DK145100B - METHOD FOR PREPARING 3-SUBSTITUTED CIS-1-HYDROXY-6,6-DIMETHY1-6,6A, 7,8,10,10A-HEXAHYDRO-9H-DIBENZO (B, D-) PYRAN-9-ONER - Google Patents

Description

(19) DENMARK (WJ

from/

(12) PRESENTATION M) 145100 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 3013/77 (51) lnt.CI.3 C 07 D 311/30 (22) Filing date 5 Jul. 1977 (24) Race day 5- Jul. 1977 (41) Aim. available 7 · Jan, 1978 (44) Posted 30 Aug 1982 (86) International application # - (86) International filing day (85) Continuation day - (62) Master application no -

(30) Priority 6 Jul. 1976, 702806, US 6 Jul. 1976, 702809, US

(71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.

(72) Inventor Charles Wilbur Ryan, US: William Allen Uay, US: Ed = ward Ralph Lavagnino, US.

(74) Associate Engineer Hofman-Bang & Bout ard.

(54) Process for Preparation of 3-Substituted Cis-1-Hydro = xy-β, 6-dimethyl-6,6a, 7,8,10,10a-he = xahydro-9H-dibenzo (b, d) py * = ran-9-ounces.

The present invention relates to a particular process for the preparation of known 3-substituted cis-1-hydroxy-6,6-dimethyl “6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyranic acid. 9-ounces of the general formula I set forth in the preamble of the claim, and the process of the invention is characterized by reacting a 5-sub-OQ-substituted resorcinol with the formula II as claimed in the claim with an O1-alkoxy-4- (1). -hydroxy-1-methylethyl) -1,4-cyclohexadiene with the i

CD

Formula III, in the presence of a catalyst selected from boron tribromide, boron trifluoride and stannous chloride in an organic -3 · y solvent.

* Q A multi-step preparation of 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9- oner is described by Fahrenholtz, Lurie and Eierstad, J. Am. Chem.

Soc., 88, 2079 (1966), 8, 5934 (1967). The synthesis comprises about 2 L of AS 100 reaction of a 5-substituted resorcinol with diethyl α-acetylglucerate to give the corresponding ethyl 4-methyl-5-hydroxy-7-substituted coumarin-3-propionate cyclized with a metal hydride to give a corresponding 1-hydroxy-3-substituted 6,7,8,10-tetrahydro-9H-dibenzo [b, d] pyran-6,9-dione. The 9-ketone group is then protected by ketone formation and treatment of the ketalen with methylmagnesium bromide followed by de-ketalization gives a corresponding 3-substituted 1-hydroxy-6,6-dimethyl-6,6a, 7,8-te -trahydro-9H-dibenzo [b, d] pyran-9-one. Reduction of the O (10a) double bond gives essentially a corresponding 3-substituted d, 1-6a, 10a-trans-1-hydroxy-6,6-dimethyl-6,6a, 7,8,10,10a-hexa. hydro-9H-dibenzo [b, d] pyran-9-one and only small amounts of the corresponding d, 1-6a, 10a-cis isomers.

Although 3-Substituted 6a, 10a-cis-1-hydroxy-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones are pharmacologically active, their activity is less than the corresponding activity of the trans-derivatives. However, the cis compounds which can be prepared in one step in the simple process of the invention are useful as intermediates for preparing the pharmacologically more active corresponding trans isomers. It has now been found that, for example, reacting a d, 1-cis-dibenzo [b, d] -pyran-9-one with aluminum chloride or aluminum bromide in a solvent such as dichloromethane gives complete isomerization to give the corresponding d, l-trans-compound. Such 3-substituted d, 1-6a, 10a-trans-1-hydroxy-6,6-dimethyl-6,6a, 7,8, -10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 -ones that have been shown to be effective in the treatment of anxiety and depression are described, for example, in U.S. Patent Nos. 3,928,598, 3,944,673, and 3,953,603.

In a preferred embodiment of the process according to the invention, the reaction mixture contains an amount of water. In particular, it is preferred to add the reaction mixture 1 mole of water for each mole of compound of formula I to be formed.

According to the invention, as mentioned, a convenient process is provided for the preparation of 6a, 10a-cis-hexahydro-dibenzo [b, d] pyran-9-ones which, as mentioned, can be readily converted to the corresponding trans isomers. The term 6a, 10a-cis refers to the relative orientation of the hydrogen atoms attached to the 6a and 3,100,110 positions of the compounds of the invention. Thus, when a compound is referred to as 6a, 10a-cis, it is a compound in which the hydrogen atoms attached to the 6a and 10a positions are oriented on the same side of the molecular plane. Obviously, two isomers are included in the 6a, 10a-cis designation. When both the 6a and 10a hydrogen atoms are oriented above the molecular plane, their configuration is denoted by 6ap and 10ap. When both the 6a and 10a hydrogen atoms are oriented below the plane, they are referred to as 6aa and 10aa.

The absolute configuration of the 6a and 10a hydrogen atoms will then not be stated, but it should be understood that the term 6a, -10a-cis includes both the separate mirror image isomers of the compound of the above formula as well as a mixture of such mirror image link isomers. For example, a 6a, 10a-cis compound prepared by the process of the invention comprises both the 6aoc, 10aa isomer and 6aP, 1C2 isomer, or a mixture of these mirror image isomers. Such a mixture of mirror image isomers will normally be referred to as a d, 1 mixture.

The product prepared by the process of the invention is essentially only the 6a, 10a-cis isomer of a 3-substituted 1-hydroxy-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] -pyran-9-one, although small amounts of the order of 5-15% by weight of the corresponding 6a, 10a trans isomers are generally detectable. Purification of such a mixture to remove the trans isomers is unnecessary as the main product, namely cis-hexa-hydrodibenzopyranone, is generally converted to the pure trans isomer by treatment with an aluminum halide as described in detail below.

In the process of the invention, a 3-substituted 6a, 10a-cis-1-hydroxy-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran is prepared. -9-one by preferably reacting an equimolar amount of a corresponding 1-alkoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene and a corresponding 5-substituted resorcinol in the presence of a catalyst selected from boron tribromide , boron trifluoride and stannous chloride.

The substituent at the 5-position of the resorcinol and at the 3-position of the product of formula I is the same group and is denoted by the symbol R. R is defined as an alkyl group of 5-10 carbon atoms and comprises groups such as 1,1-dimethylpentyl, n -pentyl, isohexyl, 4,100,100 n-hexyl, 1-methylhexyl, 1-ethyl-2-methylhexyl, 1,2-dimethylheptyl, 1,1-dimethylheptyl, n-octyl, 1,2,3-trimethylheptyl, 1 -methylnonyl, n-decyl, 1,1-dimethyloctyl and 1-ethyl-1-methylhexyl. In addition, R may be an alkenyl group having 5-10 carbon atoms, examples of which are 2-hexenyl, 3-heptenyl, 1-methyl-1-heptenyl, 1,2-dimethyl-1-heptenyl, 3-octenyl, 1-ethyl 2-octenyl, 1,1-dimethyl-3-octenyl, 3-methyl-2-butenyl, 1-pentenyl, 1,2-dimethyl-1-hexenyl, 1-ethyl-2-heptenyl, 1,1-dimethyl 2-octenyl, 3-nonenyl and 1-methyl-1-nonenyl ·

In addition, R may be a cycloalkyl group having 5-8 carbon atoms or a cycloalkenyl group having 5-8 carbon atoms. Typical cycloalkyl groups include cyclopentyl, cyclohexyl and cyclooctyl, while the cycloalkenyl groups of the group include 1-cyclopentenyl, 1-cyclohexenyl, 2-cyclo-heptenyl and 1-cyclooctenyl.

As previously stated, a 5-substituted resorcinol is reacted with a 1- alkoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in preferably equimolar amounts. If desired, the 5-substituted resorcinol can be used in excess of 0.1 to 2 molar to the molar amount.

The reaction is carried out as mentioned in the presence of a catalyst selected from boron tribromide, boron trifluoride and stannous chloride. Boron trifluoride is typically used as diethyl etherate, while stannous chloride is a preferred catalyst. The amount of catalyst used is usually an equimolar amount or a small excess relative to the molar amount. For example, a molar excess of 0.1 - 5 mol can be used. However, larger profits can be used if desired.

The reaction is carried out in an organic solvent and the particular solvent used is not critical to the process. Examples of solvents which may be used include halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, bromomethane, 1,2-di-bromoethane, i-bromo-2-chloroethane, 1- bromopropane, 1,1-dibromoethane, 2-chloropropane or 1-iodopropane; aromatic solvents such as benzene, chlorobenzene, bromobenzene, 1,2-dichlorobenzene, nitrobenzene, toluene and xylene; and ethers such as diethyl ether, methyl ethyl ether, dimethyl ether and diisopropyl ether. Preferred solvents include halogenated aliphatic hydrocarbons, especially dichloromethane, and aromatic solvents, especially benzene.

The process of the invention is carried out at any temperature from -30 to 100 ° C and conveniently carried out at -10 - + 40 ° C and most preferably at from 0 to 25 ° C. Another preferred temperature range is -20 to 100 ° C. is usually performed in 0.5-8 hours. However, longer reaction times are not detrimental to the process and can be used if desired.

Water is a preferred constituent of the reaction mixture. It has been found that the yield of the product of formula I is 20-25 per cent. higher when water is present in the reaction mixture. An equimolar amount of water, based on the amount of reactants and the expected amount of product, must be used to obtain the best results. Larger amounts of water, such as a 0.1 to 1 molar excess, can be used if desired.

The product of formula I is readily isolated by simple washing of the reaction mixture with aqueous acid, such as aqueous hydrochloric acid or aqueous sulfuric acid, or with aqueous base or with both successively and then with water. Evaporation of the reaction solvent then yields the desired 6a, 10a-cis-dibenzo [b, d] pyranone of formula I, which can be further purified, if desired, by standard methods such as chromatography or crystallization from solvents such as hexane and cyclohexane.

5-substituted resorcinols, which are necessary starting materials of the present process, are readily available; see Adams et al., J. Am. Chem. Soc. JO, 664 (1948). The 1-alkoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene can be readily prepared from commercially available corresponding β-alkoxyacetophenones. For example, a corresponding p-alkoxyacetophenone is reacted with methyl magnesium bromide to give a corresponding 1-alkoxy-4- (1-hydroxy-1-methylethyl) benzene. Reduction of the latter by reaction with lithium in liquid ammonia gives the desired corresponding 1-alkoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in high yield. Such a preparation is described in more detail by Irihoffen et al., Ann. 6, 4, 28-35 (1964).

As previously stated, 3-substituted 6a, 10a-cis-1-hydroxy-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones 6 145,100 of formula I are pharmacologically active and are also useful as intermediates in the preparation of anti-anxiety and antidepressants. For example, d, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethyl-heptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d] pyran-9-one is reacted with aluminum chloride in dichloromethane to give complete isomerization to give the corresponding d, l-6a, 10a trans-derivative, namely d, l-6a, 10a trans-l-hydro xy-3- (1,1 -dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexa hydro-9H-dibenzo [b, d] pyran -9-one. The latter compound is particularly effective in treating people suffering from anxiety and / or depression when the product is administered at a daily dose of 0.1 to 100 mg.

The following examples further illustrate the process of the invention, and Preparation 1 illustrates the preparation of a 1-alkoxy-4- (1-hydroxy-1-methylethyl) 1,4-cyclohexadiene, while Preparations 2 and 3 illustrate the conversion of d, 1-6a. 10a-cis compounds to the corresponding trans isomers.

PREPARATION 1 1-Methox2 ~ 4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene

A solution of 33.2 g of 1-methoxy-4- (1-hydroxy-1-methylethyl) benzene dissolved in 500 ml of ethyl alcohol was added dropwise over 1 hour to a stirred solution of 800 ml of liquid ammonia containing 14.0 g lithium metal shavings and 200 ml of tetrahydrofuran. After complete addition of the 1-methoxy-4- (1-hydroxy-1-methylethyl) benzene to the reaction mixture, the mixture was stirred for 15 minutes. The reaction mixture was diluted with ethyl alcohol and poured over 1000 g of crushed ice. An aqueous reaction mixture was then extracted with diethyl ether. The ether extracts were mixed, washed with saturated aqueous ammonium sulfate solution and with water and dried. Removal of the solvent gave an oil distilled to give 22 g of 1-methoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene. Bp: 85-90 ° C at 0.3 torr.

EXAMPLE 1 ^ lil§§il2§l2iSliliiZ ^ r95Zi3i (lilzdimethylheptyl) = 6i62d.imethyl-Five ml of a commercial solution of boron trifluoride diethyl etherate 7 145100 was added in one portion to a stirred solution of 504 mg of 1-methoxy-4 -hydroxy-1-methylethyl) -1,4-cyclohexadiene and 708 mg of 5- (1,1-dimethylheptyl) -resorcinol dissolved in 25 ml of benzene. The reaction mixture was stirred at 25 ° C for 5 hours and then 75 ml of 6N hydrochloric acid solution was added. The benzene was removed from the mixture by evaporation and the acidic solution was then extracted several times with diethyl ether. The ether extracts were combined, washed with water and with an aqueous solution of sodium bicarbonate and dried. Removal of the solvent by evaporation under reduced pressure gave the product as a solid which was recrystallized from hexane to give 365 mg of dl-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) - 6.6 dimethyl-6,6a, 7,8,10,1Qa-hexahydro-9H-dibenzo [b, d] pyran-9-one.

Mp: 153-158 ° C.

EXAMPLE 2 d1l-6ail10a-cis-1-Hydroxy-5-n-pentyl-6A6-diethyl-6t6a7itQi, 1Qi.l0g-r hexahydro-9H-dibenzo [b ^ d] pyran-9-one

A solution of 2.66 g of 1-methoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene and 2.9 g of 5- (n-pentyl) resorcinol dissolved in 110 ml of dichloromethane was stirred and cooled. to -5 ° C, while 4.2 ml of stannous chloride was added dropwise to the mixture over 5 minutes. The temperature of the reaction mixture was increased from -5 to 2 ° C with the addition of stannous chloride. After the stannous chloride was added, the reaction mixture was heated to about 24 ° C and stirred at this temperature for 7 hours. The reaction mixture was then washed with water and with 1N sodium hydroxide solution and dried. Removal of the solvent by evaporation under reduced pressure gave an oil which crystallized from 10 ml of n-hexane to give 450 mg of dl-6a, 10a-cis-1-hydroxy-3-n-pentyl-6,6-dimethyl-6 , 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one. Mp: 120-134 ° C.

EXAMPLE 3 §2§22Zi§ii92i9§lii®22tY ^ r2l25zdibenzoi [bidi] pyran-9-one

Following the general procedure of Example 1, 11.8 g of 5- (1,1-dimethylheptyl) resorcinol was reacted with 10 g of 1-methoxy-4- (1-8-1A 5100 hydroxy-1-methylethyl) -1,4 cyclohexadiene in 200 ml of cyclohexane-stabilized dichloromethane in the presence of 13 ml of stannous chloride. The reactants were dissolved in dichloromethane and cooled to 5 ° C before the dropwise addition of stannous chloride. The mixture was warmed to room temperature while stirring for 7 hours. The product was worked up by adding 200 ml of water to the reaction mixture, stirring and separating the phases. The organic phase was washed with water, with 2N hydrochloric acid, with water and twice with 1N sodium hydroxide and finally twice with water. The organic solution was dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from hexane to give 11.0 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10, 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which by thin layer chromatography was shown to be identical to the product of Example 1.

EXAMPLE 4 Eil§SilQaZ £ iSlll5l ^ i2iSz2liiilrdimethylhe £ tyl) = 6i6-dimethylYl3 §2§aiZi8i.l2Al22: ll £ 5§i2: ZÉi2 = 2§Z ^ i5enzo [_bid] £ yran-9-one method Example 3 was followed, however, the mixture was cooled to -10 ° C before the addition of stannous chloride and stirred for 7 hours after the addition while maintaining the temperature between 0 and 5 ° 0. The product was 11.2 g of dl-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl, 6.6a, 7,8,10,10a-hexahydro-9 dibenzo- [b, d] pyran-9-one, which was found to be identical to the product of Example 1 by thin layer chromatography.

EXAMPLE 5 d ^ l-Sa ^^ a-cis-l-Hydroxy ^ iClil ^ dimethylheptyll-e ^ e-dimethyl ^ 6 ^ 68, ^ 7 ^ 8 ^ 10.70a-hegahydro-9H-dibengo ^ b, d} The pyran-9-one procedure of Example 3 was repeated again, however, stannous chloride was added while the temperature of the reaction mixture was 5 ° C and the mixture was stirred at reflux temperature for 7 hours after the addition of stannous chloride. The product was 9.9 gd, 1-6a, 10a-cis 1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H dibenzoub, d] pyran-9-one, found by thin layer chromatography to be the same as the product of Example 1.

9 145100 EXAMPLE 6 2a2§aZa§a12.i. 1 ^ a-hexah ^ dr o ^ EH-dibenzo ^ b ^ d.Jg ^ i ^ zSzO11

Following the general method of Example 1, 4 »72 g of 5- (1,1-dimethylheptyl) resorcinol was reacted with 4.32 g of 1-ethoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in 100 ml of cyclohexane-stabilized dichloromethane. The reactants were dissolved in the dichloromethane and cooled to 0 ° C before the dropwise addition of 6 ml of stannous chloride. The mixture was stirred at 5 ° C for 6 hours and the reaction mixture worked up as described in Example 3. The residue was slurried in 25 ml of hot hexane, cooled, and the collected precipitate was identified as 3.65 gd, 1-6a, 10a-cis-1- hydroxy-3- (1,1-dimethylheptyl) - 6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one which was obtained by thin layer chromatography identified as being identical to the product of Example 1.

Example 7 ^ Alr§§ii2§l2is = l = Hydro ^ '3r (lil-dimethylheptyl2-6_16-dimethyl = 6i6aA7i8 z 10 ^ J.Oa-hexahydro-9H-dibenzo [Fig. 2

The procedure of Example 6 was repeated, however, the resorcinol was reacted with 4.7 g of 1-isopropoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene and only 3.5 ml of stannous chloride was used and the stannous chloride was added while the reactants were at -10 ° C. The product was 2.65 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d jpyran-9-on, which was identical to the product of Example 1.

The following examples illustrate the preparation of a compound of formula I in which a portion of water is added to the reaction mixture.

EXAMPLE 8 [2Zz] 2Ai22z9i2r]: ZiiZ ^ r2? Yl3-ylil-dimethylheptyl 2-6_16-dimethyl

A solution of 11.8 g of 5- (1,1-dimethylheptyl) resorcinol and 10.0 g of 1-methoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in 200 ml of commercial grade dichloromethane The mixture was stirred and cooled to -10 ° C in an ice / acetone bath. To the cold stirred reaction mixture was added in a portion of 0.9 ml of water and dropwise 13 ml of stannous chloride over a period of 15 hours. With the addition of stannous chloride to the reaction mixture, the temperature rose from -10 to 5 ° C. The temperature of the reaction mixture was maintained at 0-5 ° C and stirred for 7 hours. The reaction mixture was washed with water, 2N hydrochloric acid and with 1N sodium hydroxide and again with water. After drying the washed reaction mixture, the solvent was removed therefrom by evaporation under reduced pressure to give a product as a solid. The solid was recrystallized from 100 ml of hot n-hexane to give 15.5 g (83% yield) of d, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) - 6,6-dimethyl-6,6a, 7,8,10,10a-hexa hydro-9H-dfbenzo [b, d] pyran-9-one. Mp: 153-158 ° C. Gas-liquid chromatography showed that the product contained 13 per cent. of the d, 1-trans isomer.

EXAMPLE Q

d, 1-6a, 10a-cis-1-Hydroxy-3- (17l-dimethylheptyl) -626-dimethyl

The procedure of Example 8 was followed, however, the reaction mixture was cooled to -30 ° C before the addition of stannous chloride, which was dropped dropwise over 30 minutes. After the addition, the mixture was stirred for 7 hours at 0 ° C. The product was 16.8 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d] pyran-9-one, which by thin layer chromatography was found to be identical to the product of Example 1.

EXAMPLE 10 ^ Aii ^^ iQ ^ iSi ^ iilSYii ^^ Zl ^ -Clil-dimethylHepty ^^ eiG ^ dimethyl-

The procedure of Example 9 was followed, however, the temperature before the addition of stannous chloride was -20 ° C. The yield was 17.5 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d] pyran-9-one, which by thin layer chromatography was found to be identical to the product of Example 1.

EXAMPLE 11 6z6az7z8z 10 ^1 ^0a-Hexahydro-9H-dibenzo [b, d] pyran-9-one The procedure of Example 9 was followed again, however, the temperature was 11,100,100 before the addition of stannous chloride -9 ° C and this addition was carried out. drop in 1 hour. The product was 16.4 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexa-hydro -9H-dibenzo [b, d] pyran-9-one, which by thin layer chromatography was shown to be identical to the product in the example above.

EXAMPLE 12 ^ A ^ AlA ^^ AliSz ^ iS ^ Z ^ iSz ^ H-dibenzotb ^ dJpyran - ^ - on The procedure of Example 8 was repeated, however, the initial temperature was 10 ° C and stannous chloride was added dropwise rapidly.

After addition, the reaction mixture was heated to reflux and kept at this temperature while stirring for 7 hours. The product was 13.7 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo [b, d] pyran-9-one, which was identical to the product in the examples above.

EXAMPLE 13 ^ 2lz§§2l2§z9i®zlz? Y ^ 2 ^ z3rililrdimethylhe2tyl2-6i6-dimethyl

6i6ai72§i102l0azhexah.ydr2z2Sz2ii2S52l52 ^ JEYr2Ez2z2E

The procedure of Example 12 was followed again, however, the initial temperature was 5 ° C and the reaction mixture was allowed to warm to room temperature while stirring for 7 hours. The product was 15.1 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,1Oa-hexahydro-9H -dibenzo [b, d] pyran-9-one identical to the product of Example 1.

The following preparations illustrate the manner in which the compounds of formula I can be converted to the important pharmacologically more active 6a, 10a trans compound.

PREPARATION 2 22lz§2ji2§zir§E2ziziiY§i! 2? Zz3zl]: ilidimethylhe £ tyl2-6i6-dimethYl- §2§§2Z2§2l22lQ§zi} 252 ^ Y ^ i! 2z2iiz2i5®222lEi2-lEZr§ of 1.0 gd, 1-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H- dibenzo [b, d] -pyran-9-one in 40 ml of commercial grade dichloromethane was stirred at

Claims (1)

at 12 ° C, while 1.0 g of aluminum chloride was added. The reaction mixture was stirred at 24 ° C for 4 hours. The reaction mixture was washed with 1N hydrochloric acid and with water. After drying the organic solution, the solvent was removed by evaporation under reduced pressure to give 994 mg of the product as a solid. This was recrystallized from hexane to give 761 mg of d, 1-6a, 10a-trans-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a hexahydro-9H-dibenzo [b, d] pyran-9-one. Mp: 160-161 ° C. PREPARATION 5 ^ ill§ ^ il9§: i? §5®l3: l5Z ^ r2 ^ l5in ;; 2entyl-6i6 = dimethyl-6J, 6ai7i8i10A10a- hexahy ^ o = 9H-dibenzo £ hAd_] 2yran-9-one A solution of 400 mg of d, 1-6a, 10a-cis-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dihenzo [b, d ] pyran-9-one in 200 ml of commercial grade dichloromethane was stirred at 24 ° C while 600 mg of aluminum chloride was added. The reaction mixture was stirred at 24 ° C for 2 hours. After vaporizing the reaction mixture with water and drying the organic solution, the solvent was removed by evaporation under reduced pressure to give the product as a solid. The solid was recrystallized from n-hexane to give 220 mg of d, 1-6a, 10a-trans-1-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10 , 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one. Mp: 146-150 ° C. P_a_t_e_n_t_k_r_a_v__: Process for the preparation of 3-substituted cis-1-hydro-xy-6,6-dimethyl-6, 6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d the general formula: AH