CS202238B1 - Process for preparing new 11h-dibenz/b,f/-1,4-oxathiepine - Google Patents
Process for preparing new 11h-dibenz/b,f/-1,4-oxathiepine Download PDFInfo
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- CS202238B1 CS202238B1 CS309278A CS309278A CS202238B1 CS 202238 B1 CS202238 B1 CS 202238B1 CS 309278 A CS309278 A CS 309278A CS 309278 A CS309278 A CS 309278A CS 202238 B1 CS202238 B1 CS 202238B1
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- Czechoslovakia
- Prior art keywords
- oxathiepine
- dibenz
- boiling
- mixture
- bromobenzylsulfide
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- 238000004519 manufacturing process Methods 0.000 title description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 claims description 3
- DSCJETUEDFKYGN-UHFFFAOYSA-N 2-Methoxybenzenethiol Chemical compound COC1=CC=CC=C1S DSCJETUEDFKYGN-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 230000017858 demethylation Effects 0.000 claims description 3
- 238000010520 demethylation reaction Methods 0.000 claims description 3
- LPNFGADRCBCLAZ-UHFFFAOYSA-N 6h-benzo[b][1,5]benzoxathiepine Chemical compound C1SC2=CC=CC=C2OC2=CC=CC=C12 LPNFGADRCBCLAZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 description 1
- LJKQIQSBHFNMDV-UHFFFAOYSA-N 7-thiabicyclo[4.1.0]hepta-2,4-dien-6-ol Chemical compound C1=CC=CC2(O)C1S2 LJKQIQSBHFNMDV-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910001379 sodium hypophosphite Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
Tento vynález se týká způsobu přípravy nového llH-dibenz(b, f )-l,4-oxathiepinu vzorce I.The present invention relates to a process for the preparation of the novel 11H-dibenz (b, f) -1,4-oxathiepine of formula I.
Látka vzorce I je meziproduktem výroby farmakodynamicky účinných tricyklických sloučenin, zvláště látek neurotropních a psychotropních, a z toho důvodu je technicky důležitá.The compound of formula (I) is an intermediate product for the production of pharmacodynamically active tricyclic compounds, especially neurotrophic and psychotropic substances, and is therefore technically important.
Způsob přípravy látky I, který je předmětem tohoto vynálezu, spočívá v třístupňovém postupu, který vychází z kondensační reakce dvou známých výchozích látek, a toThe process for the preparation of the compound (I) of the present invention consists of a three-step process which proceeds from the condensation reaction of two known starting materials, namely
2-methoxythiofenolu (F. Mauthner, Ber. Deut. Chem. Ges. 39, 1348, 1906) a 2-brombenzylbromidu (R. L. Letslnger a I. H. Skoog, J. Amer. Chem. Soc. 77, 5176, 1955). Reakce se uskuteční zahříváním obou komponent v ethanolickém roztoku za přítomnosti alkalického hydroxidu. Produktem je nový 2-methoxyfenyl-2'-brombenzylsulfid vzorce II.2-methoxythiophenol (F. Mauthner, Ber. Deut. Chem. Ges. 39, 1348, 1906) and 2-bromobenzyl bromide (R. L. Letslnger and I. H. Skoog, J. Amer. Chem. Soc. 77, 5176, 1955). The reaction is carried out by heating both components in an ethanolic solution in the presence of an alkali hydroxide. The product is a novel 2-methoxyphenyl-2'-bromobenzyl sulfide of formula II.
V druhém stupni se látka vzorce II demethyluje na nový 2-hydroxyfenyl-2'-brombenzylsulfid vzorce III. Demethylaci lze provést různými způsoby, např. bromidem boritým v methylenchloridu. Nejvýhodnější však byla shledána demethylace kyselinou bromovodíkovou ve směsi kyseliny octové a acetanhydridu. Nový 2-hydroxyíenyl-2'brombenzylsulfid má vzorec III.In the second step, the compound of formula II is demethylated to a new 2-hydroxyphenyl-2'-bromobenzyl sulfide of formula III. Demethylation can be performed in various ways, such as boron tribromide in methylene chloride. However, demethylation with hydrobromic acid in a mixture of acetic acid and acetic anhydride was found to be the most advantageous. The new 2-hydroxyphenyl-2'-bromobenzyl sulfide has the formula III.
V závěrečném stupni se látka vzorce III cyklisuje varem s uhličitanem draselným a mědí v dimethylformamidu. Resultuje žádaná tricyklická látka I jako kapalina s t. v. 123 °C/27 Pa. Je charakterisována analysou a její identita bezpečně potvrzena pomocí ^-NMR spektra.In the final step, the compound of formula III is cyclized by boiling with potassium carbonate and copper in dimethylformamide. The desired tricyclic compound I is obtained as a liquid having a b.p. of 123 ° C / 27 Pa. It is characterized by analysis and its identity is safely confirmed using the 1 H-NMR spectrum.
Další podrobnosti provedení způsobu přípravy látky I podle tohoto vynálezu vyplývají z dále uvedeného příkladu provedení, který je ovšem jen ilustrací možností vynálezu a není jeho účelem všechny tyto možnosti vyčerpávajícím způsobem popisovat.Further details of embodiments of the process for the preparation of the substance I according to the invention are given by the following example, which, however, is only an illustration of the possibilities of the invention and is not intended to fully describe all these possibilities.
202 238202 238
202 238202 238
PříkladExample
K roztoku 17,2 g hydroxidu sodného v 640 ml ethapolu se přidá 60,1 g 2-methoxythiofenolu a potom se za míchání přikape během 20 minut při teplotě maximálně 56 °CTo a solution of 17.2 g of sodium hydroxide in 640 ml of ethapol is added 60.1 g of 2-methoxythiophenol and then added dropwise with stirring over a period of 20 minutes at a maximum temperature of 56 ° C.
107,3 g 2-brombenzylbromidu v dusíkové atmosféře. Směs se potom vaří v dusíkové atmosféře 10 hodin pod zpětným chladičem. Ethanol se oddestiluje, zbytek se zředí 260 ml vody a produkt se isoluje extrakcí benzenem. Po vysušení extraktu síranem sodným se benzen odpaří a zbytek se destiluje za sníženého tlaku. Získá se 112 g (85 %] žádaného 2-methoxyfenyl-2'-brombenzylsulfidu (lij s t. v. 157 °C/13 Pa.107.3 g of 2-bromobenzyl bromide under nitrogen. The mixture was then refluxed under nitrogen for 10 hours. The ethanol was distilled off, the residue was diluted with 260 ml of water and the product was isolated by extraction with benzene. After drying the extract with sodium sulfate, the benzene was evaporated and the residue was distilled under reduced pressure. 112 g (85%) of the desired 2-methoxyphenyl-2'-bromobenzylsulfide are obtained (m.p. = 157 DEG C./0.1 mbar).
K roztoku 50 g předešlého sulfidu ve 100 ml acetanhydridu se přidá 2,0 g fosfornanu sodného a přikape se 100 ml 50% kyseliny broipovodíŘové. Přidd se ještě 1Q0 ml kyseliny octové a směs se vaří v dusíkové atmosféře 4 hodiny pod zpětným chladičem. Potom se směs rozloží vodou a extrahuje benzenem. Extrakt se promyje vodou a kyselý produkt se převede protřepáním s 5% roztokem hydroxidu sodného do vodné fáze. Alkalický roztok se oddělí, okyselí 3N kyselinou chlorovodíkovou a uvolněný produkt se znovu extrahuje benzenem. Po vysušení extraktu síranem sodným se benzen odpaří. Získá se 11,5 g (25 %) surového 2-hydroxyfenyl-2'-brombenzylsulfidu, který destiluje při 153 °C/107 Pa.To a solution of 50 g of the previous sulphide in 100 ml of acetic anhydride was added 2.0 g of sodium hypophosphite and 100 ml of 50% hydrobromic acid was added dropwise. 10 ml of acetic acid are added and the mixture is refluxed for 4 hours. The mixture was then quenched with water and extracted with benzene. The extract is washed with water and the acidic product is converted by shaking with 5% sodium hydroxide solution into the aqueous phase. The alkaline solution was separated, acidified with 3N hydrochloric acid and the liberated product re-extracted with benzene. After drying the extract with sodium sulfate, the benzene was evaporated. 11.5 g (25%) of crude 2-hydroxyphenyl-2'-bromobenzylsulfide are obtained, which is distilled at 153 ° C / 107 Pa.
K roztoku 10,0 g předešlého fenolsulfidu ve 200 ml dimethylformamidu se přidá 1,0 g čerstvě vyredukované mědi a 4,6 bezvodého uhličitanu draselného a směs se v dusíkové atmosféře vaří 6 hodin pod zpětpým chladičem (160 °C). Potom se za sníženého tlaku odpaří dimethylformamid a zbytek se roztřepe mezi 150 ml vody a 150 ml benzenu. Směs se před rozdělením zfiltruje, z filtrátu se oddělí benzenová vrstva, vysuší se síranem sodným a zpracuje destilací. Získá se 4,15 g (57 %] žádaného llH-dibenz(b, fj1,4-oxathiepinu (I) s t. v. 123 °/27 Pa.To a solution of 10.0 g of the previous phenol sulfide in 200 ml of dimethylformamide was added 1.0 g of freshly reduced copper and 4.6 anhydrous potassium carbonate, and the mixture was refluxed at 160 ° C for 6 hours. Dimethylformamide was then evaporated under reduced pressure and the residue was partitioned between 150 ml of water and 150 ml of benzene. The mixture was filtered before separation, the benzene layer was separated from the filtrate, dried over sodium sulfate and worked up by distillation. 4.15 g (57%) of the desired 11H-dibenz (b, [eta] < 4 > -1,4-oxathiepine (I), m.p. 123 DEG / 27 Pa, was obtained.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS309278A CS202238B1 (en) | 1978-05-13 | 1978-05-13 | Process for preparing new 11h-dibenz/b,f/-1,4-oxathiepine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS309278A CS202238B1 (en) | 1978-05-13 | 1978-05-13 | Process for preparing new 11h-dibenz/b,f/-1,4-oxathiepine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS202238B1 true CS202238B1 (en) | 1980-12-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS309278A CS202238B1 (en) | 1978-05-13 | 1978-05-13 | Process for preparing new 11h-dibenz/b,f/-1,4-oxathiepine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS202238B1 (en) |
-
1978
- 1978-05-13 CS CS309278A patent/CS202238B1/en unknown
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