CA1100979A - Preparation of cis-1-hydroxy-3-substituted-6,6- dimethyl-6,6a-7,8,10,10a-hexahydro-9h-dibenzo[b, d]pyran-9-ones and intermediates therefor - Google Patents

Abstract

Abstract of the Disclosure The invention provides a process for preparing a novel ketal of 4-(1-hydroxy-1-methylethyl)-3-cyclohexen-1-one which is an intermediate in the process to provide substantially exclusively a 6.alpha.,10.alpha.-cis-1-hydroxy-3-sub-stituted-6,6-dimethyl-6,6.alpha.,7,8,10,10a-hexahydro-9H-dibenzo-[b,d]pyran-9-one.

Description

This invention provides a process for the prep-aration of a novel ketal of 4~ hydroxy-1-methylethyl)-3-cyclohexen-l~one which comprises reacting a cyclohexenone carboxylate ketal with methyl magnesium bromide. The `
new compounds are intermediates for hexahydrodibenzo-pyranones.
Certain dibenzopyranones are useful pharmaco-logical agents. It recently has been found that 6a, lOa~
trans-l-hydroxy-3-alkyl-6,6-dimethyl-6,6à,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones are especially useful in the treatment of pain, anxiety, and depression, see U.S.
Patent Nos. 3,928,598, 3,944,673, and 3,953,603. Such compounds can be prepared, according to the disclosure by Fahrenholtz, Lurie and Kierstead, J. Am. Chem. Soc. 88, 2079(1966), 89, 5934(1967~, by reacting a 5-alkyl resorcinol with diethyl a-acetylglutarate to form an ethyl 4-methyl-5-hydroxy-7-alkyl coumarin~3-propionate, which is cycliæed with a metal hydride to the corresponding 1-hydroxy-3-alkyl-7,10-dihydro-6H-dibenzo~b,d~pyran-6,9(8H)dione. Xetaliza-tion of the 9-keto group followed by reaction with methyl magnesium bromide and deketalization affords the correspond-ing l-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8-tetrahydro-9H-dibenzo[b,d~pyran-9-one. Reduction o~ the latter compound provides predominantly the corresponding 6a,10a-trans-1-hydroxy-3-alkyl-6,5-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenæo[b,d]pyran-9-one, with minor quantities of the less active 6a,10a-cls-isomer being formed. Such process for , :, .. :, : , :

preparing trans-dibenæopyranones suffers from being multi-step and of low ovPrall yield, in addition to requiring separation of the trans isomer from the cis isomer.
It recently has been discovered that 6a, lOa-cls-hexahydrodibenzopyranones can be converted to the correspond-ing trans isomer, and the cls-hexahydrodibenzopyranones can be prepared in high yield in only one step. ~ore particularly, a 6a,10a-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,-lO,lOa-hexahydro-9H-dibenzo[b,d]pyran-9-one can be reacted with an aluminum halide in an organic solvent to effect epimerization to provide the corresponding 6a,10a-trans-hexa-hydrodibenzopyranone. Such process is the subjec~ of our copending Canadian Application No. 281,763 filed June 30, 1977.
This invention provides a process for preparing the novel 4-(1-hydroxy-1-methylethyl)-3-cyclohexenone ketals of the formula R '\ /R' ' ZO ~/

\~o :, HO-~-CH~
~1 13 wherein n is 0 or 1, and R' and R'' independently are hydrogen, methyl or ethyl; which process comprises re-acting a cyclohexenone carboxylate ketal of the formula X~482~A -3- !

. :, : : : ' ' . ' : ~ . .: . ' .

P97~ ~

. - .

' R~(C)/R ' t t I,~ II

' ' ' with methyl magnesium bromide in ~he presence of diethyl ether at from 0C. ~o 25C.
The ketals of 4O(1-hydroxy-1-methylethyl)-3-cyclohexen-l-one of Formula I are new compounds. Such compounds are prepared, in general, by reacting a methyl Grignard reagent such as methyl magnesium bromide with the sppropriate ketal of 4-methoxycarbonyl-3-cyclohexen-1-.
one of Formula II. Ketals of 4-methoxycarbonyl-3-cyc.Lo-h~xen-l-one are prepared according to the process of Danishefsky et al., J. Am.- ChemO Soc. 96, ~807 (1974~, and J. ~. Chem. 40, 538 (1975). Spe~ifically, 1 methoxy-3-trimethylsilyloxy-1,3-butadiene is reacted with methyl acrylate to provide 3-methoxy-4-methoxycarbonyl-1-trimethyl silyloxy-l-cyclohexene.
- Rea~ti~n of the latter compound with a glycol such as 1,2-ethanediol, 1,3-propanediol, 2,2-dimethyl-1,3-propane-diol, 2-methyl-2-ethyl-1,3-propanediol~ or 2,2-diethyl-1~3-propanediol, in the presence of an acid such as para-X 4820A ~4~

toluenesulfonic acid, effects loss ~f methanol, hydrolysis of the trimethylsilyl group, and concomitant ketalization ~o provide the corresponding ketal of 4-methoxycar~onyl-3~
cycloh~xen-l-one of Formula II. Reaction of such ketal with ; -' methyl magnesium bromide in the presence of diethyl ether at from 0C. to 25C.~provides the corresponding tertiary alcohol~ namely a ketal of 4-(1-hydroxy-1-methylethyl~3 ~yclohexen-l-one of Formula I.
For example, reaction of the 2,2-~imethyl-1,3-propanediol Xetal of 4-methoxycarbonyl-3-cyclohexen-1-one with methyl magnesium bromide in a solvent such as diethyl ether for about two hours, followed by treatment of the ~;
reaction mixture with ~ueous ammonium chloride solution and removal of the reaction solvent~ provides the corresponding tertiary alcohol, namely the 2,2-dimethyl-1,3-propanediol ~:
ketal of 4-(1-hydxoxy-1-methylethyl)-3-cyclohexen-1-one of Formula I, wherein n is 1 and ~' and Rw are methyl.~ Such compounds generally need no further p~rifica~ion~ bu~ if desired can be distilled or chromato~raph~d under normal conditions.
As hereinbefore noted, the dl-6a,10a~cis-1-hydroxy-3-substituted 6,6-dimethyl-6,6a,7,8,10,1Oa-hexahydxo-9H-diben20[b,d]pyran 9-ones are pharmacologically active, are useful in the preparation of anti-anxiety and an~i-depressant drugs, and are readily prepared fxom the ketals of Formula I. For example, dl-6a,10a-cis-1-hydroxy-3-(l,l-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo [b,d ] pyran- 9-one can be reacted with alumlnum X-~ 8 2 0~ _ 5_ .

9~;19 . .
chloride in dichloro~ethane to efect complete isomeriz tion to the corresponding dl-6a,10a-tran~ derivatlve, 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. The latter compound is particularly effec~ive in treating humans 5uffering from anxiety andfor depression when given at dail~
dosages ran~ing from about 0~1 to 100 mg.
In order to demunstrate more fully the operation of the invention, the following detailed examples are pro-.10 ~ided ~y way of illustration.
Exam~e 1 aO-dimethyl-l t 4-dioxaspiro[4.5]dec-7-ene-8-methanol; the ethylene ketal of 4~ hydroxy-1-methylethyl)-3-cyclohexen l-one ~ solution of 11.0 g. of the ethylene ketal of 4-methoxycarbonyl-3-c~clohexen-1-one in 100 ml. of toluene was added dropwise o~er thirty minutes to a stirred solution of 110 millimoles of methyl magnesium bromide in diethyl ether. The reaction mixture was stirred for two hours at about 15C., and then was cooled to 5C. and added to 1~0 ml. of a 1.3 molar aqueous solution of ammonium chloride.
The organic phase was separated, washed with water, dried, and the solvent was removed therefrom by evaporation under reduced pressure to provide 6.6 g. of the ethylene ketal of 4-(l hydroxy-1-methylethyl)-3-cyclohexen-1-one.
Analysis Calc. for CllH1803 Theory: C, 66.64; H, 9.15; O, 24.21.
Found: C, 66.68; H, 9.05; O, 24.30.

X 4820~ -6-. nmr ~CDC13): ~1.3 (s, 6H~ CtC~3)2) . ~2.6 ~st lH, OH1 Example 2 ~,a,3,3-tetramethyl-1,5-dioxaspiro[5,5]-undec-5-ene~9-methanol; the 2,2-dimethyl 1,3-propanediol ketal of 4 hydroxy~l-methylethyl~-3-cyclohexen-1-one The procedure of Example 1 was followed, except that the temperature was 25C., to prepare 80 g~ of the

2,2-dimethyl 1,3-propanediol ketal of 4~ hydroxy-1-methyl-ethyl)-3~c~clohexen-1-one. M.P. 110Co ~n~lysis Calc. for C14H2403 .::
Theory: C, 69.96; H, 10.07; O, l9.g7.
Found: C, 70017; H, 10.11; O, 20.07. ::
nmr (CDC13): ~1.3 ~s, 6H, C(CH3)2-OH) ~1~0 (2s, 3~ each, C-CtCH3)2-C).
Preparation 1 dl-6~010a-cis-l-hydroxy-3-tl,l-dimethy1heptyl)-6,6-~imethyl 6,6a,7,8~}0,10a-hexahydro-9H-dibenzo~b,d]pyran-9-one A solution of 2.30 g. of the e~hylene ketal o.
4~ hydroxy-1-methylethyl) 3-cyclohexen-l'one and 2.12 g.
of S-(l,l-dimethylheptyl)resorcinol in 50 ml. o co~ercial grade dichloromethane was stirred and cooled to -10C. in an lce/acetone bath. To the cold stirred reaction mixture was aaded 3.6 ml. of stannic chloride dropwise over a five :
minute period. During the addition of the stannic chloride, the temperature of the reaction mixture increased from -10C. to 0C. Following com~lete add~i~ion of the stannic chloride to the reaction mixture, the mixture was stirred - X-482~ _7_ for four.hours while maintaining the temperatu~e at 0 to 5~C. The reaction mixture r.ext was warmed to about 25C.
and stixred an additional two hours. The reaction mixture was then washed with water and with lN sodium hydroxide solution, and dried. Removal of the .solvent by e~rapora~ion under reduced pxessure afforded a solid residue, which was then crystallized from 20 ml. of n-hexane to provide 2. 66 gO
of 89 percent pure dl~6a,10a-eis-1-hydroxy-3-(1,1-dimethyl-heptyl)-6,6-dimethyl 6,6a,7,8,10,10a-hexahydro-9H-2ibenzo-~0 [b,d]pyran-9-one. M.P. 160-162C.

Claims (8)

The embodiments of the invention for which an exclusive property or privilege is claimed are as follows:

1. A process for preparing a ketal of the formula III

wherein n is 0 or 1, and R' and R'' independently are hydrogen, methyl or ethyl; which process comprises reacting a cyclohexenone carboxylate ketal of the formula IV

with methyl magnesium bromide in the presence of diethyl ether.

2. A ketal of formula III as defined in Claim 1, whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.

3. The process of Claim 1 wherein n is 0.

4. A ketal of Formula III as defined in Claim 1 wherein n is 0, whenever prepared by the process of Claim 3 or an obvious chemical equivalent thereof.

5. The process of Claim 1 wherein n is 1.

6. A ketal of Formula III as defined in Claim 1, wherein n is 1, whenever prepared by the process of Claim 5, or an obvious chemical equivalent thereof.

7. The process of Claim 5 wherein R' and R'' both are methyl.

8. A ketal of Formula III as defined in Claim 1, wherein n is 1 and R' and R'' both are methyl, whenever prepared by the process of Claim 7 or an obvious chemical equivalent thereof.