-2-norpinanones of Formula II is not absolutely required since the optically active 6,6-dimethyl-2,4-aiacetoxy-2-norpinenes and 6,6dimethyl-2,2-diacetoxy-3-norpinenes of Formula III can be converted in one step to either an optically active cis-l-hydroxy-3-substituted-,6-dimethyl-6,6a,7,8,10,10a hexahydro-9H-dibenzo/b,d7pyran-9-one or an optically active 6a,lOa-trans-hexahydrodibenzopyranone. In particular, reaction of a 2,4-diacetoxy-2-norpinene derivative or a 2,2-diacetoxy-3-norpinene derivative with a 5-substituted resorcinol in the presence of a protonic acid such as para-toluenesulfonic acid, and in an unreactive organic solvent such as chloroform, for a period of time Of about 12 to 36 hours and at an elevated temperature of about 30 to about 80°C., provides predominantly an optically active cis-14 5 8 4 8 - 11 hydroxy-3-substituted-6,6-dimethyl-6,5a,7,8,10,10a, -hexahydro-9H-dtbenzo/D,d7pyran-9-oiie. Similarly, reaction of an optically active 2,4-diacetoxy-2norpinene or 2,2-diacetoxy-3-norpinene with a 5substituted resorcinol in the presence of a Lewis acid such as boron trifluoride, and in an unreactive organic solvent such as chloroform, at a temperature of about 0 to about 30°C. for 8 to 16 hours, provides predominantly an optically active trans-l-hydroxy-3substitutesd-f,6-dimethyl-6,6a,7,8,10,loa-hexahydro9H-dibenzo2b,d7pyran-9-one.

While the aforementioned norpinene derivatives of Formula III can, by proper selection of reaction conditions, be converted in one step to optically active 6a, lOa-cis- and 6a, IQa-trans-hexahydrodlbenzopyranones, it is believed that such reactions proceed in each instance through the optically active 4-(4substituted-2,6-dihydroxy-phenyl)-6,6-dimethyl-2norpinanones of Formula II which were described hereinbefore. According to this invention, it is preferred to carry out the reaction between the diaoetoxynorpinene derivatives c.'.d a 5-substituted resorcinol in such a way that the norp.inanone intermediate can be isolated and purified, and subsequently converted to a hexahydrodibenzopyranone. Such preferred process obviates the need for more extensive purification of the hexahydrodibenzopyranones which are produced in one step from the diacetoxynorpinenes, since in such direct conversion minor quantities of terpene impurities generally are present and are somewhat difficult to remove from the desired product. in an effort to more fully illustrate certain aspects of this invention, the following detailed examples are provided. Such examples are not intended to be limiting in any way and should not be so construed.

Example 1 ( - )-6,6-Dimethyl-2,4~diacetoxy“2-norpinene To a stirred solution under a nitrogen gas atmosphere of 18.0 g. of ( - )-norpinane enol acetate dissolved in 250 ml. of dry benzene was added in one portion 48.8 g. of lead tetraacetate which had been dried in vacuo over phosphorous pentoxide and potassium hydroxide. The reaction mixture was heated to reflux and stirred for eighteen hours. The reaction mixture then was cooled to room temperature, filtered, and the filtrate was washed with ten percent aqueous sodium bicarbonate solution and with water, dried, and the solvent was removed therefrom by evaporation under reduced pressure to provide 23.5 g. of the crude product as a clear liquid. The product so formed was distilled to provide 9.3 g. of ( - )-6,6-dimethyl-2,4diacetoxy-2-norpinene. B.P. 115-118°C. at 5 torr. Zq72°D-89.7° (c-1.0, CHC13).

H1 nmr (CDClg) δ δ δ δ δ δ .25 (m, 2H) 2.4 (m, 4H) 2.1 (s, 3H) 2.0 (s, 3H) 1.35 (s, 3H) 1.0 (Sf 3H) IR (CHC135: 1730, 1763 cm , carbonyl, mass spectrum m/e: 196 (M -CH2=C=O), Example 2 ( +)-6,6-Dimethyl-2,2-diacetoxy-3-norpinene To a stirred solution under a nitrogen gas atmosphere of 18.0 g. of { - )-norpinone enol acetate dissolved in 250 ml. of dry benzene was added in one portion 48.8 g. of lead tetraacetate which had been dried in vacuo over phosphorus pentoxide and potassium hydroxide. Tiie reaction mixture was heated to reflux and stirred for two hours. The mix', ire then was cooled to room temperature, washed with aqueous sodium bicarbonate solution and with water, dried, and the solvent was removed ty evaporation under reduced pressure to provide the product as an oil. The oil was then distilled to provide 9,3 g. of I + )-6,6-dimethyl2,2-diacetoxy-3-norpin-r.e. S,P. 1O2-1O3°C. at 5 torr.

Zc/-':0D + 32.2° (c- 1.0, CHCl.}, Analysis Calc, forC13Hi5°4 Theory: C. 65.53? H, 7.61? COCHg, 36.12. Pound: C, 55.77? 7.32; COCHg, 35.56. H1 nmr (CDClg) δ 6,4 (m 2H) δ 3.15 ir. IH} j 2.3 tm, SH; 0 2,1 is. 6H) δ IX Cs, 3H> 3 Λ. (S, 3H) mass spectrum m/e? 196 im+ ™42j. IR (CHClg) 1750 carbonyl.

Example 3 (. + j -λ«/7ι» (i, thylheptyl) -2,6-dihydroxypheny\J~G, S-diiKathyl-2-norpinanone A solution of 1.19 g. of ( - )-6»6-dimethyl2,4-diac:etoxy“2“’iorpir.a·-/ a::l 1.18 g. of 5-(1,1dimethylheptyl)-resorcinol in 50 mi. of chloroform containing 0.95 g. of gsra-toluenesuifonic acid monohydrate stood at about 25°C. for four hours. The reaction mixture was then diluted vzith 100 ml. of diethyl ether, and the resulting solution was washed with ten percent aqueous sodium bicarbonate solution, with water, dried, and the solvent was removed thereS2··*8 - 14 from by evaporation under reduced pressure to provide the product as a semi-crystalline solid. The product so formed was triturated with 25 ml. of n-hexane and filtered, thus affording 1.30 g. of ( + )-4-/4-(1,1dimethylheptyl)-2,6-dihydroxyphenyl/-6,6-dimethyl-2- norpinanone. M.P. 171-174°C. / a_72OD + 55.8° (C = 1. CHClg) Analysis Calc, for C2zlH 36°3 Theory: C, 77.38; H, 9.74. Found: C, 77.59; H, 9.83. H1 nmr (CDClg+DMSOd6) 6 8.05 (s, 2Η, phenolic OH) δ 6.35 (ε, 2Η) δ 4.05 (t, IH) δ 3.65 (m, IH) δ 2.45 (m, 5H) δ 1.35 (ε, 3H) δ 1.15 (m, 19H) δ 0.95 (s, 3H).

IR (KBr) 1668 cm \ carbonyl, mass spectrum m/e: 372 (M+) .

Following the same procedure, 1.18 g. of ( + )6,6-dimethyl-2,2-diaeetoxy-3-norpinene was converted to ( + ) -4-/Ϊ- (1,1-dimethylheptyl)*-'2,6-dihydroxyphenyl/-6,6-dimethyl-2-norpinanone having the identical physical properties as that obtained as described in Example 3.

Example 4 ( + )-4-/4-(1,1-Dimethylheptyl)“2,6-dihydroxypheny1/-6,6-dimethyl-2-norpinanone A 238 mg. portion of ( + )-6,6-dimethyl-2,2diacetoxy-3-norpinene and 236 mg. of 5-(1,l-dimethylheptyl) -resorcinol were dissolved in 12.5 ml. of dichloromethane in a flask equipped with a drying tube. 3 4 g - 15 The mixture was cooled to -1GVC., and approximately 15 mg. of boron urifiucride diethyl etherate was added. The mixture was then 'tirrefi at -10°C. for 1.5 hours, and was then allowed to warm to o°C. A solid crystallized during the period of stirring.

The reaction mixture was then poured into water, and the organic layer was v/ashed with 5 percent sodium bicarbonate solution. The organic layer was then dried and evaporated unoer vacuum to yield a light yellow oil which was dissolved in hot hexane. Upon cooling, 135 mg. of ( + )-4-23-(1,i-dira®thyih3ptyi)-2,6dihydroxypheny17t,6-dimsthyl-2-norpiaanone was recovered by filtration, The product was identical to the product of Example 3.

Ssaffile_5 ( + )-4-/3-(1,l-Dimethylheptyl)-2,6-dihydroxyphenyl/'-S,6-dimethy1-2-norpinanone Cue g. os 1 -:- )-6, e-dimethyl-2,2-diacetoxy-3norpinene and 1 g. or 3-(1,i-airaathylheptyl)resorcinol were dissolved :.n £0 ml. of 3si hexane:diethyl ether and the mixtur:· was cooled to -40°C. in a flask equipped with a drying tube. An 0.65 ml. portion of boron trifluoride diethyl etherate was then added, and the mixture was stirred at -40°C. for one hour. It was then allowed to wans to 0°C· while stirring for another hour. The mixture was then poured over ice and extracted with diethyl ether. The organic layer was washed twice with 3 percent sodium, bicarbonate solution, and dried over sodium sulfate. Evaporation of the dried organic liquid produced a yellow oil, which has dissolved in 3:1 hexane/cyclohexane and cooled to produce 0.26 g. of ( + )-4-/4-(1,1-dimethylheptyl)-2,6dihydroxy-phenyl75,6-dimethyl-2-norpinanone, which was identical to the product of Example 3, Example 6 ( + )-4-/5-(1,1-Dimethylheptyl)-2,6-dihydroxyphenyl7~6,6-dimethyl-2-norpinanone A 9.5 g. portion of ( - )-6,6-dimethy1-2,4diacetoxy-2-norpinene and 18.9 g. of 5-(1,1-dimethylheptyl) resorcinol were dissolved in 250 ml. of chloroform and the solution was cooled to -20°C. in a flask fitted with a drying tube. An 0.5 ml. portion of boron trifluoride diethyl etherate was then added, and the mixture was stirred at constant temperature for 2 hours. The mixture was then allowed to warm to 0°C., and was poured into 100 ml. of 5 percent sodium bicarbonate solution. The aqueous mixture was then extracted with diethyl ether, and the organic layer was washed with 5 percent sodium bicarbonate solution, dried over sodium sulfate and evaporated under vacuum to yield an oil.

The oil was chromatographed over silica gel and was eluted with chloroform, with chloroform containing 1-2 percent of methanol, and finally with diethyl ether.

The product-containing fractions were evaporated to dryness and combined to produce 3.35 g. of ( + )-4-/5(1,1-dimethylheptyl)-2,6-dihydroxyphenyl/-6,6-dimethyl2-norpinanone, after reerystallisation from cyclohexane/ hexane. The product was identical to the product of Example 3.

Example 7 ( + )-4-/5-(1,l-Dimethylheptyl)-2,6-dihydroxyphenyl/-6,6-dimethyl-2-norpinanone A 238 mg. portion of ( - )-6,6-dimethyI-2,4i diacetoxy-2-norpinene and 236 mg. of 5-(1,1-dimethylheptyl) resorcinol were dissolved in 12.5 ml. of benzene, and 198 mg. of para-toluenesulfonlc acid monohydrate was added. The mixture was stirred at reflux temperature for 2 hours and was diluted with diethyl ether after S 2 4 S cooling. Tha mixture was then washed 3 times with 10 percent sodium bicarbonate solution, was dried over sodium sulfate and evaporated under vacuum to yield 439 mg, of a yellow oil. The oil was extracted with hexane which was evaporated to dryness to produce 20 mg. of ( + )-4-/5-(1,1-dimethylheptyl)-2,6-dihydroxypheny!7-6,6-dimethyl-2-norpinanone, which was analytically identical to r.he product of Example 3.

Example 3 ( + )-4-/5-(1,1-OimetI.ylheptyl)-2,6-dihydroxyphenyl^-fc,S-dimethyl-2-norpinanone A 340 mg. portion of ( + )-6,6-dimethyl-2,2diacetoxy-3-ncrpinene and 330 ag. of 5-(1,1-dimethylheptyl )resorcino1 were dissolved in 12.5 ml» of dichloromethane at 0°C.r and 50 mg, of boron trifluoride diethyl etherate was added. The mixture was stirred for 1,5 hours, and was allowed to warm to room temperature while it was stirred for one hour more. The mixture was then poured into water, and was extracted with diethyl ether. Tne organic layer was washed with 5 percent sodium bicarbonate, and dried. Evaporation under vacuum produced a pale yellow oil, which was triturated with 15 ml. of hexane to produce 98 mg. of ( + )-4-/3“(1,1-dimethylheptyl)-2,6-dihydroxyphenyl76,6dlmethyl-2-norpinanone, which precipitated upon standing. The liquid was chromatographed over silica gel to produce additional product. The product was identical to the product of Example 3.

Example 9 ( + )-4-/2-(1,l-Dimethylheptyl)-2,6-dihydroxyphenyl7“6,6-dimethyl-2-norpinanone A 119 mg. portion of ( + )-6,6-dimethyl-2,2diacetoxy-3-norpinene and 118 mg. of 5-(1,1-dimethyl- - 13 heptyl)resorcinol were dissolved in 12.5 ml. of dichloromethane at room temperature, and 0.05 mg. of boron trifluoride diethyl etherate was added. The mixture was stirred for 4 hours and was then poured over ice and sodium bicarbonate and extracted with, diethyl ether. The organic layer was dried over sodium sulfate and evaporated under vacuum to yield 250 mg. of oil. The oil was triturated with 10 ml. of hexane, upon which SO mg. of ( + )-4-/4-(1,l-dimethylheptyl) -2,6-dihydroxyphenyl7-6,S-dimethyl-2-norpinanone crystallized and was recovered by filtration. The product was identical to the product of Example 3.

Example 10 ( + )-4-/4-(1,l-dimethylheptyl)-2,6-dihydroxyphenyl7“6,6-dimethy1-2-norpinanone A 119 mg. portion of ( + )-6,6-dimethyl-2,2diacetoxy-3-norpinene and 118 mg. of 5-(1,l-dimethylheptyl) resorcinol were dissolved in 12.5 ml. of benzene at room temperature, and 0.5 ml. of boron trifluoride diethyl etherate was added. The mixture was stirred at room temperature for 4 hours, and was worked up and purified as described above to produce ( + )-4-/3-(1,1dimethy lheptyl) -2,6-dihydroxypheny1/-6,6-dimethyl-2norpinanone, identical to the product of Example 3.

Example 11 ( + )-4-(4-n-Pentyl-2,6-dihydroxyphenyl)-6,6dimethyl-2-norpinanone A 1.19 g. portion of ( - )-6,6-dimethyl-2,4diacetoxy-2-norpinene and 0.9 g. of 5-n-pentylresoroinol were dissolved in 50 ml. of chloroform at room temperature and 0.95 g, of para-toluenesulfonic acid monohydrate was added. The mixture was stirred at ambient temperature for 3 hours, and was then poured into 100 ml. of diethyl ether and washed twice with sodium bicarbonate s g ZV2t,E> + «1·Ζ = -·0, CH^OK) Example 12 ( + )-4-(4-n-Sa.ityl-2,5-dihydroxyphenyl)-6,6dimethyl-2-norpinanone The process of Example 11 was repeated, starting with 1,19 g. of ( ··· > -5,5-dimethyl-2,2-diacetoxy3-norpinene. Tlie product was 810 mg. of ( + )-4-(4-npentyl-2,6“dihydroxyphenyl}-5,6-dimsthyl-2-norpinanone, analytically identical to tha product of Example 11.

The following example illustrates the preparation of haxahyd 'odibenzopyranor.es xn one step from norpinenes of Formula 111. It will be understood that this example does not illustrate a preferred embodiment of the invention, but shows a possible method in which the invention may be applied. ( - ) •'trans-l-I-iydrovy-3- (1, l-dimethylheptyl) e,6-dimethyl-S,Sa,7,8,10,13&,-hexafeyaro-9H-dibenzoZ&,d^7pyran-9-one y mixture of 2,38 g. of ί - )-6,6-dimethyl-2,4diacetoxy-2-noxpinene and 2.76 g. of 5-(1,l-dimethylheptyl) resorcinol dissolved in 50 ml. of dichloromethane containing 10.2 g. of boron trifluoride diethyl etherate was cooled to 0°C. in an ice bath and stirred for one hour. The reaction mixture then was warmed to 25°C. and stirred for an additional twelve hours. The reaction mixture next was poured into 25 g. of ice, and the resulting aqueous mixture was extracted with diethyl ether. The organic layer was separated, washed with ten percent aqueous sodium bicarbonate solution, dried, and the solvent was removed therefrom by evaporation under reduced pressure to provide 4.1 g. of a brown oil. The oil so formed was purified by chromatography over a column packed with Woelm Activity II silica gel, eluting with benzene. The appropriate fractions, shown by thin layer chromatography to contain the desired product, were combined and the solvent was evaporated therefrom to afford 1.06 g. of ( - )-trans-l-hydroxy-3-(1,115 dimethyIheptyl)-6,6-dimethyl-6,6a,7,8,10,lOa-hexahydro20 9H-dibenzo/b,d7pyran-9-one as a colorless oil, /07 θ “ 47.5° (c = 1.0, CHC13).

Following the same procedure as Set forth above, ( + )-6,6-dimethyl-2,2-diacetoxy-3-norpinene was reacted with 5-(1,1-dimethylheptyl)resorcinol in the presence of boron trifluoride diethyl etherate to afford ( - )-trans-l-hydroxy-3-(1,1-dimethylheptyl)-6,6dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo/I> ,d/pyran9-one.

Claims (62)

CLAIMS:

1, A process for preparing an optically active compound of the formula ii .- X f / OH II 5 wherein P 4 is C 5 -C lo alkyl, Cg-C, 0 alkenyl, Cg-Cg cycloalkyl, or C 5 -Cg cycloalkenyl; which process comprises reacting an optically active norpinene compound of tna formula CK,C“Q ‘χ,Ζ ' /CH, / 1 ί/ ί I κ-a, ι j “ s » XX Ill wherein is acetoxy, or taken with Rg, forms a double bond; Rg is acetoxy or, taken with Rg, forms a double bond; and Rg, taken with R^ forms a double bond, or taken with Rg forms a double bond, with a resorcinol of the formula OH HO IV wherein R^ is as defined above, in the presence of an acid in an unreactive organic solvent. alkyl.

2. A process of Claim 1 wherein R^ is Cg-C^ Q

3. A process of Claim 2 wherein the temperat' ure is from -50°C to 80°C.

4. A process of Claim 3 wherein the temperat· ure is from 0°C. to 30°C.

5. A process of Claim 4 wherein the temperature is the ambient temperature. S. A process of Claim 3 wherein the acid is a protonic acid.

6. 7. A process of Claim 3 wherein the acid is a Lewis acid. 3. A process of Claim 3 wherein the solvent is a halogenated or aromatic solvent.

7. 9. A process of Claim 8 wherein the product of Formula II is the ( + 5-isomer.

8. 10. A process of Claim 1 wherein the temperature is from -50 c C. to 80°C,

9. 11. λ process of Claim 10 wherein the temperature is from 0 J C. to 30°C.

10. 12. A process of Claim 11 wherein Rj is Cg-C^ Q alkyl. ,

11. 13. A process of Claim 12 wherein the product cf Formula II is the ( -.- )-isomer.

12. 14. A process of Claim 13 wherein the solvent is a halogenated or aromatic solvent.

13. 15. A process of Claim 14 wherein the acid is a protonic asxd.

14. 16. A process of Claim 14 wherein the acid is a Lewis acid.

15. 17. A process of any of Claims 1-16 wherein S 4 is 1,I-dimethyIheptyl and the product, of Formula II is the ( + )-isomer.

16. 18. A process of Claim 17 wherein the compound of Formula III is ( - 'j -2,4-diacetoxy-6,6-dimethyl-2norpinene.

17. 19. A process of Claim 18 wherein the acid is para-toluenesulfonic acid. 4& - 24

18. 20. A process of Claim 19 wherein the solvent is chloroform.

19. 21. A process of Claim 20 wherein the temperat ure is the ambient temperature.

20. 22. A process of Claim 19 wherein the solvent is benzene.

21. 23. A process of Claim 22 wherein the temperat ure is the reflux temperature.

22. 24. A process of Claim 18 wherein the acid is boron trifluoride.

23. 25. A process of Claim 24 wherein the solvent is chloroform.

24. 26. A process of Claim 25 wherein the temperat ure is from -20°C, to 0°C.

25. 27. A process of Claim 17 wherein the compound of Formula III is ( + )-6,6-dimethy1-2,2-diacetoxy-3norpinene.

26. 28. A process of Claim 27 wherein the acid is boron trifluoride.

27. 29. A process of Claim 28 wherein the solvent is dichloromethane.

28. 30. A process of Claim 29 wherein the temperat· ure is from -10°C. to 0°C.

29. 31. A process of Claim 29 wherein the temperat· ure is from 0°C to the ambient temperature. 4S348 - 25

30. 32. A process of Claim 29 wherein the temperat ure Is the ambient temperature.

31. 33. A process of Claim 28 wherein the solvent i? benzene.

32. 34. A process of Claim 33 wherein the temperat· ure is the ambient temperature.

33. 35. i process of claim 5 wherein R^ is 1,1dimethylhept/j. and the product of formula II is the ( + )-isomer.

34. 36. A process of Claim 35 wherein the acid is boron trifluoride.

35. 37. A process of Claim 36 wherein the solvent is a mixture of hexane and diethyl ether.

36. 38. A process of Claim 37 wherein the temperature is from ~40°C. to 0°C.

37. 39. Λ process of any cf Claims 1-16 wherein R 4 is n-pentyl and the product of Formula II is the ( + )isomer.

38. 40. A process of Claim 39 wherein the compound of Formula III is ( - )-6,6-dimethyl-2,4-diacetoxy-2norpinene.

39. 41. A process of Claim 40 wherein the acid is para-toluenesulfonic acid.

40. 42. A process of Claim 41 wherein the solvent is chloroform.

41. 43. A process of Claim 42 wherein the temperat· a 4« ure is the ambient temperature.

42. 44. A process of Claim 39 wherein the compound of Formula XII is ( + )-6,6-dimethyl-2,2-diacetoxy-3norpinene. 5

43. 45. A process of Claim 44 wherein the acid is para-toluenesulfonic acid.

44. 46. A process of Claim 45 wherein the solvent is chloroform.

45. 47. A process of Claim 46 wherein the temperat· 10 ure is the ambient temperature.

46. 48. An optically active norpinene compound of the formula C H Wherein R^ is acetoxy, or taken with Rg, forms a double 15 bond? Rg is acetoxy or, taken with Rg, forms a double bond; and Rg, taken with R·^ forms a double bond, or taken with Rg forms a double bond.

47. 49. The compound of Claim 48 which is { + )6,6-dimethyl-2,2-diacetoxy-3-norpinene»

48. 50. The compound of Claim 48 which is (-)6.6- dimethyI-2,2-diacetoxy-3-norpinene.

49. 51. The compound of Claim 48 which is (+)8.6- dimethyl-2,4-diacetoxy-2-norpinene.

50. 52. The compound oi Claim 48 vzhich is (-)6,6-dimethyl-2,4-diacetoxv-2-norpinene.

51. 53. A process for preparing an optically active norpinene compound of the formula ClbC-0 \ ,ca, cat ι ! > \'X III 10 wherein R^ is acetoxy, or taken with R,, forms a double bond; R„, is acetoxy or, taken with R g , forms a double bond; and R^, taken with Rj forms a double bond, or taken with R^ forms a double bond; which process comprises reacting an optically active norplnctie enol acetate of the formula - 28 Ο II CHgC-O ο Η with lead tetraacetate in an unreactive organic solvent.

52. 54. A process of Claim 53 wherein the reaction is carried out for from 1 to 3 hours. 5

53. 55. A process of Claim 53 wherein the reaction is carried out for from 16 to 20 hours. t

54. 56. A process of Claim 54 wherein the solvent is benzene.

55. 57. A process of Claim 55 wherein the solvent 10 is benzene.

56. 58. A process of Claim 56 wherein the temperat· ure is the reflux temperature.

57. 59. A process of Claim 57 wherein the temperat· ure is the reflux temperature.

58. 60. A process of any of Claims 53-59 wherein the product of Formula III is the ( - )-isomer. 4Sa·!® - 29

59. 61. A process of any of Claims 53-59 wherein the product of Formula III is the ( + )-isomer.

60. 62. A process as claimed in Claim 1 substantially as hereinabove described with particular reference 5 to Examples 1 to 12·

61. 63. A compound as claimed in Claim 48 substantially as hereinabove described with particular reference to Examples 1 to 12.

62. 64. A process as claimed in Claim 53 substanti10 ally as hereinabove described with particular reference to Examples 1 to 12.