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
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 thereforInfo
- Publication number
- CA1100979A CA1100979A CA356,593A CA356593A CA1100979A CA 1100979 A CA1100979 A CA 1100979A CA 356593 A CA356593 A CA 356593A CA 1100979 A CA1100979 A CA 1100979A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxy
- ketal
- dimethyl
- pyran
- dibenzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 239000000543 intermediate Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 8
- -1 cyclohexenone carboxylate Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 4
- RCZLCLVMJHKZAJ-UHFFFAOYSA-N 4-(2-hydroxypropan-2-yl)cyclohex-3-en-1-one Chemical compound CC(C)(O)C1=CCC(=O)CC1 RCZLCLVMJHKZAJ-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000875 corresponding effect Effects 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- GHMLBKRAJCXXBS-UHFFFAOYSA-N Resorcinol Natural products OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- 229940035437 1,3-propanediol Drugs 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- XMHXPSAHLRZYKH-UHFFFAOYSA-N 2,3,4,4a,6,6a-hexahydrobenzo[c]chromen-1-one Chemical class C1=CC=CC2=C3C(=O)CCCC3OCC21 XMHXPSAHLRZYKH-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- VNAWKNVDKFZFSU-UHFFFAOYSA-N 2-ethyl-2-methylpropane-1,3-diol Chemical compound CCC(C)(CO)CO VNAWKNVDKFZFSU-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- ANQAZDNMUFDCFU-UHFFFAOYSA-N cyclohexen-1-yloxysilane Chemical compound C1(=CCCCC1)O[SiH3] ANQAZDNMUFDCFU-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- SHALBPKEGDBVKK-VOTSOKGWSA-N danishefsky's diene Chemical compound CO\C=C\C(=C)O[Si](C)(C)C SHALBPKEGDBVKK-VOTSOKGWSA-N 0.000 description 1
- 238000006567 deketalization reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- MPXHGMFNVXPWFF-UHFFFAOYSA-N methyl 4-oxocyclohexene-1-carboxylate Chemical compound COC(=O)C1=CCC(=O)CC1 MPXHGMFNVXPWFF-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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.
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)
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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA356,593A CA1100979A (en) | 1976-07-06 | 1980-07-18 | 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 |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US702,804 | 1976-07-06 | ||
| US05/702,804 US4054581A (en) | 1976-07-06 | 1976-07-06 | 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 |
| CA281,764A CA1090813A (en) | 1976-07-06 | 1977-06-30 | 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 |
| CA356,593A CA1100979A (en) | 1976-07-06 | 1980-07-18 | 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100979A true CA1100979A (en) | 1981-05-12 |
Family
ID=27165165
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA356,593A Expired CA1100979A (en) | 1976-07-06 | 1980-07-18 | 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 |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1100979A (en) |
-
1980
- 1980-07-18 CA CA356,593A patent/CA1100979A/en not_active Expired
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