CH633786A5 - Process for the preparation of dl-6a,10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hex ahydro-9H-dibenzo[b,d]pyran-9-ones - Google Patents

Description

The invention relates to a new process for the preparation of dl-6a, 10a-cis-l-hydroxy-3-substituted-6,6-40-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran - 9-ones, which consists in that a resorcinol substituted in position 5 with an l-alkoxy-4- (l-hydroxy-l-methyl-ethyl) -l, 4-cyc! reacting ohexadiene in the presence of a suitable catalyst.

45 In J. Am. Chem. Soc. 88, 2079 (1966), 89, 5034 (1967) is a multi-stage process for the preparation of 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a - hexahydro-9H -dibenzo [b, d] pyran-9-ones reported. The synthesis consists in reacting a 5-sub-50-substituted resorcinol with diithyl-alpha-acetylglutarate to form the corresponding ethyl 4-methyl-5-hydroxy-7-sub-substituted-coumarin-3-propionate, the subsequent Cy -clization with a metal hydride leads to an l-hydroxy-3-substituted-6,7,8,10-tetrahydro-6H-dibenzo [bd] pyran-55 -6,9-dione. The keto group in position 9 is then protected by ketal formation, this ketal is treated with methylmagnesium bromide and the compound thus obtained is endketalized, resulting in a 1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8 -tetrahydro-6H-diben-60 zoTb, d] pyran-9-one. The reduction of the A10ll0) double bond predominantly leads to a dl-6a, 10a-trans-l-hydroxy-3-substituted-6,6-dimethyl-6,6a.7,8,10,10a-hexahy -dro-9H-dibenzo | b, d | pyran-9-one, only small amounts of the corresponding dl-6a, 10a-cis isomer being formed. 65 The dl-6a, 10a-cis-l-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran -9-ones are pharmacologically active, but their pharmacological activity is less than that of the corresponding-

3rd

633786

trans-derivatives. However, the cis compounds are suitable as intermediates for the preparation of the more pharmacologically active trans isomers. By reacting a dl-cis-dibenzo [b, d] pyran-9-one derivative with aluminum chloride or aluminum bromide in a solvent such as dichloromethane, there is complete isomerization with formation of the corresponding di-trans derivative. Such dl-6a, 10a-trans-l-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 -one are effective agents for the treatment of anxiety and depression, and reference is made, for example, to U.S. Patents 3,928,598, 3,944,673 and 3,953,603.

The invention now relates to a new process for the preparation of dl-6a, 10a-cis-l-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H -dibenzo- [b, -dJpyran-9-ones of the formula

HsC-

Ä

i V r

W \ A

CD

e

II

y \ - /

CHa

L

where R is C5-C10-alkyl, C5-C10-alkenyl, C5-C3-cycloalkyl or C5-C8-cycloalkenyl, the hydrogen atoms present at positions 6a and 10a being arranged in the cis position to one another,

which is characterized in that an l-alkoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cyclohexadiene of the formula

0-R

(II)

wherein Ri is Cj-Q-alkyl, with a resorcinol of the formula substituted in position 5

?H

r

{'\ H ° - \ /.-R

(III)

wherein R has the above meaning, in the presence of a catalyst from the group of boron tribromide, boron trifluoride or tin (IV) chloride in an inert organic solvent. The above reaction is expediently carried out at temperatures from -30 ° C. to 10 ° C.

According to a preferred embodiment of the above process, the reaction mixture contains a certain one

Amount of water. It is particularly preferred to add 1 mole of water per mole of compound of formula I formed to the reaction mixture.

According to the invention, a simple process for the preparation of a dl-6a-cis-hexahydrodibenzo [b, d] pyran-9-one is provided.

The specification 6a, 10a-cis relates to the mutual orientation of the hydrogen atoms present in positions 6a and 10a in a compound of the above formula, io. The 6a, 10a-cis compounds are therefore compounds of the above formula, where the hydrogen atoms present at positions 6a and 10a are oriented on the same side of the plane of the molecule. The designation 6a, 10a-cis includes at least 15 two isomers. In particular, the hydrogen atom in position 6a and the hydrogen atom in position 10a can each be oriented above the level of the molecule, and in this case the absolute configuration of these hydrogen atoms is denoted by 6ass and 10ass. On the other hand, the hydrogen atom in position 6a and the hydrogen atom in position 10a can also be oriented below the level of the molecule, and in this case this is denoted by 6aa and 10aa.

The absolute configuration of the hydrogen atom present in position 6a and the hydrogen atom present in position 10a is not specified below. 6a, 10a-cis should therefore be understood to mean the separate mirror image isomers of the compounds of the general formula and mixtures of such mirror image isomers. A 6a, 10a-cis compound produced by the process according to the invention should therefore include the 6aa, 10aa isomer and the 6ass, 10ass isomer or a mixture of these mirror image isomers. Such a mixture of mirror image isomers is normally referred to as dl mixture 35, and this product is usually produced in the process according to the invention.

The product obtained by the process according to the invention is practically exclusively the dl-6a, 10a-cis isomer of an l-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8, -40 10,10a -hexahydro-9H-dibenzo [b, d] pyran-9-ones, but generally small amounts of about 5 to 15 percent by weight of the corresponding dl-6a, 10a-trans isomer can also be found. It is not necessary to purify this mixture to remove the trans isomers, since the majority of the product, namely the dl-cis-hexahydrodibene-zopyranone, by treatment with an aluminum halide, which will be discussed in more detail later, into the pure dl- trans isomer is converted.

The process according to the invention for the production of a 50 dl-6a, 10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7, -8,10,10a-hexahydro-9H-dibenzo [b, d] (pyran-9-one consists in a reaction of an l-alkoxy-4- (l-hydroxy-l-methyl-ethyI) -l, 4-cycIohexadiene and a resorcinol substituted in position 5, preferably in equimolar amounts, in In the presence of a catalyst from the group of boron tribromide, boron trifluoride or tin (IV) chloride.

The substituent present in position 5 of the resorcinol and in position 3 of the product of the formula I is in each case the same and is referred to as substituent R in the above formulas. 6o The substituent R is therefore a C5-C10-alkyl group, and examples of this are 1,1-dimethyl-pcntyl, n-pentyl, isohcxyl, n-hexyl, 1-methylhexyl, 1-ethyl-2-methylhexyl , 1,2-dimethylheptyl, 1,1-dimethylheptyl, n-octyl, 1,2,3-trimethylheptyl, 1-methylnonyl, n-decyl, 1,1-65 -dimethyloctyl or 1-ethyl-l-methylhexyl. Furthermore, the substituent R can also be a CrrC] 0-alkenyl group, examples of which are 2-hexenyl, 3-heptenyl, 1-methyl-l-hepten-nyl, 1,2-dimethyl-l-heptenyl, 3-octenyl, 1-ethyl-2-octenyl,

633786

4th

l, l-dimethyl-3-octenyl, 3-methyl-2-butenyl, 1-pentenyl, 1,2-dimethyl-l-hexenyl, l-ethyl-2-heptenyl, l, l-dimethyl-2-- octenyl, 3-nonenyl or 1-methyl-1-nonenyl.

In addition to alkyl or alkenyl groups, the substituent R can also be a C5-C8-cycloalkyl radical or a C5-C8-cycloalkenyl radical. Typical cycloalkyl radicals R are cyclopentyl, cyclohexyl or cyclooctyl. Typical cycloalkenyl radicals R are 1-cyclopentenyl, 1-cyclo-heptenyl or 1-cyclooctenyl.

Examples of resorcinols which are substituted in position 5 and which can be used in the process according to the invention include 5-n-pentylresorcinol, 5-n-hexylresorcinol, 5- (l-methyl-2-ethylhexyl) resorcinol, 5- (l, l -Dimethyloctyl) resorcinol, 5- (l, 2-dimethylbutyl) resorcinol, 5- (l-hexenyl) resorcinol, 5- (l, 2 - dimethyl-1-heptenyl) resorcinol, 5- (l-ethyl-2- octenyl) resorcinol, 5-cyclohexylresorcinol, 5-cycloheptylresorcinol, 5- (l-cyclophenyl) resorcinol, 5- (l-cyclohexenyl) resorcinol, 5- (2-cycloheptenyl) resorcinol, 5- (l, 2- Dimethylheptyl) resorcinol, 5- (l-ethyl-2-methylbutyl) resorcinol, 5-n-octylresorcinol, 5- (l-hexenyl) resorcinol, 5- (l-octenyl) resorcinol, 5-cyclopentylresorcinol or 5- (2 - CycIooctenyl) resorcin.

To carry out the process according to the invention, as stated above, a resorcinol substituted in position 5 is preferably mixed with an 1-alkoxy-4- (1-hydroxy-1-methylethyl) -1,4-cyclohexadiene in approximately equimolar amounts . If desired, however, it is also possible to work with an excess of resorcinol substituted in position 5, and for example use an excess of 0.1 to 2 mol thereof.

The reaction is carried out in the presence of a catalyst from the group consisting of boron tribromide, boron trifluoride and / or tin (IV) chloride. Boron trifluoride is best used in the form of diethyl etherate. Tin (IV) chloride is preferred as the catalyst. The amount of catalyst used is generally an equimolar or slightly excess amount, based on the molar basis of the reactants. The catalyst can thus be used, for example, in a molar excess of 0.1 to 5.0. If desired, however, a larger excess can also be used.

The reaction is carried out in an inert organic solvent, but the solvent used in each case is not critical for the process. Examples of normally used solvents are halogenated hydrocarbons such as dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, bromomethane, 1,2-di-bromoethane, l-bromo-2-chloroethane, 1-bromopropane, 1,1 -Di-bromoethane, 2-chloropropane, 1-iodopropane, l-bromo-2-chloroethane, bromobenzene or 1,2-dichlorobenzene, aromatic solvents such as benzene, chlorobenzene, nitrobenzene, toluene or xylene, and ether, such as diethyl ether , Methyl ethyl ether, dimethyl ether or diisopropyl ether. Preferred solvents include the halohydrocarbons, in particular dichloromethane, and di-aromatic solvents, in particular benzene.

The process can be carried out at any temperature between -30.degree. C. and 100.degree. C., expediently at -10 to 40.degree. C., and in particular between 0.degree. C. and 25.degree. Another preferred temperature range is between -20 ° C and 100 ° C. The reaction is generally complete within 0.5 to 8.0 hours, but longer reaction times do not harm the process and can be used if desired.

A preferred component of the reaction mixture is water. The yield of product of the formula I is about 20 to 25% greater when water is added to the reaction mixture. The best results are obtained with an equimo-

laren amount of water, based on the amounts of reactants and the expected amount of product. If desired, even larger amounts of water can be used, for example a molar excess of 0.1 to 1.0.

The product of formula I can be isolated easily by the reaction mixture is washed with an aqueous acid, such as aqueous hydrochloric acid or aqueous sulfuric acid, with an aqueous base or with both in succession and then with water. Subsequent evaporation of the solvent used for the reaction can give the desired dl-6a, 10a-cis-dibenzo [b, d] pyranone derivative of the formula I, which, if desired, can be further purified by customary methods, such as chromatography or crystallization from solvents, such as hexane or cyclohexane.

Examples of dl-6a, 10a-cis-dibenzo [b, d] pyranones of the formula I which can be prepared by the present process are as follows:

dl-6a, 10a-cis-l-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7, -8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 -on,

dl-6a, 10a-cis-l-hydroxy-3- (1,2-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethyl-2-octenyl) -6,6-dimethyl-6,6a, 7,8,10 , 10a-hexahydro-9H-dibenzo [b, d] pyran - 9-one,

dl-6a, 10a-cis-l -hydroxy-3- (1,2-dimethyl-1-hexenyl) -6,6 - dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran - 9-one,

dI-6a, 10a-cis-l-hydroxy-3-cyclohexenyl-6,6-dimethyl-6, -6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one ,

dl-6a, 10a-cis-1-hydroxy-3- (1 -cycloheptenyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, dl-6a, 1 Oa-cis-l-hydroxy-3- (2-cyclohexenyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H- dibenzo [b, d] pyran-9-one.

The resorcinols which are substituted in position 5 and are required as starting materials in the process according to the invention are readily accessible, and for this purpose, for example, J. Am. Chem. Soc. 70, 664 (1948). The l-alkoxy-4- (l-hydroxy-l-methyl-ethyl) -l, 4-cyclohexadienes required as starting materials can be prepared from commercially available p-alkoxyacetophenones. By reacting a p-alkoxyacetophenone with methylmagnesium bromide, for example, an l-alkoxy-4- (l-hydroxy-l-methylethyl (benzene) is obtained. Reduction of this compound by reaction with lithium in liquid ammonia usually gives the desired l- Alkoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cyclohexadiene in high yield, please refer to Ann. 674, 28-35 (1964).

The dl-6a, 10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7.8,10,10a-hexahydro-9H-dibenzofb, d] pyran-9 - one of the As mentioned above, formula I are pharmacologically active and are particularly suitable for the production of medicaments for anxiety and depression. By reacting dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10, lOa-hexahydro ^ H-dibenzo -lb.dlpyran ^ -one with aluminum chloride in dichloromethane, for example, there is a complete isomerization to the corresponding dI-6a, 10a-trans derivative, namely to the dl-6a, 10a-trans-1-hydroxy-3- (1 , 1 -dimethylheptyl) -6,6-dimethyl-6,6a.7.8,10,10a-hexahydro-9H-dibenzo [b, dlpyran-9 - one. This compound is particularly useful for treating patients suffering from anxiety and / or depression when administered in daily doses of about 0.1 to 100 mg.

The invention is further illustrated by the following examples.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

633786

Manufacturing 1

l-methoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cyclohexadiene

A solution of 33.2 g of l-methoxy-4- (l-hydroxy-l-me-thyIäthyl) benzene in 500 ml of ethyl alcohol is added dropwise over a period of 1 hour with stirring to a solution of 800 ml of liquid ammonia, which Contains 14.0 g of lithium metal chips and 200 ml of tetrahydrofuran. After the addition of l-methoxy-4- (l-hydroxy-l-methyl-ethyl) benzene to the reaction mixture has ended, the mixture is stirred for 15 minutes. The reaction mixture is then diluted with ethyl alcohol and then poured onto 1000 g of crushed ice. The resulting aqueous reaction mixture is extracted with diethyl ether. The ether extracts are combined, washed with saturated aqueous ammonium sulfate solution and with water and finally dried. The subsequent removal of the solvent leads to an oil, the distillation of which gives 22 g of l-methoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cyclohexadiene, which is at a pressure of 0.3 Torr boils at 85 to 90 ° C.

example 1

dl-6a, 10a-cis-l-hydroxy-3- (1, l-dimethylheptyl) -6,6-dimethyl-

6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

5 ml of a commercially available solution of boron trifluoride di-ethyl etherate are added in one pour with stirring to a solution of 504 mg l-methoxy-4- (l-hydroxy-l-methylethyl) - 1,4-cyclohexadiene and 708 mg 5- ( l, l-dimethylheptyl) resor-cin in 25 ml of benzene. The reaction mixture is stirred for 5 hours at 25 ° C. and then added to 75 ml of a 6 normal hydrochloric acid. The benzene is then removed from the reaction mixture by evaporation and the acidic solution is extracted several times with diethyl ether. The ether extracts are combined, washed with water and with aqueous sodium bicarbonate solution and finally dried. Evaporation of the solvent under reduced pressure leads to a solid product, the recrystallization of which from hexane to 365 mg of dl-6a, 10a-cis-1-hydroxy-3- (1, l-dimethyIheptyl) -6,6-dimethyl- 6,6a, 7, -8.10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which melts at 153 to 158 ° C.

Example 2

dl-6 (t.I0a-cis-I-hydroxy-3-n-pentyl-6,6-dimethy! -6.6a, 7.8, -10.10a-hexahydro-9H-dibenzo [h, d] pyran-9-one

A solution of 2.66 g of l-methoxy-4- (l-hydroxy-l-methyl-ethyl) -l, 4-cyclohexadiene and 2.9 g of 5- (n-pentyl) resorcinol in 110 ml of dichloromethane is added to - 5 ° C cooled and 4.2 ml of tin (IV) chloride was added dropwise with stirring over a period of 5 minutes. During the addition of the tin (IV) chloride, the temperature of the reaction mixture increases from -5 ° C to 2 ° C. After the addition of the tin (IV) chloride has ended, the reaction mixture is heated to about 24 ° C. and stirred at this temperature for 7 hours. The reaction mixture is then washed with water and with 1 normal sodium hydroxide solution and then dried. Removal of the solvent by evaporation under reduced pressure gives an oil which is crystallized from 10 ml of n-hexane. In this way, 450 mg of dl-6a are obtained. 10a-cis-l-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10, 10a-hexahydro-9H-dibenzo [b, d] -pyran-9-one, that melts at 120 to 134 ° C.

Example 3

dl-6a, 10a-cis-l-hydroxy-3- (1, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one s According to the method described in Example 1, 11.8 g of 5- (l, l-dimethylheptyl) resorcinol are added with 10.0 g of 1-methoxy-4- (1-hydroxy-l-methylethyl) ) -l, 4-cyclohexadiene in 200 ml of dichloromethane stabilized by cyclohexene in the presence of 13 ml of tin (IV) chloride. For this purpose, the reactants are dissolved in dichloromethane and the solution is cooled to 5 ° C. before the tin (IV) chloride is added dropwise. The reaction mixture is then allowed to come to ambient temperature and is stirred for 7 hours. To work up the product, the reaction mixture is mixed with 200 ml of water, stirred and separated into its layers. The organic layer is washed with water, with 2 normal hydrochloric acid, with water, 2 times with normal sodium hydroxide and finally twice with water. The organic solution 20 is then dried over magnesium sulfate and evaporated to dryness. By recrystallizing the residue obtained from hexane, 11.0 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7 are obtained , 8,9,10,10a - hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 "on the basis of a thin-layer chromatographic analysis.

Example 4

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-30 -6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

The process described in Example 3 is repeated, except that the reaction mixture is cooled to -10 ° C. before the tin (IV) chloride is added, and is stirred at a temperature between 0 ° C. and 5 ° C. after the addition has ended. In this way, 11.2 g of dl-6a, -10a-cis-l-hydroxy-3- (1,1 -dimethyIheptyl) -6,6-dimethyl-6,6a, -7,8,10,10a are obtained -hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 on the basis of analysis by thin layer chromatography.

Example 5

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

45

The process described in Example 3 is repeated, but the tin (IV) chloride is added to the reaction mixture at a temperature of 5 ° C. and the reaction mixture is stirred for 7 hours at the reflux temperature after the addition of the tin (IV) chloride has ended. In this way, 9.9 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethyl-heptyl) -6,6-dimethyl-6,6a, 7,8,10, 10a-hexahydro-9H-dibenzo- [b, d] pyran-9-one, which is identical to the product of Example 1 based on a thin layer chromatographic analysis.

Example 6

dl-6a, 1 Oa-cis-l-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexaiiydm-9H-dihenzo [b, d] pyran-9-one

60

According to the process described in Example 1, 4.72 g of 5- (l, l-dimethylheptyl) resorcinol are added with 4.32 g of 1-ethoxy-4- (l-hydroxy-l-methylethyl) -l, 4- cyclohexadiene in 100ml dichloromethane stabilized by cyclohexane. The 65 reactants are dissolved in the dichloromethane and the solution is cooled to 0 ° C before adding 6 ml of tin (IV) chloride dropwise. The mixture is stirred at 5 ° C. for 6 hours, whereupon it is described as in Example 3

633786

6

worked up. Subsequent slurrying of the residue obtained in 25 ml of hot hexane, subsequent cooling of this slurry and subsequent collection of the precipitate gives 3.65 g of dl-6a, 10a - cis-l-hydroxy-3- (l, l-dimethylheptyl ) -6,6-dimethyl-6,6a, 7,8, -10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 on the basis of thin-layer chromatography analysis .

Example 7

dl-6a, 1 Oa-cis-l-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

The procedure described in Example 6 is repeated, except that the resorcinol is reacted differently with 4.7 g of l-isopropoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cyclo-hexadiene, only 3.5 ml of tin (IV) chloride is used and the tin (IV) chloride is added at a temperature of the reaction mixture of -10 ° C. In this way, 2.65 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a are obtained -hexahydro-9H-dibenzo [b, d] pyran - 9-one, which is identical to the product of Example 1 on the basis of a thin-layer chromatographic analysis.

The following examples illustrate syntheses of compounds of the formula I in which a certain amount of water is added to the reaction mixture.

Example 8

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

A solution of 11.8 g of 5- (l, l-dimethylheptyl) resorcinol and 10.0 g of l-methoxy-4- (l-hydroxy-l-methylethyl) -l, 4-cycIo-hexadiene in 200 ml technically pure Dichloromethane is cooled to about -10 ° C. with stirring in an ice-acetone bath. The cooled reaction mixture is then mixed with stirring in one pour with 0.9 ml of water and dropwise with 13 ml of tin (IV) chloride over a period of 15 minutes. During the addition of the tin chloride to the reaction mixture, the temperature rises from - 10 ° C to + 50C. The temperature of the reaction mixture is kept at 0 to 5 ° C. for 7 hours with stirring. The reaction mixture is then washed with water, with normal hydrochloric acid, with normal sodium hydroxide and again with water. The washed reaction mixture is then dried and the solvent is removed by evaporation under reduced pressure, giving a solid. The solid is recrystallized from 100 ml of hot n-hexane, giving 15.5 g (83% yield) of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethyl-heptyl) -6.6 -dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-diben-zo [b, d] pyran-9-one is obtained. Melting point 153 to 158 ° C.

A gas-liquid chromatographic investigation shows that this product contains about 13% of the dl-trans isomer.

Example 9

dl-6a, 10a-cis-l-hydroxy-3- (1, l-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyrcin-9-one

The procedure described in Example 8 is repeated, except that, however, the reaction mixture is cooled to −30 ° C. before the tin (IV) chloride is added, and this addition is carried out dropwise over a period of 30 minutes. After the addition of the tin chloride has ended, the reaction mixture is stirred at 0 ° C. for a further 7 hours. In this way, 16.8 g of dl-6a, 10a-cis-1-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a are obtained -hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 on the basis of a thin-layer chromatographic analysis.

Example 10

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

The procedure described in Example 9 is repeated, but the temperature of the reaction mixture before the tin (IV) chloride is added is −20 ° C. In this way, 17.5 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a are obtained -hexahydro-9H - dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 on the basis of analysis by thin layer chromatography.

Example 11

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-

-6.6 a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

The procedure described in Example 9 is repeated except that the temperature of the reaction mixture is maintained at -9 ° C before the tin (IV) chloride is added and the tin chloride is added dropwise over a period of 1 hour. In this way, 16.4 g of dl-6a, 10a - cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7, -8.10, 10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of the above examples on the basis of thin-layer chromatographic analysis.

Example 12

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H ~ dibenzo [b, d] pyran-9-one

The procedure described in Example 8 is repeated, but the initial temperature. Is 10 ° C and the addition of the tin (IV) chloride is carried out quickly. When the addition of the tin chloride has ended, the reaction mixture is heated to the reflux temperature and left at this temperature with stirring for 7 hours. In this way, 13.7 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a are obtained --hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of the above examples on the basis of thin-layer chromatographic analysis.

Example 13

dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-

-6.6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

The process described in Example 12 is repeated, but the process is carried out at an initial temperature of 5 ° C. and the reaction mixture is allowed to come to ambient temperature with stirring for 7 hours. In this way, 15.1 g of dl-6a, 10a, cis-l-hydroxy-3 - (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a are obtained -hexahydro-9H-dibenzo [b, d] pyran-9-one, which is identical to the product of Example 1 on the basis of a thin-layer chromatographic analysis.

The following examples illustrate the conversion of the compounds of the formula I into the interesting pharmaceutically particularly effective 6a, 10a-trans compounds.

Manufacturing 2

dl-6a, 10a-trans-l-hydroxy-3- (1, l-dimethylheptyl) -6,6-dime-

thyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one

A solution of 1.0 g of dl-6a, 10a-cis-l-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro- 9H-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

633786

-dibenzo [b, d] pyran-9-one in 40 ml of technically pure dichloromethane is stirred at 24 ° C. and 1.0 g of aluminum chloride are added all at once. The reaction mixture is then stirred at 24 ° C. for 5 hours. The reaction mixture is then washed with normal hydrochloric acid solution and with water.

After drying the organic solution, the solvent is removed under reduced pressure, whereby 994 mg of solid product are obtained. Recrystallization of this solid from hexane gives 761 mg of dl-6a, 10a - trans-l-hydroxy-3- (1,1-dimethylheptyl) -6,6-dimethyl-6,6a, 7, -8.10 -10a-hexahydro-9H-dibenzo [b, d] pyran-9-one, which melts at 160 to 161 ° C.

Manufacturing 3

dl-6a, 10a-trans-l-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8, -10,10a-hexahydro-9H-dibenzo [b, d] pyran-9 -on

5 A solution of 400 mg of dl-6a, 10a-cis-l-hydroxy-3-n-pentyI-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo- [ b, d] pyran-9-one in 200 ml of technically pure dichloromethane is stirred at 24 ° C. and 600 mg of aluminum chloride are added all at once.

The reaction mixture is then stirred at 24 ° C. for 2 hours. After washing the reaction mixture with water and then drying the organic solution, the solvent is removed by evaporation under reduced pressure, giving a solid product 15. By recrystallizing this solid from n-hexane, 220 mg of dl-6a, 10a-trans-l-hydroxy-3-n-pentyl-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro are obtained -9H-dibenzo- [b, d] pyran-9-one, which melts at 146 to 150 ° C.

v

Claims (6)

633786 2. The method according to claim 1, characterized in that a halogenated hydrocarbon is used as the organic solvent. 2nd PATENT CLAIMS 1. Process for the preparation of dl-6a, 10a-cis-l-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones of the formula HaO | (\ r w \ Lr y'\ r © K CH3 where R is C5-C10-alkyl, C5-C10-alkenyl, C5-C8-cycloalkyl or C5-C8-cycloalkenyl, the hydrogen atoms present at positions 6a and 10a being arranged in the cis-position to one another, characterized in that an l-alkoxy-4- (l - hydroxy-l-methylethyl) -l, 4-cyclohexadiene of the formula 0-R (II) 7. The method according to claim 6, characterized in that one works at a temperature of - 10 ° C to 40 ° C. 9. The method according to claim 8, characterized in that one works at a temperature of - 20 ° C to 100 ° C tet. 9. The method according to claim 8, characterized in that one works at a temperature of - 10 ° C to 40 ° C. 10. The method according to claim 1 to 9, characterized in that a compound of formula II with a Reacts compound of formula III, wherein R represents 1,1-dimethylheptyl. 11. The method according to claim 10, characterized in that dichloromethane is used as the organic solvent 15 used. 12. The method according to claim 11, characterized in that one works at a temperature of 5 ° C to ambient temperature. 13. The method according to claim 11, characterized in that one works at a temperature of - 10 ° C to 5 ° C. 14. The method according to claim 11, characterized in that one works at a temperature of 5 ° C to the reflux temperature. 15. The method according to claim 10, characterized in that the catalyst used is boron trifluoride. 16. The method according to claim 15, characterized in that benzene is used as the organic solvent. 17. The method according to claim 16, characterized in that one works at ambient temperature. 18. The method according to any one of claims 1 to 14, characterized in that one works with a water-containing reaction mixture. 25th 30th wherein Rx is Q-Q-alkyl, with a resorcinol of the formula r substituted in position 5 / \ H0_j \ ^ at) wherein R has the above meaning, in the presence of a catalyst from the group of boron tribromide, boron trifluoride or tin (IV) chloride in an inert organic solvent. 3. The method according to claim 2, characterized in that reacting a compound of formula II with a compound of formula III, wherein R is C5-Ci0-alkyl. 4. The method according to claim 3, characterized in that the catalyst used is boron trifuoride or tin (IV) chloride. 5. The method according to claim 4, characterized in that the catalyst used is tin (IV) chlorine. 6. The method according to claim 5, characterized in that one works at a temperature of -20 ° C to 100 ° C.