CS196375B2 - Method of producing ketals of 4-/1-hydroxy-1-methylethyl/-1/cyclohexen-1-one - Google Patents
Method of producing ketals of 4-/1-hydroxy-1-methylethyl/-1/cyclohexen-1-one Download PDFInfo
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- CS196375B2 CS196375B2 CS782223A CS222378A CS196375B2 CS 196375 B2 CS196375 B2 CS 196375B2 CS 782223 A CS782223 A CS 782223A CS 222378 A CS222378 A CS 222378A CS 196375 B2 CS196375 B2 CS 196375B2
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- hydroxy
- cyclohexen
- methylethyl
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- 238000000034 method Methods 0.000 title claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 title description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 title 1
- 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 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- -1 cyclohexenone carboxylate Chemical class 0.000 claims description 8
- 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 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000005907 ketalization reaction Methods 0.000 description 2
- MPXHGMFNVXPWFF-UHFFFAOYSA-N methyl 4-oxocyclohexene-1-carboxylate Chemical compound COC(=O)C1=CCC(=O)CC1 MPXHGMFNVXPWFF-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 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 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- KTMOWKVHUQOTAN-UHFFFAOYSA-N 2,3,4,4a,6,10b-hexahydro-1h-benzo[c]chromene Chemical class C1=CC=C2C3CCCCC3OCC2=C1 KTMOWKVHUQOTAN-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
- CRSHWFDFAKNOQK-UHFFFAOYSA-N 4-acetylcyclohex-3-en-1-one Chemical compound CC(=O)C1=CCC(=O)CC1 CRSHWFDFAKNOQK-UHFFFAOYSA-N 0.000 description 1
- GWBGUJWRDDDVBI-UHFFFAOYSA-N 5-(2-methyloctan-2-yl)benzene-1,3-diol Chemical compound CCCCCCC(C)(C)C1=CC(O)=CC(O)=C1 GWBGUJWRDDDVBI-UHFFFAOYSA-N 0.000 description 1
- SKRLDOPLNGDYAD-UHFFFAOYSA-N CC(CO)(CO)C.COC(=O)C1=CCC(CC1)=O Chemical compound CC(CO)(CO)C.COC(=O)C1=CCC(CC1)=O SKRLDOPLNGDYAD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization 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
- NNOGMCQLKMLNPL-UHFFFAOYSA-N diethyl 2-acetylpentanedioate Chemical compound CCOC(=O)CCC(C(C)=O)C(=O)OCC NNOGMCQLKMLNPL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- LGYTZKPVOAIUKX-UHFFFAOYSA-N kebuzone Chemical compound O=C1C(CCC(=O)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 LGYTZKPVOAIUKX-UHFFFAOYSA-N 0.000 description 1
- 229960000194 kebuzone Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- AFJTZYYVUBIMNH-UHFFFAOYSA-N methyl 2-methoxy-4-trimethylsilyloxycyclohex-3-ene-1-carboxylate Chemical compound COC1C=C(O[Si](C)(C)C)CCC1C(=O)OC AFJTZYYVUBIMNH-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
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- XRVCFZPJAHWYTB-UHFFFAOYSA-N prenderol Chemical compound CCC(CC)(CO)CO XRVCFZPJAHWYTB-UHFFFAOYSA-N 0.000 description 1
- 229950006800 prenderol Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(54) Způsob výrioiby ketalů 4-íl-hytíroxy-ÍniethylEthyI)3-eyklohexen-l-a:nu(54) A process for the preparation of ketals of 4-γ-hydroxyethyl-ethyl-ethyl-3-cyclohexen-1-ane
Vynález se týká způsobu výroby nových ketalů .4- (l-hydroxy-l-methylethyl) -3-cyklohexen-l-onu, který spočívá v reakci ketalu cyklohexenonkarboxylátu s methylmagnesiumbromidem. Výše zmíněné nové sloučeniny jsou vhodné, jako meziprodukty pro přípravu hexahydrodibenzopýranonů.The present invention relates to a process for the preparation of novel 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one ketals which comprises reacting a cyclohexenone carboxylate ketal with methyl magnesium bromide. The above-mentioned novel compounds are useful as intermediates for the preparation of hexahydrodibenzoprananones.
Určité dibenzopyranony jsou užitečnými farmakologickými činidly. V poslední době bylo zjištěno, že 6a,10a-trans-l-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ony jsou zvlášť užitečné při léčbě bolestivých stavů, úzkostných stavů a depresí ( viz patentní spisy US č. 3 928 598, 3 944 673 a 3 953 603). Tyto sloučeniny je možno připravit, v souhlase s postupem, který popsali Fahrenholtz, Lurie a Kierstead v J. Am. Chem. Soc. 88, 2079 (1966) a 89, 5934 (1967), reakcí 5-alkylresorcinolu s diethyl-a-acetylglutarátem, při níž . vznikne ethyl-4-methyl-5-hydroxy-7-alkylkumarin-3-propionát, který se cyklizuje působením hydridu kovu na odpovídající 1-hydroxy-3-alkyl-7i10-dihydro-6H-dibenzo[b,d]pyran-6,9(8H)-dion. Ketalizací 9-ketoskupiny, následující reakcí s methylmagnesiumbromidem a deketalizací se získá odpovídající l-hydroxy-3-alkyl-6,6-dimethyL6,6a,7,8-tetrahydroi9H-dibenzo[b,d)pyran-9-on.Certain dibenzopyranones are useful pharmacological agents. Recently, it has been found that 6α, 10α-trans-1-hydroxy-3-alkyl-6,6-dimethyl-6,6α, 7,8,10,10α-hexahydro-9H-dibenzo [b, d] pyran The 9-ones are particularly useful in the treatment of pain, anxiety and depression (see U.S. Patent Nos. 3,928,598, 3,944,673 and 3,953,603). These compounds can be prepared according to the procedure of Fahrenholtz, Lurie and Kierstead in J. Am. Chem. Soc. 88, 2079 (1966) and 89, 5934 (1967), by reacting 5-alkylresorcinol with diethyl .alpha.-acetylglutarate in which. give ethyl-4-methyl-5-hydroxy-7-alkylkumarin-3-propionate, which is cyclized with a metal hydride to the corresponding 1-hydroxy-3-alkyl-7 and 10-dihydro-6H-dibenzo [b, d] pyran -6.9 (8H) -dione. Ketalization 9-keto group, followed by reaction with methylmagnesium bromide and Deketalization afford the corresponding l-hydroxy-3-alkyl-6,6-dimethyL6,6a, 7,8-tetrahydro and 9H-dibenzo [b, d) pyran-9-one.
Redukcí posledně zmíněné sloučeniny vzniká převážně odpovídající 6a,10a-trans-l-hydroxy-3-alkyl-6,6-dimethyl-6,6a,7,8,10,10a-hexahydrp-9H-dibenzo[b,d)pyran-9-on spolu s malým; množstvím méně aktivního 6,10a-cis-isomeru. Tento postup přípravy trans-dibenzopyranpnů má nevýhody v tom,. že je mnohastup.ňový a probíhá s nízkým celkovým výtěžkem, a kromě.toho je při něm nutné oddělování trans-isomeru od cis-isomeru.Reduction of the latter gives mainly the corresponding 6α, 10α-trans-1-hydroxy-3-alkyl-6,6-dimethyl-6,6α, 7,8,10,10α-hexahydrp-9H-dibenzo [b, d) pyran -9-he along with the little one; amount of the less active 6,10α-cis isomer. This process for the preparation of trans-dibenzopyranpenes has disadvantages in that. The process is characterized in that it is multistage and proceeds with a low overall yield, and in addition it requires the separation of the trans-isomer from the cis-isomer.
V-poslední době bylo zjištěno.íže 6a,10a-cis-hexahydrodibenzopyranony je možno převést ha odpovídající trans-isomery a cis-hexahydrodibenzopyranony připravit ve vysokém výtěžku v jediném stupni, zejména že 6a,10a-ciS-l-hydroxy-3-subst.-6,6-diraethyl-6,6a,7,8,10,10a-hexahydro-9Hrdibenzo[b,d]-pyran-9-on je možno podrobit reakci s halogenidem. hlinitým v organickém, rozpouštědle, při níž dojde k epimerizaci za vzniku odpovídajícího 6a,10a-trans-hexahydrodibenzopyranonu. Tento .postup je předmětem vynálezu našeho souvisejícího československého patentního spisu se stejným datem přihlášení jako má tento vynález..Recently it has been found that 6a, 10a-cis-hexahydrodibenzopyranones can be converted to the corresponding trans-isomers and cis-hexahydrodibenzopyranones can be prepared in high yield in a single step, in particular that 6a, 10a-cis-1-hydroxy-3-subst 6,6-Di-ethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one can be reacted with a halide. Alumina in an organic solvent epimerized to give the corresponding 6α, 10α-trans-hexahydrodibenzopyranone. This procedure is the subject of the invention of our related Czechoslovak patent with the same application date as this invention.
Předmětem vynálezu je způsob výroby nových ketalů 4-(l-hydroxy-l-methylethyl ).-3-cyklohexenonu, obecného vzorce I.The present invention provides a process for the preparation of the novel 4- (1-hydroxy-1-methylethyl) -3-cyclohexenone ketals of formula (I).
198375198375
CH, (I) ve kterém n má hodnotu 0 nebo 1 aR* a R“ nezávisle na sobě představují vždy atom vodíku, methylovou nebo ethylovou skupinu, vyznačující se tím, Že se ketal cyklohexenon-karboxylátu obecného vzorce II coch3 (II) ve kterém n, R‘ a R“ mají shora uvedený význam, nechá reagovat g methylmagnesiumbromidem v přítomnosti diethyletheru při teplotě od 0 do 25 °C.CH, (I) in which n is 0 or 1 and R * and R 'are each independently hydrogen, methyl or ethyl, characterized in that the cyclohexenone carboxylate of formula II coch 3 (II) in wherein n, R 'and R' are as defined above, are reacted with methyl magnesium bromide in the presence of diethyl ether at a temperature of from 0 to 25 ° C.
Ketaly 4-(1-hydroxy-l-methylethyl)-3-cyklohexen-l-onu shora uvedeného obecného vzorce I jsou novými látkami. Tyto sloučeniny se obecně připravují reakcí Grlgnardova činidla obsahujícího methylový zbytek, jako methylmagnesiymbromidu, s příslušným ketalem 4-methoxykarbonyl-3-cyklohexen-l-oňu vzorce II. Ketaly 4-methoxykarbonyl-3-cyklohexen-l-pnu se získají postupem, který /popsali Danisheřsky a spol. v J. Am. Chem. Soc. 96, 7807 (1974) a J. Org. Chem. 40,538 (1975).The ketals of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one of formula (I) above are novel compounds. These compounds are generally prepared by reacting a Grignard reagent containing a methyl moiety, such as methylmagnesium bromide, with the appropriate 4-methoxycarbonyl-3-cyclohexen-1-one ketal of formula II. The ketals of 4-methoxycarbonyl-3-cyclohexen-1-one are obtained by the procedure described by Danish et al. in J. Am. Chem. Soc. 96, 7807 (1974) and J. Org. Chem. 40,538 (1975).
Konkrétně reakcí l-methoxý-3-trlmethylsilyloxy-l,3-butadienu s methýlakrylátem se získá 3-methoxy-4-methoxykarbonyl-l-trimethylsilyloxy-l-cyklohexen.Specifically, reaction of 1-methoxy-3-trimethylsilyloxy-1,3-butadiene with methyl acrylate affords 3-methoxy-4-methoxycarbonyl-1-trimethylsilyloxy-1-cyclohexene.
Reakce -posledně zmíněné sloučeniny s glykolem, jako 1,2-ethandiolem, 1,3-propandiolem, 2,2-dimethyl-l,3-propandiolem, 2-methyl-2-ethyl-l,3-propandiolem nebo 2,2-diethyl-l,3-propandiolem, v přítomnosti kyseliny, jako p-toluensulfonové kyseliny, vede k odštěpení methanolu, hydrolýze trlmethylsilylové skupiny a k spučasné ketalizaci za vzniku, odpovídajícího ketalu 4-methPxýkarbonyl-3-cyklohexen-l-onu, obecného vzorce II. Reakcí tohoto ketalu s methylmagnesiubromldem v přítomnosti diethyletheru při teplotě od 0 do 25 °C se pak získá odpovídající terciární alkohol, tedy ketal 4-(l-hydroxy-l-methylethyl) -β-cyklohexen-l-onu obecného vzorce I. 'Reaction of the latter compound with a glycol such as 1,2-ethanediol, 1,3-propanediol, 2,2-dimethyl-1,3-propanediol, 2-methyl-2-ethyl-1,3-propanediol or 2,2 diethyl-1,3-propanediol, in the presence of an acid such as p-toluenesulfonic acid, leads to the cleavage of methanol, hydrolysis of the trimethylsilyl group, and the immediate ketalization to give the corresponding 4-methylcarbonyl-3-cyclohexen-1-one ketal of formula II . Reaction of this ketal with methylmagnesiubromide in the presence of diethyl ether at 0-25 ° C yields the corresponding tertiary alcohol, the 4- (1-hydroxy-1-methylethyl) -β-cyclohexen-1-one ketal of general formula (I).
Tak například reakcí 2,2-dimethyl-l,3-propandiolketalu 4-methoxykarbonyl-3-cyklohexen-l-onu s, methylmagnesiumbromidem v rozpouštědle, jako v diethyletheru, po dobu cca 2 hodiny, následujícím zpracováním reakční směsi vodným roztokem chloridu amonného a odstraněním reakčního rozpouštědla se získá odpovídající terciární alkohol, tedy 2,2-dimethyl-l,3-propandiolketal 4-(l-hydroxý-l-methylethyl) -3-cyklohexen-l-on odpovídající obecnému vzorci I, ve kterém n má hodnotu 1 a R‘ a R“ znamenají methylové skupiny. Takto připravené sloučeniny obvykle nepotřebují další čištění, je-lí to však žádoucí, lze je destilovat nebo chromatografovat za normálních podmínek.For example, by reaction of the 4-methoxycarbonyl-3-cyclohexen-1-one 2,2-dimethyl-1,3-propanediol ketal with methylmagnesium bromide in a solvent such as diethyl ether for about 2 hours, followed by treating the reaction mixture with aqueous ammonium chloride solution and removal of the reaction solvent yields the corresponding tertiary alcohol, i.e. 2,2-dimethyl-1,3-propanediol ketal 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one corresponding to the general formula I, in which n has the value 1 and R 'and R' are methyl groups. The compounds thus prepared usually do not need further purification, but if desired, they can be distilled or chromatographed under normal conditions.
Jak již bylo uvedeno výše, jsou dl-6a,10a-cis-l-hýdroxy-3-subst.-6,6-dlmethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo [ b,d J pyran-9-ony íarmakologicky účinné a mimoto jsou užitečné pro přípravu léčiv proti úzkostným stavům a depresím, přičemž se snadno připravují z ketalů obecného vzorce I.As mentioned above, dl-6a, 10a-cis-1-hydroxy-3-substituted-6,6-dlmethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, The d-pyran-9-ones are pharmacologically active and, moreover, are useful for the preparation of medicaments for anxiety and depression, and are readily prepared from ketals of formula I.
Tak· například při reakci dl-6a,10a-cis-l-hydroxy-3-(l,l-diméthylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-onu s chloridem hlinitým v dichlormethanu proběhne úplná isomerizace na Odpovídající dl-6a,10a-trans-derivát, tj. na 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-on. Posledně zmíněná sloučenina je zvlášť účinná při aplikaci v denní dávce zhruba od 0,1 do 100 mg při léčbě pacientů trpících úzkostí a/nebo depresí.For example, in the reaction of dl-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 with aluminum chloride in dichloromethane undergoes complete isomerization to the corresponding dl-6a, 10a-trans-derivative, i.e. to dl-6a, 10a-trans-1-hydroxy-3- (1, 5-a). 1-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one. The latter compound is particularly effective when administered at a daily dose of about 0.1 to 100 mg in the treatment of patients suffering from anxiety and / or depression.
Vynález ilustrují následující příklady provedení, jimiž se však rozsah vynálezu v žádném směru neomezuje.The invention is illustrated by the following non-limiting examples.
Přiklad 1 «,a-Dimethyl-l,4'-dioxaspiro [ 4,5 j dec-7;en-8-methanol, tj. éthylenketanol 4-(l-hydroxy-l-meťhylethyl)-3-cyklohexen-l-onuExample 1α, α-Dimethyl-1,4'-dioxaspiro [4.5] dec-7 ; en-8-methanol, ie 4- (1-hydroxy-1-methyl-ethyl) -3-cyclohexen-1-one, ethylene ketanol
K roztoku 110 mmol methylmagnesiumbromidu v diethyletheru se za míchání během 30 minut přikape roztok 11,0 g ethylenketalu 4-methoxykarboriyl-3-cyklohexen-1-on.u ve 100 ml toluenu. Reakční směs se 2 hodiny míchá při teplotě cca 15 °C, pak se ochladí na 5 °C a vnese se do 100 ml 1,3 molárního vodného roztoků chloridu amonného. Organická fáze se oddělí, promyje se vodou, vysuší se a rozpouštědlo se odpaří za sníženého tlaku. Získá se 6,6 g ethylenketalu 4- (1-hydroxy-l-methylethyl)-3-cyklohexen-l-onu.A solution of 11.0 g of 4-methoxycarbboryl-3-cyclohexen-1-one ethylene ketal in 100 ml of toluene is added dropwise to the solution of methylmagnesium bromide (110 mmol) in diethyl ether with stirring over 30 minutes. The reaction mixture was stirred at about 15 ° C for 2 hours, then cooled to 5 ° C and added to 100 mL of 1.3 molar aqueous ammonium chloride solutions. The organic phase was separated, washed with water, dried and the solvent was evaporated under reduced pressure. 6.6 g of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one ethylene ketal are obtained.
19637S19637S
Analýza:., pro .'GiiHiaOs.,... · vypočteno:.. .Anal. Calcd.
, 66,64 % C, 9,15 % H, 24,21.% Oo ηΗΐθζθηο’, 66.64% C, 9.15% H, 24.21.% Oo ηΗΐθζθηο ’
66,68 % C, 9,05 % H, 24,30 % O.% C, 66.68;% H, 9.05;
NMR (deuterochloroform, hodnoty í): 1,3 [s, 6H, C(CH3)2]NMR (CDCl3): 1.3 [s, 6H, C (CH3) 2]
2,6 (s, IH, OH).2.6 (s, 1H, OH).
Příklad 2.Example 2.
M,«,3,3-Tetramethyl-l,5-dioxaspiro[.5,-5]undec-5-en-9-methanol, tj. 2,2-dimethyl-l,3-propandiolketal 4- (1-hydroxy-1-methylethyl) -3-cyklohexen-l-onuN, 3,3-Tetramethyl-1,5-dioxaspiro [5,5] undec-5-ene-9-methanol, ie 2,2-dimethyl-1,3-propanediol ketal 4- (1- hydroxy-1-methylethyl) -3-cyclohexen-1-one
Pracuje se stejným postupem jako v příkladu 1 pouze s tím rozdílem, že se reakce provádí při teplotě 25 °C. Získá se 80 g 2,2-dimethyl-l,3-propandiolketalu 4- (1-hydroxy-l-methylethylj-3-cyklohexen-l-onu o teplotě tání 110 °C,'The same procedure as in Example 1 was followed except that the reaction was carried out at 25 ° C. 80 g of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one 2,2-dimethyl-1,3-propanediol ketal with a melting point of 110 DEG C. are obtained.
Analýza: pro C14H24O3 vypočteno:For C14H24O3 calculated:
69,96 % C, 10,07 % H, 19,97 % O; nalezeno:% C, 69.96;% H, 10.07; found:
70,17% C, 10,11% H, 20,07 % O. NMR (deuterochloroform, hodnoty <S).C, 70.17; H, 10.11; O, 20.07%. NMR (CDCl3) .delta.
: 1,3 [s, 6H, C(CH3)2—OH] : 1.3 [s, 6H, C (CH 3) 2 —OH]
1,0 (2 s, každý 3H, C—C(CH3)2—C j.1.0 (2 s, each 3H, C-C (CH3) 2-C).
Použití ketalů podle vynálezu k. výrobě 'hexahydrodibenzopyranů ilustrují následující příklad.The use of the ketals of the invention for the production of hexahydrodibenzopyranes is illustrated by the following example.
P ř í k 1 a d 3 .Example 1 a d 3.
dl-6a,10a-cis-l-Hydroxy-3-(l,l-dimethylheptyl]-6,6-diipethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,djpyran-9-ondl-6α, 10α-cis-1-Hydroxy-3- (1,1-dimethylheptyl) -6,6-diipethyl-6,6α, 7,8,10,10α-hexahydro-9H-dibenzo [b, d] pyran- 9-on
Roztok 2,30 g ethyleketalu 4-(l-hydroxy-l-methylethyl)-3-cyklohexen-l-onu; a 2,12 gA solution of 2.30 g of 4- (1-hydroxy-1-methylethyl) -3-cyclohexen-1-one ethyl ethyl ketal; and 2.12 g
5-(l,l-dimethylheptyl)resorcinolu v 50 ml dichlormethanu obchodní jakosti se za míchání ochladí v chladicí lázni tvořené pevným kysličníkem uhličitým v acetonu na —-10 °C a k ochlazené směsi se za míchání přikape během 5 minut 3,6 ml chloridu ciničítého. Během přidávání chloridu cíničítého vystoupí teplota réakční směsi z —10 na 0 °C. Po skončeném přidávání chloridu ciničiťého se reakční směs za udržování téploty na, 0 až 5 °C míchá ještě 4 hodiny, pak se směs ohřeje na cca 25 °C a míchá se ještě další 2 hodiny. Reakční směs se promyje vodou a 1 N roztokem hydroxidu sodného, vysuší se a rozpouštědlo se odpaří za za sníženého tlaku. Pevný zbytek poskytne po krystalizací z 20 ml n-hexanu 2,66 g dl-6a,10a-cis-l-hydroxy-3-(l,l-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,ď]pyran-9-onu o teplotě tání 160 až 162 °C, o čistotě 89 %.Of 5- (1,1-dimethylheptyl) resorcinol in 50 ml of commercial grade dichloromethane was cooled with stirring in a solid carbon dioxide / acetone cooling bath to -10 ° C and 3.6 ml of chloride was added dropwise with stirring over 5 minutes ciničítého. During the addition of tin (II) chloride the temperature of the reaction mixture rises from -10 to 0 ° C. After the addition of tin tetrachloride is complete, the reaction mixture is stirred for 4 hours while maintaining the temperature at 0-5 ° C, then the mixture is warmed to about 25 ° C and stirred for a further 2 hours. The reaction mixture was washed with water and 1 N sodium hydroxide solution, dried and the solvent was evaporated under reduced pressure. The solid residue, after crystallization from 20 ml of n-hexane, gave 2.66 g of dl-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, m.p. 160-162 ° C, 89% pure.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS782223A CS196375B2 (en) | 1976-07-06 | 1978-04-05 | Method of producing ketals of 4-/1-hydroxy-1-methylethyl/-1/cyclohexen-1-one |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| CS774514A CS196374B2 (en) | 1976-07-06 | 1977-07-06 | Method of producing 6a,10a-cis-hexahydrodibenzopyranones |
| CS782223A CS196375B2 (en) | 1976-07-06 | 1978-04-05 | Method of producing ketals of 4-/1-hydroxy-1-methylethyl/-1/cyclohexen-1-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS196375B2 true CS196375B2 (en) | 1980-03-31 |
Family
ID=25746011
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS782223A CS196375B2 (en) | 1976-07-06 | 1978-04-05 | Method of producing ketals of 4-/1-hydroxy-1-methylethyl/-1/cyclohexen-1-one |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS196375B2 (en) |
-
1978
- 1978-04-05 CS CS782223A patent/CS196375B2/en unknown
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