HUP0201558A2 - Process for the preparation of spiro-[cis-4-(betha-hydroxyethyloxy)cyclohexane-(3h)indol]-2'(1'h)-one derivatives - Google Patents
Process for the preparation of spiro-[cis-4-(betha-hydroxyethyloxy)cyclohexane-(3h)indol]-2'(1'h)-one derivatives Download PDFInfo
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- HUP0201558A2 HUP0201558A2 HU0201558A HUP0201558A HUP0201558A2 HU P0201558 A2 HUP0201558 A2 HU P0201558A2 HU 0201558 A HU0201558 A HU 0201558A HU P0201558 A HUP0201558 A HU P0201558A HU P0201558 A2 HUP0201558 A2 HU P0201558A2
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- acid
- cyclohexane
- indol
- hydroxyethyloxy
- spiro
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- 238000000034 method Methods 0.000 title claims abstract description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 3
- 125000005366 cycloalkylthio group Chemical group 0.000 claims abstract description 3
- -1 phenoxy, benzyloxy Chemical group 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- 229960005215 dichloroacetic acid Drugs 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 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
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- OXNGKCPRVRBHPO-XLMUYGLTSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@@H](O)[C@@H]2NC(C)=O)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O OXNGKCPRVRBHPO-XLMUYGLTSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
A találmány tárgya eljárás I általános képletű spiro[cz\-4-(3-hidroxietiloxi)ciklohexán-[3//]indol]-2’[r77]-on származékok előállítására.The invention relates to a process for the preparation of spiro[cis-4-(3-hydroxyethyloxy)cyclohexane-[3//]indol]-2'[r77]-one derivatives of general formula I.
A spiro[cA-4-(3-hidroxietiloxi)-ciklohexán-l,3’-(5’-etoxi)-[3H]indol]-2’[r//]-on fontos közbenső terméke az SR 121463 vazopresszin V2 antagonista hatású szemek. Ezen vegyület és a megfelelő I képletű közbenső termék előállítását a WO 9715556 számú szabadalmi bejelentés ismerteti.Spiro[cA-4-(3-hydroxyethyloxy)cyclohexane-1,3'-(5'-ethoxy)-[3H]indole]-2'[r//]-one is an important intermediate in the vasopressin V2 antagonist SR 121463. The preparation of this compound and the corresponding intermediate of formula I is described in patent application WO 9715556.
Az idézett szabadalmi leírásban ismertetett eljárás szerint az I általános képletű vegyületeket a II általános képletű vegyületekből állítják elő cink-bórhidrid redukáló szerrel trimetil-klórszilán jelenlétében diklórmetán dietil-éter elegyben. Ezen eljárás szerint a szükséges cA-izomert 50 - 54%-os termeléssel lehet előállítani. A reakció idő hosszú, kb. 20 óra, a reagens cink-bórhidridet in situ kell előállítani (szintén kb. 20 óra a reakcióidő), a dietil-éter oldószerként nem helyettesíthető.According to the process described in the cited patent specification, the compounds of general formula I are prepared from the compounds of general formula II with the reducing agent zinc borohydride in the presence of trimethylchlorosilane in a dichloromethane-diethyl ether mixture. According to this process, the required cA-isomer can be prepared in 50 - 54% yield. The reaction time is long, about 20 hours, the reagent zinc borohydride must be prepared in situ (also about 20 hours of reaction time), diethyl ether cannot be replaced as a solvent.
Meglepő módon azt találtuk, hogy a reakció egyszerűbb körülmények között elvégezhető.Surprisingly, we found that the reaction can be carried out under simpler conditions.
Találmányunk tárgya eljárás I általános képletű spiro[cA-4-(p-hidroxietiloxi)ciklohexán-[3H]indol]-2’ [1 ’/7]-on előállítására - mely képletbenThe subject of our invention is a process for the preparation of spiro[cA-4-(p-hydroxyethyloxy)cyclohexane-[3H]indole]-2’ [1 ’/7]-one of general formula I - in which formula
R1 és R2 jelentése egymástól függetlenül hidrogén, CMalkil, Ci_4alkoxi, Ci.4alkiltio, Ci.4polifluoralkil, Ci.4polifluoralkoxi, C3.7 cikloalkiloxi, C3.7 cikloalkiltio, fenoxi, benziloxi vagy nitrocsoportII általános képletű dispiro[(l,3-dioxolán)-2,4’-ciklohexán-[377]indol]-2”[l”77]-on származékok redukálásával azzal jellemezve, hogy a redukciótR 1 and R 2 are independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 polyfluoroalkyl, C 1-4 polyfluoroalkoxy, C 1-7 cycloalkyloxy, C 1-7 cycloalkylthio, phenoxy, benzyloxy or nitro group II by reducing dispiro[(1,3-dioxolane)-2,4'-cyclohexane-[377]indole]-2”[1”77]-one derivatives of the general formula, characterized in that the reduction is
a) nátrium-cianobórhidriddel Lewis-sav jelenlétében, vagya) with sodium cyanoborohydride in the presence of a Lewis acid, or
b) nátrium-bórhidriddel erős szerves sav jelenlétében végezzük.b) with sodium borohydride in the presence of a strong organic acid.
A redukálószerként alkalmazott nátrium-cianobórhidrid és nátrium-bórhidrid kereskedelmi forgalomban kapható termékek.Sodium cyanoborohydride and sodium borohydride used as reducing agents are commercially available products.
A találmány szerinti eljárásban Lewis-savként aluminium-kloridot, cink-kloridot, vas/III/-kloridot, előnyösen bórtrifluorid-éterátot, erős szerves savként trifluorecetsavat, diklór-ecetsavat, metánszulfonsavat, trifluor-metánszulfonsavat, előnyösen triklórecetsavat alkalmazhatunk.In the process according to the invention, the Lewis acid used may be aluminum chloride, zinc chloride, iron (III) chloride, preferably boron trifluoride etherate, and the strong organic acid may be trifluoroacetic acid, dichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, preferably trichloroacetic acid.
A találmány szerinti eljárás további előnye, hogy a dietil-éter oldószerként való alkalmazása kiküszöbölhető, oldószerként halogénezett szénhidrogének, előnyösen diklórmetán alkalmazható.A further advantage of the process according to the invention is that the use of diethyl ether as a solvent can be eliminated, and halogenated hydrocarbons, preferably dichloromethane, can be used as a solvent.
A találmány szerinti eljárással a tiszta cis-izomer 67-75%-os termeléssel nyerhető ki. A találmányunk szerinti eljárásokat az alábbi példákkal illusztráljuk, anélkül, hogy az oltalmi kört a példákra korlátoznánk.The process of the invention yields the pure cis-isomer in 67-75% yield. The processes of the invention are illustrated by the following examples, without limiting the scope of the invention to the examples.
Példa:Example:
.) 121,3 g dispiro[(l,3-dioxolán)-2,4’-ciklohexán-r,3”-(5”-etoxi)-[377]indol]2”[l”/7]-on 1000 ml diklórmetánnal készült oldatába inert atmoszférában 37,2 g nátrium-cianobórhidridet adunk. A reakcióelegybe -5 °C-on 170,3 g bórtrifluoridéterátot csepegtetünk. Ezután az elegyet hagyjuk szobahőmérsékletre felmelegedni (kb. 45 perc), majd 1,5 órán át ezen a hőmérsékleten keverjük. A híg szuszpenzióhoz 500 ml 10%-os nátrium-hidroxid oldatot csepegtetünk, majd 30 perc keverés után a reakcióelegyből a diklórmetánt kidesztilláljuk. Szobahőmérsékletre való visszahütés után 500 ml etanolt adunk lassan a vizes elegyhez, és ezután 1 órán át keverve forraljuk. Az etanolt vákuumban kidesztilláljuk, a maradékot 300 ml vízzel hígítjuk, és 4-szerl00 ml diklórmetánnal extraháljuk, 2-szer 250 ml vízzel mossuk, nátriumszulfáttal szárítjuk, bepároljuk. A visszamaradó barna olajat 350 ml toluolban forralva felvesszük, aktív szénnel derítjük, szűrjük. A kikristályosodott anyagot leszívatjuk. A kapott 100,6 g (82 %) terméket 300 ml toluolból átkristályosítjuk. így 91 g megfelelő tisztaságú terméket kapunk. Termelés 74,5 %. Izomerarány (HPLC) cis:95,5%; trans 1,8%..) To a solution of 121.3 g of dispiro[(l,3-dioxolane)-2,4'-cyclohexane-r,3"-(5"-ethoxy)-[377]indole]2"[l"/7]-one in 1000 ml of dichloromethane, 37.2 g of sodium cyanoborohydride are added under an inert atmosphere. 170.3 g of boron trifluoride etherate are added dropwise to the reaction mixture at -5 °C. The mixture is then allowed to warm to room temperature (approx. 45 minutes) and stirred at this temperature for 1.5 hours. 500 ml of 10% sodium hydroxide solution are added dropwise to the dilute suspension, and after stirring for 30 minutes, the dichloromethane is distilled off from the reaction mixture. After cooling to room temperature, 500 ml of ethanol is slowly added to the aqueous mixture and then boiled with stirring for 1 hour. The ethanol is distilled off in vacuo, the residue is diluted with 300 ml of water and extracted 4 times with 100 ml of dichloromethane, washed 2 times with 250 ml of water, dried with sodium sulfate, evaporated. The remaining brown oil is taken up by boiling in 350 ml of toluene, clarified with activated carbon, filtered. The crystallized material is filtered off with suction. The resulting 100.6 g (82%) of product is recrystallized from 300 ml of toluene. Thus, 91 g of product of suitable purity are obtained. Yield 74.5%. Isomer ratio (HPLC) cis:95.5%; trans 1.8%.
.) 9.1 g dispiro[(l,3-dioxolán)-2,4’-ciklohexán-l’,3”-(5”-etoxi)-[3H]indol]-2”[l”7T|on-t 100 ml diklórmetánban oldunk, hozzászórunk 3,4 g nátrium-bórhidridet és 0,6 g benzil-trietilammónium-kloridot. Szobahőmérsékleten kb. 1 óra alatt hozzácsepegtetjük 29,4 g triklórecetsav 50 ml diklórmetánnal készült oldatát. Az elegyet még 1 órán át keverjük, majd 130 ml N nátriumhidroxid oldatot csurgatunk hozzá. 30 perc keverés után a diklórmetánt vákuumban ledesztilláljuk, majd 150 ml etanolt adunk hozza. Az oldatot 1 órán at forraljuk, majd az alkoholt vákuumban lehajtjuk, a maradékot 100 ml vízzel hígítjuk, diklórmetánnal extraháljuk. A szerves ··. ·.·· : ..) 9.1 g of dispiro[(l,3-dioxolane)-2,4'-cyclohexane-l',3"-(5"-ethoxy)-[3H]indole]-2"[l"7T|one are dissolved in 100 ml of dichloromethane, 3.4 g of sodium borohydride and 0.6 g of benzyltriethylammonium chloride are added. At room temperature, a solution of 29.4 g of trichloroacetic acid in 50 ml of dichloromethane is added dropwise over a period of about 1 hour. The mixture is stirred for another 1 hour, then 130 ml of N sodium hydroxide solution is added dropwise. After stirring for 30 minutes, the dichloromethane is distilled off under vacuum, then 150 ml of ethanol is added. The solution is boiled for 1 hour, then the alcohol is evaporated off in vacuo, the residue is diluted with 100 ml of water and extracted with dichloromethane. The organic ··. ·.·· : .
fázist bepároljuk, a kapott olajos maradékot 50 ml toluolból átkristályosítjuk. 6,25 g terméket kapunk, op.: 123-124 °C. Termelés 68 %. Izomer arány 98,7% cis, 1 % transz (HPLC).The second phase is evaporated, the resulting oily residue is recrystallized from 50 ml of toluene. 6.25 g of product are obtained, mp: 123-124 °C. Yield 68%. Isomer ratio 98.7% cis, 1% trans (HPLC).
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0201558A HUP0201558A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of spiro-[cis-4-(betha-hydroxyethyloxy)cyclohexane-(3h)indol]-2'(1'h)-one derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9902377A HU225703B1 (en) | 1999-07-15 | 1999-07-15 | Process for producing spiro[cis-4-(betha-hydroxy-ethyloxi)-cyclohexane-[3h]indole]-2'[1'h]-one derivatives |
| HU0201558A HUP0201558A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of spiro-[cis-4-(betha-hydroxyethyloxy)cyclohexane-(3h)indol]-2'(1'h)-one derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HUP0201558A2 true HUP0201558A2 (en) | 2002-09-28 |
| HUP0201558A3 HUP0201558A3 (en) | 2003-03-28 |
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ID=89998751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU0201558A HUP0201558A3 (en) | 1999-07-15 | 2000-07-13 | Process for the preparation of spiro-[cis-4-(betha-hydroxyethyloxy)cyclohexane-(3h)indol]-2'(1'h)-one derivatives |
Country Status (1)
| Country | Link |
|---|---|
| HU (1) | HUP0201558A3 (en) |
-
2000
- 2000-07-13 HU HU0201558A patent/HUP0201558A3/en unknown
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| Publication number | Publication date |
|---|---|
| HUP0201558A3 (en) | 2003-03-28 |
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